Section I. Basic Principles Chapter 1. Introduction Definitions Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulatory processes in parasites infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, which is often defined as the science of substances used to prevent, diagnose, and treat disease. Toxicology is that branch of pharmacology which deals with the undesirable effects of chemicals on living systems, from individual cells to complex ecosystems. History of Pharmacology Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. The earliest written records from China and from Egypt list remedies of many types, including a few still recognized today as useful drugs. Most, however, were worthless or actually harmful. In the 2500 years or so preceding the modern era there were sporadic attempts to introduce rational methods into medicine, but none were successful owing to the dominance of systems of thought that purported to explain all of biology and disease without the need for experimentation and observation. These schools promulgated bizarre notions such as the idea that disease was caused by excesses of bile or blood in the body, that wounds could be healed by applying a salve to the weapon that caused the wound, and so on. Around the end of the 17th century, reliance on observation and experimentation began to replace theorizing in medicine, following the example of the physical sciences. As the value of these methods in the study of disease became clear, physicians in Great Britain and on the Continent began to apply them to the effects of traditional drugs used in their own practices. Thus, materia medica—the science of drug preparation and the medical use of drugs—began to develop as the precursor to pharmacology. However, any understanding of the mechanisms of action of drugs was prevented by the absence of methods for purifying active agents from the crude materials that were available and—even more—by the lack of methods for testing hypotheses about the nature of drug actions.
In the late 18th and early 19th centuries, François Magendie and later his student Claude Bernard began to develop the methods of experimental animal physiology and pharmacology. Advances in chemistry and the further development of physiology in the 18th, 19th, and early 20th centuries laid the foundation needed for understanding how drugs work at the organ and tissue levels. Paradoxically, real advances in basic pharmacology during this time were accompanied by an outburst of unscientific promotion by manufacturers and marketers of worthless "patent medicines." It was not until the concepts of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine—about 50 years ago—that it became possible to accurately evaluate therapeutic claims. About 50 years ago, there also began a major expansion of research efforts in all areas of biology. As new concepts and new techniques were introduced, information accumulated about drug action and the biologic substrate of that action, the receptor. During the last half-century, many fundamentally new drug groups and new members of old groups were introduced. The last 3 decades have seen an even more rapid growth of information and understanding of the molecular basis for drug action. The molecular mechanisms of action of many drugs have now been identified, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identification methods (described in Chapter 2: Drug Receptors & Pharmacodynamics) has led to the discovery of many orphan receptors—receptors for which no ligand has been discovered and whose function can only be surmised. Studies of the local molecular environment of receptors have shown that receptors and effectors do not function in isolation—they are strongly influenced by companion regulatory proteins. Decoding of the genomes of many species—from bacteria to humans—has led to the recognition of unsuspected relationships between receptor families. Pharmacogenomics—the relation of the individual's genetic makeup to his or her response to specific drugs—is close to becoming a practical area of therapy (see Pharmacology & Genetics). Much of that progress is summarized in this resource. The extension of scientific principles into everyday therapeutics is still going on, though the medication-consuming public, unfortunately, is still exposed to vast amounts of inaccurate, incomplete, or unscientific information regarding the pharmacologic effects of chemicals. This has resulted in the faddish use of innumerable expensive, ineffective, and sometimes harmful remedies and the growth of a huge "alternative health care" industry. Conversely, lack of understanding of basic scientific principles in biology and statistics and the absence of critical thinking about public health issues has led to rejection of medical science by a segment of the public and a common tendency to assume that all adverse drug effects are the result of malpractice. Two general principles that the student should always remember are, first, that all substances can under certain circumstances be toxic; and second, that all therapies promoted as health-enhancing should meet the same standards of evidence of efficacy and safety, ie, there should be no artificial separation between scientific medicine and "alternative" or "complementary" medicine. Pharmacology & Genetics During the last 5 years, the genomes of humans, mice, and many other organisms have been decoded in considerable detail. This has opened the door to a remarkable range of new approaches to research and treatment. It has been known for centuries that certain diseases are inherited, and we now understand that individuals with such diseases have a heritable abnormality in their DNA. It is now possible in the case of some inherited diseases to define exactly which DNA base pairs are anomalous and in which chromosome they appear. In a small number of animal models of such diseases, it has been possible to correct the abnormality by "gene therapy," ie, insertion of an appropriate "healthy" gene into somatic cells. Human somatic cell gene therapy has been attempted, but the technical difficulties are great.
Studies of a newly discovered receptor or endogenous ligand are often confounded by incomplete knowledge of the exact role of that receptor or ligand. One of the most powerful of the new genetic techniques is the ability to breed animals (usually mice) in which the gene for the receptor or its endogenous ligand has been "knocked out," ie, mutated so that the gene product is absent or nonfunctional. Homozygous "knockout" mice will usually have complete suppression of that function, while heterozygous animals will usually have partial suppression. Observation of the behavior, biochemistry, and physiology of the knockout mice will often define the role of the missing gene product very clearly. When the products of a particular gene are so essential that even heterozygotes do not survive to birth, it is sometimes possible to breed "knockdown" versions with only limited suppression of function. Conversely, "knockin" mice have been bred that overexpress certain receptors of interest. Some patients respond to certain drugs with greater than usual sensitivity. (Such variations are discussed in Chapter 4: Drug Biotransformation.) It is now clear that such increased sensitivity is often due to a very small genetic modification that results in decreased activity of a particular enzyme responsible for eliminating that drug. Pharmacogenomics (or pharmacogenetics) is the study of the genetic variations that cause individual differences in drug response. Future clinicians may screen every patient for a variety of such differences before prescribing a drug. The Nature of Drugs In the most general sense, a drug may be defined as any substance that brings about a change in biologic function through its chemical actions. In the great majority of cases, the drug molecule interacts with a specific molecule in the biologic system that plays a regulatory role. This molecule is called a receptor. The nature of receptors is discussed more fully in Chapter 2: Drug Receptors & Pharmacodynamics. In a very small number of cases, drugs known as chemical antagonists may interact directly with other drugs, while a few other drugs (eg, osmotic agents) interact almost exclusively with water molecules. Drugs may be synthesized within the body (eg, hormones) or may be chemicals not synthesized in the body, ie, xenobiotics (from Gr xenos "stranger"). Poisons are drugs. Toxins are usually defined as poisons of biologic origin, ie, synthesized by plants or animals, in contrast to inorganic poisons such as lead and arsenic. In order to interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, and atomic composition. Furthermore, a drug is often administered at a location distant from its intended site of action, eg, a pill given orally to relieve a headache. Therefore, a useful drug must have the necessary properties to be transported from its site of administration to its site of action. Finally, a practical drug should be inactivated or excreted from the body at a reasonable rate so that its actions will be of appropriate duration. The Physical Nature of Drugs Drugs may be solid at room temperature (eg, aspirin, atropine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide). These factors often determine the best route of administration. For example, some liquid drugs are easily vaporized and can be inhaled in that form, eg, halothane, amyl nitrite. The most common routes of administration are listed in Table 3–3. The various classes of organic compounds—carbohydrates, proteins, lipids, and their constituents—are all represented in pharmacology. Many drugs are weak acids or bases. This fact has important implications for the way they are handled by the body, because pH differences in the various compartments of the body may alter the degree of ionization of such drugs (see below). Drug Size
The molecular size of drugs varies from very small (lithium ion, MW 7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). However, the vast majority of drugs have molecular weights between 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. In order to have a good "fit" to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, etc, to prevent its binding to other receptors. To achieve such selective binding, it appears that a molecule should in most cases be at least 100 MW units in size. The upper limit in molecular weight is determined primarily by the requirement that drugs be able to move within the body (eg, from site of administration to site of action). Drugs much larger than MW 1000 will not diffuse readily between compartments of the body (see Permeation, below). Therefore, very large drugs (usually proteins) must be administered directly into the compartment where they have their effect. In the case of alteplase, a clot-dissolving enzyme, the drug is administered directly into the vascular compartment by intravenous infusion. Drug Reactivity and Drug-Receptor Bonds Drugs interact with receptors by means of chemical forces or bonds. These are of three major types: covalent, electrostatic, and hydrophobic. Covalent bonds are very strong and in many cases not reversible under biologic conditions. Thus, the covalent bond formed between the activated form of phenoxybenzamine and the receptor for norepinephrine (which results in blockade of the receptor) is not readily broken. The blocking effect of phenoxybenzamine lasts long after the free drug has disappeared from the bloodstream and is reversed only by the synthesis of new receptors, a process that takes about 48 hours. Other examples of highly reactive, covalent bond-forming drugs are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the neoplastic tissue. Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced dipole interactions such as van der Waals forces and similar phenomena. Electrostatic bonds are weaker than covalent bonds. Hydrophobic bonds are usually quite weak and are probably important in the interactions of highly lipid-soluble drugs with the lipids of cell membranes and perhaps in the interaction of drugs with the internal walls of receptor "pockets." The specific nature of a particular drug-receptor bond is of less practical importance than the fact that drugs which bind through weak bonds to their receptors are generally more selective than drugs which bind through very strong bonds. This is because weak bonds require a very precise fit of the drug to its receptor if an interaction is to occur. Only a few receptor types are likely to provide such a precise fit for a particular drug structure. Thus, if we wished to design a highly selective shortacting drug for a particular receptor, we would avoid highly reactive molecules that form covalent bonds and instead choose molecules that form weaker bonds. A few substances that are almost completely inert in the chemical sense nevertheless have significant pharmacologic effects. For example, xenon, an "inert gas," has anesthetic effects at elevated pressures. Drug Shape The shape of a drug molecule must be such as to permit binding to its receptor site. Optimally, the drug's shape is complementary to that of the receptor site in the same way that a key is complementary to a lock. Furthermore, the phenomenon of chirality (stereoisomerism) is so
common in biology that more than half of all useful drugs are chiral molecules, ie, they exist as enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a sympathomimetic drug. In the great majority of cases, one of these enantiomers will be much more potent than its mirror image enantiomer, reflecting a better fit to the receptor molecule. For example, the (S)(+) enantiomer of methacholine, a parasympathomimetic drug, is over 250 times more potent than the (R)(–) enantiomer. If one imagines the receptor site to be like a glove into which the drug molecule must fit to bring about its effect, it is clear why a "left-oriented" drug will be more effective in binding to a left-hand receptor than will its "right-oriented" enantiomer. The more active enantiomer at one type of receptor site may not be more active at another type, eg, a receptor type that may be responsible for some unwanted effect. For example, carvedilol, a drug that interacts with adrenoceptors, has a single chiral center and thus two enantiomers (Table 1–1). One of these enantiomers, the (S)(–) isomer, is a potent -receptor blocker. The (R)(+) isomer is 100-fold weaker at the receptor. However, the isomers are approximately equipotent as -receptor blockers. Ketamine is an intravenous anesthetic. The (+) enantiomer is a more potent anesthetic and is less toxic than the (–) enantiomer. Unfortunately, the drug is still used as the racemic mixture. Table 1–1. Dissociation Constants (Kd) of the Enantiomers and Racemate of Carvedilol.1
Form of Carvedilol
Inverse of Affinity for Receptors (Kd, nmol/L)
Inverse of Affinity for Receptors (Kd, nmol/L)
R(+) enantiomer
14
45
S(–) enantiomer
16
0.4
R,S(+/–) enantiomers
11
0.9
Note: The Kd is the concentration for 50% saturation of the receptors and is inversely proportionate to the affinity of the drug for the receptors. 1
Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Pharmacol 1990;38:S82.
Finally, because enzymes are usually stereoselective, one drug enantiomer is often more susceptible than the other to drug-metabolizing enzymes. As a result, the duration of action of one enantiomer may be quite different from that of the other. Unfortunately, most studies of clinical efficacy and drug elimination in humans have been carried out with racemic mixtures of drugs rather than with the separate enantiomers. At present, only about 45% of the chiral drugs used clinically are marketed as the active isomer—the rest are available only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more is either inactive or actively toxic. However, there is increasing interest—at both the scientific and the regulatory levels—in making more chiral drugs available as their active enantiomers. Rational Drug Design Rational design of drugs implies the ability to predict the appropriate molecular structure of a drug on the basis of information about its biologic receptor. Until recently, no receptor was known in
sufficient detail to permit such drug design. Instead, drugs were developed through random testing of chemicals or modification of drugs already known to have some effect (see Chapter 5: Basic & Clinical Evaluation of New Drugs). However, during the past 3 decades, many receptors have been isolated and characterized. A few drugs now in use were developed through molecular design based on a knowledge of the three-dimensional structure of the receptor site. Computer programs are now available that can iteratively optimize drug structures to fit known receptors. As more becomes known about receptor structure, rational drug design will become more feasible. Receptor Nomenclature The spectacular success of newer, more efficient ways to identify and characterize receptors (see Chapter 2: Drug Receptors & Pharmacodynamics, How Are New Receptors Discovered?) has resulted in a variety of differing systems for naming them. This in turn has led to a number of suggestions regarding more rational methods of naming them. The interested reader is referred for details to the efforts of the International Union of Pharmacology (IUPHAR) Committee on Receptor Nomenclature and Drug Classification (reported in various issues of Pharmacological Reviews) and to the annual Receptor and Ion Channel Nomenclature Supplements published as special issues by the journal Trends in Pharmacological Sciences (TIPS). The chapters in this book mainly use these sources for naming receptors. Drug-Body Interactions The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamic processes; the principles of pharmacodynamics are presented in greater detail in Chapter 2: Drug Receptors & Pharmacodynamics. These properties determine the group in which the drug is classified and often play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic processes and are described in Chapters 3 and 4. Pharmacokinetic processes govern the absorption, distribution, and elimination of drugs and are of great practical importance in the choice and administration of a particular drug for a particular patient, eg, one with impaired renal function. The following paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics. Pharmacodynamic Principles As noted above, most drugs must bind to a receptor to bring about an effect. However, at the molecular level, drug binding is only the first in what is often a complex sequence of steps. Types of Drug-Receptor Interactions Agonist drugs bind to and activate the receptor in some fashion, which directly or indirectly brings about the effect. Some receptors incorporate effector machinery in the same molecule, so that drug binding brings about the effect directly, eg, opening of an ion channel or activation of enzyme activity. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule. The several types of drug-receptor-effector coupling systems are discussed in Chapter 2: Drug Receptors & Pharmacodynamics. Pharmacologic antagonist drugs, by binding to a receptor, prevent binding by other molecules. For example, acetylcholine receptor blockers such as atropine are antagonists because they prevent access of acetylcholine and similar agonist drugs to the acetylcholine receptor and they stabilize the receptor in its inactive state. These agents reduce the effects of acetylcholine and similar drugs in the body.
"Agonists" That Inhibit Their Binding Molecules and Partial Agonists Some drugs mimic agonist drugs by inhibiting the molecules responsible for terminating the action of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction of endogenous acetylcholine, cause cholinomimetic effects that closely resemble the actions of cholinoceptor agonist molecules even though cholinesterase inhibitors do not—or only incidentally do—bind to cholinoceptors (see Chapter 7: Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs). Other drugs bind to receptors and activate them but do not evoke as great a response as socalled full agonists. Thus, pindolol, a adrenoceptor "partial agonist," may act as either an agonist (if no full agonist is present) or as an antagonist (if a full agonist such as isoproterenol is present). (See Chapter 2: Drug Receptors & Pharmacodynamics.) Duration of Drug Action Termination of drug action at the receptor level results from one of several processes. In some cases, the effect lasts only as long as the drug occupies the receptor, so that dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the action may persist after the drug has dissociated, because, for example, some coupling molecule is still present in activated form. In the case of drugs that bind covalently to the receptor, the effect may persist until the drug-receptor complex is destroyed and new receptors are synthesized, as described previously for phenoxybenzamine. Finally, many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules continue to be present for long periods. See Chapter 2: Drug Receptors & Pharmacodynamics for additional details. Receptors and Inert Binding Sites To function as a receptor, an endogenous molecule must first be selective in choosing ligands (drug molecules) to bind; and second, it must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered. The first characteristic is required to avoid constant activation of the receptor by promiscuous binding of many different ligands. The second characteristic is clearly necessary if the ligand is to cause a pharmacologic effect. The body contains many molecules that are capable of binding drugs, however, and not all of these endogenous molecules are regulatory molecules. Binding of a drug to a nonregulatory molecule such as plasma albumin will result in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. Such binding is not completely without significance, however, since it affects the distribution of drug within the body and will determine the amount of free drug in the circulation. Both of these factors are of pharmacokinetic importance (see below and Chapter 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action). Pharmacokinetic Principles In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route. In some cases, a chemical that is readily absorbed and distributed is administered and then converted to the active drug by biologic processes—inside the body. Such a chemical is called a prodrug. In only a few situations is it possible to directly apply a drug to its target tissue, eg, by topical application of an anti-inflammatory agent to inflamed skin or mucous membrane. Most often, a drug is administered into one body compartment, eg, the gut, and must move to its site of action in another compartment, eg, the brain. This requires that the drug be absorbed into the blood from its site of administration and distributed to its site of action,
permeating through the various barriers that separate these compartments. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that comprise the wall of the intestine, the walls of the capillaries that perfuse the gut, and the "blood-brain barrier," the walls of the capillaries that perfuse the brain. Finally, after bringing about its effect, a drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the body, or by a combination of these processes. Permeation Drug permeation proceeds by four primary mechanisms. Passive diffusion in an aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too large to diffuse readily. Aqueous Diffusion Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000–30,000.* *
The capillaries of the brain, the testes, and some other tissues are characterized by absence of the pores that permit aqueous diffusion of many drug molecules into the tissue. They may also contain high concentrations of drug export pumps (MDR pumps; see text). These tissues are therefore "protected" or "sanctuary" sites from many circulating drugs. Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement described by Fick's law (see below). Drug molecules that are bound to large plasma proteins (eg, albumin) will not permeate these aqueous pores. If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential and—in parts of the nephron—the transtubular potential). Lipid Diffusion
Lipid diffusion is the most important limiting factor for drug permeation because of the large number of lipid barriers that separate the compartments of the body. Because these lipid barriers separate aqueous compartments, the lipid:aqueous partition coefficient of a drug determines how readily the molecule moves between aqueous and lipid media. In the case of weak acids and weak bases (which gain or lose electrical charge-bearing protons, depending on the pH), the ability to move from aqueous to lipid or vice versa varies with the pH of the medium, because charged molecules attract water molecules. The ratio of lipid-soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbalch equation (see below). Special Carriers Special carrier molecules exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membranes, eg, peptides, amino acids, glucose. These carriers bring about movement by active transport or facilitated diffusion and, unlike passive diffusion, are saturable and inhibitable. Because many drugs are or resemble such naturally occurring peptides, amino acids, or sugars, they can use these carriers to cross membranes.
Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules, eg, the P-glycoprotein or multidrug-resistance type 1 (MDR1) transporter found in the brain, testes, and other tissues, and in some drug-resistant neoplastic cells. A similar transport molecule, the multidrug resistance-associated protein-type 2 (MRP2) transporter, plays an important role in excretion of some drugs or their metabolites into urine and bile. Endocytosis and Exocytosis A few substances are so large or impermeant that they can enter cells only by endocytosis, the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released inside the cytosol by breakdown of the vesicle membrane. This process is responsible for the transport of vitamin B12, complexed with a binding protein (intrinsic factor), across the wall of the gut into the blood. Similarly, iron is transported into hemoglobin-synthesizing red blood cell precursors in association with the protein transferrin. Specific receptors for the transport proteins must be present for this process to work. The reverse process (exocytosis) is responsible for the secretion of many substances from cells. For example, many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contents into the extracellular space (see Chapter 6: Introduction to Autonomic Pharmacology). Fick's Law of Diffusion The passive flux of molecules down a concentration gradient is given by Fick's law:
where C1 is the higher concentration, C2 is the lower concentration, area is the area across which diffusion is occurring, permeability coefficient is a measure of the mobility of the drug molecules in the medium of the diffusion path, and thickness is the thickness (length) of the diffusion path. In the case of lipid diffusion, the lipid:aqueous partition coefficient is a major determinant of mobility of the drug, since it determines how readily the drug enters the lipid membrane from the aqueous medium. Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation The electrostatic charge of an ionized molecule attracts water dipoles and results in a polar, relatively water-soluble and lipid-insoluble complex. Since lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes. A very large fraction of the drugs in use are weak acids or weak bases (Table 1–2). For drugs, a weak acid is best defined as a neutral molecule that can reversibly dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion). For example, aspirin dissociates as follows:
Table 1–2. Ionization Constants of Some Common Drugs.
Drug
pKa1
Weak acids Acetaminophen
9.5
Acetazolamide
7.2
Ampicillin
2.5
Aspirin
3.5
Chlorothiazide
6.8, 9.42
Chlorpropamide
5.0
Ciprofloxacin
6.09, 8.742
Cromolyn
2.0
Ethacrynic acid
2.5
Furosemide
3.9
Ibuprofen
4.4, 5.22
Levodopa
2.3
Methotrexate
4.8
Methyldopa
2.2, 9.22
Penicillamine
1.8
Pentobarbital
8.1
Phenobarbital
7.4
Phenytoin
8.3
Propylthiouracil
8.3
Salicylic acid
3.0
Sulfadiazine
6.5
Sulfapyridine
8.4
Theophylline
8.8
Tolbutamide
5.3
Warfarin
5.0
Weak bases Albuterol (salbutamol)
9.3
Allopurinol
9.4, 12.3
Alprenolol
9.6
Amiloride
8.7
Amiodarone
6.56
Amphetamine
9.8
Atropine
9.7
Bupivacaine
8.1
Chlordiazepoxide
4.6
Chloroquine
10.8, 8.42
Chlorpheniramine
9.2
Chlorpromazine
9.3
Clonidine
8.3
Cocaine
8.5
Codeine
8.2
Cyclizine
8.2
Desipramine
10.2
Diazepam
3
Dihydrocodeine
3
Diphenhydramine
8.8
Diphenoxylate
7.1
Ephedrine
9.6
Epinephrine
8.7
Ergotamine
6.3
Fluphenazine
8.0, 3.92
Guanethidine
11.4, 8.32
Hydralazine
7.1
Imipramine
9.5
Isoproterenol
8.6
Kanamycin
7.2
Lidocaine
7.9
Metaraminol
8.6
Methadone
8.4
Methamphetamine
10.0
Methyldopa
10.6
Metoprolol
9.8
Morphine
7.9
Nicotine
7.9, 3.12
Norepinephrine
8.6
Pentazocine
7.9
Phenylephrine
9.8
Physostigmine
7.9, 1.82
Pilocarpine
6.9, 1.42
Pindolol
8.6
Procainamide
9.2
Procaine
9.0
Promazine
9.4
Promethazine
9.1
Propranolol
9.4
Pseudoephedrine
9.8
Pyrimethamine
7.0
Quinidine
8.5, 4.42
Scopolamine
8.1
Strychnine
8.0, 2.32
Terbutaline
10.1
Thioridazine
9.5
Tolazoline
10.6
A drug that is a weak base can be defined as a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton. For example, pyrimethamine, an antimalarial drug, undergoes the following association-dissociation process:
Note that the protonated form of a weak acid is the neutral, more lipid-soluble form, whereas the unprotonated form of a weak base is the neutral form. The law of mass action requires that these reactions move to the left in an acid environment (low pH, excess protons available) and to the right in an alkaline environment. The Henderson-Hasselbalch equation relates the ratio of protonated to unprotonated weak acid or weak base to the molecule's pKa and the pH of the medium as follows:
This equation applies to both acidic and basic drugs. Inspection confirms that the lower the pH relative to the pKa, the greater will be the fraction of drug in the protonated form. Because the uncharged form is the more lipid-soluble, more of a weak acid will be in the lipid-soluble form at acid pH, while more of a basic drug will be in the lipid-soluble form at alkaline pH. An application of this principle is in the manipulation of drug excretion by the kidney. Almost all drugs are filtered at the glomerulus. If a drug is in a lipid-soluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by simple passive diffusion. If the goal is to accelerate excretion of the drug, it is important to prevent its reabsorption from the tubule. This can often be accomplished by adjusting urine pH to make certain that most of the drug is in the ionized state, as shown in Figure 1–1. As a result of this pH partitioning effect, the drug will be "trapped" in the urine. Thus, weak acids are usually excreted faster in alkaline urine; weak bases are usually excreted faster in acidic urine. Other body fluids in which pH differences from blood pH may cause trapping or reabsorption are the contents of the stomach and small intestine; breast milk; aqueous humor; and vaginal and prostatic secretions (Table 1–3). Figure 1–1.
Trapping of a weak base (pyrimethamine) in the urine when the urine is more acidic than the blood. In the hypothetical case illustrated, the diffusible uncharged form of the drug has equilibrated across the membrane but the total concentration (charged plus uncharged) in the urine is almost eight times higher than in the blood. Table 1–3. Body Fluids with Potential for Drug "Trapping" Through the pH-Partitioning Phenomenon.
Body Fluid
Range of pH
Urine
5.0–8.0 2
Total Fluid: Blood Concentration Ratios for Sulfadiazine (acid, pKa 6.5)1
Total Fluid: Blood Concentration Ratios for Pyrimethamine (base, pKa 7.0)1
0.12–4.65
72.24–0.79
0.2–1.77
3.56–0.89
Breast milk
6.4–7.6
Jejunum, ileum contents
7.5–8.03 1.23–3.54
Stomach contents
1.92– 2.592
0.114
85,993–18,386
Prostatic secretions
6.45– 7.42
0.21
3.25–1.0
Vaginal secretions
3.4–4.23 0.114
0.94–0.79
2848–452
1
Body fluid protonated-to-unprotonated drug ratios were calculated using each of the pH extremes cited; a blood pH of 7.4 was used for blood:drug ratio. For example, the steady-state urine:blood ratio for sulfadiazine is 0.12 at a urine pH of 5.0; this ratio is 4.65 at a urine pH of 8.0. Thus, sulfadiazine is much more effectively trapped and excreted in alkaline urine. 2
Lentner C (editor): Geigy Scientific Tables, vol 1, 8th ed. Ciba Geigy, 1981.
3
Bowman WC, Rand MJ: Textbook of Pharmacology, 2nd ed. Blackwell, 1980.
4
Insignificant change in ratios over the physiologic pH range.
As suggested by Table 1–2, a large number of drugs are weak bases. Most of these bases are aminecontaining molecules. The nitrogen of a neutral amine has three atoms associated with it plus a pair of unshared electrons—see the display below. The three atoms may consist of one carbon (designated "R") and two hydrogens (a primary amine), two carbons and one hydrogen (a secondary amine), or three carbon atoms (a tertiary amine). Each of these three forms may reversibly bind a proton with the unshared electrons. Some drugs have a fourth carbon-nitrogen bond; these are quaternary amines. However, the quaternary amine is permanently charged and has no unshared electrons with which to reversibly bind a proton. Therefore, primary, secondary, and tertiary amines may undergo reversible protonation and vary their lipid solubility with pH, but quaternary amines are always in the poorly lipid-soluble charged form.
Drug Groups
To learn each pertinent fact about each of the many hundreds of drugs mentioned in this book would be an impractical goal and, fortunately, is in any case unnecessary. Almost all of the several thousand drugs currently available can be arranged in about 70 groups. Many of the drugs within each group are very similar in pharmacodynamic actions and often in their pharmacokinetic properties as well. For most groups, one or more prototype drugs can be identified that typify the most important characteristics of the group. This permits classification of other important drugs in the group as variants of the prototype, so that only the prototype must be learned in detail and, for the remaining drugs, only the differences from the prototype. Sources of Information Students who wish to review the field of pharmacology in preparation for an examination are referred to Pharmacology: Examination and Board Review, by Trevor, Katzung, and Masters (McGraw-Hill, 2002) or USMLE Road Map: Pharmacology, by Katzung and Trevor (McGraw-Hill, 2003). The references at the end of each chapter in this book were selected to provide information specific to those chapters. Specific questions relating to basic or clinical research are best answered by resort to the general pharmacology and clinical specialty serials. For the student and the physician, three periodicals can be recommended as especially useful sources of current information about drugs: The New England Journal of Medicine, which publishes much original drug-related clinical research as well as frequent reviews of topics in pharmacology; The Medical Letter on Drugs and Therapeutics, which publishes brief critical reviews of new and old therapies, mostly pharmacologic; and Drugs, which publishes extensive reviews of drugs and drug groups. Other sources of information pertinent to the USA should be mentioned as well. The "package insert" is a summary of information the manufacturer is required to place in the prescription sales package; Physicians' Desk Reference (PDR) is a compendium of package inserts published annually with supplements twice a year; Facts and Comparisons is a more complete loose-leaf drug information service with monthly updates; and the USP DI (vol 1, Drug Information for the Health Care Professional) is a large drug compendium with monthly updates that is now published on the Internet by the Micromedex Corporation. The package insert consists of a brief description of the pharmacology of the product. While this brochure contains much practical information, it is also used as a means of shifting liability for untoward drug reactions from the manufacturer onto the practitioner. Therefore, the manufacturer typically lists every toxic effect ever reported, no matter how rare. A useful and objective handbook that presents information on drug toxicity and interactions is Drug Interactions. Finally, the FDA has an Internet World Wide Web site that carries news regarding recent drug approvals, withdrawals, warnings, etc. It can be reached using a personal computer equipped with Internet browser software at http://www.fda.gov. The following addresses are provided for the convenience of readers wishing to obtain any of the publications mentioned above: Drug Interactions Lea & Febiger 600 Washington Square Philadelphia, PA 19106 Facts and Comparisons
111 West Port Plaza, Suite 300 St. Louis, MO 63146 Pharmacology: Examination & Board Review, 6th ed McGraw-Hill Companies, Inc 2 Penn Plaza 12th Floor New York, NY 10121-2298 USMLE Road Map: Pharmacology McGraw-Hill Companies, Inc 2 Penn Plaza 12th Floor New York, NY 10121-2298 The Medical Letter on Drugs and Therapeutics 56 Harrison Street New Rochelle, NY 10801 The New England Journal of Medicine 10 Shattuck Street Boston, MA 02115 Physicians' Desk Reference Box 2017 Mahopac, NY 10541 United States Pharmacopeia Dispensing Information Micromedex, Inc. 6200 S. Syracuse Way, Suite 300 Englewood, CO 80111
Chapter 2. Drug Receptors & Pharmacodynamics Drug Receptors & Pharmacodynamics: Introduction Therapeutic and toxic effects of drugs result from their interactions with molecules in the patient. Most drugs act by associating with specific macromolecules in ways that alter the macromolecules' biochemical or biophysical activities. This idea, more than a century old, is embodied in the term receptor: the component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug's observed effects. Receptors have become the central focus of investigation of drug effects and their mechanisms of action (pharmacodynamics). The receptor concept, extended to endocrinology, immunology, and molecular biology, has proved essential for explaining many aspects of biologic regulation. Many drug receptors have been isolated and characterized in detail, thus opening the way to precise understanding of the molecular basis of drug action. The receptor concept has important practical consequences for the development of drugs and for arriving at therapeutic decisions in clinical practice. These consequences form the basis for
understanding the actions and clinical uses of drugs described in almost every chapter of this book. They may be briefly summarized as follows: (1) Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects. The receptor's affinity for binding a drug determines the concentration of drug required to form a significant number of drug-receptor complexes, and the total number of receptors may limit the maximal effect a drug may produce. (2) Receptors are responsible for selectivity of drug action. The molecular size, shape, and electrical charge of a drug determine whether—and with what affinity—it will bind to a particular receptor among the vast array of chemically different binding sites available in a cell, tissue, or patient. Accordingly, changes in the chemical structure of a drug can dramatically increase or decrease a new drug's affinities for different classes of receptors, with resulting alterations in therapeutic and toxic effects. (3) Receptors mediate the actions of both pharmacologic agonists and antagonists. Some drugs and many natural ligands, such as hormones and neurotransmitters, regulate the function of receptor macromolecules as agonists; ie, they activate the receptor to signal as a direct result of binding to it. Other drugs function as pharmacologic antagonists; ie, they bind to receptors but do not activate generation of a signal; consequently, they interfere with the ability of an agonist to activate the receptor. Thus, the effect of a so-called "pure" antagonist on a cell or in a patient depends entirely on its preventing the binding of agonist molecules and blocking their biologic actions. Some of the most useful drugs in clinical medicine are pharmacologic antagonists. Macromolecular Nature of Drug Receptors Most receptors are proteins, presumably because the structures of polypeptides provide both the necessary diversity and the necessary specificity of shape and electrical charge. The section How Are New Receptors Discovered? describes some of the methods by which receptors are discovered and defined. The best-characterized drug receptors are regulatory proteins, which mediate the actions of endogenous chemical signals such as neurotransmitters, autacoids, and hormones. This class of receptors mediates the effects of many of the most useful therapeutic agents. The molecular structures and biochemical mechanisms of these regulatory receptors are described in a later section entitled Signaling Mechanisms & Drug Action. Other classes of proteins that have been clearly identified as drug receptors include enzymes, which may be inhibited (or, less commonly, activated) by binding a drug (eg, dihydrofolate reductase, the receptor for the antineoplastic drug methotrexate); transport proteins (eg, Na+/K+ ATPase, the membrane receptor for cardioactive digitalis glycosides); and structural pro-teins (eg, tubulin, the receptor for colchicine, an anti-inflammatory agent). This chapter deals with three aspects of drug receptor function, presented in increasing order of complexity: (1) Receptors as determinants of the quantitative relation between the concentration of a drug and the pharmacologic response. (2) Receptors as regulatory proteins and components of chemical signaling mechanisms that provide targets for important drugs. (3) Receptors as key determinants of the therapeutic and toxic effects of drugs in patients. How Are New Receptors Discovered?
Because today's new receptor sets the stage for tomorrow's new drug, it is important to know how new receptors are discovered. Receptor discovery often begins by studying the relations between structures and activities of a group of drugs on some conveniently measured response. Binding of radioactive ligands defines the molar abundance and binding affinities of the putative receptor and provides an assay to aid in its biochemical purification. Analysis of the pure receptor protein identifies the number of its subunits, its size, and (sometimes) provides a clue to how it works (eg, agonist-stimulated autophosphorylation on tyrosine residues, seen with receptors for insulin and many growth factors). These classic steps in receptor identification serve as a warming-up exercise for molecular cloning of the segment of DNA that encodes the receptor. Receptors within a specific class or subclass generally contain highly conserved regions of similar or identical amino acid (and therefore DNA) sequence. This has led to an entirely different approach toward identifying receptors by sequence homology to already known (cloned) receptors. Cloning of new receptors by sequence homology has identified a number of subtypes of known receptor classes, such as -adrenoceptors and serotonin receptors, the diversity of which was only partially anticipated from pharmacologic studies. This approach has also led to the identification of receptors whose existence was not anticipated from pharmacologic studies. These putative receptors, identified only by their similarity to other known receptors, are termed orphan receptors until their native ligands are identified. Identifying such receptors and their ligands is of great interest because this process may elucidate entirely new signaling pathways and therapeutic targets. Relation between Drug Concentration & Response The relation between dose of a drug and the clinically observed response may be complex. In carefully controlled in vitro systems, however, the relation between concentration of a drug and its effect is often simple and can be described with mathematical precision. This idealized relation underlies the more complex relations between dose and effect that occur when drugs are given to patients. Concentration-Effect Curves & Receptor Binding of Agonists Even in intact animals or patients, responses to low doses of a drug usually increase in direct proportion to dose. As doses increase, however, the response increment diminishes; finally, doses may be reached at which no further increase in response can be achieved. In idealized or in vitro systems, the relation between drug concentration and effect is described by a hyperbolic curve (Figure 2–1 A) according to the following equation:
where E is the effect observed at concentration C, Emax is the maximal response that can be produced by the drug, and EC50 is the concentration of drug that produces 50% of maximal effect. Figure 2–1.
Relations between drug concentration and drug effect (panel A) or receptor-bound drug (panel B). The drug concentrations at which effect or receptor occupancy is half-maximal are denoted EC50 and KD, respectively.
This hyperbolic relation resembles the mass action law, which predicts association between two molecules of a given affinity. This resemblance suggests that drug agonists act by binding to ("occupying") a distinct class of biologic molecules with a characteristic affinity for the drug receptor. Radioactive receptor ligands have been used to confirm this occupancy assumption in many drug-receptor systems. In these systems, drug bound to receptors (B) relates to the concentration of free (unbound) drug (C) as depicted in Figure 2–1 B and as described by an analogous equation:
in which Bmax indicates the total concentration of receptor sites (ie, sites bound to the drug at infinitely high concentrations of free drug). KD (the equilibrium dissociation constant) represents the concentration of free drug at which half-maximal binding is observed. This constant characterizes the receptor's affinity for binding the drug in a reciprocal fashion: If the KD is low, binding affinity is high, and vice versa. The EC50 and KD may be identical, but need not be, as discussed below. Dose-response data is often presented as a plot of the drug effect (ordinate) against the logarithm of the dose or concentration (abscissa). This mathematical maneuver transforms the hyperbolic curve of Figure 2–1 into a sigmoid curve with a linear midportion (eg, Figure 2–2). This expands the scale of the concentration axis at low concentrations (where the effect is changing rapidly) and compresses it at high concentrations (where the effect is changing slowly), but has no special biologic or pharmacologic significance. Figure 2–2.
Logarithmic transformation of the dose axis and experimental demonstration of spare receptors, using different concentrations of an irreversible antagonist. Curve A shows agonist response in the absence of antagonist. After treatment with a low concentration of antagonist (curve B), the curve is shifted to the right; maximal responsiveness is preserved, however, because the remaining available receptors are still in excess of the number required. In curve C, produced after treatment with a larger concentration of antagonist, the available receptors are no longer "spare"; instead, they are just sufficient to mediate an undiminished maximal response. Still higher concentrations of antagonist (curves D and E) reduce the number of available receptors to the point that maximal response is diminished. The apparent EC50 of the agonist in curves D and E may approximate the KD that characterizes the binding affinity of the agonist for the receptor. Receptor-Effector Coupling & Spare Receptors When a receptor is occupied by an agonist, the resulting conformational change is only the first of many steps usually required to produce a pharmacologic response. The transduction process between occupancy of receptors and drug response is often termed coupling. The relative efficiency of occupancy-response coupling is partially determined by the initial conformational change in the receptor—thus, the effects of full agonists can be considered more efficiently coupled to receptor occupancy than can the effects of partial agonists, as described below. Coupling efficiency is also determined by the biochemical events that transduce receptor occupancy into cellular response. High efficiency of receptor-effector interaction may also be envisioned as the result of spare receptors. Receptors are said to be "spare" for a given pharmacologic response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors. Spare receptors are not qualitatively different from nonspare receptors. They are not hidden or unavailable, and when they are occupied they can be coupled to response. Experimentally, spare receptors may be demonstrated by using irreversible antagonists to prevent binding of agonist to a proportion of available receptors and showing that high concentrations of agonist can still produce an undiminished maximal response (Figure 2–2). Thus, a
maximal inotropic response of heart muscle to catecholamines can be elicited even under conditions where 90% of the -adrenoceptors are occupied by a quasi-irreversible antagonist. Accordingly, myocardial cells are said to contain a large proportion of spare -adrenoceptors. How can we account for the phenomenon of spare receptors? In a few cases, the biochemical mechanism is understood, such as for drugs that act on some regulatory receptors. In this situation, the effect of receptor activation—eg, binding of guanosine triphosphate (GTP) by an intermediate— may greatly outlast the agonist-receptor interaction (see the following section on G Proteins & Second Messengers). In such a case, the "spareness" of receptors is temporal in that the response initiated by an individual ligand-receptor binding event persists longer than the binding event itself. In other cases, where the biochemical mechanism is not understood, we imagine that the receptors might be spare in number. If the concentration or amount of a cellular component other than the receptor limits the coupling of receptor occupancy to response, then a maximal response can occur without occupancy of all receptors. This concept helps explain how the sensitivity of a cell or tissue to a particular concentration of agonist depends not only on the affinity of the receptor for binding the agonist (characterized by the KD) but also on the degree of spareness—the total number of receptors present compared to the number actually needed to elicit a maximal biologic response. The KD of the agonist-receptor interaction determines what fraction (B/Bmax) of total receptors will be occupied at a given free concentration (C) of agonist regardless of the receptor concentration:
Imagine a responding cell with four receptors and four effectors. Here the number of effectors does not limit the maximal response, and the receptors are not spare in number. Consequently, an agonist present at a concentration equal to the KD will occupy 50% of the receptors, and half of the effectors will be activated, producing a half-maximal response (ie, two receptors stimulate two effectors). Now imagine that the number of receptors increases 10-fold to 40 receptors but that the total number of effectors remains constant. Most of the receptors are now spare in number. As a result, a much lower concentration of agonist suffices to occupy two of the 40 receptors (5% of the receptors), and this same low concentration of agonist is able to elicit a half-maximal response (two of four effectors activated). Thus, it is possible to change the sensitivity of tissues with spare receptors by changing the receptor concentration. Competitive & Irreversible Antagonists Receptor antagonists bind to receptors but do not activate them. In general, the effects of these antagonists result from preventing agonists (other drugs or endogenous regulatory molecules) from binding to and activating receptors. Such antagonists are divided into two classes depending on whether or not they reversibly compete with agonists for binding to receptors. In the presence of a fixed concentration of agonist, increasing concentrations of a competitive antagonist progressively inhibit the agonist response; high antagonist concentrations prevent response completely. Conversely, sufficiently high concentrations of agonist can completely surmount the effect of a given concentration of the antagonist; ie, the Emax for the agonist remains the same for any fixed concentration of antagonist (Figure 2–3 A). Because the antagonism is competitive, the presence of antagonist increases the agonist concentration required for a given degree of response, and so the agonist concentration-effect curve is shifted to the right.
Figure 2–3.
Changes in agonist concentration-effect curves produced by a competitive antagonist (panel A) or by an irreversible antagonist (panel B). In the presence of a competitive antagonist, higher concentrations of agonist are required to produce a given effect; thus the agonist concentration (C') required for a given effect in the presence of concentration [I] of an antagonist is shifted to the right, as shown. High agonist concentrations can overcome inhibition by a competitive antagonist. This is not the case with an irreversible antagonist, which reduces the maximal effect the agonist can achieve, although it may not change its EC50. The concentration (C') of an agonist required to produce a given effect in the presence of a fixed concentration ([I]) of competitive antagonist is greater than the agonist concentration (C) required to produce the same effect in the absence of the antagonist. The ratio of these two agonist concentrations (the "dose ratio") is related to the dissociation constant (KI) of the antagonist by the Schild equation:
Pharmacologists often use this relation to determine the KI of a competitive antagonist. Even without knowledge of the relationship between agonist occupancy of the receptor and response, the KI can be determined simply and accurately. As shown in Figure 2–3, concentration response curves are obtained in the presence and in the absence of a fixed concentration of competitive antagonist; comparison of the agonist concentrations required to produce identical degrees of pharmacologic effect in the two situations reveals the antagonist's KI. If C' is twice C, for example, then [I] = KI. For the clinician, this mathematical relation has two important therapeutic implications:
(1) The degree of inhibition produced by a competitive antagonist depends on the concentration of antagonist. Different patients receiving a fixed dose of propranolol, for example, exhibit a wide range of plasma concentrations, owing to differences in clearance of the drug. As a result, the effects of a fixed dose of this competitive antagonist of norepinephrine may vary widely in patients, and the dose must be adjusted accordingly. (2) Clinical response to a competitive antagonist depends on the concentration of agonist that is competing for binding to receptors. Here also propranolol provides a useful example: When this competitive -adrenoceptor antagonist is administered in doses sufficient to block the effect of basal levels of the neurotransmitter norepinephrine, resting heart rate is decreased. However, the increase in release of norepinephrine and epinephrine that occurs with exercise, postural changes, or emotional stress may suffice to overcome competitive antagonism by propranolol and increase heart rate, and thereby can influence therapeutic response. Some receptor antagonists bind to the receptor in an irreversible or nearly irreversible fashion, ie, not competitive. The antagonist's affinity for the receptor may be so high that for practical purposes, the receptor is unavailable for binding of agonist. Other antagonists in this class produce irreversible effects because after binding to the receptor they form covalent bonds with it. After occupancy of some proportion of receptors by such an antagonist, the number of remaining unoccupied receptors may be too low for the agonist (even at high concentrations) to elicit a response comparable to the previous maximal response (Figure 2–3 B). If spare receptors are present, however, a lower dose of an irreversible antagonist may leave enough receptors unoccupied to allow achievement of maximum response to agonist, although a higher agonist concentration will be required (Figures 2–2 B and C; see Receptor-Effector Coupling and Spare Receptors, above). Therapeutically, irreversible antagonists present distinctive advantages and disadvantages. Once the irreversible antagonist has occupied the receptor, it need not be present in unbound form to inhibit agonist responses. Consequently, the duration of action of such an irreversible antagonist is relatively independent of its own rate of elimination and more dependent on the rate of turnover of receptor molecules. Phenoxybenzamine, an irreversible -adrenoceptor antagonist, is used to control the hypertension caused by catecholamines released from pheochromocytoma, a tumor of the adrenal medulla. If administration of phenoxybenzamine lowers blood pressure, blockade will be maintained even when the tumor episodically releases very large amounts of catecholamine. In this case, the ability to prevent responses to varying and high concentrations of agonist is a therapeutic advantage. If overdose occurs, however, a real problem may arise. If the -adrenoceptor blockade cannot be overcome, excess effects of the drug must be antagonized "physiologically," ie, by using a pressor agent that does not act via receptors. Partial Agonists Based on the maximal pharmacologic response that occurs when all receptors are occupied, agonists can be divided into two classes: partial agonists produce a lower response, at full receptor occupancy, than do full agonists. Partial agonists produce concentration-effect curves that resemble those observed with full agonists in the presence of an antagonist that irreversibly blocks some of the receptor sites (compare Figures 2–2 [curve D] and 2–4 B). It is important to emphasize that the failure of partial agonists to produce a maximal response is not due to decreased affinity for binding to receptors. Indeed, a partial agonist's inability to cause a maximal pharmacologic response, even when present at high concentrations that saturate binding to all receptors, is indicated by the fact
that partial agonists competitively inhibit the responses produced by full agonists (Figure 2–4 C). Many drugs used clinically as antagonists are in fact weak partial agonists. Figure 2–4.
Panel A: The percentage of receptor occupancy resulting from full agonist (present at a single concentration) binding to receptors in the presence of increasing concentrations of a partial agonist. Because the full agonist (filled squares) and the partial agonist (open squares) compete to bind to the same receptor sites, when occupancy by the partial agonist increases, binding of the full agonist decreases. Panel B: When each of the two drugs is used alone and response is measured, occupancy of all the receptors by the partial agonist produces a lower maximal response than does similar occupancy by the full agonist. Panel C: Simultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist produces the response patterns shown in the bottom panel. The fractional response caused by a single concentration of the full agonist (filled squares) decreases as increasing concentrations of the partial agonist compete to bind to the receptor with increasing success; at the same time the portion of the response caused by the partial agonist (open squares) increases, while the total response—ie, the sum of responses to the two drugs (filled triangles)—gradually decreases, eventually reaching the value produced by partial agonist alone (compare panel B).
Other Mechanisms of Drug Antagonism Not all of the mechanisms of antagonism involve interactions of drugs or endogenous ligands at a single type of receptor. Indeed, chemical antagonists need not involve a receptor at all. Thus, one drug may antagonize the actions of a second drug by binding to and inactivating the second drug. For example, protamine, a protein that is positively charged at physiologic pH, can be used clinically to counteract the effects of heparin, an anticoagulant that is negatively charged; in this case, one drug antagonizes the other simply by binding it and making it unavailable for interactions with proteins involved in formation of a blood clot. The clinician often uses drugs that take advantage of physiologic antagonism between endogenous regulatory pathways. For example, several catabolic actions of the glucocorticoid hormones lead to increased blood sugar, an effect that is physiologically opposed by insulin. Although glucocorticoids and insulin act on quite distinct receptor-effector systems, the clinician must sometimes administer insulin to oppose the hyperglycemic effects of glucocorticoid hormone, whether the latter is elevated by endogenous synthesis (eg, a tumor of the adrenal cortex) or as a result of glucocorticoid therapy. In general, use of a drug as a physiologic antagonist produces effects that are less specific and less easy to control than are the effects of a receptor-specific antagonist. Thus, for example, to treat bradycardia caused by increased release of acetylcholine from vagus nerve endings, the physician could use isoproterenol, a -adrenoceptor agonist that increases heart rate by mimicking sympathetic stimulation of the heart. However, use of this physiologic antagonist would be less rational—and potentially more dangerous—than would use of a receptor-specific antagonist such as atropine (a competitive antagonist at the receptors at which acetylcholine slows heart rate). Signaling Mechanisms & Drug Action Until now we have considered receptor interactions and drug effects in terms of equations and concentration-effect curves. We must also understand the molecular mechanisms by which a drug acts. Such understanding allows us to ask basic questions with important clinical implications: • • • • •
Why do some drugs produce effects that persist for minutes, hours, or even days after the drug is no longer present? Why do responses to other drugs diminish rapidly with prolonged or repeated administration? How do cellular mechanisms for amplifying external chemical signals explain the phenomenon of spare receptors? Why do chemically similar drugs often exhibit extraordinary selectivity in their actions? Do these mechanisms provide targets for developing new drugs?
Most transmembrane signaling is accomplished by a small number of different molecular mechanisms. Each type of mechanism has been adapted, through the evolution of distinctive protein families, to transduce many different signals. These protein families include receptors on the cell surface and within the cell, as well as enzymes and other components that generate, amplify, coordinate, and terminate postreceptor signaling by chemical second messengers in the cytoplasm. This section first discusses the mechanisms for carrying chemical information across the plasma membrane and then outlines key features of cytoplasmic second messengers. Five basic mechanisms of transmembrane signaling are well understood (Figure 2–5). Each uses a different strategy to circumvent the barrier posed by the lipid bilayer of the plasma membrane.
These strategies use (1) a lipid-soluble ligand that crosses the membrane and acts on an intracellular receptor; (2) a transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein's extracellular domain; (3) a transmembrane receptor that binds and stimulates a protein tyrosine kinase; (4) a ligand-gated transmembrane ion channel that can be induced to open or close by the binding of a ligand; or (5) a transmembrane receptor protein that stimulates a GTP-binding signal transducer protein (G protein), which in turn modulates production of an intracellular second messenger. Figure 2–5.
Known transmembrane signaling mechanisms: 1: A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription); 2: the signal binds to the extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain; 3: the signal binds to the extracellular domain of a transmembrane receptor bound to a protein tyrosine kinase, which it activates; 4: the signal binds to and directly regulates the opening of an ion channel; 5: the signal binds to a cell-surface receptor linked to an effector enzyme by a G protein. (A,C, substrates; B, D, products; R, receptor; G, G protein; E, effector [enzyme or ion channel]; Y, tyrosine; P, phosphate.) While the five established mechanisms do not account for all the chemical signals conveyed across cell membranes, they do transduce many of the most important signals exploited in pharmacotherapy. Intracellular Receptors for Lipid-Soluble Agents Several biologic signals are sufficiently lipid-soluble to cross the plasma membrane and act on intracellular receptors. One of these is a gas, nitric oxide (NO), that acts by stimulating an intracellular enzyme, guanylyl cyclase, which produces cyclic guanosine monophosphate (cGMP). Signaling via cGMP is described in more detail later in this chapter. Receptors for another class of ligands—including corticosteroids, mineralocorticoids, sex steroids, vitamin D, and thyroid hormone—stimulate the transcription of genes in the nucleus by binding to specific DNA sequences
near the gene whose expression is to be regulated. Many of the target DNA sequences (called response elements) have been identified. These "gene-active" receptors belong to a protein family that evolved from a common precursor. Dissection of the receptors by recombinant DNA techniques has provided insights into their molecular mechanism. For example, binding of glucocorticoid hormone to its normal receptor protein relieves an inhibitory constraint on the transcription-stimulating activity of the protein. Figure 2–6 schematically depicts the molecular mechanism of glucocorticoid action: In the absence of hormone, the receptor is bound to hsp90, a protein that appears to prevent normal folding of several structural domains of the receptor. Binding of hormone to the ligand-binding domain triggers release of hsp90. This allows the DNA-binding and transcription-activating domains of the receptor to fold into their functionally active conformations, so that the activated receptor can initiate transcription of target genes. Figure 2–6.
Mechanism of glucocorticoid action. The glucocorticoid receptor polypeptide is schematically depicted as a protein with three distinct domains. A heat-shock protein, hsp90, binds to the receptor in the absence of hormone and prevents folding into the active conformation of the receptor. Binding of a hormone ligand (steroid) causes dissociation of the hsp90 stabilizer and permits conversion to the active configuration.
The mechanism used by hormones that act by regulating gene expression has two therapeutically important consequences: (1) All of these hormones produce their effects after a characteristic lag period of 30 minutes to several hours—the time required for the synthesis of new proteins. This means that the geneactive hormones cannot be expected to alter a pathologic state within minutes (eg, glucocorticoids will not immediately relieve the symptoms of acute bronchial asthma). (2) The effects of these agents can persist for hours or days after the agonist concentration has been reduced to zero. The persistence of effect is primarily due to the relatively slow turnover of most enzymes and proteins, which can remain active in cells for hours or days after they have been synthesized. Consequently, it means that the beneficial (or toxic) effects of a gene-active hormone will usually decrease slowly when administration of the hormone is stopped. Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases This class of receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor- (TGF- ), and many other trophic hormones. These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase (Figure 2–7). In all these receptors, the two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane. Figure 2–7.
Mechanism of activation of the epidermal growth factor (EGF) receptor, a representative receptor tyrosine kinase. The receptor polypeptide has extracellular and cytoplasmic domains, depicted above and below the plasma membrane. Upon binding of EGF (circle), the receptor converts from its inactive monomeric state (left) to an active dimeric state (right), in which two receptor
polypeptides bind noncovalently in the plane of the membrane. The cytoplasmic domains become phosphorylated (P) on specific tyrosine residues (Y) and their enzymatic activities are activated, catalyzing phosphorylation of substrate proteins (S). The receptor tyrosine kinase signaling pathway begins with ligand binding to the receptor's extracellular domain. The resulting change in receptor conformation causes receptor molecules to bind to one another, which in turn brings together the tyrosine kinase domains, which become enzymatically active, and phosphorylate one another as well as additional downstream signaling proteins. Activated receptors catalyze phosphorylation of tyrosine residues on different target signaling proteins, thereby allowing a single type of activated receptor to modulate a number of biochemical processes. Insulin, for example, uses a single class of receptors to trigger increased uptake of glucose and amino acids and to regulate metabolism of glycogen and triglycerides in the cell. Similarly, each of the growth factors initiates in its specific target cells a complex program of cellular events ranging from altered membrane transport of ions and metabolites to changes in the expression of many genes. At present, a few compounds have been found to produce effects that may be due to inhibition of tyrosine kinase activities. It is easy to imagine therapeutic uses for specific inhibitors of growth factor receptors, especially in neoplastic disorders where excessive growth factor signaling is often observed. For example, a monoclonal antibody (trastuzumab) that acts as an antagonist of the HER2/neu receptor tyrosine kinase is effective in therapy of human breast cancers associated with overexpression of this growth factor receptor. The intensity and duration of action of EGF, PDGF, and other agents that act via receptor tyrosine kinases are limited by receptor down-regulation. Ligand binding induces accelerated endocytosis of receptors from the cell surface, followed by the degradation of those receptors (and their bound ligands). When this process occurs at a rate faster than de novo synthesis of receptors, the total number of cell-surface receptors is reduced (down-regulated) and the cell's responsiveness to ligand is correspondingly diminished. A well-understood process by which many tyrosine kinases are down-regulated is via ligand-induced internalization of receptors followed by trafficking to lysosomes, where receptors are proteolyzed. EGF causes internalization and subsequent proteolytic down-regulation after binding to the EGF receptor protein tyrosine kinase; genetic mutations that interfere with this process of down-regulation cause excessive growth factor–induced cell proliferation and are associated with an increased susceptibility to certain types of cancer. Internalization of certain receptor tyrosine kinases, most notably receptors for nerve growth factor, serves a very different function. Internalized nerve growth factor receptors are not rapidly degraded. Instead, receptors remain intact and are translocated in endocytic vesicles from the distal axon (where receptors are activated by nerve growth factor released from the innervated tissue) to the cell body (where the signal is transduced to transcription factors regulating the expression of genes controlling cell survival). This process effectively transports a critical survival signal released from the target tissue over a remarkably long distance—more than 1 meter in certain sensory neurons. A number of regulators of growth and differentiation, including TGF- , act on another class of transmembrane receptor enzymes that phosphorylate serine and threonine residues. ANP, an important regulator of blood volume and vascular tone, acts on a transmembrane receptor whose intracellular domain, a guanylyl cyclase, generates cGMP (see below). Receptors in both groups, like the receptor tyrosine kinases, are active in their dimeric forms. Cytokine Receptors Cytokine receptors respond to a heterogeneous group of peptide ligands that includes growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation. These receptors use a mechanism (Figure 2–8) closely resembling that of receptor tyrosine kinases, except that in this case, the protein tyrosine kinase activity is not intrinsic to the
receptor molecule. Instead, a separate protein tyrosine kinase, from the Janus-kinase (JAK) family, binds noncovalently to the receptor. As in the case of the EGF-receptor, cytokine receptors dimerize after they bind the activating ligand, allowing the bound JAKs to become activated and to phosphorylate tyrosine residues on the receptor. Tyrosine phosphates on the receptor then set in motion a complex signaling dance by binding another set of proteins, called STATs (signal transducers and activators of transcription). The bound STATs are themselves phosphorylated by the JAKs, two STAT molecules dimerize (attaching to one another's tyrosine phosphates), and finally the STAT/STAT dimer dissociates from the receptor and travels to the nucleus, where it regulates transcription of specific genes. Figure 2–8.
Cytokine receptors, like receptor tyrosine kinases, have extracellular and intracellular domains and form dimers. However, after activation by an appropriate ligand, separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in phosphorylation of signal transducers and activation of transcription (STAT) molecules. STAT dimers then travel to the nucleus, where they regulate transcription. Ligand-Gated Channels Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels. The natural ligands include acetylcholine, serotonin, -aminobutyric acid (GABA), and the excitatory amino acids (eg, glycine, aspartate, and glutamate). All of these agents are synaptic transmitters. Each of their receptors transmits its signal across the plasma membrane by increasing transmembrane conductance of the relevant ion and thereby altering the electrical potential across the membrane. For example, acetylcholine causes the opening of the ion channel in the nicotinic
acetylcholine receptor (AChR), which allows Na+ to flow down its concentration gradient into cells, producing a localized excitatory postsynaptic potential—a depolarization. The AChR (Figure 2–9) is one of the best-characterized of all cell-surface receptors for hormones or neurotransmitters. One form of this receptor is a pentamer made up of five polypeptide subunits (eg, two chains plus one , one , and one chain, all with molecular weights ranging from 43,000 to 50,000). These polypeptides, each of which crosses the lipid bilayer four times, form a cylindric structure 8 nm in diameter. When acetylcholine binds to sites on the subunits, a conformational change occurs that results in the transient opening of a central aqueous channel through which sodium ions penetrate from the extracellular fluid into the cell. Figure 2–9.
The nicotinic acetylcholine receptor, a ligand-gated ion channel. The receptor molecule is depicted as embedded in a rectangular piece of plasma membrane, with extracellular fluid above and cytoplasm below. Composed of five subunits (two , one , one , and one ), the receptor opens a central transmembrane ion channel when acetylcholine (ACh) binds to sites on the extracellular domain of its subunits. The time elapsed between the binding of the agonist to a ligand-gated channel and the cellular response can often be measured in milliseconds. The rapidity of this signaling mechanism is crucially important for moment-to-moment transfer of information across synapses. Ligand-gated ion channels can be regulated by multiple mechanisms, including phosphorylation and internalization. In the central nervous system, these mechanisms contribute to synaptic plasticity involved in learning and memory. G Proteins & Second Messengers Many extracellular ligands act by increasing the intracellular concentrations of second messengers such as cyclic adenosine-3',5'-monophosphate (cAMP), calcium ion, or the phosphoinositides
(described below). In most cases they use a transmembrane signaling system with three separate components. First, the extracellular ligand is specifically detected by a cell-surface receptor. The receptor in turn triggers the activation of a G protein located on the cytoplasmic face of the plasma membrane. The activated G protein then changes the activity of an effector element, usually an enzyme or ion channel. This element then changes the concentration of the intracellular second messenger. For cAMP, the effector enzyme is adenylyl cyclase, a transmembrane protein that converts intracellular adenosine triphosphate (ATP) to cAMP. The corresponding G protein, Gs, stimulates adenylyl cyclase after being activated by hormones and neurotransmitters that act via a specific receptor (Table 2–1). Table 2–1. A Partial List of Endogenous Ligands and Their Associated Second Messengers.
Ligand
Second Messenger
Adrenocorticotropic hormone
cAMP
Acetylcholine (muscarinic receptors)
Ca2+, phosphoinositides
Angiotensin
Ca2+, phosphoinositides
Catecholamines ( 1-adrenoceptors)
Ca2+, phosphoinositides
Catecholamines ( -adrenoceptors)
cAMP
Chorionic gonadotropin
cAMP
Follicle-stimulating hormone
cAMP
Glucagon
cAMP
Histamine (H2 receptors)
cAMP
Luteinizing hormone
cAMP
Melanocyte-stimulating hormone
cAMP
Parathyroid hormone
cAMP
Platelet-activating factor
Ca2+, phosphoinositides
Prostacyclin, prostaglandin E2
cAMP
Serotonin (5-HT4 receptors)
cAMP
Serotonin (5-HT1C and 5-HT2 receptors)
Ca2+, phosphoinositides
Thyrotropin
cAMP
Thyrotropin-releasing hormone
Ca2+, phosphoinositides
Vasopressin (V1 receptors)
Ca2+, phosphoinositides
Vasopressin (V2 receptors)
cAMP
Key: cAMP = cyclic adenosine monophosphate. Gs and other G proteins use a molecular mechanism that involves binding and hydrolysis of GTP (Figure 2–10). This mechanism allows the transduced signal to be amplified. For example, a neurotransmitter such as norepinephrine may encounter its membrane receptor for only a few milliseconds. When the encounter generates a GTP-bound Gs molecule, however, the duration of activation of adenylyl cyclase depends on the longevity of GTP binding to Gs rather than on the receptor's affinity for norepinephrine. Indeed, like other G proteins, GTP-bound Gs may remain active for tens of seconds, enormously amplifying the original signal. This mechanism explains how signaling by G proteins produces the phenomenon of spare receptors (described above). At low concentrations of agonist the proportion of agonist-bound receptors may be much less than the proportion of G proteins in the active (GTP-bound) state; if the proportion of active G proteins correlates with pharmacologic response, receptors will appear to be spare (ie, a small fraction of receptors occupied by agonist at any given time will appear to produce a proportionately larger response). Figure 2–10.
The guanine nucleotide-dependent activation-inactivation cycle of G proteins. The agonist activates the receptor (R), which promotes release of GDP from the G protein (G), allowing entry of GTP into the nucleotide binding site. In its GTP-bound state (G-GTP), the G protein regulates activity of an effector enzyme or ion channel (E). The signal is terminated by hydrolysis of GTP, followed by return of the system to the basal unstimulated state. Open arrows denote regulatory effects. (Pi, inorganic phosphate.)
The family of G proteins contains several functionally diverse subfamilies (Table 2–2), each of which mediates effects of a particular set of receptors to a distinctive group of effectors. Receptors coupled to G proteins comprise a family of "seven-transmembrane" or "serpentine" receptors, so called because the receptor polypeptide chain "snakes" across the plasma membrane seven times (Figure 2–11). Receptors for adrenergic amines, serotonin, acetylcholine (muscarinic but not
nicotinic), many peptide hormones, odorants, and even visual receptors (in retinal rod and cone cells) all belong to the serpentine family. All were derived from a common evolutionary precursor. Some serpentine receptors exist as dimers, but it is thought that dimerization is not usually required for activation. Table 2–2. G Proteins and Their Receptors and Effectors.
G Protein
Receptors for:
Gs
-Adrenergic amines, glucagon, histamine, serotonin, and many other hormones
Gi1, Gi2, Gi3
Effector/Signaling Pathway Adenylyl cyclase
cAMP
amines, acetylcholine Several, including: (muscarinic), opioids, serotonin, and many others Adenylyl cyclase
cAMP
2-Adrenergic
Open cardiac K+ channels rate Adenylyl cyclase
heart
Golf
Odorants (olfactory epithelium)
cAMP
Go
Neurotransmitters in brain (not yet specifically identified)
Not yet clear
Gq
Acetylcholine (eg, muscarinic), bombesin, serotonin (5-HT1C), and many others
Phospholipase C IP3, diacylglycerol, cytoplasmic Ca2+
Gt1, Gt2
Photons (rhodopsin and color opsins in retinal rod and cone cells)
cGMP phosphodiesterase (phototransduction)
cGMP
Key: cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate. Serpentine receptors transduce signals across the plasma membrane in essentially the same way. Often the agonist ligand—eg, a catecholamine, acetylcholine, or the photon-activated chromophore of retinal photoreceptors—is bound in a pocket enclosed by the transmembrane regions of the receptor (as in Figure 2–11). The resulting change in conformation of these regions is transmitted to cytoplasmic loops of the receptor, which in turn activate the appropriate G protein by promoting replacement of GDP by GTP, as described above. Considerable biochemical evidence indicates that G proteins interact with amino acids in the third cytoplasmic loop of the serpentine receptor polypeptide (shown by arrows in Figure 2–11). The carboxyl terminal tails of these receptors, also located in the cytoplasm, can regulate the receptors' ability to interact with G proteins, as described below. Figure 2–11.
Transmembrane topology of a typical serpentine receptor. The receptor's amino (N) terminal is extracellular (above the plane of the membrane), and its carboxyl (C) terminal intracellular. The terminals are connected by a polypeptide chain that traverses the plane of the membrane seven times. The hydrophobic transmembrane segments (light color) are designated by roman numerals (I–VII). The agonist (Ag) approaches the receptor from the extracellular fluid and binds to a site surrounded by the transmembrane regions of the receptor protein. G proteins (G) interact with cytoplasmic regions of the receptor, especially with portions of the third cytoplasmic loop between transmembrane regions V and VI. The receptor's cytoplasmic terminal tail contains numerous serine and threonine residues whose hydroxyl (–OH) groups can be phosphorylated. This phosphorylation may be associated with diminished receptor-G protein interaction. Receptor Regulation Receptor-mediated responses to drugs and hormonal agonists often desensitize with time (Figure 2– 12, top). After reaching an initial high level, the response (eg, cellular cAMP accumulation, Na+ influx, contractility, etc) gradually diminishes over seconds or minutes, even in the continued presence of the agonist. This desensitization is usually reversible; a second exposure to agonist, if provided a few minutes after termination of the first exposure, results in a response similar to the initial response. Figure 2–12.
Possible mechanism for desensitization of the -adrenoceptor. The upper part of the figure depicts the response to a -adrenoceptor agonist (ordinate) versus time (abscissa). The break in the time axis indicates passage of time in the absence of agonist. Temporal duration of exposure to agonist is indicated by the light-colored bar. The lower part of the figure schematically depicts agonistinduced phosphorylation (P) by -adrenoceptor kinase ( -adrenergic receptor kinase, ARK) of carboxyl terminal hydroxyl groups (–OH) of the -adrenoceptor. This phosphorylation induces binding of a protein, -arrestin ( -arr), which prevents the receptor from interacting with Gs. Removal of agonist for a short period of time allows dissociation of -arr, removal of phosphate (Pi) from the receptor by phosphatases (P'ase), and restoration of the receptor's normal responsiveness to agonist. Although many kinds of receptors undergo desensitization, the mechanism is in many cases obscure. A molecular mechanism of desensitization has been worked out in some detail, however, in the case of the -adrenoceptor (Figure 2–12, bottom). The agonist-induced change in conformation of the receptor causes it to bind, activate, and serve as a substrate for a specific kinase, -adrenoceptor kinase (also called ARK). ARK then phosphorylates serine or threonine
residues in the receptor's carboxyl terminal tail. The presence of phosphoserines increases the receptor's affinity for binding a third protein, -arrestin. Binding of -arrestin to cytoplasmic loops of the receptor diminishes the receptor's ability to interact with Gs, thereby reducing the agonist response (ie, stimulation of adenylyl cyclase). Upon removal of agonist, however, cellular phosphatases remove phosphates from the receptor and ARK stops putting them back on, so that the receptor—and consequently the agonist response—return to normal. This mechanism of desensitization, which rapidly and reversibly modulates the ability of the receptor to signal to G protein, turns out to regulate many G protein–coupled receptors. Another important regulatory process is down-regulation. Down-regulation, which decreases the actual number of receptors present in the cell or tissue, occurs more slowly than rapid desensitization and is less readily reversible. This is because down-regulation involves a net degradation of receptors present in the cell, requiring new receptor biosynthesis for recovery, in contrast to rapid desensitization which involves reversible phosphorylation of existing receptors. Many G protein–coupled receptors are down-regulated by undergoing ligand-induced endocytosis and delivery to lysosomes, similar to down-regulation of protein tyrosine kinases such as the EGF receptor. Down-regulation generally occurs only after prolonged or repeated exposure of cells to agonist (over hours to days). Brief periods of agonist exposure (several minutes) can also induce internalization of receptors. In this case, many receptors, including the -adrenoceptor, do not down-regulate but instead recycle intact to the plasma membrane. This rapid cycling through endocytic vesicles promotes dephosphorylation of receptors, increasing the rate at which fully functional receptors are replenished in the plasma membrane. Thus, depending on the particular receptor and duration of activation, internalization can mediate quite different effects on receptor signaling and regulation. Well-Established Second Messengers Cyclic Adenosine Monophosphate (cAMP) Acting as an intracellular second messenger, cAMP mediates such hormonal responses as the mobilization of stored energy (the breakdown of carbohydrates in liver or triglycerides in fat cells stimulated by -adrenomimetic catecholamines), conservation of water by the kidney (mediated by vasopressin), Ca2+ homeostasis (regulated by parathyroid hormone), and increased rate and contraction force of heart muscle ( -adrenomimetic catecholamines). It also regulates the production of adrenal and sex steroids (in response to corticotropin or follicle-stimulating hormone), relaxation of smooth muscle, and many other endocrine and neural processes. cAMP exerts most of its effects by stimulating cAMP-dependent protein kinases (Figure 2–13). These kinases are composed of a cAMP-binding regulatory (R) dimer and two catalytic (C) chains. When cAMP binds to the R dimer, active C chains are released to diffuse through the cytoplasm and nucleus, where they transfer phosphate from ATP to appropriate substrate proteins, often enzymes. The specificity of cAMP's regulatory effects resides in the distinct protein substrates of the kinases that are expressed in different cells. For example, liver is rich in phosphorylase kinase and glycogen synthase, enzymes whose reciprocal regulation by cAMP-dependent phosphorylation governs carbohydrate storage and release. Figure 2–13.
The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits, protein substrates (S) of the kinases, and phosphatases (P'ase), which remove phosphates from substrate proteins. Open arrows denote regulatory effects. When the hormonal stimulus stops, the intracellular actions of cAMP are terminated by an elaborate series of enzymes. cAMP-stimulated phosphorylation of enzyme substrates is rapidly reversed by a diverse group of specific and nonspecific phosphatases. cAMP itself is degraded to 5'-AMP by several cyclic nucleotide phosphodiesterases (PDE, Figure 2–13). Competitive inhibition of cAMP degradation is one way caffeine, theophylline, and other methylxanthines produce their effects (see Chapter 20: Drugs Used in Asthma). Calcium and Phosphoinositides Another well-studied second messenger system involves hormonal stimulation of phosphoinositide hydrolysis (Figure 2–14). Some of the hormones, neurotransmitters, and growth factors that trigger this pathway (see Table 2–1) bind to receptors linked to G proteins, while others bind to receptor tyrosine kinases. In all cases, the crucial step is stimulation of a membrane enzyme, phospholipase C (PLC), which splits a minor phospholipid component of the plasma membrane, phosphatidylinositol-4,5-bisphosphate (PIP2), into two second messengers, diacylglycerol and inositol-1,4,5-trisphosphate (IP3 or InsP3). Diacylglycerol is confined to the membrane where it activates a phospholipid- and calcium-sensitive protein kinase called protein kinase C. IP3 is watersoluble and diffuses through the cytoplasm to trigger release of Ca2+ from internal storage vesicles. Elevated cytoplasmic Ca2+ concentration promotes the binding of Ca2+ to the calcium-binding
protein calmodulin, which regulates activities of other enzymes, including calcium-dependent protein kinases. Figure 2–14.
The Ca2+-phosphoinositide signaling pathway. Key proteins include hormone receptors (R), a G protein (G), a phosphoinositide-specific phospholipase C (PLC), protein kinase C substrates of the kinase (S), calmodulin (CaM), and calmodulin-binding enzymes (E), including kinases, phosphodiesterases, etc. (PIP2, phosphatidylinositol-4,5-bisphosphate; DAG, diacylglycerol. Asterisk denotes activated state. Open arrows denote regulatory effects.) With its multiple second messengers and protein kinases, the phosphoinositide signaling pathway is much more complex than the cAMP pathway. For example, different cell types may contain one or more specialized calcium- and calmodulin-dependent kinases with limited substrate specificity (eg, myosin light chain kinase) in addition to a general calcium- and calmodulin-dependent kinase that can phosphorylate a wide variety of protein substrates. Furthermore, at least nine structurally distinct types of protein kinase C have been identified. As in the cAMP system, multiple mechanisms damp or terminate signaling by this pathway. IP3 is inactivated by dephosphorylation; diacylglycerol is either phosphorylated to yield phosphatidic acid, which is then converted back into phospholipids, or it is deacylated to yield arachidonic acid; Ca2+ is actively removed from the cytoplasm by Ca2+ pumps. These and other nonreceptor elements of the calcium-phosphoinositide signaling pathway are now becoming targets for drug development. For example, the therapeutic effects of lithium ion, an established agent for treating manic-depressive illness, may be mediated by effects on the metabolism of phosphoinositides (see Chapter 29: Antipsychotic Agents & Lithium). Cyclic Guanosine Monophosphate (cGMP)
Unlike cAMP, the ubiquitous and versatile carrier of diverse messages, cGMP has established signaling roles in only a few cell types. In intestinal mucosa and vascular smooth muscle, the cGMP-based signal transduction mechanism closely parallels the cAMP-mediated signaling mechanism. Ligands detected by cell surface receptors stimulate membrane-bound guanylyl cyclase to produce cGMP, and cGMP acts by stimulating a cGMP-dependent protein kinase. The actions of cGMP in these cells are terminated by enzymatic degradation of the cyclic nucleotide and by dephosphorylation of kinase substrates. Increased cGMP concentration causes relaxation of vascular smooth muscle by a kinase-mediated mechanism that results in dephosphorylation of myosin light chains (see Figure 12–2). In these smooth muscle cells, cGMP synthesis can be elevated by two different transmembrane signaling mechanisms utilizing two different guanylyl cyclases. ANP, a blood-borne peptide hormone, stimulates a transmembrane receptor by binding to its extracellular domain, thereby activating the guanylyl cyclase activity that resides in the receptor's intracellular domain. The other mechanism mediates responses to NO (see Chapter 19: Nitric Oxide, Donors, & Inhibitors), which is generated in vascular endothelial cells in response to natural vasodilator agents such as acetylcholine and histamine (NO is also called endothelium-derived relaxing factor [EDRF]). After entering the target cell, NO binds to and activates a cytoplasmic guanylyl cyclase. A number of useful vasodilating drugs act by generating or mimicking NO, or by interfering with the metabolic breakdown of cGMP by phosphodiesterase (see Chapter 11: Antihypertensive Agents and Chapter 12: Vasodilators & the Treatment of Angina Pectoris). Interplay among Signaling Mechanisms The calcium-phosphoinositide and cAMP signaling pathways oppose one another in some cells and are complementary in others. For example, vasopressor agents that contract smooth muscle act by IP3-mediated mobilization of Ca2+, whereas agents that relax smooth muscle often act by elevation of cAMP. In contrast, cAMP and phosphoinositide second messengers act together to stimulate glucose release from the liver. Phosphorylation: A Common Theme Almost all second messenger signaling involves reversible phosphorylation, which performs two principal functions in signaling: amplification and flexible regulation. In amplification, rather like GTP bound to a G protein, the attachment of a phosphoryl group to a serine, threonine, or tyrosine residue powerfully amplifies the initial regulatory signal by recording a molecular memory that the pathway has been activated; dephosphorylation erases the memory, taking a longer time to do so than is required for dissociation of an allosteric ligand. In flexible regulation, differing substrate specificities of the multiple protein kinases regulated by second messengers provide branch points in signaling pathways that may be independently regulated. In this way, cAMP, Ca2+, or other second messengers can use the presence or absence of particular kinases or kinase substrates to produce quite different effects in different cell types. Inhibitors of protein kinases have great potential as therapeutic agents, particularly in neoplastic diseases. Trastuzumab, an antibody that antagonizes growth factor receptor signaling, was discussed earlier as a therapeutic agent for breast cancer. Another example of this general approach is imatinib (Gleevec, STI571), a small molecule inhibitor of the cytoplasmic tyrosine kinase Bcr/Abl, which is activated by growth factor signaling pathways and is overexpressed in chronic myelogenous leukemia (CML). This compound, a promising agent for treating CML, was recently approved by the US Food and Drug Administration (FDA) for clinical use.
Receptor Classes & Drug Development The existence of a specific drug receptor is usually inferred from studying the structure-activity relationship of a group of structurally similar congeners of the drug that mimic or antagonize its effects. Thus, if a series of related agonists exhibits identical relative potencies in producing two distinct effects, it is likely that the two effects are mediated by similar or identical receptor molecules. In addition, if identical receptors mediate both effects, a competitive antagonist will inhibit both responses with the same KI; a second competitive antagonist will inhibit both responses with its own characteristic KI. Thus, studies of the relation between structure and activity of a series of agonists and antagonists can identify a species of receptor that mediates a set of pharmacologic responses. Exactly the same experimental procedure can show that observed effects of a drug are mediated by different receptors. In this case, effects mediated by different receptors may exhibit different orders of potency among agonists and different KI values for each competitive antagonist. Wherever we look, evolution has created many different receptors that function to mediate responses to any individual chemical signal. In some cases, the same chemical acts on completely different structural receptor classes. For example, acetylcholine uses ligand-gated ion channels (nicotinic AChRs) to initiate a fast excitatory postsynaptic potential (EPSP) in postganglionic neurons. Acetylcholine also activates a separate class of G protein–coupled receptors (muscarinic AChRs), which modulate responsiveness of the same neurons to the fast EPSP. In addition, each structural class usually includes multiple subtypes of receptor, often with significantly different signaling or regulatory properties. For example, norepinephrine activates many structurally related receptors, including -adrenergic (stimulation of Gs, increased heart rate), 1-adrenergic (stimulation of Gq, vasoconstriction), and 2-adrenergic (stimulation of Gi, opening of K+ channels) (see Table 2–2). The existence of multiple receptor classes and subtypes for the same endogenous ligand has created important opportunities for drug development. For example, propranolol, a selective antagonist of -adrenergic receptors, can reduce an accelerated heart rate without preventing the sympathetic nervous system from causing vasoconstriction, an effect mediated by 1 receptors. The principle of drug selectivity may even apply to structurally identical receptors expressed in different cells, eg, receptors for steroids such as estrogen (Figure 2–6). Different cell types express different accessory proteins, which interact with steroid receptors and change the functional effects of drug-receptor interaction. For example, tamoxifen acts as an antagonist on estrogen receptors expressed in mammary tissue but as an agonist on estrogen receptors in bone. Consequently, tamoxifen may be useful not only in the treatment and prophylaxis of breast cancer but also in the prevention of osteoporosis by increasing bone density (see Chapter 40: The Gonadal Hormones & Inhibitors and Chapter 42: Agents That Affect Bone Mineral Homeostasis). Tamoxifen may also create complications in postmenopausal women, however, by exerting an agonist action in the uterus, stimulating endometrial cell proliferation. New drug development is not confined to agents that act on receptors for extracellular chemical signals. Pharmaceutical chemists are now determining whether elements of signaling pathways distal to the receptors may also serve as targets of selective and useful drugs. For example, clinically useful agents might be developed that act selectively on specific G proteins, kinases, phosphatases, or the enzymes that degrade second messengers.
Relation between Drug Dose & Clinical Response We have dealt with receptors as molecules and shown how receptors can quantitatively account for the relation between dose or concentration of a drug and pharmacologic responses, at least in an idealized system. When faced with a patient who needs treatment, the prescriber must make a choice among a variety of possible drugs and devise a dosage regimen that is likely to produce maximal benefit and minimal toxicity. In order to make rational therapeutic decisions, the prescriber must understand how drug-receptor interactions underlie the relations between dose and response in patients, the nature and causes of variation in pharmacologic responsiveness, and the clinical implications of selectivity of drug action. Dose & Response in Patients Graded Dose-Response Relations To choose among drugs and to determine appropriate doses of a drug, the prescriber must know the relative pharmacologic potency and maximal efficacy of the drugs in relation to the desired therapeutic effect. These two important terms, often confusing to students and clinicians, can be explained by refering to Figure 2–15, which depicts graded dose-response curves that relate dose of four different drugs to the magnitude of a particular therapeutic effect. Figure 2–15.
Graded dose-response curves for four drugs, illustrating different pharmacologic potencies and different maximal efficacies. (See text.) Potency Drugs A and B are said to be more potent than drugs C and D because of the relative positions of their dose-response curves along the dose axis of Figure 2–15. Potency refers to the concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug's maximal effect. Thus, the pharmacologic potency of drug A in Figure 2–15 is less than that of drug B, a partial agonist,
because the EC50 of A is greater than the EC50 of B. Potency of a drug depends in part on the affinity (KD) of receptors for binding the drug and in part on the efficiency with which drugreceptor interaction is coupled to response. Note that some doses of drug A can produce larger effects than any dose of drug B, despite the fact that we describe drug B as pharmacologically more potent. The reason for this is that drug A has a larger maximal efficacy, as described below. For clinical use, it is important to distinguish between a drug's potency and its efficacy. The clinical effectiveness of a drug depends not on its potency (EC50), but on its maximal efficacy (see below) and its ability to reach the relevant receptors. This ability can depend on its route of administration, absorption, distribution through the body, and clearance from the blood or site of action. In deciding which of two drugs to administer to a patient, the prescriber must usually consider their relative effectiveness rather than their relative potency. Pharmacologic potency can largely determine the administered dose of the chosen drug. For therapeutic purposes, the potency of a drug should be stated in dosage units, usually in terms of a particular therapeutic end point (eg, 50 mg for mild sedation, 1 g/kg/min for an increase in heart rate of 25 beats/min). Relative potency, the ratio of equi-effective doses (0.2, 10, etc), may be used in comparing one drug with another. Maximal Efficacy This parameter reflects the limit of the dose-response relation on the response axis. Drugs A, C, and D in Figure 2–15 have equal maximal efficacy, while all have greater maximal efficacy than drug B. The maximal efficacy (sometimes referred to simply as efficacy) of a drug is obviously crucial for making clinical decisions when a large response is needed. It may be determined by the drug's mode of interactions with receptors (as with partial agonists, described above)* or by characteristics of the receptor-effector system involved. *
Note that "maximal efficacy," used in a therapeutic context, does not have exactly the same meaning the term denotes in the more specialized context of drug-receptor interactions described earlier in this chapter. In an idealized in vitro system, efficacy denotes the relative maximal efficacy of agonists and partial agonists that act via the same receptor. In therapeutics, efficacy denotes the extent or degree of an effect that can be achieved in the intact patient. Thus, therapeutic efficacy may be affected by the characteristics of a particular drug-receptor interaction, but it also depends on a host of other factors as noted in the text. Thus, diuretics that act on one portion of the nephron may produce much greater excretion of fluid and electrolytes than diuretics that act elsewhere. In addition, the practical efficacy of a drug for achieving a therapeutic end point (eg, increased cardiac contractility) may be limited by the drug's propensity to cause a toxic effect (eg, fatal cardiac arrhythmia) even if the drug could otherwise produce a greater therapeutic effect. Shape of Dose-Response Curves While the responses depicted in curves A, B, and C of Figure 2–15 approximate the shape of a simple Michaelis-Menten relation (transformed to a logarithmic plot), some clinical responses do not. Extremely steep dose-response curves (eg, curve D) may have important clinical consequences if the upper portion of the curve represents an undesirable extent of response (eg, coma caused by a sedative-hypnotic). Steep dose-response curves in patients could result from cooperative interactions of several different actions of a drug (eg, effects on brain, heart, and peripheral vessels, all contributing to lowering of blood pressure).
Quantal Dose-Effect Curves Graded dose-response curves of the sort described above have certain limitations in their application to clinical decision making. For example, such curves may be impossible to construct if the pharmacologic response is an either-or (quantal) event, such as prevention of convulsions, arrhythmia, or death. Furthermore, the clinical relevance of a quantitative dose-response relationship in a single patient, no matter how precisely defined, may be limited in application to other patients, owing to the great potential variability among patients in severity of disease and responsiveness to drugs. Some of these difficulties may be avoided by determining the dose of drug required to produce a specified magnitude of effect in a large number of individual patients or experimental animals and plotting the cumulative frequency distribution of responders versus the log dose (Figure 2–16). The specified quantal effect may be chosen on the basis of clinical relevance (eg, relief of headache) or for preservation of safety of experimental subjects (eg, using low doses of a cardiac stimulant and specifying an increase in heart rate of 20 beats/min as the quantal effect), or it may be an inherently quantal event (eg, death of an experimental animal). For most drugs, the doses required to produce a specified quantal effect in individuals are lognormally distributed; ie, a frequency distribution of such responses plotted against the log of the dose produces a gaussian normal curve of variation (colored area, Figure 2–16). When these responses are summated, the resulting cumulative frequency distribution constitutes a quantal dose-effect curve (or dose-percent curve) of the proportion or percentage of individuals who exhibit the effect plotted as a function of log dose (Figure 2–16). Figure 2–16.
Quantal dose-effect plots. Shaded boxes (and the accompanying curves) indicate the frequency distribution of doses of drug required to produce a specified effect; ie, the percentage of animals
that required a particular dose to exhibit the effect. The open boxes (and the corresponding curves) indicate the cumulative frequency distribution of responses, which are lognormally distributed. The quantal dose-effect curve is often characterized by stating the median effective dose (ED50), the dose at which 50% of individuals exhibit the specified quantal effect. (Note that the abbreviation ED50 has a different meaning in this context from its meaning in relation to graded dose-effect curves, described above.) Similarly, the dose required to produce a particular toxic effect in 50% of animals is called the median toxic dose (TD50) If the toxic effect is death of the animal, a median lethal dose (LD50) may be experimentally defined. Such values provide a convenient way of comparing the potencies of drugs in experimental and clinical settings: Thus, if the ED50s of two drugs for producing a specified quantal effect are 5 and 500 mg, respectively, then the first drug can be said to be 100 times more potent than the second for that particular effect. Similarly, one can obtain a valuable index of the selectivity of a drug's action by comparing its ED50s for two different quantal effects in a population (eg, cough suppression versus sedation for opioid drugs). Quantal dose-effect curves may also be used to generate information regarding the margin of safety to be expected from a particular drug used to produce a specified effect. One measure, which relates the dose of a drug required to produce a desired effect to that which produces an undesired effect, is the therapeutic index. In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50 for some therapeutically relevant effect. The precision possible in animal experiments may make it useful to use such a therapeutic index to estimate the potential benefit of a drug in humans. Of course, the therapeutic index of a drug in humans is almost never known with real precision; instead, drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses. The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated. For example, the dose range that provides relief from an ordinary headache in the great majority of patients should be very much lower than the dose range that produces serious toxicity, even if the toxicity occurs in a small minority of patients. However, for treatment of a lethal disease such as Hodgkin's lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller. Finally, note that the quantal dose-effect curve and the graded dose-response curve summarize somewhat different sets of information, although both appear sigmoid in shape on a semilogarithmic plot (compare Figures 2–15 and 2–16). Critical information required for making rational therapeutic decisions can be obtained from each type of curve. Both curves provide information regarding the potency and selectivity of drugs; the graded dose-response curve indicates the maximal efficacy of a drug, and the quantal dose-effect curve indicates the potential variability of responsiveness among individuals. Variation in Drug Responsiveness Individuals may vary considerably in their responsiveness to a drug; indeed, a single individual may respond differently to the same drug at different times during the course of treatment. Occasionally, individuals exhibit an unusual or idiosyncratic drug response, one that is infrequently observed in most patients. The idiosyncratic responses are usually caused by genetic differences in metabolism of the drug or by immunologic mechanisms, including allergic reactions. Quantitative variations in drug response are in general more common and more clinically important. An individual patient is hyporeactive or hyperreactive to a drug in that the intensity of effect of a given dose of drug is diminished or increased in comparison to the effect seen in most individuals. (Note: The term hypersensitivity usually refers to allergic or other immunologic responses to
drugs.) With some drugs, the intensity of response to a given dose may change during the course of therapy; in these cases, responsiveness usually decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug's effects. When responsiveness diminishes rapidly after administration of a drug, the response is said to be subject to tachyphylaxis. Even before administering the first dose of a drug, the prescriber should consider factors that may help in predicting the direction and extent of possible variations in responsiveness. These include the propensity of a particular drug to produce tolerance or tachyphylaxis as well as the effects of age, sex, body size, disease state, genetic factors, and simultaneous administration of other drugs. Four general mechanisms may contribute to variation in drug responsiveness among patients or within an individual patient at different times. Alteration in Concentration of Drug That Reaches the Receptor Patients may differ in the rate of absorption of a drug, in distributing it through body compartments, or in clearing the drug from the blood (see Chapter 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action). By altering the concentration of drug that reaches relevant receptors, such pharmacokinetic differences may alter the clinical response. Some differences can be predicted on the basis of age, weight, sex, disease state, liver and kidney function, and by testing specifically for genetic differences that may result from inheritance of a functionally distinctive complement of drug-metabolizing enzymes (see Chapter 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action and Chapter 4: Drug Biotransformation). Variation in Concentration of an Endogenous Receptor Ligand This mechanism contributes greatly to variability in responses to pharmacologic antagonists. Thus, propranolol, a -adrenoceptor antagonist, will markedly slow the heart rate of a patient whose endogenous catecholamines are elevated (as in pheochromocytoma) but will not affect the resting heart rate of a well-trained marathon runner. A partial agonist may exhibit even more dramatically different responses: Saralasin, a weak partial agonist at angiotensin II receptors, lowers blood pressure in patients with hypertension caused by increased angiotensin II production and raises blood pressure in patients who produce small amounts of angiotensin. Alterations in Number or Function of Receptors Experimental studies have documented changes in drug responsiveness caused by increases or decreases in the number of receptor sites or by alterations in the efficiency of coupling of receptors to distal effector mechanisms. In some cases, the change in receptor number is caused by other hormones; for example, thyroid hormones increase both the number of receptors in rat heart muscle and cardiac sensitivity to catecholamines. Similar changes probably contribute to the tachycardia of thyrotoxicosis in patients and may account for the usefulness of propranolol, a adrenoceptor antagonist, in ameliorating symptoms of this disease. In other cases, the agonist ligand itself induces a decrease in the number (eg, down-regulation) or coupling efficiency (eg, desensitization) of its receptors. These mechanisms (discussed above, under Signaling Mechanisms & Drug Actions) may contribute to two clinically important phenomena: first, tachyphylaxis or tolerance to the effects of some drugs (eg, biogenic amines and their congeners), and second, the "overshoot" phenomena that follow withdrawal of certain drugs. These
phenomena can occur with either agonists or antagonists. An antagonist may increase the number of receptors in a critical cell or tissue by preventing down-regulation caused by an endogenous agonist. When the antagonist is withdrawn, the elevated number of receptors can produce an exaggerated response to physiologic concentrations of agonist. Potentially disastrous withdrawal symptoms can result for the opposite reason when administration of an agonist drug is discontinued. In this situation, the number of receptors, which has been decreased by drug-induced downregulation, is too low for endogenous agonist to produce effective stimulation. For example, the withdrawal of clonidine (a drug whose 2-adrenoceptor agonist activity reduces blood pressure) can produce hypertensive crisis, probably because the drug down-regulates 2-adrenoceptors (see Chapter 11: Antihypertensive Agents). Genetic factors also can play an important role in altering the number or function of specific receptors. For example, a specific genetic variant of the 2C-adrenoceptor—when inherited together with a specific variant of the 1-adrenoceptor—confers a greatly increased risk for developing congestive heart failure which may be reduced by early intervention using antagonist drugs. The identification of such genetic factors, part of the rapidly developing field of pharmacogenetics, holds exciting promise for clinical diagnosis and may help physicians design the most appropriate pharmacologic therapy for individual patients. Changes in Components of Response Distal to the Receptor Although a drug initiates its actions by binding to receptors, the response observed in a patient depends on the functional integrity of biochemical processes in the responding cell and physiologic regulation by interacting organ systems. Clinically, changes in these postreceptor processes represent the largest and most important class of mechanisms that cause variation in responsiveness to drug therapy. Before initiating therapy with a drug, the prescriber should be aware of patient characteristics that may limit the clinical response. These characteristics include the age and general health of the patient and—most importantly—the severity and pathophysiologic mechanism of the disease. The most important potential cause of failure to achieve a satisfactory response is that the diagnosis is wrong or physiologically incomplete. Drug therapy will always be most successful when it is accurately directed at the pathophysiologic mechanism responsible for the disease. When the diagnosis is correct and the drug is appropriate, an unsatisfactory therapeutic response can often be traced to compensatory mechanisms in the patient that respond to and oppose the beneficial effects of the drug. Compensatory increases in sympathetic nervous tone and fluid retention by the kidney, for example, can contribute to tolerance to antihypertensive effects of a vasodilator drug. In such cases, additional drugs may be required to achieve a useful therapeutic response. Clinical Selectivity: Beneficial Versus Toxic Effects of Drugs Although we classify drugs according to their principal actions, it is clear that no drug causes only a single, specific effect. Why is this so? It is exceedingly unlikely that any kind of drug molecule will bind to only a single type of receptor molecule, if only because the number of potential receptors in every patient is astronomically large. Even if the chemical structure of a drug allowed it to bind to only one kind of receptor, the biochemical processes controlled by such receptors would take place in multiple cell types and would be coupled to many other biochemical functions; as a result, the patient and the prescriber would probably perceive more than one drug effect. Accordingly, drugs are only selective—rather than specific—in their actions, because they bind to one or a few types of
receptor more tightly than to others and because these receptors control discrete processes that result in distinct effects. It is only because of their selectivity that drugs are useful in clinical medicine. Selectivity can be measured by comparing binding affinities of a drug to different receptors or by comparing ED50s for different effects of a drug in vivo. In drug development and in clinical medicine, selectivity is usually considered by separating effects into two categories: beneficial or therapeutic effects versus toxic effects. Pharmaceutical advertisements and prescribers occasionally use the term side effect, implying that the effect in question is insignificant or occurs via a pathway that is to one side of the principal action of the drug; such implications are frequently erroneous. Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism Much of the serious drug toxicity in clinical practice represents a direct pharmacologic extension of the therapeutic actions of the drug. In some of these cases (bleeding caused by anticoagulant therapy; hypoglycemic coma due to insulin), toxicity may be avoided by judicious management of the dose of drug administered, guided by careful monitoring of effect (measurements of blood coagulation or serum glucose) and aided by ancillary measures (avoiding tissue trauma that may lead to hemorrhage; regulation of carbohydrate intake). In still other cases, the toxicity may be avoided by not administering the drug at all, if the therapeutic indication is weak or if other therapy is available. In certain situations, a drug is clearly necessary and beneficial but produces unacceptable toxicity when given in doses that produce optimal benefit. In such situations, it may be necessary to add another drug to the treatment regimen. In treating hypertension, for example, administration of a second drug often allows the prescriber to reduce the dose and toxicity of the first drug (see Chapter 11: Antihypertensive Agents). Beneficial and Toxic Effects Mediated by Identical Receptors But in Different Tissues or by Different Effector Pathways Many drugs produce both their desired effects and adverse effects by acting on a single receptor type in different tissues. Examples discussed in this book include: digitalis glycosides, which act by inhibiting Na+/K+ ATPase in cell membranes; methotrexate, which inhibits the enzyme dihydrofolate reductase; and glucocorticoid hormones. Three therapeutic strategies are used to avoid or mitigate this sort of toxicity. First, the drug should always be administered at the lowest dose that produces acceptable benefit. Second, adjunctive drugs that act through different receptor mechanisms and produce different toxicities may allow lowering the dose of the first drug, thus limiting its toxicity (eg, use of other immunosuppressive agents added to glucocorticoids in treating inflammatory disorders). Third, selectivity of the drug's actions may be increased by manipulating the concentrations of drug available to receptors in different parts of the body, for example, by aerosol administration of a glucocorticoid to the bronchi in asthma. Beneficial and Toxic Effects Mediated by Different Types of Receptors Therapeutic advantages resulting from new chemical entities with improved receptor selectivity were mentioned earlier in this chapter and are described in detail in later chapters. Such drugs include the - and -selective adrenoceptor agonists and antagonists, the H1 and H2 antihistamines, nicotinic and muscarinic blocking agents, and receptor-selective steroid hormones. All of these
receptors are grouped in functional families, each responsive to a small class of endogenous agonists. The receptors and their associated therapeutic uses were discovered by analyzing effects of the physiologic chemical signals—catecholamines, histamine, acetylcholine, and corticosteroids. A number of other drugs were discovered by exploiting therapeutic or toxic effects of chemically similar agents observed in a clinical context. Examples include quinidine, the sulfonylureas, thiazide diuretics, tricyclic antidepressants, opioid drugs, and phenothiazine antipsychotics. Often the new agents turn out to interact with receptors for endogenous substances (eg, opioids and phenothiazines for endogenous opioid and dopamine receptors, respectively). It is likely that other new drugs will be found to do so in the future, perhaps leading to the discovery of new classes of receptors and endogenous ligands for future drug development. Thus, the propensity of drugs to bind to different classes of receptor sites is not only a potentially vexing problem in treating patients, it also presents a continuing challenge to pharmacology and an opportunity for developing new and more useful drugs.
Chapter 3. Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action
Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action: Introduction The goal of therapeutics is to achieve a desired beneficial effect with minimal adverse effects. When a medicine has been selected for a patient, the clinician must determine the dose that most closely achieves this goal. A rational approach to this objective combines the principles of pharmacokinetics with pharmacodynamics to clarify the dose-effect relationship (Figure 3–1). Pharmacodynamics governs the concentration-effect part of the interaction, whereas pharmacokinetics deals with the dose-concentration part (Holford & Sheiner, 1981). The pharmacokinetic processes of absorption, distribution, and elimination determine how rapidly and for how long the drug will appear at the target organ. The pharmacodynamic concepts of maximum response and sensitivity determine the magnitude of the effect at a particular concentration (see Emax and EC50, Chapter 2: Drug Receptors & Pharmacodynamics). Figure 3–1.
The relationship between dose and effect can be separated into pharmacokinetic (doseconcentration) and pharmacodynamic (concentration-effect) components. Concentration provides the link between pharmacokinetics and pharmacodynamics and is the focus of the target concentration approach to rational dosing. The three primary processes of pharmacokinetics are absorption, distribution, and elimination. Figure 3–1 illustrates a fundamental hypothesis of pharmacology, namely, that a relationship exists between a beneficial or toxic effect of a drug and the concentration of the drug. This hypothesis has been documented for many drugs, as indicated by the Target Concentrations and Toxic Concentrations columns in Table 3–1. The apparent lack of such a relationship for some drugs does not weaken the basic hypothesis but points to the need to consider the time course of concentration at the actual site of pharmacologic effect (see below). Table 3–1. Pharmacokinetic and Pharmacodynamic Parameters for Selected Drugs. (See Speight & Holford, 1997, for a More Comprehensive Listing.)
Drug
Oral Availabi lity (F) (%)
Urinar y Excreti on (%)
Boun d in Plas ma (%)
Cleara nce (L/h/70 kg)1
Volume HalfTarget Toxic of Life (h) Concentrat Concentrat Distribut ions ions ion (L/70 kg)
Acetaminoph 88 en
3
21
67
2
15 mg/L
>300 mg/L
Acyclovir
23
75
15
19.8
48
2.4
...
...
Amikacin
...
98
4
5.46
19
2.3
...
...
Amoxicillin
93
86
18
10.8
15
1.7
...
...
4
90
1.92
53
18
...
...
Amphoterici . . . n
Ampicillin
62
82
18
16.2
20
1.3
...
...
Aspirin
68
1
49
39
11
0.25
...
...
Atenolol
56
94
5
10.2
67
6.1
1 mg/L
...
Atropine
50
57
18
24.6
120
4.3
...
...
Captopril
65
38
30
50.4
57
2.2
50 ng/mL
...
Carbamazepi 70 ne
1
74
5.34
98
15
6 mg/L
>9 mg/L
Cephalexin
90
91
14
18
18
0.9
...
...
Cephalothin
...
52
71
28.2
18
0.57
...
...
Chloramphen 80 icol
25
53
10.2
66
2.7
...
...
Chlordiazepo 100 xide
1
97
2.28
21
10
1 mg/L
...
Chloroquine 89
61
61
45
13000
214
20 ng/mL
250 ng/mL
Chlorpropam 90 ide
20
96
0.126
6.8
33
...
...
Cimetidine
62
62
19
32.4
70
1.9
0.8 mg/L
...
Ciprofloxaci 60 n
65
40
25.2
130
4.1
...
...
Clonidine
62
20
12.6
150
12
1 ng/mL
...
Cyclosporine 23
1
93
24.6
85
5.6
200 ng/mL
>400 ng/mL
Diazepam
100
1
99
1.62
77
43
300 ng/mL
...
Digitoxin
90
32
97
0.234
38
161
10 ng/mL
>35 ng/mL
Digoxin
70
60
25
7
500
50
1 ng/mL
>2 ng/mL
Diltiazem
44
4
78
50.4
220
3.7
...
...
Disopyramid 83 e
55
2
5.04
41
6
3 mg/L
>8 mg/L
Enalapril
95
90
55
9
40
3
> 0.5 ng/mL . . .
Erythromyci 35 n
12
84
38.4
55
1.6
...
...
Ethambutol
77
79
5
36
110
3.1
...
>10 mg/L
Fluoxetine
60
3
94
40.2
2500
53
...
...
Furosemide
61
66
99
8.4
7.7
1.5
...
>25 mg/L
Gentamicin
...
90
10
5.4
18
2.5
...
...
Hydralazine
40
10
87
234
105
1
100 ng/mL
...
Imipramine
40
2
90
63
1600
18
200 ng/mL
>1 mg/L
Indomethacin 98
15
90
8.4
18
2.4
1 mg/L
>5 mg/L
Labetalol
18
5
50
105
660
4.9
0.1 mg/L
...
Lidocaine
35
2
70
38.4
77
1.8
3 mg/L
>6 mg/L
95
Lithium
100
95
1.5
55
22
0.7 mEq/L
>2 mEq/L
Meperidine
52
12
58
72
310
3.2
0.5 mg/L
...
Methotrexate 70
48
34
9
39
7.2
750 M-h3
>950 M-h
Metoprolol
38
10
11
63
290
3.2
25 ng/mL
...
Metronidazol 99 e
10
10
5.4
52
8.5
4 mg/L
...
Midazolam
44
56
95
27.6
77
1.9
...
...
Morphine
24
8
35
60
230
1.9
60 ng/mL
...
Nifedipine
50
96
29.4
55
1.8
50 ng/mL
...
Nortriptyline 51
2
92
30
1300
31
100 ng/mL
>500 ng/mL
Phenobarbita 100 l
24
51
0.258
38
98
15 mg/L
>30 mg/L
Phenytoin
90
2
89
Conc- 45 depende nt4
Conc- 10 mg/L depende nt5
>20 mg/L
Prazosin
68
1
95
12.6
42
2.9
...
...
Procainamide 83
67
16
36
130
3
5 mg/L
>14 mg/L
Propranolol
1
87
50.4
270
3.9
20 ng/mL
...
Pyridostigmi 14 ne
85
...
36
77
1.9
75 ng/mL
...
Quinidine
80
18
87
19.8
190
6.2
3 mg/L
>8 mg/L
Ranitidine
52
69
15
43.8
91
2.1
100 ng/mL
...
Rifampin
?
7
89
14.4
68
3.5
...
...
Salicylic acid 100
15
85
0.84
12
13
200 mg/L
>200 mg/L
Sulfamethox 100 azole
14
62
1.32
15
10
...
...
Terbutaline
14
56
20
14.4
125
14
2 ng/mL
...
Tetracycline 77
58
65
7.2
105
11
...
...
Theophylline 96
18
56
2.8
35
8.1
10 mg/L
>20 mg/L
Tobramycin
...
90
10
4.62
18
2.2
...
...
Tocainide
89
38
10
10.8
210
14
10 mg/L
...
Tolbutamide 93
96
1.02
7
5.9
100 mg/L
...
Trimethopri m
100
69
44
9
130
11
...
...
Tubocurarine . . .
63
50
8.1
27
2
0.6 mg/L
...
Valproic acid 100
2
93
0.462
9.1
14
75 mg/L
>150 mg/L
Vancomycin . . .
79
30
5.88
27
5.6
...
...
Verapamil
3
90
63
350
4
...
...
26
22
Warfarin
93
3
99
0.192
9.8
37
...
...
Zidovudine
63
18
25
61.8
98
1.1
...
...
1
Convert to mL/min by multiplying the number given by 16.6.
2
Varies with concentration.
3
Target area under the concentration time curve after a single dose.
4
Can be estimated from measured Cp using CL = Vmax/(Km + Cp); Vmax = 415 mg/d, Km = 5 mg/L. See text. 5
Varies because of concentration-dependent clearance.
Knowing the relationship between dose, drug concentration and effects allows the clinician to take into account the various pathologic and physiologic features of a particular patient that make him or her different from the average individual in responding to a drug. The importance of pharmacokinetics and pharmacodynamics in patient care thus rests upon the improvement in therapeutic benefit and reduction in toxicity that can be achieved by application of these principles. Pharmacokinetics The "standard" dose of a drug is based on trials in healthy volunteers and patients with average ability to absorb, distribute, and eliminate the drug (see Clinical Trials: The IND and NDA in Chapter 5: Basic & Clinical Evaluation of New Drugs). This dose will not be suitable for every patient. Several physiologic processes (eg, maturation of organ function in infants) and pathologic processes (eg, heart failure, renal failure) dictate dosage adjustment in individual patients. These processes modify specific pharmacokinetic parameters. The two basic parameters are clearance, the measure of the ability of the body to eliminate the drug; and volume of distribution, the measure of the apparent space in the body available to contain the drug. These parameters are illustrated schematically in Figure 3–2, where the volume of the compartments into which the drugs diffuse represents the volume of distribution and the size of the outflow "drain" in Figures 3–2 B and D represents the clearance. Figure 3–2.
Models of drug distribution and elimination. The effect of adding drug to the blood by rapid intravenous injection is represented by expelling a known amount of the agent into a beaker. The time course of the amount of drug in the beaker is shown in the graphs at the right. In the first example (A), there is no movement of drug out of the beaker, so the graph shows only a steep rise to maximum followed by a plateau. In the second example (B), a route of elimination is present, and the graph shows a slow decay after a sharp rise to a maximum. Because the level of material in the beaker falls, the "pressure" driving the elimination process also falls, and the slope of the curve decreases. This is an exponential decay curve. In the third model (C), drug placed in the first compartment ("blood") equilibrates rapidly with the second compartment ("extravascular volume") and the amount of drug in "blood" declines exponentially to a new steady state. The fourth model (D) illustrates a more realistic combination of elimination mechanism and extravascular equilibration. The resulting graph shows an early distribution phase followed by the slower elimination phase. Volume of Distribution Volume of distribution (Vd) relates the amount of drug in the body to the concentration of drug (C) in blood or plasma:
The volume of distribution may be defined with respect to blood, plasma, or water (unbound drug), depending on the concentration used in equation (1) (C = Cb, Cp, or Cu). That the Vd calculated from equation (1) is an apparent volume may be appreciated by comparing the volumes of distribution of drugs such as digoxin or chloroquine (Table 3–1) with some of the physical volumes of the body (Table 3–2). Volume of distribution can vastly exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water. Drugs with very high volumes of distribution have much higher concentrations in extravascular tissue than in the vascular compartment, ie, they are not homogeneously distributed. Drugs that are completely retained within the vascular compartment, on the other hand, have a minimum possible volume of distribution equal to the blood component in which they are distributed, eg, 0.04 L/kg body weight or 2.8 L/70 kg (Table 3–2) for a drug that is restricted to the plasma compartment. Table 3–2. Physical Volumes (in L/Kg Body Weight) of Some Body Compartments into Which Drugs May Be Distributed.
Compartment and Volume
Examples of Drugs
Water Total body water (0.6 L/kg1)
Small water-soluble molecules: eg, ethanol.
Extracellular water (0.2 L/kg)
Larger water-soluble molecules: eg, gentamicin.
Blood (0.08 L/kg); plasma (0.04 Strongly plasma protein-bound molecules and very large L/kg) molecules: eg, heparin. Fat (0.2–0.35 L/kg)
Highly lipid-soluble molecules: eg, DDT.
Bone (0.07 L/kg)
Certain ions: eg, lead, fluoride.
1
An average figure. Total body water in a young lean man might be 0.7 L/kg; in an obese woman, 0.5 L/kg. Clearance Drug clearance principles are similar to the clearance concepts of renal physiology. Clearance of a drug is the factor that predicts the rate of elimination in relation to the drug concentration:
Clearance, like volume of distribution, may be defined with respect to blood (CLb), plasma (CLp), or unbound in water (CLu), depending on the concentration measured. It is important to note the additive character of clearance. Elimination of drug from the body may involve processes occurring in the kidney, the lung, the liver, and other organs. Dividing the rate of elimination at each organ by the concentration of drug presented to it yields the respective clearance at that organ. Added together, these separate clearances equal total systemic clearance:
"Other" tissues of elimination could include the lungs and additional sites of metabolism, eg, blood or muscle. The two major sites of drug elimination are the kidneys and the liver. Clearance of unchanged drug in the urine represents renal clearance. Within the liver, drug elimination occurs via biotransformation of parent drug to one or more metabolites, or excretion of unchanged drug into the bile, or both. The pathways of biotransformation are discussed in Chapter 4: Drug Biotransformation. For most drugs, clearance is constant over the concentration range encountered in clinical settings, ie, elimination is not saturable, and the rate of drug elimination is directly proportional to concentration (rearranging equation [2]):
This is usually referred to as first-order elimination. When clearance is first-order, it can be estimated by calculating the area under the curve (AUC) of the time-concentration profile after a dose. Clearance is calculated from the dose divided by the AUC.
Capacity-Limited Elimination For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the concentration of drug that is achieved (Table 3–1). Capacity-limited elimination is also known as saturable, dose- or concentration-dependent, nonlinear, and Michaelis-Menten elimination. Most drug elimination pathways will become saturated if the dose is high enough. When blood flow to an organ does not limit elimination (see below), the relation between elimination rate and concentration (C) is expressed mathematically in equation (5):
The maximum elimination capacity is Vmax, and Km is the drug concentration at which the rate of elimination is 50% of Vmax. At concentrations that are high relative to the Km, the elimination rate is almost independent of concentration—a state of "pseudo-zero order" elimination. If dosing rate exceeds elimination capacity, steady state cannot be achieved: The concentration will keep on rising as long as dosing continues. This pattern of capacity-limited elimination is important for three drugs in common use: ethanol, phenytoin, and aspirin. Clearance has no real meaning for drugs with capacity-limited elimination, and AUC cannot be used to describe the elimination of such drugs. Flow-Dependent Elimination In contrast to capacity-limited drug elimination, some drugs are cleared very readily by the organ of elimination, so that at any clinically realistic concentration of the drug, most of the drug in the blood perfusing the organ is eliminated on the first pass of the drug through it. The elimination of these drugs will thus depend primarily on the rate of drug delivery to the organ of elimination. Such drugs (see Table 4–7) can be called "high-extraction" drugs since they are almost completely extracted from the blood by the organ. Blood flow to the organ is the main determinant of drug delivery, but plasma protein binding and blood cell partitioning may also be important for extensively bound drugs that are highly extracted. Half-Life Half-life (t1/2) is the time required to change the amount of drug in the body by one-half during elimination (or during a constant infusion). In the simplest case—and the most useful in designing drug dosage regimens—the body may be considered as a single compartment (as illustrated in Figure 3–2 B) of a size equal to the volume of distribution (Vd). The time course of drug in the body will depend on both the volume of distribution and the clearance:
*
The constant 0.7 in equation (6) is an approximation to the natural logarithm of 2. Because drug elimination can be described by an exponential process, the time taken for a twofold decrease can be shown to be proportional to ln(2). Half-life is useful because it indicates the time required to attain 50% of steady state—or to decay 50% from steady-state conditions—after a change in the rate of drug administration. Figure 3–3
shows the time course of drug accumulation during a constant-rate drug infusion and the time course of drug elimination after stopping an infusion that has reached steady state. Figure 3–3.
The time course of drug accumulation and elimination. Solid line: Plasma concentrations reflecting drug accumulation during a constant rate infusion of a drug. Fifty percent of the steadystate concentration is reached after one half-life, 75% after two half-lives, and over 90% after four half-lives. Dashed line: Plasma concentrations reflecting drug elimination after a constant rate infusion of a drug had reached steady state. Fifty percent of the drug is lost after one half-life, 75% after two half-lives, etc. The "rule of thumb" that four half-lives must elapse after starting a drugdosing regimen before full effects will be seen is based on the approach of the accumulation curve to over 90% of the final steady-state concentration. Disease states can affect both of the physiologically related primary pharmacokinetic parameters: volume of distribution and clearance. A change in half-life will not necessarily reflect a change in drug elimination. For example, patients with chronic renal failure have decreased renal clearance of digoxin but also a decreased volume of distribution; the increase in digoxin half-life is not as great as might be expected based on the change in renal function. The decrease in volume of distribution is due to the decreased renal and skeletal muscle mass and consequent decreased tissue binding of digoxin to Na+/K+ ATPase. Many drugs will exhibit multicompartment pharmacokinetics (as illustrated in Figures 3–2 C and D). Under these conditions, the "true" terminal half-life, as given in Table 3–1, will be greater than that calculated from equation (6). Drug Accumulation Whenever drug doses are repeated, the drug will accumulate in the body until dosing stops. This is because it takes an infinite time (in theory) to eliminate all of a given dose. In practical terms, this means that if the dosing interval is shorter than four half-lives, accumulation will be detectable. Accumulation is inversely proportional to the fraction of the dose lost in each dosing interval. The fraction lost is 1 minus the fraction remaining just before the next dose. The fraction remaining can be predicted from the dosing interval and the half-life. A convenient index of accumulation is the accumulation factor.
For a drug given once every half-life, the accumulation factor is 1/0.5, or 2. The accumulation factor predicts the ratio of the steady-state concentration to that seen at the same time following the first dose. Thus, the peak concentrations after intermittent doses at steady state will be equal to the peak concentration after the first dose multiplied by the accumulation factor. Bioavailability Bioavailability is defined as the fraction of unchanged drug reaching the systemic circulation following administration by any route (Table 3–3). The area under the blood concentration-time curve (area under the curve, AUC) is a common measure of the extent of bioavailability for a drug given by a particular route (Figure 3–4). For an intravenous dose of the drug, bioavailability is assumed to be equal to unity. For a drug administered orally, bioavailability may be less than 100% for two main reasons—incomplete extent of absorption and first-pass elimination. Table 3–3. Routes of Administration, Bioavailability, and General Characteristics.
Route
Bioavailability (%)
Characteristics
Intravenous (IV) 100 (by definition)
Most rapid onset
Intramuscular (IM)
75 to 100
Large volumes often feasible; may be painful
Subcutaneous (SC)
75 to 100
Smaller volumes than IM; may be painful
Oral (PO)
5 to Section II. Autonomic Drugs > Chapter 9. AdrenoceptorActivating & Other Sympathomimetic Drugs > Basic Pharmacology of Sympathomimetic Drugs Identification of Adrenoceptors The effort to understand the molecular mechanisms by which catecholamines act has a long and rich history. A great conceptual debt is owed to the work done by John Langley and Paul Ehrlich 100 years ago in developing the hypothesis that drugs have their effects by interacting with specific "receptive" substances. Raymond Ahlquist in 1948 rationalized a large body of observations by his conjecture that catecholamines acted via two principal receptors. He termed these receptors and . Alpha receptors are those that have the comparative potencies epinephrine norepinephrine >> isoproterenol. Beta receptors have the comparative potencies isoproterenol > epinephrine norepinephrine. Ahlquist's hypothesis was dramatically confirmed by the development of drugs that selectively antagonize receptors but not receptors (see Chapter 10: Adrenoceptor Antagonist Drugs). More recent evidence suggests that receptors comprise two major families. At present, therefore, it appears appropriate to classify adrenoceptors into three major groups, namely, , 1, and 2 receptors. Each of these major groups of receptors has also three subtypes. Beta Adrenoceptors Soon after the demonstration of separate and receptors, it was found that there were at least two subtypes of receptors, designated 1 and 2. Beta1 and 2 Receptors are operationally defined by their affinities for epinephrine and norepinephrine: 1 receptors have approximately equal affinity for epinephrine and norepinephrine, whereas 2 receptors have a higher affinity for epinephrine than for norepinephrine. Subsequently, 3 receptors were identified as a novel and distinct third adrenoceptor subtype. Some of the properties of each of these receptor types are listed in Table 9–1. Table 9–1. Adrenoceptor Types and Subtypes.
Receptor 1
type
1A
Agonist
Antagonist
Effects
Phenylephrine, methoxamine
Prazosin, corynanthine
IP3, DAG common to all
WB4101,
Gene on Chromosome
C5
prazosin CEC (irreversible)
1B
WB4101
1D
2
type 2A
Rauwolscine, yohimbine
Prazosin
2C
Prazosin
1
2
3
Dopamine type
Isoproterenol Dobutamine Procaterol, terbutaline
C20
cAMP; Ca2+ channels cAMP
C2
C4
cAMP common to all
Betaxolol
cAMP
C10
Butoxamine
cAMP
C5
cAMP
C8
cAMP
C5
Dopamine Fenoldopam
D2
Bromocriptine
D3
Quinpirol
D5
Propranolol
BRL37344
D1
D4
cAMP common to all
cAMP; K+channels; C10 Ca2+ channels
Clonidine, BHT920 Oxymetazoline
2B
type
C8
AJ76
Clozapine
cAMP; K+ channels; Ca2+ channels
C11
cAMP; K+ channels; Ca2+ channels
C3
cAMP
C11
cAMP
C4
Key: BRL37344 = Sodium-4-(2-[2-hydroxy-{3-chlorophenyl}ethylamino]propyl)phenoxyacetate BHT920 = 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-[4,5-d]-azepine
CEC = Chloroethylclonidine DAG = Diacylglycerol IP3 = Inositol trisphosphate WB4101 = N-[2-(2,6-dimethoxyphenoxy)ethyl]-2,3-dihydro-1,4-benzodioxan-2-methanamine Alpha Adrenoceptors Following the demonstration of the subtypes, it was found that there are two major groups of receptors: 1 and 2. These receptors were originally identified with antagonist drugs that distinguished between 1 and 2 receptors. For example, adrenoceptors were identified in a variety of tissues by measuring the binding of radiolabeled antagonist compounds that are considered to have a high affinity for these receptors, eg, dihydroergocryptine ( 1 and 2), prazosin ( 1), and yohimbine ( 2). These radioligands were used to measure the number of receptors in tissues and to determine the affinity (by displacement of the radiolabeled ligand) of other drugs that interact with the receptors. The concept of subtypes within the 1 group emerged out of pharmacologic experiments that demonstrated complex shapes of agonist dose-response curves of smooth muscle contraction as well as differences in antagonist affinities in inhibiting contractile responses in various tissues. These experiments demonstrated the existence of two subtypes of 1 receptor that could be distinguished on the basis of their reversible affinities for a variety of drugs and experimental compounds. A third 1 receptor subtype was subsequently identified by molecular cloning techniques. These 1 receptors are termed 1A, 1B, and 1D receptors. There is evidence that the 1A receptor has splice variants. A major current area of investigation is determining the importance of each of these various subtypes in mediating 1 receptor responses in a variety of organs. The hypothesis that there are subtypes of 2 receptors emerged from pharmacologic experiments and molecular cloning. It is now known that there are three subtypes of 2 receptors, termed 2A, 2B, and 2C, that are products of distinct genes. Dopamine Receptors The endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (Table 9–1). These receptors are distinct from and receptors and are particularly important in the brain (see Chapter 21: Introduction to the Pharmacology of CNS Drugs and Chapter 29: Antipsychotic Agents & Lithium) and in the splanchnic and renal vasculature. There is now considerable evidence for the existence of at least five subtypes of dopamine receptors. Pharmacologically distinct dopamine receptor subtypes, termed D1 and D2, have been known for some time. Molecular cloning has identified several distinct genes encoding each of these subtypes. Further complexity occurs because of the presence of introns within the coding region of the D2-like receptor genes, which allows for alternative splicing of the exons in this major subtype. There is extensive polymorphic variation in the D4 human receptor gene. The terminology of the various subtypes is D1, D2, D3, D4, and D5. They comprise two D1-like receptors (D1 and D5) and three D2-like (D2, D3, and D4). These subtypes may have importance for understanding the efficacy and adverse effects of novel antipsychotic drugs (see Chapter 29: Antipsychotic Agents & Lithium). Receptor Selectivity
Examples of clinically useful sympathomimetic agonists that are relatively selective for 1-, 2-, and -adrenoceptor subgroups are compared with some nonselective agents in Table 9–2. Selectivity means that a drug may preferentially bind to one subgroup of receptors at concentrations too low to interact extensively with another subgroup. For example, norepinephrine preferentially activates 1 receptors as compared with 2 receptors. However, selectivity is not usually absolute (nearly absolute selectivity has been termed "specificity"), and at higher concentrations related classes of receptor may also interact with the drug. As a result, the "numeric" subclassification of adrenoceptors is clinically important mainly for drugs that have relatively marked selectivity. Given interpatient variations in drug kinetics and dynamics, the extent of a drug's selectivity should be kept in mind if this property is viewed as clinically important in the treatment of an individual patient. Table 9–2. Relative Selectivity of Adrenoceptor Agonists.
Relative Receptor Affinities Alpha agonists Phenylephrine, methoxamine
1
>
2
>>>>>
Clonidine, methylnorepinephrine
2
>
1
>>>>>
Norepinephrine
1
=
2;
1
>>
Epinephrine
1
=
2;
1
=
Dobutamine1
1
>
2
>>>>
Isoproterenol
1
=
2
>>>>
Terbutaline, metaproterenol, albuterol, ritodrine
2
>>>
Mixed alpha and beta agonists 2
2
Beta agonists
1
>>>>
Dopamine agonists
1
Dopamine
D1 = D2 >>> >>>
Fenoldopam
D1 >>> D2
See text.
The exact number of adrenoceptor subtypes that are actually expressed in human tissues is uncertain, but expression of subtypes has been demonstrated in tissues where the physiologic or
tissue. For example, determining which blood vessels express which subtypes of 1 and 2 receptors could lead to design of drugs having selectivity for certain vascular beds such as the splanchnic or coronary vessels. Similarly, there has been extensive investigation into the 1 receptor subtypes mediating pharmacologic responses in the human prostate. Molecular Mechanisms of Sympathomimetic Action The effects of catecholamines are mediated by cell surface receptors. As described in Chapter 2: Drug Receptors & Pharmacodynamics, these receptors are coupled by G proteins to the various effector proteins whose activities are regulated by those receptors. Each G protein is a heterotrimer consisting of , , and subunits. G proteins are classified on the basis of their distinctive subunits. G proteins of particular importance for adrenoceptor function include Gs, the stimulatory G protein of adenylyl cyclase; Gi, the inhibitory G protein of adenylyl cyclase; and Gq, the protein coupling receptors to phospholipase C. The activation of G protein-coupled receptors by catecholamines promotes the dissociation of GDP from the subunit of the appropriate G protein. GTP then binds to this G protein, and the subunit dissociates from the - unit. The activated GTP-bound subunit then regulates the activity of its effector. Effectors of adrenoceptor-activated subunits include adenylyl cyclase, cGMP phosphodiesterase, phospholipase C, and ion channels. The subunit is inactivated by hydrolysis of the bound GTP to GDP and Pi, and the subsequent reassociation of the subunit with the - subunit. The - subunits have additional independent effects, acting on a variety of effectors such as ion channels and enzymes. Receptor Types Alpha Receptors Alpha1 receptors stimulate polyphosphoinositide hydrolysis, leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Figure 9–1). G proteins in the Gq family couple 2+ 1 receptors to phospholipase C. IP3 promotes the release of sequestered Ca from intracellular stores, which increases the cytoplasmic concentration of free Ca2+ and the activation of various calcium-dependent protein kinases. Activation of these receptors may also increase influx of calcium across the cell's plasma membrane. Inositol 1,4,5-trisphosphate is sequentially dephosphorylated, which ultimately leads to the formation of free inositol. DAG activates protein kinase C that modulates activity of many signaling pathways. In addition, 1 receptors activate signal transduction pathways that were originally described for peptide growth factor receptors which activate tyrosine kinases. For example, 1 receptors have been found to activate mitogenactivated kinases (MAP kinases) and polyphosphoinositol-3-kinase (PI-3-kinase). These pathways may have importance for the 1 receptor-mediated stimulation of cell growth and proliferation through the regulation of gene expression. The physiologic significance of this "cross talk" between major signaling pathways remains to be determined. Figure 9–1.
Activation of 1 responses. Stimulation of 1 receptors by catecholamines leads to the activation of a Gq coupling protein. The subunit of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5-P2). IP3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca2+. Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C. See text for additional effects of 1 receptor activation.
Alpha2 receptors inhibit adenylyl cyclase activity and cause intracellular cAMP levels to decrease. In addition to this well-documented effect, activation of 2-receptors utilize additional signaling pathways, including regulation of ion channel activities and the activities of important enzymes involved in signal transduction. Alpha2-receptor–mediated inhibition of adenylyl cyclase activity is transduced by the inhibitory regulatory protein, Gi, which couples 2 receptors to the inhibition of adenylyl cyclase (Figure 9–2). How the activation of Gi leads to the inhibition of adenylyl cyclase is unclear, but it is likely that both and the - subunits of Gi contribute to this response. In addition, some of the effects of 2 adrenoceptors are independent of their ability to inhibit adenylyl cyclase; for example, 2-receptor agonists cause platelet aggregation and a decrease in platelet cAMP levels, but it is not clear that aggregation is the result of the decrease in cAMP or other mechanisms involving Gi-regulated effectors. Figure 9–2.
Activation and inhibition of adenylyl cyclase by agonists that bind to catecholamine receptors. Binding to adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its subunit charged with GTP. This s subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. Alpha2 adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an i subunit charged with GTP and a - unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. cAMP binds to the regulatory subunit (R) of cAMP-dependent protein kinase, leading to the liberation of active catalytic subunits (C) that phosphorylate specific protein substrates and modify their activity. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. See text for other actions of and 2 adrenoceptors. Beta Receptors The mechanism of action of agonists has been studied in considerable detail. Activation of all three receptor subtypes ( 1, 2, and 3) results in activation of adenylyl cyclase and increased conversion of ATP to cAMP (Figure 9–2). Activation of the cyclase enzyme is mediated by the stimulatory coupling protein Gs. cAMP is the major second messenger of -receptor activation. For example, in the liver of many species, -receptor activation increases cAMP synthesis, which leads to a cascade of events culminating in the activation of glycogen phosphorylase. In the heart, receptor activation increases the influx of calcium across the cell membrane and its sequestration inside the cell. Beta-receptor activation also promotes the relaxation of smooth muscle. While the mechanism is uncertain, it may involve the phosphorylation of myosin light chain kinase to an inactive form (see Figure 12–1). Beta adrenoceptors may activate voltage-sensitive calcium
channels in the heart via Gs-mediated enhancement independently of changes in cAMP concentration. Under certain circumstances, 2 receptors may couple to Gi proteins. These receptors have been demonstrated to activate additional kinases, such as MAP kinases, by forming multisubunit complexes, found within cells, containing multiple signaling molecules. In addition, recent evidence suggests that formation of dimers of receptors themselves (both homodimers and heterodimers of 1 and 2 receptors) is importantly involved in their signaling mechanisms. Dopamine Receptors The D1 receptor is typically associated with the stimulation of adenylyl cyclase (Table 9–1); for example, D1-receptor-induced smooth muscle relaxation is presumably due to cAMP accumulation in the smooth muscle of those vascular beds where dopamine is a vasodilator. D2 receptors have been found to inhibit adenylyl cyclase activity, open potassium channels, and decrease calcium influx. Receptor Regulation Responses mediated by adrenoceptors are not fixed and static. The number and function of adrenoceptors on the cell surface and their responses may be regulated by catecholamines themselves, other hormones and drugs, age, and a number of disease states. These changes may modify the magnitude of a tissue's physiologic response to catecholamines and can be important clinically during the course of treatment. One of the best-studied examples of receptor regulation is the desensitization of adrenoceptors that may occur after exposure to catecholamines and other sympathomimetic drugs. After a cell or tissue has been exposed for a period of time to an agonist, that tissue often becomes less responsive to further stimulation by that agent. Other terms such as tolerance, refractoriness, and tachyphylaxis have also been used to denote desensitization. This process has potential clinical significance because it may limit the therapeutic response to sympathomimetic agents. Many mechanisms have been found to contribute to desensitization. Operating at transcriptional, translational, and protein levels, some mechanisms function relatively slowly—over the course of hours or days. Other mechanisms of desensitization occur quickly, within minutes. Rapid modulation of receptor function in desensitized cells may involve critical covalent modification of the receptor, especially by phosphorylation on specific amino acid residues, association of these receptors with other proteins, or changes in their subcellular location. There are two major categories of desensitization of responses mediated by G protein coupled receptors. Homologous desensitization refers to loss of responsiveness exclusively of the receptors that have been exposed to repeated or sustained activation by a drug. Heterologous desensitization refers to loss of responsiveness of some cell surface receptors that have not been directly activated by the drug in question. A major mechanism of desensitization that occurs rapidly involves phosphorylation of receptors by members of the G protein-coupled receptor kinase (GRK) family, of which there are at least seven members. Specific adrenoreceptors are substrates for these kinases only when they are bound to an agonist. This mechanism is an example of homologous desensitization since it specifically involves only agonist-occupied receptors. Phosphorylation of these receptors enhances their affinity for -arrestins; upon binding of a arrestin molecule, the capacity of the receptor to activate G proteins is blunted, presumably due to steric hindrance (see Figure 2–12). Arrestins constitute another large family of widely expressed
proteins. Receptor phosphorylation followed by -arrestin binding has been linked to subsequent endocytosis of the receptor. This response may be facilitated by the capacity of -arrestins to bind to the structural protein clathrin. In addition to blunting responses requiring the presence of the receptor on the cell surface, these regulatory processes may also contribute to novel mechanisms of receptor signaling via intracellular pathways. Receptor desensitization may also be mediated by second-messenger feedback. For example, adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A; protein kinase A can phosphorylate residues on receptors, resulting in inhibition of receptor function. For example, for the 2 receptor, phosphorylation occurs on serine residues both in the third cytoplasmic loop and carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by Gqcoupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes. Adrenoreceptor Polymorphisms Since elucidation of the sequences of the genes encoding the 1, 2, and subtypes of adrenoceptors, it has become clear that there are relatively common genetic polymorphisms for many of these receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic importance. There is evidence that some of these polymorphisms may change the susceptibility to diseases such as heart failure, alter the propensity of a receptor to desensitize, and alter therapeutic responses to drugs in diseases such as asthma. Chemistry & Pharmacokinetics of Sympathomimetic Drugs Phenylethylamine may be considered the parent compound from which sympathomimetic drugs are derived (Figure 9–3). This compound consists of a benzene ring with an ethylamine side chain. Substitutions may be made (1) on the terminal amino group, (2) on the benzene ring, and (3) on the or carbons. Substitution by –OH groups at the 3 and 4 positions yields sympathomimetic drugs collectively known as catecholamines. The effects of modification of phenylethylamine are to change the affinity of the drugs for and receptors as well as to influence the intrinsic ability to activate the receptors. In addition, chemical structure determines the pharmacokinetic properties of these molecules. Sympathomimetic drugs may activate both and receptors; however, the relative -receptor versus -receptor activity spans the range from almost pure activity (methoxamine) to almost pure activity (isoproterenol). Figure 9–3.
Phenylethylamine and some important catecholamines. Catechol is shown for reference. Substitution on the Amino Group Increasing the size of alkyl substituents on the amino group tends to increase -receptor activity. For example, methyl substitution on norepinephrine, yielding epinephrine, enhances activity at 2 receptors. Beta activity is further enhanced with isopropyl substitution at the amino nitrogen (isoproterenol). Beta2-selective agonists generally require a large amino substituent group. The larger the substituent on the amino group, the lower the activity at receptors; eg, isoproterenol is very weak at receptors. Substitution on the Benzene Ring Maximal and activity are found with catecholamines (drugs having –OH groups at the 3 and 4 positions). The absence of one or the other of these groups, particularly the hydroxyl at C3, without other substitutions on the ring may dramatically reduce the potency of the drugs. For example, phenylephrine (Figure 9–4) is much less potent than epinephrine; indeed, receptor affinity is decreased about 100-fold and activity is almost negligible except at very high concentrations. However, catecholamines are subject to inactivation by catechol-O-methyltransferase (COMT), an enzyme found in gut and liver (see Chapter 6: Introduction to Autonomic Pharmacology). Therefore, absence of one or both –OH groups on the phenyl ring increases the bioavailability after oral administration and prolongs the duration of action. Furthermore, absence of ring –OH groups tends to increase the distribution of the molecule to the central nervous system. For example, ephedrine and amphetamine (Figure 9–4) are orally active, have a prolonged duration of action, and produce central nervous system effects not typically observed with the catecholamines. Figure 9–4.
Some examples of noncatecholamine sympathomimetic drugs. Substitution on the Alpha Carbon Substitutions at the carbon block oxidation by monoamine oxidase (MAO) and prolong the action of such drugs, particularly the noncatecholamines. Ephedrine and amphetamine are examples of substituted compounds (Figure 9–4). Alpha-methyl compounds are also called phenylisopropylamines. In addition to their resistance to oxidation by MAO, some phenylisopropylamines have an enhanced ability to displace catecholamines from storage sites in noradrenergic nerves. Therefore, a portion of their activity is dependent upon the presence of normal norepinephrine stores in the body; they are indirectly acting sympathomimetics. Substitution on the Beta Carbon Direct-acting agonists typically have a -hydroxyl group, though dopamine does not. In addition to activating adrenoceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles. Organ System Effects of Sympathomimetic Drugs General outlines of the cellular actions of sympathomimetics are presented in Tables 6–3 and 9–3. The net effect of a given drug in the intact organism depends on its relative receptor affinity ( or ), intrinsic activity, and the compensatory reflexes evoked by its direct actions. Table 9–3. Distribution of Adrenoceptor Subtypes.
Type Tissue 1
Actions
Most vascular smooth muscle (innervated)
Contraction
Pupillary dilator muscle
Contraction (dilates pupil)
Pilomotor smooth muscle
Erects hair
Prostate
Contraction
Heart
Increases force of contraction
Postsynaptic CNS adrenoceptors
Probably multiple
Platelets
Aggregation
Adrenergic and cholinergic nerve terminals
Inhibition of transmitter release
Some vascular smooth muscle
Contraction
Fat cells
Inhibition of lipolysis
1
Heart
Increases force and rate of contraction
2
Respiratory, uterine, and vascular smooth muscle Promotes smooth muscle relaxation
2
Skeletal muscle
Promotes potassium uptake
Human liver
Activates glycogenolysis
Fat cells
Activates lipolysis
D1
Smooth muscle
Dilates renal blood vessels
D2
Nerve endings
Modulates transmitter release
3
Cardiovascular System Blood Vessels Vascular smooth muscle tone is regulated by adrenoceptors; consequently, catecholamines are important in controlling peripheral vascular resistance and venous capacitance. Alpha receptors increase arterial resistance, whereas 2 receptors promote smooth muscle relaxation. There are major differences in receptor types in the various vascular beds (Table 9–4). The skin vessels have predominantly receptors and constrict in the presence of epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether or receptors are activated. Consequently, the overall effects of a sympathomimetic drug on blood vessels depend on the relative activities of that drug at and receptors and the anatomic sites of the vessels affected. In addition, D1 receptors promote vasodilation of renal, splanchnic, coronary, cerebral, and perhaps other resistance vessels. Activation of the D1 receptors in the renal vasculature may play a major role in the natriuresis induced by pharmacologic administration of dopamine. Heart Direct effects on the heart are determined largely by 1 receptors, although 2 and to a lesser extent receptors are also involved. Beta-receptor activation results in increased calcium influx in cardiac cells. This has both electrical (Figure 9–5) and mechanical consequences. Pacemaker activity, both normal (sinoatrial node) and abnormal (eg, Purkinje fibers), is increased (positive chronotropic effect). Conduction velocity in the atrioventricular node is increased, and the refractory period is decreased. Intrinsic contractility is increased (positive inotropic effect), and relaxation is accelerated. As a result, the twitch response of isolated cardiac muscle is increased in tension but abbreviated in duration. In the intact heart, intraventricular pressure rises and falls more rapidly, and ejection time is decreased. These direct effects are easily demonstrated in the absence of reflexes evoked by changes in blood pressure, eg, in isolated myocardial preparations and in patients with ganglionic blockade. In the presence of normal reflex activity, the direct effects on heart rate may
be dominated by a reflex response to blood pressure changes. Physiologic stimulation of the heart by catecholamines tends to increase coronary blood flow. Figure 9–5.
Effect of epinephrine on the transmembrane potential of a pacemaker cell in the frog heart. The arrowed trace was recorded after the addition of epinephrine. Note the increased slope of diastolic depolarization and decreased interval between action potentials. This pacemaker acceleration is typical of 1-stimulant drugs. (Modified and reproduced, with permission, from Brown H, Giles W, Noble S: Membrane currents underlying rhythmic activity in frog sinus venosus. In: The Sinus Node: Structure, Function, and Clinical Relevance. Bonke FIM [editor]. Martinus Nijhoff, 1978.) Blood Pressure The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on the heart, the peripheral vascular resistance, and the venous return (see Figure 6–7 and Table 9–4). A relatively pure agonist such as phenylephrine increases peripheral arterial resistance and decreases venous capacitance. The enhanced arterial resistance usually leads to a dosedependent rise in blood pressure (Figure 9–6). In the presence of normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate, which may be quite marked. However, cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume; furthermore, direct -adrenoceptor stimulation of the heart may have a modest positive inotropic action. While these are the expected effects of pure agonists in normal subjects, their use in hypotensive patients usually does not lead to brisk reflex responses because in this situation blood pressure is returning to normal, not exceeding normal. Figure 9–6.
Effects of an -selective (phenylephrine), -selective (isoproterenol), and nonselective (epinephrine) sympathomimetic, given as an intravenous bolus injection to a dog. (BP, blood pressure; HR, heart rate.) Reflexes are blunted but not eliminated in this anesthetized animal. The blood pressure response to a pure -adrenoceptor agonist is quite different. Stimulation of receptors in the heart increases cardiac output. A relatively pure agonist such as isoproterenol also decreases peripheral resistance by activating 2 receptors, leading to vasodilation in certain vascular beds (Table 9–4). The net effect is to maintain or slightly increase systolic pressure while permitting a fall in diastolic pressure owing to enhanced diastolic runoff (Figure 9–6). The actions of drugs with both and effects (eg, epinephrine and norepinephrine) are discussed below. Table 9–4. Cardiovascular Responses to Sympathomimetic Amines.1
Phenylephrine Epinephrine Isoproterenol Vascular resistance (tone) Cutaneous, mucous membranes ( ) Skeletal muscle ( 2, )
0 or
Renal ( , ) Splanchnic ( )
or
2
Total peripheral resistance
or
2
Venous tone ( , ) Cardiac Contractility ( 1) Heart rate (predominantly Stroke volume
0 or 1)
(vagal reflex) or 0, ,
Cardiac output Blood pressure Mean Diastolic
or
Systolic Pulse pressure
2
0 or 0
1
= increase; = decrease; 0 = no change.
2
Small doses decrease, large doses increase.
Eye The radial pupillary dilator muscle of the iris contains receptors; activation by drugs such as phenylephrine causes mydriasis (Figure 6–9). Alpha and stimulants also have important effects on intraocular pressure. Present evidence suggests that agonists increase the outflow of aqueous humor from the eye, while antagonists decrease the production of aqueous humor. These effects are important in the treatment of glaucoma (see Chapter 10: Adrenoceptor Antagonist Drugs), a leading cause of blindness. Beta stimulants relax the ciliary muscle to a minor degree, causing an insignificant decrease in accommodation. In addition, adrenergic drugs may directly protect neuronal cells in the retina. Respiratory Tract Bronchial smooth muscle contains 2 receptors that cause relaxation. Activation of these receptors results in bronchodilation (see Chapter 20: Drugs Used in Asthma and Table 9–3). The blood vessels of the upper respiratory tract mucosa contain receptors; the decongestant action of adrenoceptor stimulants is clinically useful (see Clinical Pharmacology). Gastrointestinal Tract Relaxation of gastrointestinal smooth muscle can be brought about by both - and -stimulant agents. Beta receptors appear to be located directly on the smooth muscle cells and mediate relaxation via hyperpolarization and decreased spike activity in these cells. Alpha stimulants, especially 2-selective agonists, decrease muscle activity indirectly by presynaptically reducing the release of acetylcholine and possibly other stimulants within the enteric nervous system (see
Chapter 6: Introduction to Autonomic Pharmacology). The -receptor-mediated response is probably of greater pharmacologic significance than the -stimulant response. Alpha2 receptors may also decrease salt and water flux into the lumen of the intestine. Genitourinary Tract The human uterus contains and 2 receptors. The fact that the receptors mediate relaxation may be clinically useful in pregnancy (see Clinical Pharmacology). The bladder base, urethral sphincter, and prostate contain receptors that mediate contraction and therefore promote urinary continence. The specific subtype of 1 receptor involved in mediating constriction of the bladder base and prostate is uncertain, but 1A receptors probably play an important role. The 2 receptors of the bladder wall mediate relaxation. Ejaculation depends upon normal -receptor (and possibly purinergic receptor) activation in the ductus deferens, seminal vesicles, and prostate. The detumescence of erectile tissue that normally follows ejaculation is also brought about by norepinephrine (and possibly neuropeptide Y) released from sympathetic nerves. Alpha activation appears to have a similar detumescent effect on erectile tissue in female animals. Exocrine Glands The salivary glands contain adrenoceptors that regulate the secretion of amylase and water. However, certain sympathomimetic drugs, eg, clonidine, produce symptoms of dry mouth. The mechanism of this effect is uncertain; it is likely that central nervous system effects are responsible, though peripheral effects may contribute. The apocrine sweat glands, located on the palms of the hands and a few other areas, respond to adrenoceptor stimulants with increased sweat production. These are the apocrine nonthermoregulatory glands usually associated with psychologic stress. (The diffusely distributed thermoregulatory eccrine sweat glands are regulated by sympathetic cholinergic postganglionic nerves that activate muscarinic cholinoceptors; see Chapter 6: Introduction to Autonomic Pharmacology.) Metabolic Effects Sympathomimetic drugs have important effects on intermediary metabolism. Activation of adrenoceptors in fat cells leads to increased lipolysis with enhanced release of free fatty acids and glycerol into the blood. Beta3 adrenoceptors play a role in mediating this response. There is considerable interest in developing 3 receptor-selective agonists, which could be useful in some metabolic disorders. Human lipocytes also contain 2 receptors that inhibit lipolysis by decreasing intracellular cAMP. Sympathomimetic drugs enhance glycogenolysis in the liver, which leads to increased glucose release into the circulation. In the human liver, the effects of catecholamines are probably mediated mainly by receptors, though 1 receptors may also play a role. Catecholamines in high concentration may also cause metabolic acidosis. Activation of 2 adrenoceptors by endogenous epinephrine or by sympathomimetic drugs promotes the uptake of potassium into cells, leading to a fall in extracellular potassium. This may lead to a fall in the plasma potassium concentration during stress or protect against a rise in plasma potassium during exercise. Blockade of these receptors may accentuate the rise in plasma potassium that occurs during exercise. Beta receptors and 2 receptors that are expressed in pancreatic islets tend to increase and decrease, respectively, insulin secretion, although the major regulator of insulin release is the plasma concentration of glucose. Effects on Endocrine Function & Leukocytosis
Catecholamines are important endogenous regulators of hormone secretion from a number of glands. As mentioned above, insulin secretion is stimulated by receptors and inhibited by 2 receptors. Similarly, renin secretion is stimulated by 1 and inhibited by 2 receptors; indeed, receptor antagonist drugs may lower plasma renin and blood pressure in patients with hypertension at least in part by this mechanism. Adrenoceptors also modulate the secretion of parathyroid hormone, calcitonin, thyroxine, and gastrin; however, the physiologic significance of these control mechanisms is probably limited. In high concentrations, epinephrine and related agents cause leukocytosis, in part by promoting demargination of white blood cells sequestered away from the general circulation. Effects on the Central Nervous System The action of sympathomimetics on the central nervous system varies dramatically, depending on their ability to cross the blood-brain barrier. The catecholamines are almost completely excluded by this barrier, and subjective central nervous system effects are noted only at the highest rates of infusion. These effects have been described as ranging from "nervousness" to "a feeling of impending disaster," sensations that are undesirable. Furthermore, peripheral effects of adrenoceptor agonists such as tachycardia and tremor are similar to the somatic manifestations of anxiety. In contrast, noncatecholamines with indirect actions, such as amphetamines, which readily enter the central nervous system from the circulation, produce qualitatively very different central nervous system effects. These actions vary from mild alerting, with improved attention to boring tasks; through elevation of mood, insomnia, euphoria, and anorexia; to full-blown psychotic behavior. These effects are not readily assigned to either - or -mediated actions and may represent enhancement of dopamine-mediated processes or other effects of these drugs in the central nervous system. Specific Sympathomimetic Drugs Catecholamines Epinephrine (adrenaline) is a very potent vasoconstrictor and cardiac stimulant. The rise in systolic blood pressure that occurs after epinephrine release or administration is caused by its positive inotropic and chronotropic actions on the heart (predominantly 1 receptors) and the vasoconstriction induced in many vascular beds ( receptors). Epinephrine also activates 2 receptors in some vessels (eg, skeletal muscle blood vessels), leading to their dilation. Consequently, total peripheral resistance may actually fall, explaining the fall in diastolic pressure that is sometimes seen with epinephrine injection (Figure 9–6; Table 9–4). Activation of these 2 receptors in skeletal muscle contributes to increased blood flow during exercise. Under physiologic conditions, ephinephrine functions largely as a hormone; after release from the adrenal medulla into the blood, it acts on distant cells. Norepinephrine (levarterenol, noradrenaline) and epinephrine have similar effects on 1 receptors in the heart and similar potency at receptors. Norepinephrine has relatively little effect on 2 receptors. Consequently, norepinephrine increases peripheral resistance and both diastolic and systolic blood pressure. Compensatory vagal reflexes tend to overcome the direct positive chronotropic effects of norepinephrine; however, the positive inotropic effects on the heart are maintained (Table 9–4). Isoproterenol (isoprenaline) is a very potent -receptor agonist and has little effect on receptors. The drug has positive chronotropic and inotropic actions; because isoproterenol activates receptors almost exclusively, it is a potent vasodilator. These actions lead to a marked increase in cardiac
output associated with a fall in diastolic and mean arterial pressure and a lesser decrease or a slight increase in systolic pressure (Table 9–4; Figure 9–6). Dopamine, the immediate metabolic precursor of norepinephrine, activates D1 receptors in several vascular beds, which leads to vasodilation. The effect this has on renal blood flow may be of clinical value, though this is uncertain. The activation of presynaptic D2 receptors, which suppress norepinephrine release, contributes to these effects to an unknown extent. In addition, dopamine activates 1 receptors in the heart. At low doses, peripheral resistance may decrease. At higher rates of infusion, dopamine activates vascular receptors, leading to vasoconstriction, including in the renal vascular bed. Consequently, high rates of infusion of dopamine may mimic the actions of epinephrine. Fenoldopam is a D1 receptor agonist that selectively leads to peripheral vasodilation in some vascular beds. The primary indication for fenoldopam is as an intravenously administered drug for the treatment of severe hypertension (Chapter 11: Antihypertensive Agents). Continuous infusions of the drug have prompt effects on blood pressure. Dopamine agonists with central actions are of considerable value for the treatment of Parkinson's disease and prolactinemia. These agents are discussed in Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders and Chapter 37: Hypothalamic & Pituitary Hormones. Dobutamine is a relatively also activates 1 receptors.
1-selective
synthetic catecholamine. As discussed below, dobutamine
Other Sympathomimetics These agents are of interest because of pharmacokinetic features (oral activity, distribution to the central nervous system) or because of relative selectivity for specific receptor subclasses. Phenylephrine was previously described as an example of a relatively pure agonist (Table 9–2). It acts directly on the receptors. Because it is not a catechol derivative (Figure 9–4), it is not inactivated by COMT and has a much longer duration of action than the catecholamines. It is an effective mydriatic and decongestant and can be used to raise the blood pressure (Figure 9–6). Methoxamine acts pharmacologically like phenylephrine, since it is predominantly a direct-acting 1-receptor agonist. It may cause a prolonged increase in blood pressure due to vasoconstriction; it also causes a vagally mediated bradycardia. Methoxamine is available for parenteral use, but clinical applications are rare and limited to hypotensive states. Midodrine is a prodrug that is enzymatically hydrolyzed to desglymidodrine, an 1 receptorselective agonist. The peak concentration of desglymidodrine is achieved about 1 hour after midodrine is administered. The primary indication for midodrine is the treatment of postural hypotension, typically due to impaired autonomic nervous system function. While the drug has efficacy in diminishing the fall of blood pressure when the patient is standing, it may cause hypertension when the subject is supine. Ephedrine occurs in various plants and has been used in China for over 2000 years; it was introduced into Western medicine in 1924 as the first orally active sympathomimetic drug. It is found in Ma-huang, a popular herbal medication (see Chapter 65: Botanicals ("Herbal Medications") & Nutritional Supplements). Ma-huang contains multiple ephedrine-like alkaloids in
addition to ephedrine. Because ephedrine is a noncatechol phenylisopropylamine (Figure 9–4), it has high bioavailability and a relatively long duration of action—hours rather than minutes. As is the case with many other phenylisopropylamines, a significant fraction of the drug is excreted unchanged in the urine. Since it is a weak base, its excretion can be accelerated by acidification of the urine. Ephedrine has not been extensively studied in humans in spite of its long history of use. Its ability to activate receptors probably accounted for its earlier use in asthma. Because it gains access to the central nervous system, it is a mild stimulant. Ingestion of ephedrine alkaloids contained in Mahuang has raised important safety concerns. Pseudoephedrine, one of four ephedrine enantiomers, is available over the counter as a component of many decongestant mixtures. Xylometazoline and oxymetazoline are direct-acting agonists. These drugs have been used as topical decongestants because of their ability to promote constriction of the nasal mucosa. When taken in large doses, oxymetazoline may cause hypotension, presumably because of a central clonidine-like effect (Chapter 11: Antihypertensive Agents). (As noted in Table 9–1, oxymetazoline has significant affinity for 2A receptors.) Amphetamine is a phenylisopropylamine (Figure 9–4) that is important chiefly because of its use and misuse as a central nervous system stimulant (see Chapter 32: Drugs of Abuse). Its pharmacokinetics are similar to those of ephedrine; however, amphetamine very readily enters the central nervous system, where it has marked stimulant effects on mood and alertness and a depressant effect on appetite. Its peripheral actions are mediated primarily through the release of catecholamines. Methamphetamine (N-methylamphetamine) is very similar to amphetamine with an even higher ratio of central to peripheral actions. Phenmetrazine (see Figure 32–1) is a variant phenylisopropylamine with amphetamine-like effects. It has been promoted as an anorexiant and is also a popular drug of abuse. Methylphenidate and pemoline are amphetamine variants whose major pharmacologic effects and abuse potential are similar to those of amphetamine. These two drugs appear to have efficacy in some children with attention deficit hyperactivity disorder (see Clinical Pharmacology). Pemoline must be used with great caution because of an association with life-threatening hepatic failure. Modafinil is a new drug with both similarities to and differences from amphetamine. It has significant effects on central 1B receptors but in addition appears to affect GABAergic, glutaminergic, and serotonergic synapses (see Clinical Pharmacology). Phenylpropanolamine (PPA) is a sympathomimetic drug that for many years was used as an overthe-counter agent in numerous weight reduction and cold medications. It has been withdrawn from over-the-counter use in the USA because of concerns regarding an association with hemorrhagic stroke. Receptor-Selective Sympathomimetic Drugs Alpha2-selective agonists have an important ability to decrease blood pressure through actions in the central nervous system even though direct application to a blood vessel may cause vasoconstriction. Such drugs (eg, clonidine, methyldopa, guanfacine, guanabenz) are useful in the treatment of hypertension (and some other conditions) and are discussed in Chapter 11: Antihypertensive Agents. Dexmedetomidine is a centrally acting 2-selective agonist that is indicated for sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care setting. Beta-selective agonists are very important because of the separation of 1 and 2 effects that has been achieved (Table 9–2). Although this separation is incomplete, it is sufficient to reduce adverse effects in several clinical applications.
Beta1-selective agents include dobutamine and a partial agonist, prenalterol (Figure 9–7). Because they are less effective in activating vasodilator 2 receptors, they may increase cardiac output with less reflex tachycardia than occurs with nonselective agonists such as isoproterenol. Dobutamine consists of two isomers, administered as a racemic mixture. The (+) isomer is a potent 1 agonist and an 1 receptor antagonist. The (–) isomer is a potent 1 agonist, capable of causing significant vasoconstriction when given alone. This action tends to reduce vasodilation and may also contribute to the positive inotropic action caused by the isomer with predominantly -receptor activity. A major limitation with these drugs—as with other direct-acting sympathomimetic agents—is that tolerance to their effects may develop with prolonged use and the likelihood that chronic cardiac stimulation in patients with heart failure may worsen long-term outcome. Figure 9–7.
Examples of
1-
and
2-selective
agonists.
Beta2-selective agents have achieved an important place in the treatment of asthma and are discussed in Chapter 20: Drugs Used in Asthma. An additional application is to achieve uterine relaxation in premature labor (ritodrine; see below). Some examples of 2-selective drugs currently in use are shown in Figures 9–7 and 20–4; many more are available or under investigation. Special Sympathomimetics Cocaine is a local anesthetic with a peripheral sympathomimetic action that results from inhibition of transmitter reuptake at noradrenergic synapses (see Chapter 6: Introduction to Autonomic Pharmacology). It readily enters the central nervous system and produces an amphetamine-like effect that is shorter lasting and more intense. The major action of cocaine in the central nervous system is to inhibit dopamine reuptake into neurons in the "pleasure centers" of the brain. These properties and the fact that it can be smoked, "snorted" into the nose, or injected for rapid onset of
effect have made it a heavily abused drug (see Chapter 32: Drugs of Abuse). Interestingly, dopamine-transporter knockout mice still self-administer cocaine, suggesting that cocaine may have additional pharmacologic targets. Tyramine (see Figure 6–5) is a normal by-product of tyrosine metabolism in the body and is also found in high concentrations in fermented foods such as cheese (Table 9–5). It is readily metabolized by MAO in the liver and is normally inactive when taken orally because of a very high first-pass effect, ie, low bioavailability. If administered parenterally, it has an indirect sympathomimetic action caused by the release of stored catecholamines. Consequently, its spectrum of action is similar to that of norepinephrine. In patients treated with MAO inhibitors—particularly inhibitors of the MAO-A isoform—this effect of tyramine may be greatly intensified, leading to marked increases in blood pressure. This occurs on account of increased bioavailability of tyramine and increased neuronal stores of catecholamines. Patients taking MAO inhibitors must be very careful to avoid tyramine-containing foods. There are differences in the effects of various MAO inhibitors on tyramine bioavailability, and isoform-specific or reversible enzyme antagonists may be safer (see Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders and Chapter 30: Antidepressant Agents). Table 9–5. Foods Reputed to Have a High Content of Tyramine or Other Sympathomimetic Agents.
Food
Tyramine Content of an Average Serving
Beer
(No data)
Broad beans, fava beans
Negligible (but contains dopamine)
Cheese, natural or aged
Nil to 130 mg (Cheddar, Gruyère, and Stilton especially high)
Chicken liver
Nil to 9 mg
Chocolate
Negligible (but contains phenylethylamine)
Sausage, fermented (eg, salami, pepperoni, summer sausage)
Nil to 74 mg
Smoked or pickled fish (eg, pickled herring)
Nil to 198 mg
Snails
(No data)
Wine (red)
Nil to 3 mg
Yeast (eg, dietary brewer's yeast supplements) 2–68 mg
Note: In a patient taking an irreversible MAO inhibitor drug, 20–50 mg of tyramine in a meal may increase the blood pressure significantly (see also Chapter 30: Antidepressant Agents). Note that only cheese, sausage, pickled fish, and yeast supplements contain sufficient tyramine to be consistently dangerous. This does not rule out the possibility that some preparations of other foods might contain significantly greater than average amounts of tyramine.
Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 9. AdrenoceptorActivating & Other Sympathomimetic Drugs > Clinical Pharmacology of Sympathomimetic Drugs The rationale for the use of sympathomimetic drugs in therapy rests on a knowledge of the physiologic effects of catecholamines on tissues. Selection of a particular sympathomimetic drug from the host of compounds available depends upon such factors as whether activation of , 1, or 2 receptors is desired; the duration of action desired; and the preferred route of administration. Sympathomimetic drugs are very potent and can have profound effects on a variety of organ systems, particularly the heart and peripheral circulation. Therefore, great caution is indicated when these agents are used parenterally. In most cases, rather than using fixed doses of the drugs, careful monitoring of pharmacologic response is required to determine the appropriate dosage, especially if the drug is being infused. Generally, it is desirable to use the minimum dose required to achieve the desired response. The adverse effects of these drugs are generally understandable in terms of their known physiologic effects. Cardiovascular Applications Conditions in Which Blood Flow or Pressure Is to Be Enhanced Hypotension may occur in a variety of settings such as decreased blood volume, cardiac arrhythmias, neurologic disease, adverse reactions to medications such as antihypertensive drugs, and infection. If cerebral, renal, and cardiac perfusion is maintained, hypotension itself does not usually require vigorous direct treatment. Rather, placing the patient in the recumbent position and ensuring adequate fluid volume—while the primary problem is determined and treated—is usually the correct course of action. The use of sympathomimetic drugs merely to elevate a blood pressure that is not an immediate threat to the patient may increase morbidity (see Toxicity of Sympathomimetic Drugs, below). Sympathomimetic drugs may be used in a hypotensive emergency to preserve cerebral and coronary blood flow. Such situations might arise in severe hemorrhage, spinal cord injury, or overdoses of antihypertensive or central nervous system depressant medications. The treatment is usually of short duration while the appropriate intravenous fluid or blood is being administered. Direct-acting agonists such as norepinephrine, phenylephrine, or methoxamine have been utilized in this setting if vasoconstriction is desired. For the treatment of chronic orthostatic hypotension, oral ephedrine has been the traditional therapy. Midodrine, an orally active agonist, may be the preferred sympathomimetic in this application if further studies confirm its long-term safety and efficacy. Shock is a complex acute cardiovascular syndrome that results in a critical reduction in perfusion of vital tissues and a wide range of systemic effects. Shock is usually associated with hypotension, an altered mental state, oliguria, and metabolic acidosis. If untreated, shock usually progresses to a refractory deteriorating state and death. The three major mechanisms responsible for shock are hypovolemia, cardiac insufficiency, and altered vascular resistance. Volume replacement and treatment of the underlying disease are the mainstays of the treatment of shock. While sympathomimetic drugs have been used in the treatment of virtually all forms of shock, their efficacy is unclear. In most forms of shock, vasoconstriction mediated by the sympathetic nervous system is already intense. Indeed, efforts aimed at reducing rather than increasing peripheral resistance may be more fruitful if cerebral, coronary, and renal perfusion are improved. A decision to use vasoconstrictors or vasodilators is best made on the basis of information about the underlying cause, which may require invasive monitoring.
Cardiogenic shock, usually due to massive myocardial infarction, has a poor prognosis. Mechanically assisted perfusion and emergency cardiac surgery have been utilized in some settings. Optimal fluid replacement requires monitoring of pulmonary capillary wedge pressure and other parameters of cardiac function. Positive inotropic agents such as dopamine or dobutamine may have a role in this situation. In low to moderate doses, these drugs may increase cardiac output and, compared with norepinephrine, cause relatively little peripheral vasoconstriction. Isoproterenol increases heart rate and work more than either dopamine or dobutamine. See Chapter 13: Drugs Used in Heart Failure and Table 13–6 for a discussion of shock associated with myocardial infarction. Unfortunately, the patient with shock may not respond to any of these therapeutic maneuvers; the temptation is then great to use vasoconstrictors to maintain adequate blood pressure. While coronary perfusion may be improved, this gain may be offset by increased myocardial oxygen demands as well as more severe vasoconstriction in blood vessels to the abdominal viscera. Therefore, the goal of therapy in shock should be to optimize tissue perfusion, not blood pressure. Conditions in Which Blood Flow Is to Be Reduced Reduction of regional blood flow is desirable for achieving hemostasis in surgery, for reducing diffusion of local anesthetics away from the site of administration, and for reducing mucous membrane congestion. In each instance, -receptor activation is desired, and the choice of agent depends upon the maximal efficacy required, the desired duration of action, and the route of administration. Effective pharmacologic hemostasis, often necessary for facial, oral, and nasopharyngeal surgery, requires drugs of high efficacy that can be administered in high concentration by local application. Epinephrine is usually applied topically in nasal packs (for epistaxis) or in a gingival string (for gingivectomy). Cocaine is still sometimes used for nasopharyngeal surgery, because it combines a hemostatic effect with local anesthesia. Occasionally, cocaine is mixed with epinephrine for maximum hemostasis and local anesthesia. Combining agonists with some local anesthetics greatly prolongs the duration of infiltration nerve block; the total dose of local anesthetic (and the probability of toxicity) can therefore be reduced. Epinephrine, 1:200,000, is the favored agent for this application, but norepinephrine, phenylephrine, and other agonists have also been used. Systemic effects on the heart and peripheral vasculature may occur even with local drug administration. Mucous membrane decongestants are agonists that reduce the discomfort of hay fever and, to a lesser extent, the common cold by decreasing the volume of the nasal mucosa. These effects are probably mediated by 1 receptors. Unfortunately, rebound hyperemia may follow the use of these agents, and repeated topical use of high drug concentrations may result in ischemic changes in the mucous membranes, probably as a result of vasoconstriction of nutrient arteries. Constriction of these vessels may involve activation of 2 receptors. For example, phenylephrine is often used in nasal decongestant sprays. A longer duration of action—at the cost of much lower local concentrations and greater potential for cardiac and central nervous system effects—can be achieved by the oral administration of agents such as ephedrine or one of its isomers, pseudoephedrine. Long-acting topical decongestants include xylometazoline and oxymetazoline. All of these mucous membrane decongestants are available as over-the-counter products. Cardiac Applications
Catecholamines such as isoproterenol and epinephrine have been utilized in the temporary emergency management of complete heart block and cardiac arrest. Epinephrine may be useful in cardiac arrest in part by redistributing blood flow during cardiopulmonary resuscitation to coronaries and to the brain. However, electronic pacemakers are both safer and more effective in heart block and should be inserted as soon as possible if there is any indication of continued highdegree block. Heart failure may respond to the positive inotropic effects of drugs such as dobutamine. These applications are discussed in Chapter 13: Drugs Used in Heart Failure. The development of tolerance or desensitization is a major limitation to the use of catecholamines in heart failure. Pulmonary Applications One of the most important uses of sympathomimetic drugs is in the therapy of bronchial asthma. This use is discussed in Chapter 20: Drugs Used in Asthma. Nonselective drugs (epinephrine), selective agents (isoproterenol), and 2-selective agents (metaproterenol, terbutaline, albuterol) are all available for this indication. Sympathomimetics other than the 2-selective drugs are now rarely used because they are likely to have more adverse effects than the selective drugs. Anaphylaxis Anaphylactic shock and related immediate (type I) IgE-mediated reactions affect both the respiratory and the cardiovascular systems. The syndrome of bronchospasm, mucous membrane congestion, angioedema, and severe hypotension usually responds rapidly to the parenteral administration of epinephrine, 0.3–0.5 mg (0.3–0.5 mL of 1:1000 epinephrine solution). Intramuscular injection may be the preferred route of administration, since skin blood flow (and hence systemic drug absorption from subcutaneous injection) may be unpredictable in hypotensive patients. In some patients with impaired cardiovascular function, very cautious intravenous injection of epinephrine may be required. Epinephrine is the agent of choice because of extensive experimental and clinical experience with the drug in anaphylaxis and because epinephrine activates , 1, and 2 receptors, all of which may be important in reversing the pathophysiologic processes underlying anaphylaxis. Glucocorticoids and antihistamines (both H1 and H2 receptor antagonists) may be useful as secondary therapy in anaphylaxis; however, epinephrine is the initial treatment. Ophthalmic Applications Phenylephrine is an effective mydriatic agent frequently used to facilitate examination of the retina. It is also a useful decongestant for minor allergic hyperemia and itching of the conjunctival membranes. Sympathomimetics administered as ophthalmic drops are also useful in localizing the lesion in Horner's syndrome. (See An Application of Basic Pharmacology to a Clinical Problem.) Glaucoma responds to a variety of sympathomimetic and sympathoplegic drugs. (See box in Chapter 10: Adrenoceptor Antagonist Drugs: The Treatment of Glaucoma.) Epinephrine and its prodrug dipivefrin are now rarely used, but -blocking agents are among the most important therapies. Apraclonidine and brimonidine are 2-selective agonists that also lower intraocular pressure and are approved for use in glaucoma. The mechanism of action of these drugs in treating glaucoma is still uncertain; direct neuroprotective effects may be involved in addition to the benefits of lowering intraocular pressure. Genitourinary Applications
As noted above, 2-selective agents relax the pregnant uterus. Ritodrine, terbutaline, and similar drugs have been used to suppress premature labor. The goal is to defer labor long enough to ensure adequate maturation of the fetus. These drugs may delay labor for several days. This may afford time to administer corticosteroid drugs, which decrease the incidence of neonatal respiratory distress syndrome. However, meta-analysis of older trials and a randomized study suggest that agonist therapy may have no significant benefit on perinatal infant mortality and may increase maternal morbidity. Oral sympathomimetic therapy is occasionally useful in the treatment of stress incontinence. Ephedrine or pseudoephedrine may be tried. Central Nervous System Applications As noted above, the amphetamines have a mood-elevating (euphoriant) effect; this effect is the basis for the widespread abuse of this drug and some of its analogs (see Chapter 32: Drugs of Abuse). The amphetamines also have an alerting, sleep-deferring action that is manifested by improved attention to repetitive tasks and by acceleration and desynchronization of the EEG. A therapeutic application of this effect is in the treatment of narcolepsy. Modafinil, a new amphetamine substitute, is approved for use in narcolepsy and is claimed to have fewer disadvantages (excessive mood changes, insomnia, abuse potential) than amphetamine in this condition. The appetite-suppressing effect of these agents is easily demonstrated in experimental animals. In obese humans, an encouraging initial response may be observed, but there is no evidence that long-term improvement in weight control can be achieved with amphetamines alone, especially when administered for a relatively short course. A final application of the CNS-active sympathomimetics is in the attention-deficit hyperactivity disorder (ADHD) of children, a poorly defined and overdiagnosed behavioral syndrome consisting of short attention span, hyperkinetic physical behavior, and learning problems. Some patients with this syndrome respond well to low doses of methylphenidate and related agents or to clonidine. Extended-release formulations of methylphenidate may simplify dosing regimens and increase adherence to therapy, especially in school-age children. Evidence from several clinical trials suggests that modafinil may also be useful in ADHD. Additional Therapeutic Uses While the primary use of the 2 agonist clonidine is in the treatment of hypertension (Chapter 11: Antihypertensive Agents), the drug has been found to have efficacy in the treatment of diarrhea in diabetics with autonomic neuropathy, perhaps due to its ability to enhance salt and water absorption from the intestines. In addition, clonidine has efficacy in diminishing craving for narcotics and alcohol during withdrawal and may facilitate cessation of cigarette smoking. Clonidine has also been used to diminish menopausal hot flushes and is being used experimentally to reduce hemodynamic instability during general anesthesia. Dexmedetomidine is indicated for sedation under intensive care circumstances. Toxicity of Sympathomimetic Drugs The adverse effects of adrenoceptor agonists are primarily extensions of their pharmacologic effects in the cardiovascular and central nervous systems. Adverse cardiovascular effects seen with intravenously infused pressor agents include marked elevations in blood pressure that cause increased cardiac work, which may precipitate cardiac ischemia and failure. Systemically administered receptor-stimulant drugs may cause sinus
tachycardia and may even provoke serious ventricular arrhythmias. Sympathomimetic drugs may lead to myocardial damage, particularly after prolonged infusion. Special caution is indicated in elderly patients or those with hypertension or coronary artery disease. To avoid excessive pharmacologic responses, it is essential to monitor the blood pressure when administering sympathomimetic drugs parenterally. If an adverse sympathomimetic effect requires urgent reversal, a specific adrenoceptor antagonist can be used (see Chapter 10: Adrenoceptor Antagonist Drugs). Central nervous system toxicity is rarely observed with catecholamines or drugs such as phenylephrine. In moderate doses, amphetamines commonly cause restlessness, tremor, insomnia, and anxiety; in high doses, a paranoid state may be induced. Cocaine may precipitate convulsions, cerebral hemorrhage, arrhythmias, or myocardial infarction. Therapy is discussed in Chapter 59: Management of the Poisoned Patient. Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 9. AdrenoceptorActivating & Other Sympathomimetic Drugs > An Application of Basic Pharmacology to a Clinical Problem Horner's syndrome is a condition—usually unilateral—that results from interruption of the sympathetic nerves to the face. The effects include vasodilation, ptosis, miosis, and loss of sweating on the side affected. The syndrome can be caused by either a preganglionic or a postganglionic lesion, such as a tumor. Knowledge of the location of the lesion (preganglionic or postganglionic) helps determine the optimal therapy. An understanding of the effects of denervation on neurotransmitter metabolism permits the clinician to use drugs to localize the lesion. In most situations, a localized lesion in a nerve will cause degeneration of the distal portion of that fiber and loss of transmitter contents from the degenerated nerve ending—without affecting neurons innervated by the fiber. Therefore, a preganglionic lesion will leave the postganglionic adrenergic neuron intact, whereas a postganglionic lesion results in degeneration of the adrenergic nerve endings and loss of stored catecholamines from them. Because indirectly acting sympathomimetics require normal stores of catecholamines, such drugs can be used to test for the presence of normal adrenergic nerve endings. The iris, because it is easily visible and responsive to topical sympathomimetics, is a convenient assay tissue in the patient. If the lesion of Horner's syndrome is postganglionic, indirectly acting sympathomimetics (eg, cocaine, hydroxyamphetamine) will not dilate the abnormally constricted pupil—because catecholamines have been lost from the nerve endings in the iris. In contrast, the pupil will dilate in response to phenylephrine, which acts directly on the receptors on the smooth muscle of the iris. A patient with a preganglionic lesion, on the other hand, will show a normal response to both drugs, since the postganglionic fibers and their catecholamine stores remain intact in this situation.
Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 9. AdrenoceptorActivating & Other Sympathomimetic Drugs > Preparations Available1
Amphetamine, racemic mixture (generic) Oral: 5, 10 mg tablets Oral (Adderall): 1:1:1:1 mixtures of amphetamine sulfate, amphetamine aspartate, dextroamphetamine sulfate, and dextroamphetamine saccharate, formulated to contain a total of 5, 7.5, 10, 12.5, 15, 20, or 30 mg in tablets; or 10, 20, or 30 mg in capsules Apraclonidine(Iopidine) Topical: 0.5, 1% solutions Brimonidine (Alphagan) Topical: 0.15, 0.2% solution Dexmedetomidine (Precedex) Parenteral: 100 g/mL Dexmethylphenidate (Focalin) Oral: 2.5, 5, 10 mg tablets Dextroamphetamine(generic, Dexedrine) Oral: 5, 10 mg tablets Oral sustained-release: 5, 10, 15 mg capsules Oral mixtures with amphetamine: see Amphetamine (Adderall) Dipivefrin (generic, Propine) Topical: 0.1% ophthalmic solution Dobutamine (generic, Dobutrex) Parenteral: 12.5 mg/mL in 20 mL vials for injection Dopamine(generic, Intropin) Parenteral: 40, 80, 160 mg/mL for injection; 80, 160, 320 mg/100 mL in 5% D/W for injection Ephedrine (generic) Oral: 25 mg capsules Parenteral: 50 mg/mL for injection
Nasal: 0.25% spray Epinephrine(generic, Adrenalin Chloride, others) Parenteral: 1:1000 (1 mg/mL), 1:2000 (0.5 mg/mL), 1:10,000 (0.1 mg/mL), 1:100,000 (0.01 mg/mL) for injection Parenteral autoinjector (Epipen): 1:2000 (0.5 mg/mL) Ophthalmic: 0.1, 0.5, 1, 2% drops Nasal: 0.1% drops and spray Aerosol for bronchospasm (Primatene Mist, Bronkaid Mist): 0.16, 0.2 mg/spray Solution for aerosol: 1:100 Fenoldopam(Corlopam) Parenteral: 10 mg/mL for IV infusion Hydroxyamphetamine (Paredrine) Ophthalmic: 1% drops Isoproterenol (generic, Isuprel) Parenteral: 1:5000 (0.2 mg/mL), 1:50,000 (0.02 mg/mL) for injection Mephentermine (Wyamine Sulfate) Parenteral: 15, 30 mg/mL for injection Metaraminol (Aramine) Parenteral: 10 mg/mL for injection Methamphetamine (Desoxyn) Oral: 5 mg tablets Methoxamine (Vasoxyl) Parenteral: 20 mg/mL for injection Methylphenidate(generic, Ritalin, Ritalin-SR) Oral: 5, 10, 20 mg tablets Oral sustained-release: 10, 18, 20, 27, 36, 54 mg tablets; 20, 30, 40 mg capsules
Midodrine(ProAmatine) Oral: 2.5, 5 mg tablets Modafinil(Provigil) Oral: 100, 200 mg tablets Naphazoline (Privine) Nasal: 0.05% drops and spray Ophthalmic: 0.012, 0.02, 0.03% drops Norepinephrine(generic, Levophed) Parenteral: 1 mg/mL for injection Oxymetazoline(generic, Afrin, Neo-Synephrine 12 Hour, others) Nasal: 0.025, 0.05% sprays Ophthalmic: 0.025% drops Pemoline (generic, Cylert) Oral: 18.75, 37.5, 75 mg tables; 37.5 mg chewable tablets Phendimetrazine (generic) Oral: 35 mg tablets, capsules; 105 mg sustained-release capsules Phenylephrine(generic, Neo-Synephrine) Oral: 10 mg chewable tablets Parenteral: 10 mg/mL for injection Nasal: 0.125, 0.16, 0.25, 0.5, 1% drops and spray; 0.5% jelly Pseudoephedrine(generic, Sudafed, others) Oral: 30, 60 mg tablets; 60 mg capsules; 15, 30 mg/5 mL syrups; 7.5 mg/0.8 mL drops Oral extended-release: 120, 240 mg tablets, capsules Tetrahydrozoline(generic, Tyzine) Nasal: 0.05, 0.1% drops
Ophthalmic: 0.05% drops Xylometazoline(generic, Otrivin, Neo-Synephrine Long-Acting, Chlorohist LA) Nasal: 0.05 drops, 0.1% drops and spray 1
2-Agonists used in hypertension are listed in Chapter 11: Antihypertensive Agents. used in asthma are listed in Chapter 20: Drugs Used in Asthma.
2-Agonists
Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 9. AdrenoceptorActivating & Other Sympathomimetic Drugs >
Chapter 10. Adrenoceptor Antagonist Drugs Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > Adrenoceptor Anatagonist Drugs: Introduction Since catecholamines play a role in a variety of physiologic and pathophysiologic responses, drugs that block adrenoceptors have important effects, some of which are of great clinical value. These effects vary dramatically according to the drug's selectivity for and receptors. The classification of adrenoceptors into 1, 2, and subtypes and the effects of activating these receptors are discussed in Chapters 6 and 9. Blockade of peripheral dopamine receptors is of no recognized clinical importance at present. In contrast, blockade of central nervous system dopamine receptors is very important; drugs that act on these receptors are discussed in Chapters 21 and 29. This chapter deals with pharmacologic antagonist drugs whose major effect is to occupy either 1, 2, or receptors outside the central nervous system and prevent their activation by catecholamines and related agonists. For pharmacologic research, 1- and 2-adrenoceptor antagonist drugs have been very useful in the experimental exploration of autonomic nervous system function. In clinical therapeutics, nonselective antagonists have been used in the treatment of pheochromocytoma (tumors that secrete catecholamines), and 1-selective antagonists are used in primary hypertension and benign prostatic hyperplasia. Beta-receptor antagonist drugs have been found useful in a much wider variety of clinical conditions and are firmly established in the treatment of hypertension, ischemic heart disease, arrhythmias, endocrinologic and neurologic disorders, and other conditions. Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > Basic Pharmacology of the Alpha-Receptor Antagonist Drugs Mechanism of Action Alpha-receptor antagonists may be reversible or irreversible in their interaction with these receptors. Reversible antagonists dissociate from receptors; irreversible drugs do not. Phentolamine (Figure 10–1) and tolazoline are examples of reversible antagonists. Prazosin (and analogs) and labetalol—drugs used primarily for their antihypertensive effects—as well as several ergot
derivatives (see Chapter 16: Histamine, Serotonin, & the Ergot Alkaloids) are also reversible adrenoceptor antagonists. Phenoxybenzamine, an agent related to the nitrogen mustards, forms a reactive ethyleneimonium intermediate (Figure 10–1) that covalently binds to receptors, resulting in irreversible blockade. Figure 10–2 illustrates the effects of a reversible drug in comparison with those of an irreversible agent. Figure 10–1.
Structure of several -receptor-blocking drugs. Figure 10–2.
Dose-response curves to norepinephrine in the presence of two different -adrenoceptor-blocking drugs. The tension produced in isolated strips of cat spleen, a tissue rich in receptors, was measured in response to graded doses of norepinephrine. Left: Tolazoline, a reversible blocker, shifted the curve to the right without decreasing the maximum response when present at concentrations of 10 and 20 mol/L. Right: Dibenamine, an analog of phenoxybenzamine and irreversible in its action, reduced the maximum response attainable at both concentrations tested. (Modified and reproduced, with permission, from Bickerton RK: The response of isolated strips of cat spleen to sympathomimetic drugs and their antagonists. J Pharmacol Exp Ther 1963;142:99.) The duration of action of a reversible antagonist is largely dependent on the half-life of the drug in the body and the rate at which it dissociates from its receptor: The shorter the half-life of the drug in the body or of binding to its receptor, the less time it takes for the effects of the drug to dissipate. However, the effects of an irreversible antagonist may persist long after the drug has been cleared from the plasma. In the case of phenoxybenzamine, the restoration of tissue responsiveness after extensive -receptor blockade is dependent on synthesis of new receptors, which may take several days. The rate of return of 1 adrenoceptor drug effect may be particularly important in patients having a sudden cardiovascular event or who become candidates for urgent surgery. Pharmacologic Effects Cardiovascular Effects Because arteriolar and venous tone are determined to a large extent by receptors on vascular smooth muscle, -receptor antagonist drugs cause a lowering of peripheral vascular resistance and blood pressure (Figure 10–3). These drugs can prevent the pressor effects of usual doses of agonists; indeed, in the case of agonists with both and 2 effects (eg, epinephrine), selective 1 receptor antagonism may convert a pressor to a depressor response (Figure 10–3). This change in response is called epinephrine reversal; it illustrates how the activation of both and receptors in the same tissue may lead to opposite responses. Alpha-receptor antagonists may cause postural hypotension and reflex tachycardia. Postural hypotension is due to antagonism of sympathetic nervous system stimulation of 1 receptors in venous smooth muscle; contraction of veins is an
important component of the capacity to maintain blood pressure in the upright position since it decreases venous pooling in the periphery. Constriction of arterioles in the legs may also contribute to the postural response. Tachycardia may be more marked with agents that block 2-presynaptic receptors in the heart (Table 10–1), since the augmented release of norepinephrine will further stimulate receptors in the heart. Figure 10–3.
Top: Effects of phentolamine, an receptor-blocking drug, on blood pressure in an anesthetized dog. Epinephrine reversal is demonstrated by tracings showing the response to epinephrine before (middle) and after (bottom) phentolamine. All drugs given intravenously. (BP, blood pressure; HR, heart rate.) Other Effects Minor effects that signal the blockade of receptors in other tissues include miosis and nasal stuffiness. Alpha1-receptor blockade of the base of the bladder and the prostate is associated with decreased resistance to the flow of urine. Individual agents may have other important effects in addition to -receptor antagonism (see below). Specific Agents Phentolamine, an imidazoline derivative, is a potent competitive antagonist at both 1 and 2 receptors (Table 10–1). Phentolamine causes a reduction in peripheral resistance through blockade
of 1 receptors and possibly 2 receptors on vascular smooth muscle. The cardiac stimulation induced by phentolamine is due to sympathetic stimulation of the heart resulting from baroreflex mechanisms. Furthermore, since phentolamine potently blocks 2 receptors, antagonism of presynaptic 2 receptors may lead to enhanced release of norepinephrine from sympathetic nerves. Enhanced norepinephrine release may contribute to cardiac stimulation via unblocked adrenoceptors, especially after intravenous injection. In addition to being an 1- and 2-receptor antagonist, phentolamine also inhibits responses to serotonin and may be an agonist at muscarinic and H1 and H2 histamine receptors. Consequently, phentolamine has multiple potential actions, though it is not clear which if any of these are clinically significant. Table 10–1. Relative Selectivity of Antagonists for Adrenoceptors.
Receptor Affinity Antagonists Prazosin, terazosin, doxazosin
1
>>>>
Phenoxybenzamine
1
>
Phentolamine
1
= alpha;2
Rauwolscine, yohimbine, tolazoline
2
>>>
1
=
Metoprololol, acebutolol, alprenolol, atenolol, betaxolol, celiprolol, esmolol
1
>>>
Propranolol, carteolol, penbutolol, pindolol, timolol
1
=
Butoxamine
2
>>>
2
2
1
Mixed antagonists Labetalol, carvedilol
2
1
>
2
Antagonists 2
2
1
Phentolamine has limited absorption after oral administration. Its pharmacokinetic properties are not well known; it may reach peak concentrations within an hour after oral administration and has a half-life of about 5–7 hours. The principal adverse effects are related to cardiac stimulation, which may cause severe tachycardia, arrhythmias, and myocardial ischemia, especially after intravenous administration. With oral administration, adverse effects include tachycardia, nasal congestion, and headache. Phentolamine has been used in the treatment of pheochromocytoma—especially intraoperatively— as well as for male erectile dysfunction by injection intracavernosally and when taken orally (see below).
Tolazoline is similar to phentolamine. Tolazoline has very limited clinical application in the treatment of pulmonary hypertension in newborn infants with respiratory distress syndrome. Its efficacy in this condition is doubtful, and the drug is rarely used. Ergot derivatives—eg, ergotamine, dihydroergotamine—cause reversible -receptor blockade. However, most of the clinically significant effects of these drugs are the result of other actions; eg, ergotamine probably acts at serotonin receptors in the treatment of migraine (Chapter 16: Histamine, Serotonin, & the Ergot Alkaloids). Phenoxybenzamine binds covalently to receptors, causing irreversible blockade of long duration (14–48 hours or longer). It is somewhat selective for 1 receptors but less so than prazosin (Table 10–1). The drug also inhibits reuptake of released norepinephrine by presynaptic adrenergic nerve terminals. Phenoxybenzamine blocks histamine (H1), acetylcholine, and serotonin receptors as well as receptors (see Chapter 16: Histamine, Serotonin, & the Ergot Alkaloids). The pharmacologic actions of phenoxybenzamine are primarily related to antagonism of -receptormediated events. Most importantly, phenoxybenzamine attenuates catecholamine-induced vasoconstriction. While phenoxybenzamine causes relatively little fall in blood pressure in normal supine individuals, it reduces blood pressure when sympathetic tone is high, eg, as a result of upright posture or because of reduced blood volume. Cardiac output may be increased because of reflex effects and because of some blockade of presynaptic 2 receptors in cardiac sympathetic nerves. Phenoxybenzamine is absorbed after oral administration, although bioavailability is low and its kinetic properties are not well known. The drug is usually given orally, starting with low doses of 10–20 mg/d and progressively increasing the dose until the desired effect is achieved. Less than 100 mg/d is usually sufficient to achieve adequate -receptor blockade. The major use of phenoxybenzamine is in the treatment of pheochromocytoma (see below). Many of the adverse effects of phenoxybenzamine derive from its -receptor-blocking action; the most important are postural hypotension and tachycardia. Nasal stuffiness and inhibition of ejaculation also occur. Since phenoxybenzamine enters the central nervous system, it may cause less specific effects, including fatigue, sedation, and nausea. Since phenoxybenzamine is an alkylating agent, it may have other adverse effects that have not yet been characterized. Phenoxybenzamine causes tumors in animals, but the clinical implications of this observation are unknown. Prazosin is a piperazinyl quinazoline effective in the management of hypertension (see Chapter 11: Antihypertensive Agents). It is highly selective for 1 receptors, having relatively low affinity for 2 receptors (typically 1000-fold less potent). This may partially explain the relative absence of tachycardia seen with prazosin as compared to what is reported with phentolamine and phenoxybenzamine. Prazosin leads to relaxation of both arterial and venous smooth muscle due to blockade of 1 receptors. Prazosin is extensively metabolized in humans; because of metabolic degradation by the liver, only about 50% of the drug is available after oral administration. The halflife is normally about 3 hours. Terazosin is another reversible 1-selective antagonist that is effective in hypertension (Chapter 11: Antihypertensive Agents); it has also been approved for use in men with urinary symptoms due to benign prostatic hyperplasia (BPH). Terazosin has high bioavailability but is extensively metabolized in the liver, with only a small fraction of unchanged drug excreted in the urine. The half-life of terazosin is 9–12 hours.
Doxazosin is efficacious in the treatment of hypertension and BPH. It differs from prazosin and terazosin in having a longer half-life of about 22 hours. It has moderate bioavailability and is extensively metabolized, with very little parent drug excreted in urine or feces. Doxazosin has active metabolites, although their contribution to the drug's effects is probably small. Tamsulosin is a competitive 1 antagonist with a structure quite different from that of most other 1-receptor blockers. It has high bioavailability and a long half-life of 9–15 hours. It is metabolized extensively in the liver. Tamsulosin has higher affinity for 1A and 1D receptors than for the 1B subtype. The drug's efficacy in BPH suggests that the 1A subtype may be the most important subtype mediating prostate smooth muscle contraction. Evidence suggests that tamsulosin has relatively greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle, compared with other 1-selective antagonists, which have equal or greater effects in vascular smooth muscle. This finding suggests that 1A receptors are less important in mediating contraction in human arteries and veins. Furthermore, compared with other antagonists, tamsulosin has less effect on standing blood pressure in patients. Nonetheless, caution is appropriate in using any antagonist in patients with diminished sympathetic nervous system function. Other Alpha-Adrenoceptor Antagonists Alfuzosin is an 1-selective quinazoline derivative that has also been shown to be efficacious in BPH. It has a bioavailability of about 60%, is extensively metabolized, and has an elimination halflife of about 5 hours. This drug is not currently available in the USA. Indoramin is another 1selective antagonist that also has efficacy as an antihypertensive. Urapidil is an 1 antagonist (its primary effect) that also has weak 2-agonist and 5-HT1A-agonist actions and weak antagonist action at 1 receptors. It is used in Europe as an antihypertensive agent and for benign prostatic hyperplasia. Labetalol has both 1-selective and -antagonistic effects; it is discussed below. Neuroleptic drugs such as chlorpromazine and haloperidol are potent dopamine receptor antagonists but may also be antagonists at receptors. Their antagonism of receptors probably contributes to some of their adverse effects, particularly hypotension. Similarly, the antidepressant trazodone has the capacity to block 1 receptors. Yohimbine, an indole alkaloid, is an 2-selective antagonist. It has no established clinical role. Theoretically, it could be useful in autonomic insufficiency by promoting neurotransmitter release through blockade of presynaptic 2 receptors. It has been suggested that yohimbine improves male sexual function; however, evidence for this effect in humans is limited. Yohimbine can abruptly reverse the antihypertensive effects of an 2-adrenoceptor agonist such as clonidine—a potentially serious adverse drug interaction. Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > Clinical Pharmacology of the Alpha-Receptor-Blocking Drugs Pheochromocytoma The major clinical use of both phenoxybenzamine and phentolamine is in the management of pheochromocytoma. Pheochromocytoma is a tumor usually found in the adrenal medulla that releases a mixture of epinephrine and norepinephrine. Patients have many symptoms and signs of catecholamine excess, including intermittent or sustained hypertension, headaches, palpitations, and increased sweating.
The diagnosis of pheochromocytoma is usually made on the basis of chemical assay of circulating catecholamines and urinary excretion of catecholamine metabolites, especially 3-hydroxy-4methoxymandelic acid, metanephrine, and normetanephrine. Measurement of plasma metanephrines has shown promise as an effective diagnostic tool. A variety of diagnostic techniques are available to localize a pheochromocytoma diagnosed biochemically, including CT and MRI scans as well as scanning with various radioisotopes. Infusion of phentolamine was advocated in the past as a diagnostic test when pheochromocytoma was suspected, since patients with this tumor often manifest a greater drop in blood pressure in response to -blocking drugs than do patients with primary hypertension. Provocative testing by infusion of histamine was occasionally used because this vasodilator drug may elicit a marked reflex rise in pressure in patients with pheochromocytoma. These tests are obsolete because measurement of circulating catecholamines and urinary catecholamines and their metabolites is a safer and far more reliable diagnostic approach. Unavoidable release of stored catecholamines sometimes occurs during operative manipulation of pheochromocytoma; the resulting hypertension may be controlled with phentolamine or nitroprusside. Nitroprusside has many advantages, particularly since its effects can be more readily titrated and it has a shorter duration of action. Alpha-receptor antagonists are most useful in the preoperative management of patients with pheochromocytoma (Figure 10–4). Administration of phenoxybenzamine in the preoperative period will help control hypertension and will tend to reverse chronic changes resulting from excessive catecholamine secretion such as plasma volume contraction, if present. Furthermore, the patient's operative course may be simplified. Oral doses of 10–20 mg/d may be increased at intervals of several days until hypertension is controlled. Some physicians give phenoxybenzamine to patients with pheochromocytoma for 1–3 weeks before surgery. Other surgeons prefer to operate on patients in the absence of treatment with phenoxybenzamine, counting on modern anesthetic techniques to control blood pressure and heart rate during surgery. Phenoxybenzamine may be very useful in the chronic treatment of inoperable or metastatic pheochromocytoma. Although there is less experience with alternative drugs, hypertension in patients with pheochromocytoma may also respond to reversible 1-selective antagonists or to conventional calcium channel antagonists. Beta-receptor antagonists may be required after -receptor blockade has been instituted to reverse the cardiac effects of excessive catecholamines. Beta antagonists should not be employed prior to establishing effective -receptor blockade, since unopposed -receptor blockade could theoretically cause blood pressure elevation from increased vasoconstriction. Figure 10–4.
Effects of phenoxybenzamine (Dibenzyline) on blood pressure in a patient with pheochromocytoma. Dosage of the drug was begun in the third week as shown by the shaded bar. Supine systolic and diastolic pressures are indicated by the circles, the standing pressures by triangles and the hatched area. Note that the -blocking drug dramatically reduced blood pressure. The reduction in orthostatic hypotension, which was marked before treatment, is probably due to normalization of blood volume, a variable that is sometimes markedly reduced in patients with long-standing pheochromocytoma-induced hypertension. (Redrawn and reproduced, with permission, from Engelman E, Sjoerdsma A: Chronic medical therapy for pheochromocytoma. Ann Intern Med 1961;61:229.) Pheochromocytoma is rarely treated with metyrosine ( -methyltyrosine), the -methyl analog of tyrosine. This agent is a competitive inhibitor of tyrosine hydroxylase and, in oral doses of 1–4 g/d, interferes with synthesis of dopamine (see Figure 6–5), thereby decreasing the amounts of norepinephrine and epinephrine secreted by the tumor. Metyrosine, while not an -adrenoceptor antagonist, may act additively with phenoxybenzamine and a -adrenoceptor antagonist in the treatment of pheochromocytoma. Metyrosine is especially useful in symptomatic patients with inoperable or metastatic pheochromocytoma. Hypertensive Emergencies The -adrenoceptor antagonist drugs have limited application in the management of hypertensive emergencies, although labetalol has been used in this setting. In theory, -adrenoceptor antagonists
are most useful when increased blood pressure reflects excess circulating concentrations of agonists. In this circumstance, which may result from pheochromocytoma, overdosage of sympathomimetic drugs, or clonidine withdrawal, phentolamine can be used to control high blood pressure. However, other drugs are generally preferable (see Chapter 11: Antihypertensive Agents), since considerable experience is necessary to use phentolamine safely in these settings and few physicians have such experience. Chronic Hypertension Members of the prazosin family of 1-selective antagonists are efficacious drugs in the treatment of mild to moderate systemic hypertension. They are generally well tolerated by most patients. However, their efficacy in preventing heart failure when used as monotherapy for hypertension has been questioned. Their major adverse effect is postural hypotension, which may be severe after the first dose but is otherwise uncommon (see Chapter 11: Antihypertensive Agents). Nonselective antagonists are not used in primary systemic hypertension. Prazosin and related drugs may also be associated with feelings of dizziness. This symptom may not be due to a fall in blood pressure, but postural changes in blood pressure should be checked routinely in any patient being treated for hypertension. Interestingly, the use of -adrenoceptor antagonists such as prazosin has been found to be associated with either no changes in plasma lipids or increased concentrations of HDL, which could be a favorable alteration. The mechanism for this effect is not known. Peripheral Vascular Disease Although -receptor-blocking drugs have been tried in the treatment of peripheral vascular occlusive disease, there is no evidence that the effects are significant when morphologic changes limit flow in the vessels. Occasionally, individuals with Raynaud's phenomenon and other conditions involving excessive reversible vasospasm in the peripheral circulation do benefit from phentolamine, prazosin, or phenoxybenzamine, although calcium channel blockers may be preferable for many patients. Local Vasoconstrictor Excess Phentolamine has been used to reverse the intense local vasoconstriction caused by inadvertent infiltration of agonists (eg, norepinephrine) into subcutaneous tissue during intended intravenous administration. The antagonist is administered by local infiltration into the ischemic tissue. Urinary Obstruction Benign prostatic hyperplasia is a prevalent disorder in elderly men. A variety of surgical treatments are effective in relieving the urinary symptoms of BPH; however, drug therapy is efficacious in many patients. Alpha-receptor blockade was first found to be helpful in BPH using phenoxybenzamine in selected patients who were poor operative risks. The mechanism of action in improving urine flow involves partial reversal of smooth muscle contraction in the enlarged prostate and in the bladder base. It has been suggested that some 1-receptor antagonists may have additional effects on cells in the prostate that help improve symptoms. A number of well-controlled studies have demonstrated reproducible efficacy of several 1-receptor antagonists in patients with BPH—lasting for several years in many cases. Prazosin, doxazocin, and terazosin are efficacious. These drugs are particularly useful in patients who also have hypertension.
Considerable interest has focused on which 1-receptor subtype is most important for smooth muscle contraction in the prostate: subtype-selective 1A-receptor antagonists might lead to improved efficacy and safety in treating this disease. As indicated above, tamsulosin is also efficacious in BPH and has little if any effect on blood pressure. This drug may be preferred in patients who have experienced postural hypotension with other 1-receptor antagonists. Some evidence suggests that the efficacy of 1-receptor antagonists exceeds that of finasteride, the 5 reductase inhibitor (see Chapter 40: The Gonadal Hormones & Inhibitors). Erectile Dysfunction A combination of the -adrenoceptor antagonist phentolamine with the nonspecific vasodilator papaverine, when injected directly into the penis, may cause erections in men with sexual dysfunction. Fibrotic reactions may occur, especially with long-term administration. Systemic absorption may lead to orthostatic hypotension; priapism may require direct treatment with an adrenoceptor agonist such as phenylephrine. Orally administered phentolamine is being investigated in patients with erectile dysfunction (and in women with disorders of arousal.) Alternative therapies include prostaglandins (see Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds), sildenafil, a cGMP phosphodiesterase inhibitor (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris), and apomorphine. Applications of Alpha2 Antagonists Alpha2 antagonists have relatively little clinical usefulness. There has been experimental interest in the development of highly selective antagonists for use in Raynaud's phenomenon to inhibit smooth muscle contraction and in the treatment of type 2 diabetes ( 2 receptors inhibit insulin secretion) and psychiatric depression. It is not known to what extent the recognition of multiple subtypes of 2 receptors will lead to development of clinically useful subtype-selective new drugs. Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > Basic Pharmacology of the Beta-Receptor-Antagonist Drugs Drugs in this category share the common feature of antagonizing the effects of catecholamines at adrenoceptors. Beta-blocking drugs occupy receptors and competitively reduce receptor occupancy by catecholamines and other agonists. (A few members of this group, used only for experimental purposes, bind irreversibly to receptors.) Most -blocking drugs in clinical use are pure antagonists; ie, the occupancy of a receptor by such a drug causes no activation of the receptor. However, some are partial agonists; ie, they cause partial activation of the receptor, albeit less than that caused by the full agonists epinephrine and isoproterenol. As described in Chapter 2: Drug Receptors & Pharmacodynamics, partial agonists inhibit the activation of receptors in the presence of high catecholamine concentrations but moderately activate the receptors in the absence of endogenous agonists. Another major difference among the many -receptor-blocking drugs concerns their relative affinities for 1 and 2 receptors (Table 10–1). Some of these antagonists have a higher affinity for 1 than for 2 receptors, and this selectivity may have important clinical implications. Since none of the clinically available receptor antagonists are absolutely specific for 1 receptors, the selectivity is dose-related, ie, it tends to diminish at higher drug concentrations. Other major differences among antagonists relate to their pharmacokinetic characteristics and local anesthetic membrane-stabilizing effects. Chemically, the -receptor-antagonist drugs (Figure 10–5) resemble isoproterenol (see Figure 9–3),
a potent receptor agonist. Figure 10–5.
Structures of some -receptor antagonists. Pharmacokinetic Properties of the Beta-Receptor Antagonists Absorption
Most of the drugs in this class are well absorbed after oral administration; peak concentrations occur 1–3 hours after ingestion. Sustained-release preparations of propranolol and metoprolol are available. Bioavailability Propranolol undergoes extensive hepatic (first-pass) metabolism; its bioavailability is relatively low (Table 10–2). The proportion of drug reaching the systemic circulation increases as the dose is increased, suggesting that hepatic extraction mechanisms may become saturated. A major consequence of the low bioavailability of propranolol is that oral administration of the drug leads to much lower drug concentrations than are achieved after intravenous injection of the same dose. Because the first-pass effect varies among individuals, there is great individual variability in the plasma concentrations achieved after oral propranolol. Bioavailability is limited to varying degrees for most antagonists with the exception of betaxolol, penbutolol, pindolol, and sotalol. Table 10–2. Properties of Several Beta-Receptor-Blocking Drugs.
Selectivity Partial Agonist Activity
Local Anesthetic Action
Lipid Elimination Solubility Half-Life
Approximate Bioavailability
Acebutolol
1
Yes
Yes
Low
3–4 hours
50
Atenolol
1
No
No
Low
6–9 hours
40
Betaxolol
1
No
Slight
Low
14–22 hours
90
Bisoprolol
1
No
No
Low
9–12 hours
80
Yes
No
Low
6 hours
85
Carvedilol None
No
No
No data
6–8 hours
25–35
Celiprolol
1
Yes2
No
No data
4–5 hours
70
Esmolol
1
No
No
Low
10 minutes
–0
Yes1
Yes
Moderate
5 hours
30
No
Yes
Moderate
3–4 hours
50
No
No
Low
14–24 hours
33
Penbutolol None
Yes
No
High
5 hours
>90
Pindolol
Yes
Yes
Moderate
3–4 hours
90
No
Yes
High
3.5–6 hours
303
Carteolol
None 1
Labetalol1 Metoprolol Nadolol
None 1
None None
Propranolol None
Sotalol
None
No
No
Low
12 hours
90
Timolol
None
No
No
Moderate
4–5 hours
50
1
Carvedilol and labetalol also cause
2
Partial agonist effects at
3
Bioavailability is dose-dependent.
2
1
adrenoceptor blockade.
receptors.
Distribution and Clearance The antagonists are rapidly distributed and have large volumes of distribution. Propranolol and penbutolol are quite lipophilic and readily cross the blood-brain barrier (Table 10–2). Most antagonists have half-lives in the range of 3–10 hours. A major exception is esmolol, which is rapidly hydrolyzed and has a half-life of approximately 10 minutes. Propranolol and metoprolol are extensively metabolized in the liver, with little unchanged drug appearing in the urine. The cytochrome P450 2D6 (CYP2D6) genotype is a major determinant of interindividual differences in metoprolol plasma clearance (Chapter 4: Drug Biotransformation). Poor metabolizers exhibit threefold to tenfold higher plasma concentrations after administration of metoprolol than extensive metabolizers. Atenolol, celiprolol, and pindolol are less completely metabolized. Nadolol is excreted unchanged in the urine and has the longest half-life of any available antagonist (up to 24 hours). The half-life of nadolol is prolonged in renal failure. The elimination of drugs such as propranolol may be prolonged in the presence of liver disease, diminished hepatic blood flow, or hepatic enzyme inhibition. It is notable that the pharmacodynamic effects of these drugs are often prolonged well beyond the time predicted from half-life data. Pharmacodynamics of the -Receptor-Antagonist Drugs Most of the effects of these drugs are due to occupancy and blockade of receptors. However, some actions may be due to other effects, including partial agonist activity at receptors and local anesthetic action, which differ among the -blockers (Table 10–2). Effects on the Cardiovascular System Beta-blocking drugs given chronically lower blood pressure in patients with hypertension. The mechanisms involved may include effects on the heart and blood vessels, suppression of the reninangiotensin system, and perhaps effects in the central nervous system or elsewhere. Betaadrenoceptor-blocking drugs are of major clinical importance in the treatment of hypertension (see Chapter 11: Antihypertensive Agents). In contrast, conventional doses of these drugs do not usually cause hypotension in healthy individuals with normal blood pressure. Beta-receptor antagonists have prominent effects on the heart (Figure 10–6). The negative inotropic and chronotropic effects are predictable from the role of adrenoceptors in regulating these functions. Slowed atrioventricular conduction with an increased PR interval is a related result of adrenoceptor blockade in the atrioventricular node. These effects may be clinically valuable in some patients but are potentially hazardous in others. In the vascular system, -receptor blockade opposes 2mediated vasodilation. This may acutely lead to a rise in peripheral resistance from unopposed receptor-mediated effects as the sympathetic nervous system discharges in response to lowered blood pressure due to the fall in cardiac output. Beta-blocking drugs antagonize the release of renin
caused by the sympathetic nervous system. As noted in Chapter 11: Antihypertensive Agents, the relation between the effects on renin release and those on blood pressure is unclear. In any event, while the acute effects of these drugs may include a rise in peripheral resistance, chronic drug administration leads to a fall in peripheral resistance in patients with hypertension. How this adjustment occurs is not yet clear. Figure 10–6.
The effect in an anesthetized dog of the injection of epinephrine before and after propranolol. In the presence of a -receptor-blocking agent, epinephrine no longer augments the force of contraction (measured by a strain gauge attached to the ventricular wall) nor increases cardiac rate. Blood pressure is still elevated by epinephrine because vasoconstriction is not blocked. (Reproduced, with permission, from Shanks RG: The pharmacology of b sympathetic blockade. Am J Cardiol 1966;18:312.) Effects on the Respiratory Tract Blockade of the 2 receptors in bronchial smooth muscle may lead to an increase in airway resistance, particularly in patients with asthma. Beta1-receptor antagonists such as metoprolol or atenolol may have some advantage over nonselective antagonists when blockade of 1 receptors in the heart is desired and 2-receptor blockade is undesirable. However, no currently available 1selective antagonist is sufficiently specific to completely avoid interactions with 2 adrenoceptors. Consequently, these drugs should generally be avoided in patients with asthma. On the other hand, some patients with chronic obstructive pulmonary disease (COPD) may tolerate these drugs quite well. Effects on the Eye Several -blocking agents reduce intraocular pressure, especially in glaucomatous eyes. The mechanism usually reported is decreased aqueous humor production. (See Clinical Pharmacology and The Treatment of Glaucoma.)
Metabolic and Endocrine Effects Beta-receptor antagonists such as propranolol inhibit sympathetic nervous system stimulation of lipolysis. The effects on carbohydrate metabolism are less clear, though glycogenolysis in the human liver is at least partially inhibited after 2-receptor blockade. However, glucagon is the primary hormone employed to combat hypoglycemia. It is unclear to what extent antagonists impair recovery from hypoglycemia, but they should be used with caution in insulin-dependent diabetic patients. This may be particularly important in diabetic patients with inadequate glucagon reserve and in pancreatectomized patients since catecholamines may be the major factors in stimulating glucose release from the liver in response to hypoglycemia. Beta1-receptor-selective drugs may be less prone to inhibit recovery from hypoglycemia. Beta-receptor antagonists are much safer in those type 2 diabetic patients who do not have hypoglycemic episodes. The chronic use of -adrenoceptor antagonists has been associated with increased plasma concentrations of VLDL and decreased concentrations of HDL cholesterol. Both of these changes are potentially unfavorable in terms of risk of cardiovascular disease. Although LDL concentrations generally do not change, there is a variable decline in the HDL cholesterol/ LDL cholesterol ratio that may increase the risk of coronary artery disease. These changes tend to occur with both selective and nonselective -blockers, though they are perhaps less likely to occur with -blockers possessing intrinsic sympathomimetic activity (partial agonists). The mechanisms by which receptor antagonists cause these changes are not understood, though changes in sensitivity to insulin action may contribute. Effects Not Related to Beta-Blockade Partial -agonist activity was significant in the first -blocking drug synthesized, dichloroisoproterenol. It has been suggested that retention of some intrinsic sympathomimetic activity is desirable to prevent untoward effects such as precipitation of asthma or excessive bradycardia. Pindolol and other partial agonists are noted in Table 10–2. It is not yet clear to what extent partial agonism is clinically valuable. Furthermore, these drugs may not be as effective as the pure antagonists in secondary prevention of myocardial infarction. However, they may be useful in patients who develop symptomatic bradycardia or bronchoconstriction in response to pure antagonist -adrenoceptor drugs, but only if they are strongly indicated for a particular clinical indication. Local anesthetic action, also known as "membrane-stabilizing" action, is a prominent effect of several -blockers (Table 10–2). This action is the result of typical local anesthetic blockade of sodium channels and can be demonstrated experimentally in isolated neurons, heart muscle, and skeletal muscle membrane. However, it is unlikely that this effect is important after systemic administration of these drugs, since the concentration in plasma usually achieved by these routes is too low for the anesthetic effects to be evident. These drugs are not used topically on the eye, where local anesthesia of the cornea would be highly undesirable. Sotalol is a nonselective -receptor antagonist that lacks local anesthetic action but has marked class III antiarrhythmic effects, reflecting potassium channel blockade (see Chapter 14: Agents Used in Cardiac Arrhythmias). Specific Agents (See Table 10–2.) Propranolol is the prototypical -blocking drug. It has low and dose-dependent bioavailability, the result of extensive first-pass metabolism in the liver. A long-acting form of propranolol is available;
prolonged absorption of the drug may occur over a 24-hour period. The drug has negligible effects at and muscarinic receptors; however, it may block some serotonin receptors in the brain, though the clinical significance is unclear. It has no detectable partial agonist action at receptors. Metoprolol, atenolol, and several other drugs (see Table 10–2) are members of the 1-selective group. These agents may be safer in patients who experience bronchoconstriction in response to propranolol. Since their 1 selectivity is rather modest, they should be used with great caution, if at all, in patients with a history of asthma. However, in selected patients with chronic obstructive lung disease the benefits may exceed the risks, eg, in patients with myocardial infarction. Beta1-selective antagonists may be preferable in patients with diabetes or peripheral vascular disease when therapy with a -blocker is required since 2 receptors are probably important in liver (recovery from hypoglycemia) and blood vessels (vasodilation). Nadolol is noteworthy for its very long duration of action; its spectrum of action is similar to that of timolol. Timolol is a nonselective agent with no local anesthetic activity. It has excellent ocular hypotensive effects when administered topically in the eye. Levobunonol (nonselective) and betaxolol ( 1-selective) are used for topical ophthalmic application in glaucoma; the latter drug may be less likely to induce bronchoconstriction than nonselective antagonists. Carteolol is a nonselective -receptor antagonist. Pindolol, acebutolol, carteolol, bopindolol,* oxprenolol,* celiprolol, and penbutolol are of interest because they have partial -agonist activity. * Not available in the USA. They are effective in the major cardiovascular applications of the -blocking group (hypertension and angina). Although these partial agonists may be less likely to cause bradycardia and abnormalities in plasma lipids than are antagonists, the overall clinical significance of intrinsic sympathomimetic activity remains uncertain. Pindolol, perhaps as a result of actions on serotonin signaling, may potentiate the action of traditional antidepressant medications. Celiprolol* is a 1selective antagonist with a modest capacity to activate 2 receptors. * Not available in the USA. There is limited evidence suggesting that celiprolol may have less adverse bronchoconstrictor effects in asthma and may even promote bronchodilation. Acebutolol is also a 1-selective antagonist. Labetalol is a reversible adrenoceptor antagonist available as a racemic mixture of two pairs of chiral isomers (the molecule has two centers of asymmetry). The (S,S)- and (R,S)-isomers are inactive, (S,R)- is a potent -blocker, and the (R,R)-isomer is a potent -blocker. Labetalol's affinity for receptors is less than that of phentolamine, but labetalol is 1-selective. Its -blocking potency is somewhat lower than that of propranolol. Hypotension induced by labetalol is accompanied by less tachycardia than occurs with phentolamine and similar -blockers. Carvedilol, medroxalol,* and bucindolol* are nonselective -receptor antagonists with some capacity to block 1-adrenergic receptors. * Not available in the USA. Carvedilol antagonizes the actions of catecholamines more potently at receptors than at receptors.
The drug has a half-life of 6–8 hours. It is extensively metabolized in the liver, and stereoselective metabolism of its two isomers is observed. Since metabolism of (R)-carvedilol is influenced by polymorphisms in cytochrome P450 2D6 activity and by drugs that inhibit this enzyme's activity (such as quinidine and fluoxetine), drug interactions may occur. Carvedilol also appears to attenuate oxygen free radical-initiated lipid peroxidation and to inhibit vascular smooth muscle mitogenesis independently of adrenoceptor blockade. These effects may contribute to the clinical benefits of the drug in chronic heart failure (see Chapter 13: Drugs Used in Heart Failure). Esmolol is an ultra-short–acting 1-selective adrenoceptor antagonist. The structure of esmolol contains an ester linkage; esterases in red blood cells rapidly metabolize esmolol to a metabolite that has a low affinity for receptors. Consequently, esmolol has a short half-life (about 10 minutes). Therefore, during continuous infusions of esmolol, steady state concentrations are achieved quickly, and the therapeutic actions of the drug are terminated rapidly when its infusion is discontinued. Esmolol is potentially safer to use than longer-acting antagonists in critically ill patients who require a -adrenoceptor antagonist. Esmolol is useful in controlling supraventricular arrhythmias, arrhythmias associated with thyrotoxicosis, perioperative hypertension, and myocardial ischemia in acutely ill patients. Butoxamine is selective for 2 receptors. Selective 2-blocking drugs have not been actively sought because there is no obvious clinical application for them and none are availale for clinical use. Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > The Treatment of Glaucoma Glaucoma is a major cause of blindness and of great pharmacologic interest because the chronic form often responds to drug therapy. The primary manifestation is increased intraocular pressure not initially associated with symptoms. Without treatment, increased intraocular pressure results in damage to the retina and optic nerve, with restriction of visual fields and, eventually, blindness. Intraocular pressure is easily measured as part of the routine ophthalmologic examination. Two major types of glaucoma are recognized: open-angle and closed-angle (or narrow-angle). The closed-angle form is associated with a shallow anterior chamber, in which a dilated iris can occlude the outflow drainage pathway at the angle between the cornea and the ciliary body (Figure 6–9). This form is associated with acute and painful increases of pressure, which must be controlled on an emergency basis with drugs or prevented by surgical removal of part of the iris (iridectomy). The open-angle form of glaucoma is a chronic condition, and treatment is largely pharmacologic. Because intraocular pressure is a function of the balance between fluid input and drainage out of the globe, the strategies for the treatment of closed-angle glaucoma fall into two classes: reduction of aqueous humor secretion and enhancement of aqueous outflow. Five general groups of drugs— cholinomimetics, agonists, -blockers, prostaglandin F2a analogs, and diuretics—have been found to be useful in reducing intraocular pressure and can be related to these strategies as shown in Table 10–3. Of the five drug groups listed in Table 10–3, the prostaglandin analogs and the -blockers are the most popular. This popularity results from convenience (once- or twice-daily dosing) and relative lack of adverse effects (except, in the case of -blockers, in patients with asthma or cardiac pacemaker or conduction pathway disease). Other drugs that have been reported to reduce intraocular pressure include prostaglandin E2 and marijuana. The use of drugs in acute closed-angle glaucoma is limited to cholinomimetics, acetazolamide, and osmotic agents preceding surgery. The onset of action of the other agents is too slow in this situation.
Table 10–3. Drugs Used in Open-Angle Glaucoma.
Mechanism
Methods of Administration
Cholinomimetics Pilocarpine, carbachol, physostigmine, echothiophate, demecarium
Ciliary muscle contraction, Topical drops or gel; opening of trabecular meshwork; plastic film slow-release increased outflow insert
Alpha agonists Unselective
Increased outflow
Topical drops
Epinephrine, dipivefrin Alpha2-selective
Decreased aqueous secretion
Apraclonidine
Topical, postlaser only
Brimonidine
Topical
Beta-blockers Timolol, betaxolol, carteolol, levobunolol, metipranolol
Decreased aqueous secretion from the ciliary epithelium
Topical drops
Decreased secretion due to lack of HCO3-
Topical
Increased outflow
Topical
Diuretics Dorzolamide, brinzolamide Acetazolamide, dichlorphenamide, methazolamide
Oral
Prostaglandins Latanoprost, unoprostone
Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > Clinical Pharmacology of the Beta-Receptor-Blocking Drugs Hypertension The -adrenoceptor-blocking drugs have proved to be effective and well tolerated in hypertension. While many hypertensive patients will respond to a -blocker used alone, the drug is often used with either a diuretic or a vasodilator. In spite of the short half-life of many antagonists, these drugs may be administered once or twice daily and still have an adequate therapeutic effect. Labetalol, a competitive and antagonist, is effective in hypertension, though its ultimate role is yet to be determined. Use of these agents is discussed in detail in Chapter 11: Antihypertensive Agents. There is some evidence that drugs in this class may be less effective in blacks and the elderly. However, these differences are relatively small and may not apply to an individual patient. Indeed, since effects on blood pressure are easily measured, the therapeutic outcome for this indication can be readily detected in any patient.
Ischemic Heart Disease Beta-adrenoceptor blockers reduce the frequency of anginal episodes and improve exercise tolerance in many patients with angina (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris). These actions relate to the blockade of cardiac receptors, resulting in decreased cardiac work and reduction in oxygen demand. Slowing and regularization of the heart rate may contribute to clinical benefits (Figure 10–7). Multiple large-scale prospective studies indicate that the longterm use of timolol, propranolol, or metoprolol in patients who have had a myocardial infarction prolongs survival (Figure 10–8). At the present time, data are less compelling for the use of other than the three mentioned -adrenoceptor antagonists for this indication. Importantly, surveys in many populations have indicated that the -receptor antagonists are underused, leading to unnecessary morbidity and mortality. Studies in experimental animals suggest that use of -receptor antagonists during the acute phase of a myocardial infarction may limit infarct size. However, this use is still controversial. Figure 10–7.
Heart rate in a patient with ischemic heart disease measured by telemetry while watching television. Measurements were begun 1 hour after receiving placebo (upper line, black) or 40 mg of oxprenolol (color), a nonselective -antagonist with partial agonist activity. Not only was the heart rate decreased by the drug under the conditions of this experiment; it also varied much less in response to stimuli. (Modified and reproduced, with permission, from Taylor SH: Oxprenolol in clinical practice. Am J Cardiol 1983;52:34D.) Cardiac Arrhythmias Beta antagonists are effective in the treatment of both supraventricular and ventricular arrhythmias (see Chapter 14: Agents Used in Cardiac Arrhythmias). It has been suggested that the improved
survival following myocardial infarction in patients using -antagonists (Figure 10–8; see above) is due to suppression of arrhythmias, but this has not been proved. By increasing the atrioventricular nodal refractory period, antagonists slow ventricular response rates in atrial flutter and fibrillation. These drugs can also reduce ventricular ectopic beats, particularly if the ectopic activity has been precipitated by catecholamines. Sotalol has additional antiarrhythmic effects involving ion channel blockade in addition to its -blocking action; these are discussed in Chapter 14: Agents Used in Cardiac Arrhythmias. Figure 10–8.
Effects of -blocker therapy on life-table cumulated rates of mortality from all causes over 6 years among 1884 patients surviving myocardial infarctions. Patients were randomly assigned to treatment with placebo (dashed line) or timolol (color). (Reproduced, with permission, from Pederson TR: Six-year follow-up of the Norwegian multicenter study on timolol after acute myocardial infarction. N Engl J Med 1985;313:1055.) Other Cardiovascular Disorders Beta-receptor antagonists have been found to increase stroke volume in some patients with obstructive cardiomyopathy. This beneficial effect is thought to result from the slowing of ventricular ejection and decreased outflow resistance. Beta-antagonists are useful in dissecting aortic aneurysm to decrease the rate of development of systolic pressure. Clinical trials have demonstrated that at least three antagonists—metoprolol, bisoprolol, and carvedilol—are effective in treating chronic heart failure in selected patients. While administration of these drugs may acutely worsen congestive heart failure, cautious long-term use with gradual dose increments in patients who tolerate them may prolong life. While mechanisms are uncertain, there appear to be beneficial effects on myocardial remodeling and in decreasing the risk of sudden death (see Chapter 13: Drugs Used in Heart Failure). Glaucoma See The Treatment of Glaucoma.
Systemic administration of -blocking drugs for other indications was found serendipitously to reduce intraocular pressure in patients with glaucoma. Subsequently, it was found that topical administration also reduces intraocular pressure. The mechanism appears to involve reduced production of aqueous humor by the ciliary body, which is physiologically activated by cAMP. Timolol and related antagonists are suitable for local use in the eye because they lack local anesthetic properties. Beta antagonists appear to have an efficacy comparable to that of epinephrine or pilocarpine in open-angle glaucoma and are far better tolerated by most patients. While the maximal daily dose applied locally (1 mg) is small compared with the systemic doses commonly used in the treatment of hypertension or angina (10–60 mg), sufficient timolol may be absorbed from the eye to cause serious adverse effects on the heart and airways in susceptible individuals. Topical timolol may interact with orally administered verapamil and increase the risk of heart block. Betaxolol, carteolol, levobunolol, and metipranolol are newer -receptor antagonists approved for the treatment of glaucoma. Betaxolol has the potential advantage of being 1-selective; to what extent this potential advantage might diminish systemic adverse effects remains to be determined. The drug apparently has caused worsening of pulmonary symptoms in some patients. Hyperthyroidism Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38: Thyroid & Antithyroid Drugs). The antagonists have salutary effects in this condition. These beneficial effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism); it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure. Neurologic Diseases Several studies show a beneficial effect of propranolol in reducing the frequency and intensity of migraine headache. Other -receptor antagonists with preventive efficacy include metoprolol and probably also atenolol, timolol, and nadolol. The mechanism is not known. Since sympathetic activity may enhance skeletal muscle tremor, it is not surprising that antagonists have been found to reduce certain tremors (see Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders). The somatic manifestations of anxiety may respond dramatically to low doses of propranolol, particularly when taken prophylactically. For example, benefit has been found in musicians with performance anxiety ("stage fright"). Propranolol may contribute to the symptomatic treatment of alcohol withdrawal in some patients. Miscellaneous Beta-receptor antagonists have been found to diminish portal vein pressure in patients with cirrhosis. There is evidence that both propranolol and nadolol decrease the incidence of the first episode of bleeding from esophageal varices and decrease the mortality rate associated with bleeding in patients with cirrhosis. Nadolol in combination with isosorbide mononitrate appears to be more efficacious than sclerotherapy in preventing re-bleeding in patients who have previously bled from esophageal varices.
Choice of a Beta-Adrenoceptor Antagonist Drug Propranolol is the standard against which newer antagonists developed for systemic use have been compared. In many years of very wide use, it has been found to be a safe and effective drug for many indications. Since it is possible that some actions of a -receptor antagonist may relate to some other effect of the drug, these drugs should not be considered interchangeable for all applications. For example, only antagonists known to be effective in hyperthyroidism or in prophylactic therapy after myocardial infarction should be used for those indications. It is possible that the beneficial effects of one drug in these settings might not be shared by another drug in the same class. The possible advantages and disadvantages of receptor antagonists that are partial agonists have not been clearly defined in clinical settings, although current evidence suggests that they are probably less efficacious in secondary prevention after a myocardial infarction compared to pure antagonists. Clinical Toxicity of the Beta-Receptor Antagonist Drugs A variety of minor toxic effects have been reported for propranolol. Rash, fever, and other manifestations of drug allergy are rare. Central nervous system effects include sedation, sleep disturbances, and depression. Rarely, psychotic reactions may occur. Discontinuing the use of blockers in any patient who develops a depression should be seriously considered if clinically feasible. It has been claimed that -receptor antagonist drugs with low lipid solubility are associated with a lower incidence of central nervous system adverse effects than compounds with higher lipid solubility (Table 10–2). Further studies designed to compare the central nervous system adverse effects of various drugs are required before specific recommendations can be made, though it seems reasonable to try the hydrophilic drugs nadolol or atenolol in a patient who experiences unpleasant central nervous system effects with other -blockers. The major adverse effects of -receptor antagonist drugs relate to the predictable consequences of blockade. Beta2-receptor blockade associated with the use of nonselective agents commonly causes worsening of preexisting asthma and other forms of airway obstruction without having these consequences in normal individuals. Indeed, relatively trivial asthma may become severe after blockade. However, because of their life-saving possibilities in cardiovascular disease, strong consideration should be given to individualized therapeutic trials in some classes of patients, eg, those with chronic obstructive pulmonary disease who have appropriate indications for -blockers. While 1-selective drugs may have less effect on airways than nonselective antagonists, they must be used very cautiously, if at all, in patients with reactive airways. While 1-selective antagonists are generally well tolerated in patients with mild to moderate peripheral vascular disease, caution is required in patients with severe peripheral vascular disease or vasospastic disorders. Beta-receptor blockade depresses myocardial contractility and excitability. In patients with abnormal myocardial function, cardiac output may be dependent on sympathetic drive. If this stimulus is removed by blockade, cardiac decompensation may ensue. Thus, caution must be exercised in using -receptor antagonists in patients with compensated heart failure even though long-term use of these drugs in these patients may prolong life. A life-threatening adverse cardiac effect of a antagonist may be overcome directly with isoproterenol or with glucagon (glucagon stimulates the heart via glucagon receptors, which are not blocked by antagonists), but neither of these methods is without hazard. A very small dose of a antagonist (eg, 10 mg of propranolol) may provoke severe cardiac failure in a susceptible individual. Beta-blockers may interact with the calcium antagonist verapamil; severe hypotension, bradycardia, heart failure, and cardiac conduction abnormalities have all been described. These adverse effects may even arise in
susceptible patients taking a topical (ophthalmic) -blocker and oral verapamil. Some hazards are associated with abruptly discontinuing antagonist therapy after chronic use. Evidence suggests that patients with ischemic heart disease may be at increased risk if blockade is suddenly interrupted. The mechanism of this effect is uncertain but might involve up-regulation of the number of receptors. Until better evidence is available regarding the magnitude of the risk, prudence dictates the gradual tapering rather than abrupt cessation of dosage when these drugs are discontinued, especially drugs with short half-lives, such as propranolol and metoprolol. The incidence of hypoglycemic episodes in diabetics that are exacerbated by -blocking agents is unknown. Nevertheless, it is inadvisable to use antagonists in insulin-dependent diabetic patients who are subject to frequent hypoglycemic reactions if alternative therapies are available. Beta1selective antagonists offer some advantage in these patients, since the rate of recovery from hypoglycemia may be faster compared with diabetics receiving nonselective adrenoceptor antagonists. There is considerable potential benefit from these drugs in diabetics after a myocardial infarction, so the balance of risk versus benefit must be evaluated in individual patients. Katzung PHARMACOLOGY, 9e > Section II. Autonomic Drugs > Chapter 10. Adrenoceptor Antagonist Drugs > Preparations Available Alpha Blockers Doxazosin (generic, Cardura) Oral: 1, 2, 4, 8 mg tablets Phenoxybenzamine (Dibenzyline) Oral: 10 mg capsules Phentolamine (generic, Regitine) Parenteral: 5 mg/vial for injection Prazosin (generic, Minipress) Oral: 1, 2, 5 mg capsules Tamsulosin (Flomax) Oral: 0.4 mg capsule Terazosin (generic, Hytrin) Oral: 1, 2, 5, 10 mg tablets, capsules Tolazoline (Priscoline)
Parenteral: 25 mg/mL for injection Beta Blockers Acebutolol (generic, Sectral) Oral: 200, 400 mg capsules Atenolol (generic, Tenormin) Oral: 25, 50, 100 mg tablets Parenteral: 0.5 mg/mL for IV injection Betaxolol Oral: 10, 20 mg tablets (Kerlone) Ophthalmic: 0.25%, 0.5% drops (generic, Betoptic) Bisoprolol (Zebeta) Oral: 5, 10 mg tablets Carteolol Oral: 2.5, 5 mg tablets (Cartrol) Ophthalmic: 1% drops (generic, Ocupress) Carvedilol (Coreg) Oral: 3.125, 6.25, 12.5, 25 mg tablets Esmolol (Brevibloc) Parenteral: 10 mg/mL for IV injection; 250 mg/mL for IV infusion Labetalol (generic, Normodyne, Trandate) Oral: 100, 200, 300 mg tablets Parenteral: 5 mg/mL for injection Levobunolol (Betagan Liquifilm, others) Ophthalmic: 0.25, 0.5% drops Metipranolol (Optipranolol)
Ophthalmic: 0.3% drops Metoprolol (generic, Lopressor, Toprol) Oral: 50, 100 mg tablets Oral sustained-release: 25, 50, 100, 200 mg tablets Parenteral: 1 mg/mL for injection Nadolol (generic, Corgard) Oral: 20, 40, 80, 120, 160 mg tablets Penbutolol (Levatol) Oral: 20 mg tablets Pindolol (generic, Visken) Oral: 5, 10 mg tablets Propranolol (generic, Inderal) Oral: 10, 20, 40, 60, 80, 90 mg tablets; 4, 8, 80 mg/mL solutions Oral sustained release: 60, 80, 120, 160 mg capsules Parenteral: 1 mg/mL for injection Sotalol (generic, Betapace) Oral: 80, 120, 160, 240 mg tablets Timolol Oral: 5, 10, 20 mg tablets (generic, Blocadren) Ophthalmic: 0.25, 0.5% drops, gel (generic, Timoptic) Synthesis Inhibitor Metyrosine (Demser) Oral: 250 mg capsules
Section III. Cardiovascular-Renal Drugs Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents > Antihypertensive Agents: Introduction Hypertension is the most common cardiovascular disease. Thus, the third National Health and Nutrition Examination Survey (NHANES III), conducted from 1992 to 1994, found that 27% of the USA adult population had hypertension. The prevalence varies with age, race, education, and many other variables. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, cardiac failure, and stroke. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates. Many effective drugs are available. Knowledge of their antihypertensive mechanisms and sites of action allows accurate prediction of efficacy and toxicity. As a result, rational use of these agents, alone or in combination, can lower blood pressure with minimal risk of serious toxicity in most patients. Hypertension & Regulation of Blood Pressure Diagnosis The diagnosis of hypertension is based on repeated, reproducible measurements of elevated blood pressure. The diagnosis serves primarily as a prediction of consequences for the patient; it seldom includes a statement about the cause of hypertension. Epidemiologic studies indicate that the risks of damage to kidney, heart, and brain are directly related to the extent of blood pressure elevation. Even mild hypertension (blood pressure 140/90 mm Hg) in young or middle-aged adults increases the risk of eventual end organ damage. The risks—and therefore the urgency of instituting therapy—increase in proportion to the magnitude of blood pressure elevation. The risk of end organ damage at any level of blood pressure or age is greater in black people and relatively less in premenopausal women than in men. Other positive risk factors include smoking, hyperlipidemia, diabetes, manifestations of end organ damage at the time of diagnosis, and a family history of cardiovascular disease. It should be noted that the diagnosis of hypertension depends on measurement of blood pressure and not on symptoms reported by the patient. In fact, hypertension is usually asymptomatic until overt end organ damage is imminent or has already occurred. Etiology of Hypertension A specific cause of hypertension can be established in only 10–15% of patients. It is important to consider specific causes in each case, however, because some of them are amenable to definitive surgical treatment: renal artery constriction, coarctation of the aorta, pheochromocytoma, Cushing's disease, and primary aldosteronism. Patients in whom no specific cause of hypertension can be found are said to have essential hypertension.* * The adjective originally was intended to convey the now abandoned idea that blood pressure elevation was essential for adequate perfusion of diseased tissues.
In most cases, elevated blood pressure is associated with an overall increase in resistance to flow of blood through arterioles, while cardiac output is usually normal. Meticulous investigation of autonomic nervous system function, baroreceptor reflexes, the renin-angiotensin-aldosterone system, and the kidney has failed to identify a primary abnormality as the cause of increased peripheral vascular resistance in essential hypertension. Elevated blood pressure is usually caused by a combination of several abnormalities (multifactorial). Epidemiologic evidence points to genetic inheritance, psychological stress, and environmental and dietary factors (increased salt and decreased potassium or calcium intake) as perhaps contributing to the development of hypertension. Increase in blood pressure with aging does not occur in populations with low daily sodium intake. Patients with labile hypertension appear more likely than normal controls to have blood pressure elevations after salt loading. The heritability of essential hypertension is estimated to be about 30%. Mutations in several genes have been linked to various rare causes of hypertension. Functional variations of the genes for angiotensinogen, angiotensin-converting enzyme (ACE), and the 2 adrenoceptor appear to contribute to some cases of essential hypertension. Normal Regulation of Blood Pressure According to the hydraulic equation, arterial blood pressure (BP) is directly proportionate to the product of the blood flow (cardiac output, CO) and the resistance to passage of blood through precapillary arterioles (peripheral vascular resistance, PVR):
Physiologically, in both normal and hypertensive individuals, blood pressure is maintained by moment-to-moment regulation of cardiac output and peripheral vascular resistance, exerted at three anatomic sites (Figure 11–1): arterioles, postcapillary venules (capacitance vessels), and heart. A fourth anatomic control site, the kidney, contributes to maintenance of blood pressure by regulating the volume of intravascular fluid. Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function at these four control sites and to maintain normal blood pressure. Finally, local release of hormones from vascular endothelium may also be involved in the regulation of vascular resistance. For example, nitric oxide (see Chapter 19: Nitric Oxide, Donors, & Inhibitors) dilates and endothelin-1 (see Chapter 17: Vasoactive Peptides) constricts blood vessels. Figure 11–1.
Anatomic sites of blood pressure control. Blood pressure in a hypertensive patient is controlled by the same mechanisms that are operative in normotensive subjects. Regulation of blood pressure in hypertensive patients differs from healthy patients in that the baroreceptors and the renal blood volume-pressure control systems appear to be "set" at a higher level of blood pressure. All antihypertensive drugs act by interfering with these normal mechanisms, which are reviewed below. Postural Baroreflex Baroreflexes are responsible for rapid, moment-to-moment adjustments in blood pressure, such as in transition from a reclining to an upright posture (Figure 11–2). Central sympathetic neurons arising from the vasomotor area of the medulla are tonically active. Carotid baroreceptors are stimulated by the stretch of the vessel walls brought about by the internal pressure (blood pressure). Baroreceptor activation inhibits central sympathetic discharge. Conversely, reduction in stretch results in a reduction in baroreceptor activity. Thus, in the case of a transition to upright posture, baroreceptors sense the reduction in arterial pressure that results from pooling of blood in the veins below the level of the heart as reduced wall stretch, and sympathetic discharge is disinhibited. The reflex increase in sympathetic outflow acts through nerve endings to increase peripheral vascular resistance (constriction of arterioles) and cardiac output (direct stimulation of the heart and constriction of capacitance vessels, which increases venous return to the heart), thereby restoring normal blood pressure. The same baroreflex acts in response to any event that lowers arterial pressure, including a primary reduction in peripheral vascular resistance (eg, caused by a vasodilating agent) or a reduction in intravascular volume (eg, due to hemorrhage or to loss of salt and water via the kidney). Figure 11–2.
Baroreceptor reflex arc. Renal Response to Decreased Blood Pressure By controlling blood volume, the kidney is primarily responsible for long-term blood pressure control. A reduction in renal perfusion pressure causes intrarenal redistribution of blood flow and increased reabsorption of salt and water. In addition, decreased pressure in renal arterioles as well as sympathetic neural activity (via -adrenoceptors) stimulates production of renin, which increases production of angiotensin II (see Figure 11–1 and Chapter 17: Vasoactive Peptides). Angiotensin II causes (1) direct constriction of resistance vessels and (2) stimulation of aldosterone synthesis in the adrenal cortex, which increases renal sodium absorption and intravascular blood volume. Vasopressin released from the posterior pituitary gland also plays a role in maintenance of blood pressure through its ability to regulate water reabsorption by the kidney (see Chapter 17: Vasoactive Peptides). Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents > Basic Pharmacology of Antihypertensive Agents All antihypertensive agents act at one or more of the four anatomic control sites depicted in Figure 11–1 and produce their effects by interfering with normal mechanisms of blood pressure regulation. A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act (Figure 11–3). Because of their common mechanisms of action, drugs within each category tend to produce a similar spectrum of toxicities. The categories include the following: (1) Diuretics, which lower blood pressure by depleting the body of sodium and reducing blood
volume and perhaps by other mechanisms. (2) Sympathoplegic agents, which lower blood pressure by reducing peripheral vascular resistance, inhibiting cardiac function, and increasing venous pooling in capacitance vessels. (The latter two effects reduce cardiac output.) These agents are further subdivided according to their putative sites of action in the sympathetic reflex arc (see below). (3) Direct vasodilators, which reduce pressure by relaxing vascular smooth muscle, thus dilating resistance vessels and—to varying degrees—increasing capacitance as well. (4) Agents that block production or action of angiotensin and thereby reduce peripheral vascular resistance and (potentially) blood volume. Figure 11–3.
Sites of action of the major classes of antihypertensive drugs. The fact that these drug groups act by different mechanisms permits the combination of drugs from two or more groups with increased efficacy and, in some cases, decreased toxicity. (See Monotherapy versus Polypharmacy in Hypertension.)
Drugs That Alter Sodium & Water Balance Dietary sodium restriction has been known for many years to decrease blood pressure in hypertensive patients. With the advent of diuretics, sodium restriction was thought to be less important. However, there is now general agreement that dietary control of blood pressure is a relatively nontoxic therapeutic measure and may even be preventive. Several studies have shown that even modest dietary sodium restriction lowers blood pressure (although to varying extents) in many hypertensive individuals. Mechanisms of Action & Hemodynamic Effects of Diuretics Diuretics lower blood pressure primarily by depleting body sodium stores. Initially, diuretics reduce blood pressure by reducing blood volume and cardiac output; peripheral vascular resistance may increase. After 6–8 weeks, cardiac output returns toward normal while peripheral vascular resistance declines. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to increased sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or sodium restriction. Some diuretics have direct vasodilating effects in addition to their diuretic action. Indapamide is a nonthiazide sulfonamide diuretic with both diuretic and vasodilator activity. As a consequence of vasodilation, cardiac output remains unchanged or increases slightly. Amiloride inhibits smooth muscle responses to contractile stimuli, probably through effects on transmembrane and intracellular calcium movement that are independent of its action on sodium excretion. Diuretics are effective in lowering blood pressure by 10–15 mm Hg in most patients, and diuretics alone often provide adequate treatment for mild or moderate essential hypertension. In more severe hypertension, diuretics are used in combination with sympathoplegic and vasodilator drugs to control the tendency toward sodium retention caused by these agents. Vascular responsiveness—ie, the ability to either constrict or dilate—is diminished by sympathoplegic and vasodilator drugs, so that the vasculature behaves like an inflexible tube. As a consequence, blood pressure becomes exquisitely sensitive to blood volume. Thus, in severe hypertension, when multiple drugs are used, blood pressure may be well controlled when blood volume is 95% of normal but much too high when blood volume is 105% of normal. Use of Diuretics The sites of action within the kidney and the pharmacokinetics of various diuretic drugs are discussed in Chapter 15: Diuretic Agents. Thiazide diuretics are appropriate for most patients with mild or moderate hypertension and normal renal and cardiac function. More powerful diuretics (eg, those acting on the loop of Henle) are necessary in severe hypertension, when multiple drugs with sodium-retaining properties are used; in renal insufficiency, when glomerular filtration rate is less than 30 or 40 mL/min; and in cardiac failure or cirrhosis, where sodium retention is marked. Potassium-sparing diuretics are useful both to avoid excessive potassium depletion, particularly in patients taking digitalis, and to enhance the natriuretic effects of other diuretics. Some pharmacokinetic characteristics and the initial and usual maintenance dosages of hydrochlorothiazide are listed in Table 11–1. Although thiazide diuretics are more natriuretic at higher doses (up to 100–200 mg of hydrochlorothiazide), when used as a single agent, lower doses (25–50 mg) exert as much antihypertensive effect as do higher doses. In contrast to thiazides, the
blood pressure response to loop diuretics continues to increase at doses many times greater than the usual therapeutic dose. Table 11–1. Pharmacokinetic Characteristics and Dosage of Selected Oral Antihypertensive Drugs.
Drug
Half- Bioavailability Suggested life (percent ) Initial (h) Dose
Usual Maintenance Dose Range
Reduction of Dosage Required in Moderate Renal Insufficiency1
Atenolol
6
60
50 mg/d
50–100 mg/d
Yes
Captopril
2.2
65
50–75 mg/d 75–150 mg/d
Yes
Clonidine
8–12 95
0.2 mg/d
0.2–1.2 mg/d
Yes
Guanethidine
5d
3–50
10 mg/d
25–50 mg/d
Yes
Hydralazine
1
25
100 mg/d
40–200 mg/d
No
Hydrochlorothiazide 12
70
25 mg/d
25–50 mg/d
No
Lisinopril
12
25
10 mg/d
10–80 mg/d
Yes
Losartan
1–22
36
50 mg/d
2.5–100 mg/d
No
Methyldopa
2
25
1 g/d
1–2 g/d
No
Minoxidil
4
90
5–10 mg/d
40 mg/d
No
Nifedipine
2
50
30 mg/d
30–90 mg/d
No
Prazosin
3–4
70
3 mg/d
10–30 mg/d
No
Propranolol
3–6
25
80 mg/d
80–480 mg/d
No
Reserpine
24–48 NA
0.25 mg/d
0.25 mg/d
No
Verapamil
4–6
180 mg/d
240–480 mg/d
No
22
1
Creatinine clearance 30 mL/min. Many of these drugs do require dosage adjustment if creatinine clearance falls below 30 mL/min. 2
The active metabolite of losartan has a half-life of 3–4 hours.
Toxicity of Diuretics In the treatment of hypertension, the most common adverse effect of diuretics (except for potassium-sparing diuretics) is potassium depletion. Although mild degrees of hypokalemia are tolerated well by many patients, hypokalemia may be hazardous in persons taking digitalis, those who have chronic arrhythmias, or those with acute myocardial infarction or left ventricular dysfunction. Potassium loss is coupled to reabsorption of sodium, and restriction of dietary sodium intake will therefore minimize potassium loss. Diuretics may also cause magnesium depletion, impair glucose tolerance, and increase serum lipid concentrations. Diuretics increase uric acid concentrations and may precipitate gout. The use of low doses minimizes these adverse metabolic
effects without impairing the antihypertensive action. Several case-control studies have reported a small but significant excess risk of renal cell carcinoma associated with diuretic use. Drugs That Alter Sympathetic Nervous System Function In patients with moderate to severe hypertension, most effective drug regimens include an agent that inhibits function of the sympathetic nervous system. Drugs in this group are classified according to the site at which they impair the sympathetic reflex arc (Figure 11–2). This neuroanatomic classification explains prominent differences in cardiovascular effects of drugs and allows the clinician to predict interactions of these drugs with one another and with other drugs. Most importantly, the subclasses of drugs exhibit different patterns of potential toxicity. Drugs that lower blood pressure by actions on the central nervous system tend to cause sedation and mental depression and may produce disturbances of sleep, including nightmares. Drugs that act by inhibiting transmission through autonomic ganglia produce toxicity from inhibition of parasympathetic regulation, in addition to profound sympathetic blockade. Drugs that act chiefly by reducing release of norepinephrine from sympathetic nerve endings cause effects that are similar to those of surgical sympathectomy, including inhibition of ejaculation, and hypotension that is increased by upright posture and after exercise. Drugs that block postsynaptic adrenoceptors produce a more selective spectrum of effects depending on the class of receptor to which they bind. Finally, one should note that all of the agents that lower blood pressure by altering sympathetic function can elicit compensatory effects through mechanisms that are not dependent on adrenergic nerves. Thus, the antihypertensive effect of any of these agents used alone may be limited by retention of sodium by the kidney and expansion of blood volume. For these reasons, sympathoplegic antihypertensive drugs are most effective when used concomitantly with a diuretic. Centrally Acting Sympathoplegic Drugs Mechanisms & Sites of Action These agents reduce sympathetic outflow from vasopressor centers in the brainstem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the antihypertensive and toxic actions of these drugs are generally less dependent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons. Methyldopa (L- -methyl-3,4-dihydroxyphenylalanine) is an analog of L-dopa and is converted to -methyldopamine and -methylnorepinephrine; this pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6–5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. However, this replacement of norepinephrine by a false transmitter in peripheral neurons is not responsible for methyldopa's antihypertensive effect, because the -methylnorepinephrine released is an effective agonist at the -adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. Direct electrical stimulation of sympathetic nerves in methyldopa-treated animals produces sympathetic responses similar to those observed in untreated animals. Indeed, methyldopa's antihypertensive action appears to be due to stimulation of central adrenoceptors by -methylnorepinephrine or -methyldopamine, based on the following evidence: (1) Much lower doses of methyldopa are required to lower blood pressure in animals when the drug is administered centrally by cerebral intraventricular injection rather than intravenously. (2) -
Receptor antagonists, especially 2-selective antagonists, administered centrally, block the antihypertensive effect of methyldopa, whether the latter is given centrally or intravenously. (3) Potent inhibitors of dopa decarboxylase, administered centrally, block methyldopa's antihypertensive effect, thus showing that metabolism of the parent drug in the central nervous system is necessary for its action. The antihypertensive action of clonidine, a 2-imidazoline derivative, was discovered in the course of testing the drug for use as a topically applied nasal decongestant. After intravenous injection, clonidine produces a brief rise in blood pressure followed by more prolonged hypotension. The pressor response is due to direct stimulation of -adrenoceptors in arterioles. The drug is classified as a partial agonist at -receptors because it also inhibits pressor effects of other -agonists. Considerable evidence indicates that the hypotensive effect of clonidine is exerted at adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of -antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brainstem pressor centers to inhibition by baroreflexes. Thus, studies of clonidine and methyldopa suggest that normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and methylnorepinephrine bind more tightly to 2- than to 1-adrenoceptors. As noted in Chapter 6: Introduction to Autonomic Pharmacology, 2-receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and -methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic 2-adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects. Methyldopa and clonidine produce slightly different hemodynamic effects: clonidine lowers heart rate and cardiac output more than does methyldopa. This difference suggests that these two drugs do not have identical sites of action. They may act primarily on different populations of neurons in the vasomotor centers of the brainstem. Guanabenz and guanfacine are centrally active antihypertensive drugs that share the central adrenoceptor-stimulating effects of clonidine. They do not appear to offer any advantages over clonidine. Methyldopa Methyldopa is useful in the treatment of mild to moderately severe hypertension. It lowers blood pressure chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output. Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly dependent on maintenance of upright posture. Postural (orthostatic) hypotension sometimes occurs, particularly in volume-depleted patients. One potential advantage of methyldopa is that it causes reduction in renal vascular resistance.
Pharmacokinetics & Dosage Pharmacokinetic characteristics of methyldopa are listed in Table 11–1. Methyldopa enters the brain via an aromatic amino acid transporter. An oral dose of methyldopa produces its maximal antihypertensive effect in 4–6 hours, and the effect can persist for up to 24 hours. Because the effect depends on accumulation and storage of a metabolite ( -methylnorepinephrine) in the vesicles of nerve endings, the action persists after the parent drug has disappeared from the circulation. Toxicity The most frequent undesirable effect of methyldopa is overt sedation, particularly at the onset of treatment. With long-term therapy, patients may complain of persistent mental lassitude and impaired mental concentration. Nightmares, mental depression, vertigo, and extrapyramidal signs may occur but are relatively infrequent. Lactation, associated with increased prolactin secretion, can occur both in men and in women treated with methyldopa. This toxicity is probably mediated by inhibition of dopaminergic mechanisms in the hypothalamus. Other important adverse effects of methyldopa are development of a positive Coombs test (occurring in 10–20% of patients undergoing therapy for longer than 12 months), which sometimes makes cross-matching blood for transfusion difficult and rarely is associated with hemolytic anemia, as well as hepatitis and drug fever. Discontinuation of the drug usually results in prompt reversal of these abnormalities. Clonidine Hemodynamic studies indicate that blood pressure lowering by clonidine results from reduction of cardiac output due to decreased heart rate and relaxation of capacitance vessels, with a reduction in peripheral vascular resistance, particularly when patients are upright (when sympathetic tone is normally increased). Reduction in arterial blood pressure by clonidine is accompanied by decreased renal vascular resistance and maintenance of renal blood flow. As with methyldopa, clonidine reduces blood pressure in the supine position and only rarely causes postural hypotension. Pressor effects of clonidine are not observed after ingestion of therapeutic doses of clonidine, but severe hypertension can complicate overdosage.
Pharmacokinetics & Dosage Typical pharmacokinetic characteristics are listed in Table 11–1. Clonidine is lipid-soluble and rapidly enters the brain from the circulation. Because of its relatively short half-life and the fact that its antihypertensive effect is directly related to blood concentration, oral clonidine must be given twice a day to maintain smooth blood pressure control. However, as is not the case with methyldopa, the dose-response curve of clonidine is such that increasing doses are more effective (but also more toxic). A transdermal preparation of clonidine that reduces blood pressure for 7 days after a single application is also available. This preparation appears to produce less sedation than clonidine tablets but is often associated with local skin reactions. Toxicity Dry mouth and sedation are frequent and may be severe. Both effects are centrally mediated and dose-dependent and coincide temporally with the drug's antihypertensive effect. The drug should not be given to patients who are at risk for mental depression and should be withdrawn if depression occurs during therapy. Concomitant treatment with tricyclic antidepressants may block the antihypertensive effect of clonidine. The interaction is believed to be due to -adrenoceptor-blocking actions of the tricyclics. Withdrawal of clonidine after protracted use, particularly with high dosages (greater than 1 mg/d), can result in life-threatening hypertensive crisis mediated by increased sympathetic nervous activity. Patients exhibit nervousness, tachycardia, headache, and sweating after omitting one or two doses of the drug. Although the incidence of severe hypertensive crisis is unknown, it is high enough to require that all patients who take clonidine be carefully warned of the possibility. If the drug must be stopped, this should be done gradually while other antihypertensive agents are being substituted. Treatment of the hypertensive crisis consists of reinstitution of clonidine therapy or administration of - and -adrenoceptor-blocking agents. Ganglion-Blocking Agents Historically, drugs that block stimulation of postganglionic autonomic neurons by acetylcholine were among the first agents used in the treatment of hypertension. Most such drugs are no longer available clinically because of intolerable toxicities related to their primary action (see below). Ganglion blockers competitively block nicotinic cholinoceptors on postganglionic neurons in both sympathetic and parasympathetic ganglia. In addition, these drugs may directly block the nicotinic acetylcholine channel, in the same fashion as neuromuscular nicotinic blockers (see Figure 27–5).
The adverse effects of ganglion blockers are direct extensions of their pharmacologic effects. These effects include both sympathoplegia (excessive orthostatic hypotension and sexual dysfunction) and parasympathoplegia (constipation, urinary retention, precipitation of glaucoma, blurred vision, dry mouth, etc). These severe toxicities are the major reason for the abandonment of ganglion blockers for the therapy of hypertension. Adrenergic Neuron-Blocking Agents These drugs lower blood pressure by preventing normal physiologic release of norepinephrine from postganglionic sympathetic neurons. Guanethidine In high enough doses, guanethidine can produce profound sympathoplegia. The resulting high maximal efficacy of this agent made it the mainstay of outpatient therapy of severe hypertension for many years. For the same reason, guanethidine can produce all of the toxicities expected from "pharmacologic sympathectomy," including marked postural hypotension, diarrhea, and impaired ejaculation. Because of these adverse effects, guanethidine is now rarely used.
Guanethidine is too polar to enter the central nervous system. As a result, this drug has none of the central effects seen with many of the other antihypertensive agents described in this chapter. Guanadrel is a guanethidine-like drug that is also available in the USA. Bethanidine and debrisoquin, antihypertensive agents not available for clinical use in the USA, are similar to guanethidine in mechanism of antihypertensive action. Mechanism & Sites of Action Guanethidine inhibits the release of norepinephrine from sympathetic nerve endings (Figure 11–4). This effect is probably responsible for most of the sympathoplegia that occurs in patients. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (uptake 1), and uptake is essential for the drug's action. Once guanethidine has entered the nerve, it is concentrated in transmitter vesicles, where it replaces norepinephrine. Because it replaces norepinephrine, the drug causes a gradual depletion of norepinephrine stores in the nerve ending. Figure 11–4.
Guanethidine actions and drug interactions involving the adrenergic neuron. (G, guanethidine; NE, norepinephrine; TCA, tricyclic antidepressants.) Inhibition of norepinephrine release is probably caused by guanethidine's local anesthetic properties on sympathetic nerve terminals. Although the drug does not impair axonal conduction in sympathetic fibers, local blockade of membrane electrical activity may occur in nerve endings because the nerve endings specifically take up and concentrate the drug. Because neuronal uptake is necessary for the hypotensive activity of guanethidine, drugs that block the catecholamine uptake process or displace amines from the nerve terminal (see Chapter 6: Introduction to Autonomic Pharmacology) block its effects. These include cocaine, amphetamine, tricyclic antidepressants, phenothiazines, and phenoxybenzamine. Guanethidine increases sensitivity to the hypertensive effects of exogenously administered sympathomimetic amines. This results from inhibition of neuronal uptake of such amines and, after long-term therapy with guanethidine, supersensitivity of effector smooth muscle cells, in a fashion analogous to the process that follows surgical sympathectomy (see Chapter 6: Introduction to Autonomic Pharmacology). The hypotensive action of guanethidine early in the course of therapy is associated with reduced cardiac output, due to bradycardia and relaxation of capacitance vessels. With long-term therapy, peripheral vascular resistance decreases. Compensatory sodium and water retention may be marked
during guanethidine therapy. Pharmacokinetics & Dosage Because of its long half-life (5 days) the onset of sympathoplegia is gradual (maximal effect in 1–2 weeks), and sympathoplegia persists for a comparable period after cessation of therapy. The dose should not ordinarily be increased at intervals shorter than 2 weeks. Toxicity Therapeutic use of guanethidine is often associated with symptomatic postural hypotension and hypotension following exercise, particularly when the drug is given in high doses, and may produce dangerously decreased blood flow to heart and brain or even overt shock. Guanethidine-induced sympathoplegia in men may be associated with delayed or retrograde ejaculation (into the bladder). Guanethidine commonly causes diarrhea, which results from increased gastrointestinal motility due to parasympathetic predominance in controlling the activity of intestinal smooth muscle. Interactions with other drugs may complicate guanethidine therapy. Sympathomimetic agents, at doses available in over-the-counter cold preparations, can produce hypertension in patients taking guanethidine. Similarly, guanethidine can produce hypertensive crisis by releasing catecholamines in patients with pheochromocytoma. When tricyclic antidepressants are administered to patients taking guanethidine, the drug's antihypertensive effect is attenuated, and severe hypertension may follow. Reserpine Reserpine, an alkaloid extracted from the roots of an Indian plant, Rauwolfia serpentina, was one of the first effective drugs used on a large scale in the treatment of hypertension. At present, it is considered an effective and relatively safe drug for treating mild to moderate hypertension.
Mechanism & Sites of Action Reserpine blocks the ability of aminergic transmitter vesicles to take up and store biogenic amines, probably by interfering with an uptake mechanism that depends on Mg2+ and ATP (Figure 6–4, carrier B). This effect occurs throughout the body, resulting in depletion of norepinephrine, dopamine, and serotonin in both central and peripheral neurons. Chromaffin granules of the adrenal
medulla are also depleted of catecholamines, although to a lesser extent than are the vesicles of neurons. Reserpine's effects on adrenergic vesicles appear irreversible; trace amounts of the drug remain bound to vesicular membranes for many days. Although sufficiently high doses of reserpine in animals can reduce catecholamine stores to zero, lower doses cause inhibition of neurotransmission that is roughly proportionate to the degree of amine depletion. Depletion of peripheral amines probably accounts for much of the beneficial antihypertensive effect of reserpine, but a central component cannot be ruled out. The effects of low but clinically effective doses resemble those of centrally acting agents (eg, methyldopa) in that sympathetic reflexes remain largely intact, blood pressure is reduced in supine as well as in standing patients, and postural hypotension is mild. Reserpine readily enters the brain, and depletion of cerebral amine stores causes sedation, mental depression, and parkinsonism symptoms. At lower doses used for treatment of mild hypertension, reserpine lowers blood pressure by a combination of decreased cardiac output and decreased peripheral vascular resistance. Pharmacokinetics & Dosage See Table 11–1. Toxicity At the low doses usually administered, reserpine produces little postural hypotension. Most of the unwanted effects of reserpine result from actions on the brain or gastrointestinal tract. High doses of reserpine characteristically produce sedation, lassitude, nightmares, and severe mental depression; occasionally, these occur even in patients receiving low doses (0.25 mg/d). Much less frequently, ordinary low doses of reserpine produce extrapyramidal effects resembling Parkinson's disease, probably as a result of dopamine depletion in the corpus striatum. Although these central effects are uncommon, it should be stressed that they may occur at any time, even after months of uneventful treatment. Patients with a history of mental depression should not receive reserpine, and the drug should be stopped if depression appears. Reserpine rather often produces mild diarrhea and gastrointestinal cramps and increases gastric acid secretion. The drug should probably not be given to patients with a history of peptic ulcer. Adrenoceptor Antagonists The pharmacology of drugs that antagonize catecholamines at - and -adrenoceptors is presented in Chapter 10: Adrenoceptor Antagonist Drugs. This chapter will concentrate on two prototypical drugs, propranolol and prazosin, primarily in relation to their use in treatment of hypertension. Other adrenoceptor antagonists will be considered only briefly. Propranolol Propranolol was the first -blocker shown to be effective in hypertension and ischemic heart disease. It is now clear that all -adrenoceptor-blocking agents are very useful for lowering blood pressure in mild to moderate hypertension. In severe hypertension, -blockers are especially useful in preventing the reflex tachycardia that often results from treatment with direct vasodilators. Beta blockers have been shown to reduce mortality in patients with heart failure, and they are particularly advantageous for treating hypertension in that population (see Chapter 13: Drugs Used in Heart
Failure). Mechanism & Sites of Action Propranolol's efficacy in treating hypertension as well as most of its toxic effects result from nonselective -blockade. Propranolol decreases blood pressure primarily as a result of a decrease in cardiac output. Other -blockers may decrease cardiac output or decrease peripheral vascular resistance to various degrees, depending on cardioselectivity and partial agonist activities. Beta-blockade in brain, kidney, and peripheral adrenergic neurons has been proposed as contributing to the antihypertensive effect observed with -receptor blockers. In spite of conflicting evidence, the brain appears unlikely to be the primary site of the hypotensive action of these drugs, because some -blockers that do not readily cross the blood-brain barrier (eg, nadolol, described below) are nonetheless effective antihypertensive agents. Propranolol inhibits the stimulation of renin production by catecholamines (mediated by Beta1receptors). It is likely that propranolol's effect is due in part to depression of the renin-angiotensinaldosterone system. Although most effective in patients with high plasma renin activity, propranolol also reduces blood pressure in hypertensive patients with normal or even low renin activity. Beta blockers might also act on peripheral presynaptic -adrenoceptors to reduce sympathetic vasoconstrictor nerve activity. In mild to moderate hypertension, propranolol produces a significant reduction in blood pressure without prominent postural hypotension. Pharmacokinetics & Dosage See Table 11–1. Resting bradycardia and a reduction in the heart rate during exercise are indicators of propranolol's -blocking effect. Measures of these responses may be used as guides in regulating dosage. Propranolol can be administered once or twice daily. Toxicity The principal toxicities of propranolol result from blockade of cardiac, vascular, or bronchial receptors and are described in more detail in Chapter 10: Adrenoceptor Antagonist Drugs. The most important of these predictable extensions of the -blocking action occur in patients with bradycardia or cardiac conduction disease, asthma, peripheral vascular insufficiency, and diabetes. When propranolol is discontinued after prolonged regular use, some patients experience a withdrawal syndrome, manifested by nervousness, tachycardia, increased intensity of angina, or increase of blood pressure. Myocardial infarction has been reported in a few patients. Although the incidence of these complications is probably low, propranolol should not be discontinued abruptly. The withdrawal syndrome may involve up-regulation or supersensitivity of -adrenoceptors. Other Beta-Adrenoceptor-Blocking Agents Of the large number of -blockers tested, most have been shown to be effective in lowering blood pressure. The pharmacologic properties of several of these agents differ from those of propranolol in ways that may confer therapeutic benefits in certain clinical situations. Metoprolol
Metoprolol is approximately equipotent to propranolol in inhibiting stimulation of 1-adrenoceptors such as those in the heart but 50- to 100-fold less potent than propranolol in blocking 2-receptors. Although metoprolol is in other respects very similar to propranolol, its relative cardioselectivity may be advantageous in treating hypertensive patients who also suffer from asthma, diabetes, or peripheral vascular disease. Studies of small numbers of asthmatic patients have shown that metoprolol causes less bronchial constriction than propranolol at doses that produce equal inhibition of 1-adrenoceptor responses. The cardioselectivity is not complete, however, and asthmatic symptoms have been exacerbated by metoprolol. Usual antihypertensive doses of metoprolol range from 100 to 450 mg/d. Nadolol, Carteolol, Atenolol, Betaxolol, & Bisoprolol Nadolol and carteolol, nonselective -receptor antagonists, and atenolol, a 1-selective blocker, are not appreciably metabolized and are excreted to a considerable extent in the urine. Betaxolol and bisoprolol are 1-selective blockers that are primarily metabolized in the liver but have long halflives. Because of these relatively long half-lives, these drugs can be administered once daily. Nadolol is usually begun at a dosage of 40 mg/d, atenolol at 50 mg/d, carteolol at 2.5 mg/d, betaxolol at 10 mg/d, and bisoprolol at 5 mg/d. Increases in dosage to obtain a satisfactory therapeutic effect should take place no more often than every 4 or 5 days. Patients with reduced renal function should receive correspondingly reduced doses of nadolol, carteolol, and atenolol. It is claimed that atenolol produces fewer central nervous system-related effects than other more lipidsoluble -antagonists. Pindolol, Acebutolol, & Penbutolol Pindolol, acebutolol, and penbutolol are partial agonists, ie, -blockers with intrinsic sympathomimetic activity. They lower blood pressure by decreasing vascular resistance and appear to depress cardiac output or heart rate less than other -blockers, perhaps because of significantly greater agonist than antagonist effects at 2-receptors. This may be particularly beneficial for patients with bradyarrhythmias or peripheral vascular disease. Daily doses of pindolol start at 10 mg; of acebutolol, at 400 mg; and of penbutolol, at 20 mg. Labetalol & Carvedilol Labetalol is formulated as a racemic mixture of four isomers (it has two centers of asymmetry). Two of these isomers—the (S,S)- and (R,S)-isomers—are inactive, a third (S,R)- is a potent blocker, and the last (R,R)- is a potent -blocker. The -blocking isomer is thought to have selective 2-agonist and nonselective -antagonist action. Labetalol has a 3:1 ratio of : antagonism after oral dosing. Blood pressure is lowered by reduction of systemic vascular resistance without significant alteration in heart rate or cardiac output. Because of its combined - and -blocking activity, labetalol is useful in treating the hypertension of pheochromocytoma and hypertensive emergencies. Oral daily doses of labetalol range from 200 to 2400 mg/d. Labetalol is given as repeated intravenous bolus injections of 20–80 mg to treat hypertensive emergencies. Carvedilol, like labetalol, is administered as a racemic mixture. The S(–) isomer is a nonselective adrenoceptor blocker, but both S(–) and R(+) isomers have approximately equal -blocking potency. The isomers are stereoselectively metabolized in the liver, which means that their elimination half-lives may differ. The average half-life is 7–10 hours. The usual starting dosage of carvedilol for ordinary hypertension is 6.25 mg twice daily. Esmolol
Esmolol is a 1-selective blocker that is rapidly metabolized via hydrolysis by red blood cell esterases. It has a short half-life (9 minutes) and is administered by constant intravenous infusion. Esmolol is generally administered as a loading dose (0.5–1 mg/kg), followed by a constant infusion. The infusion is typically started at 50–150 g/kg/min, and the dose increased every 5 minutes, up to 300 g/kg/min, as needed to achieve the desired therapeutic effect. Esmolol is used for management of intraoperative and postoperative hypertension, and sometimes for hypertensive emergencies, particularly when hypertension is associated with tachycardia. Prazosin & Other Alpha1 Blockers Mechanism & Sites of Action Prazosin, terazosin, and doxazosin produce most of their antihypertensive effect by blocking 1receptors in arterioles and venules. Selectivity for 1-receptors may explain why these agents produce less reflex tachycardia than do nonselective -antagonists such as phentolamine. This receptor selectivity allows norepinephrine to exert unopposed negative feedback (mediated by presynaptic 2-receptors) on its own release (see Chapter 6: Introduction to Autonomic Pharmacology); in contrast, phentolamine blocks both presynaptic and postsynaptic -receptors, with the result that reflex stimulation of sympathetic neurons produces greater release of transmitter onto -receptors and correspondingly greater cardioacceleration. Alpha blockers reduce arterial pressure by dilating both resistance and capacitance vessels. As expected, blood pressure is reduced more in the upright than in the supine position. Retention of salt and water occurs when these drugs are administered without a diuretic. The drugs are more effective when used in combination with other agents, such as a -blocker and a diuretic, than when used alone. Pharmacokinetics & Dosage Pharmacokinetic characteristics of prazosin are listed in Table 11–1. Terazosin is also extensively metabolized but undergoes very little first-pass metabolism and has a half-life of 12 hours. Doxazosin has an intermediate bioavailability and a half-life of 22 hours. Terazosin can often be given once daily, with doses of 5–20 mg/d. Doxazosin is usually given once daily starting at 1 mg/d and progressing to 4 mg/d or more as needed. Although long-term treatment with these -blockers causes relatively little postural hypotension, precipitous drop in standing blood pressure develops in a number of patients shortly after the first dose is absorbed. For this reason, the first dose should be small and should be administered at bedtime. While the mechanism of this first-dose phenomenon is not clear, it occurs more commonly in patients who are salt- and volume-depleted. Aside from the first-dose phenomenon, the reported toxicities of the 1-blockers are relatively infrequent and mild. These include dizziness, palpitations, headache, and lassitude. Some patients develop a positive test for antinuclear factor in serum while on prazosin therapy, but this has not been associated with rheumatic symptoms. The 1-blockers do not adversely and may even beneficially affect plasma lipid profiles but this action has not been shown to confer any benefit on clinical outcomes. Other Alpha Adrenoceptor-Blocking Agents Investigational
1-selective
blockers include pinacidil, urapidil, and cromakalim. The nonselective
agents, phentolamine and phenoxybenzamine, are useful in diagnosis and treatment of pheochromocytoma and in other clinical situations associated with exaggerated release of catecholamines (eg, phentolamine may be combined with propranolol to treat the clonidine withdrawal syndrome, described above). Their pharmacology is described in Chapter 10: Adrenoceptor Antagonist Drugs. Vasodilators Mechanism & Sites of Action Within this class of drugs are the oral vasodilators, hydralazine and minoxidil, which are used for long-term outpatient therapy of hypertension; the parenteral vasodilators, nitroprusside, diazoxide, and fenoldopam, which are used to treat hypertensive emergencies; and the calcium channel blockers, which are used in both circumstances. Chapter 12 contains a general discussion of vasodilators. All of the vasodilators useful in hypertension relax smooth muscle of arterioles, thereby decreasing systemic vascular resistance. Sodium nitroprusside also relaxes veins. Decreased arterial resistance and decreased mean arterial blood pressure elicit compensatory responses, mediated by baroreceptors and the sympathetic nervous system (Figure 11–5), as well as renin, angiotensin, and aldosterone. Because sympathetic reflexes are intact, vasodilator therapy does not cause orthostatic hypotension or sexual dysfunction. Figure 11–5.
Compensatory responses to vasodilators; basis for combination therapy with -blockers and diuretics. Effect blocked by diuretics. Effect blocked by -blockers. Vasodilators work best in combination with other antihypertensive drugs that oppose the compensatory cardiovascular responses. (See Monotherapy versus Polypharmacy in Hypertension.) Hydralazine Hydralazine, a hydrazine derivative, dilates arterioles but not veins. It has been available for many years, although it was initially thought not to be particularly effective because tachyphylaxis to hypertensive effects developed rapidly. The benefits of combination therapy are now recognized, and hydralazine may be used more effectively, particularly in severe hypertension.
Pharmacokinetics & Dosage Hydralazine is well absorbed and rapidly metabolized by the liver during the first pass, so that bioavailability is low (averaging 25%) and variable among individuals. It is metabolized in part by acetylation at a rate that appears to be bimodally distributed in the population (see Chapter 4: Drug Biotransformation). As a consequence, rapid acetylators have greater first-pass metabolism, lower bioavailability, and less antihypertensive benefit from a given dose than do slow acetylators. The half-life of hydralazine ranges from 2 to 4 hours, but vascular effects appear to persist longer than do blood concentrations, possibly due to avid binding to vascular tissue. Usual dosage ranges from 40 mg/d to 200 mg/d. The higher dosage was selected as the dose at which there is a small possibility of developing the lupus erythematosus-like syndrome described in the next section. However, higher dosages result in greater vasodilation and may be used if necessary. Dosing two or three times daily provides smooth control of blood pressure. Toxicity The most common adverse effects of hydralazine are headache, nausea, anorexia, palpitations, sweating, and flushing. In patients with ischemic heart disease, reflex tachycardia and sympathetic stimulation may provoke angina or ischemic arrhythmias. With dosages of 400 mg/d or more, there is a 10–20% incidence—chiefly in persons who slowly acetylate the drug—of a syndrome characterized by arthralgia, myalgia, skin rashes, and fever that resembles lupus erythematosus. The syndrome is not associated with renal damage and is reversed by discontinuance of hydralazine. Peripheral neuropathy and drug fever are other serious but uncommon adverse effects. Minoxidil Minoxidil is a very efficacious orally active vasodilator. The effect appears to result from the opening of potassium channels in smooth muscle membranes by minoxidil sulfate, the active metabolite. This action stabilizes the membrane at its resting potential and makes contraction less likely. Like hydralazine, minoxidil dilates arterioles but not veins. Because of its greater potential antihypertensive effect, minoxidil should replace hydralazine when maximal doses of the latter are not effective or in patients with renal failure and severe hypertension, who do not respond well to hydralazine.
Pharmacokinetics & Dosage Pharmacokinetic parameters of minoxidil are listed in Table 11–1.
Even more than with hydralazine, the use of minoxidil is associated with reflex sympathetic stimulation and sodium and fluid retention. Minoxidil must be used in combination with a -blocker and a loop diuretic. Toxicity Tachycardia, palpitations, angina, and edema are observed when doses of -blockers and diuretics are inadequate. Headache, sweating, and hirsutism, which is particularly bothersome in women, are relatively common. Minoxidil illustrates how one person's toxicity may become another person's therapy. Topical minoxidil (as Rogaine) is now used as a stimulant to hair growth for correction of baldness. Sodium Nitroprusside Sodium nitroprusside is a powerful parenterally administered vasodilator that is used in treating hypertensive emergencies as well as severe heart failure. Nitroprusside dilates both arterial and venous vessels, resulting in reduced peripheral vascular resistance and venous return. The action occurs as a result of activation of guanylyl cyclase, either via release of nitric oxide or by direct stimulation of the enzyme. The result is increased intracellular cGMP, which relaxes vascular smooth muscle. In the absence of heart failure, blood pressure decreases, owing to decreased vascular resistance, while cardiac output does not change or decreases slightly. In patients with heart failure and low cardiac output, output often increases owing to afterload reduction.
Pharmacokinetics & Dosage Nitroprusside is a complex of iron, cyanide groups, and a nitroso moiety. It is rapidly metabolized by uptake into red blood cells with liberation of cyanide. Cyanide in turn is metabolized by the mitochondrial enzyme rhodanase, in the presence of a sulfur donor, to the less toxic thiocyanate. Thiocyanate is distributed in extracellular fluid and slowly eliminated by the kidney. Nitroprusside rapidly lowers blood pressure, and its effects disappear within 1–10 minutes after discontinuation. The drug is given by intravenous infusion. Sodium nitroprusside in aqueous solution is sensitive to light and must therefore be made up fresh before each administration and covered with opaque foil. Infusion solutions should be changed after several hours. Dosage typically begins at 0.5 g/kg/min and may be increased up to 10 g/kg/min as necessary to control
blood pressure. Higher rates of infusion, if continued for more than an hour, may result in toxicity. Because of its efficacy and rapid onset of effect, the drug should be administered by infusion pump and arterial blood pressure continuously monitored via intra-arterial recording. Toxicity Other than excessive blood pressure lowering, the most serious toxicity is related to accumulation of cyanide; metabolic acidosis, arrhythmias, excessive hypotension, and death have resulted. In a few cases, toxicity after relatively low doses of nitroprusside suggested a defect in cyanide metabolism. Administration of sodium thiosulfate as a sulfur donor facilitates metabolism of cyanide. Hydroxocobalamin combines with cyanide to form the nontoxic cyanocobalamin. Both have been advocated for prophylaxis or treatment of cyanide poisoning during nitroprusside infusion. Thiocyanate may accumulate over the course of prolonged administration, usually a week or more, particularly in patients with renal insufficiency who do not excrete thiocyanate at a normal rate. Thiocyanate toxicity is manifested as weakness, disorientation, psychosis, muscle spasms, and convulsions, and the diagnosis is confirmed by finding serum concentrations greater than 10 mg/dL. Rarely, delayed hypothyroidism occurs, owing to thiocyanate inhibition of iodide uptake by the thyroid. Methemoglobinemia during infusion of nitroprusside has also been reported. Diazoxide Diazoxide is an effective and relatively long-acting parenterally administered arteriolar dilator that is occasionally used to treat hypertensive emergencies. Injection of diazoxide results in a rapid fall in systemic vascular resistance and mean arterial blood pressure associated with substantial tachycardia and increase in cardiac output. Studies of its mechanism suggest that it prevents vascular smooth muscle contraction by opening potassium channels and stabilizing the membrane potential at the resting level.
Pharmacokinetics & Dosage Diazoxide is similar chemically to the thiazide diuretics but has no diuretic activity. It is bound extensively to serum albumin and to vascular tissue. Diazoxide is both metabolized and excreted unchanged; its metabolic pathways are not well characterized. Its half-life is approximately 24 hours, but the relationship between blood concentration and hypotensive action is not well established. The blood pressure-lowering effect after a rapid injection is established within 5 minutes and lasts for 4–12 hours. When diazoxide was first marketed, a dose of 300 mg by rapid injection was recommended. It appears, however, that excessive hypotension can be avoided by beginning with smaller doses (50– 150 mg). If necessary, doses of 150 mg may be repeated every 5 minutes until blood pressure is lowered satisfactorily. Nearly all patients respond to a maximum of three or four doses. Alternatively, diazoxide may be administered by intravenous infusion at rates of 15–30 mg/min. Because of reduced protein binding, hypotension occurs after smaller doses in persons with chronic
renal failure, and smaller doses should be administered to these patients. The hypotensive effects of diazoxide are also greater if patients are pretreated with -blockers to prevent the reflex tachycardia and associated increase in cardiac output. Toxicity The most significant toxicity from diazoxide has been excessive hypotension, resulting from the recommendation to use a fixed dose of 300 mg in all patients. Such hypotension has resulted in stroke and myocardial infarction. The reflex sympathetic response can provoke angina, electrocardiographic evidence of ischemia, and cardiac failure in patients with ischemic heart disease, and diazoxide should be avoided in this situation. Diazoxide inhibits insulin release from the pancreas (probably by opening potassium channels in the cell membrane) and is used to treat hypoglycemia secondary to insulinoma. Occasionally, hyperglycemia complicates diazoxide use, particularly in persons with renal insufficiency. In contrast to the structurally related thiazide diuretics, diazoxide causes renal salt and water retention. However, because the drug is used for short periods only, this is rarely a problem. Fenoldopam Fenoldopam is a newer peripheral arteriolar dilator used for hypertensive emergencies and postoperative hypertension. It acts primarily as an agonist of dopamine D1 receptors, resulting in dilation of peripheral arteries and natriuresis. The commercial product is a racemic mixture with the (R)-isomer mediating the pharmacologic activity. Fenoldopam is rapidly metabolized, primarily by conjugation. Its half-life is 10 minutes. The drug is administered by continuous intravenous infusion. Fenoldopam is initiated at a low dosage (0.1 g/kg/min), and the dose is then titrated upward every 15 or 20 minutes up to a maximum dose of 1.6 g/kg/min or until the desired blood pressure reduction is achieved. As with other direct vasodilators, the major toxicities are reflex tachycardia, headache, and flushing. Fenoldopam also increases intraocular pressure and should be avoided in patients with glaucoma. Calcium Channel Blockers In addition to their antianginal (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris) and antiarrhythmic effects (see Chapter 14: Agents Used in Cardiac Arrhythmias), calcium channel blockers also dilate peripheral arterioles and reduce blood pressure. The mechanism of action in hypertension (and, in part, in angina) is inhibition of calcium influx into arterial smooth muscle cells. Verapamil, diltiazem, and the dihydropyridine family (amlodipine, felodipine, isradipine, nicardipine, nifedipine, and nisoldipine) are all equally effective in lowering blood pressure, and various formulations are currently approved for this use in the USA. Several others are under study. Hemodynamic differences among calcium channel blockers may influence the choice of a particular agent. Nifedipine and the other dihydropyridine agents are more selective as vasodilators and have less cardiac depressant effect than verapamil and diltiazem. Reflex sympathetic activation with slight tachycardia maintains or increases cardiac output in most patients given dihydropyridines. Verapamil has the greatest depressant effect on the heart and may decrease heart rate and cardiac output. Diltiazem has intermediate actions. The pharmacology and toxicity of these drugs is
discussed in more detail in Chapter 12: Vasodilators & the Treatment of Angina Pectoris. Doses of calcium channel blockers used in treating hypertension are similar to those used in treating angina. Some epidemiologic studies reported an increased risk of myocardial infarction or mortality in patients receiving short-acting nifedipine for hypertension. While there is still debate about causation, it is recommended that short-acting dihydropyridines not be used for hypertension. Sustained-release calcium blockers or calcium blockers with long half-lives provide smoother blood pressure control and are more appropriate for treatment of chronic hypertension. Intravenous nicardipine is available for the treatment of hypertension when oral therapy is not feasible, although parenteral verapamil and diltiazem could be used for the same indication. Nicardipine is typically infused at rates of 2–15 mg/h. Oral short-acting nifedipine has been used in emergency management of severe hypertension. Inhibitors of Angiotensin Although the causative roles of renin, angiotensin, and aldosterone in essential hypertension are still controversial, there do appear to be differences in the activity of this system among individuals. Approximately 20% of patients with essential hypertension have inappropriately low and 20% have inappropriately high plasma renin activity. Blood pressure of patients with high-renin hypertension responds well to -adrenoceptor blockers, which lower plasma renin activity, and to angiotensin inhibitors—supporting a role for excess renin and angiotensin in this population. Mechanism & Sites of Action Renin release from the kidney cortex is stimulated by reduced renal arterial pressure, sympathetic neural stimulation, and reduced sodium delivery or increased sodium concentration at the distal renal tubule (see Chapter 17: Vasoactive Peptides). Renin acts upon angiotensinogen to split off the inactive precursor decapeptide angiotensin I. Angiotensin I is then converted, primarily by endothelial ACE, to the arterial vasoconstrictor octapeptide angiotensin II (Figure 11–6), which is in turn converted in the adrenal gland to angiotensin III. Angiotensin II has vasoconstrictor and sodium-retaining activity. Angiotensin II and III both stimulate aldosterone release. Angiotensin may contribute to maintaining high vascular resistance in hypertensive states associated with high plasma renin activity, such as renal arterial stenosis, some types of intrinsic renal disease, and malignant hypertension, as well as in essential hypertension after treatment with sodium restriction, diuretics, or vasodilators. However, even in low-renin hypertensive states, these drugs can lower blood pressure (see below). Figure 11–6.
Sites of action of ACE inhibitors and angiotensin II receptor blockers. Site of receptor blockade.
Site of ACE blockade.
A parallel system for angiotensin generation exists in several other tissues (eg, heart) and may be responsible for trophic changes such as cardiac hypertrophy. The converting enzyme involved in tissue angiotensin II synthesis is also inhibited by the ACE inhibitors. Two classes of drugs act specifically on the renin-angiotensin system: the ACE inhibitors and the competitive inhibitors of angiotensin at its receptors, including losartan and other nonpeptide antagonists, and the peptide saralasin. (Saralasin is no longer in clinical use.) Angiotensin-Converting Enzyme (ACE) Inhibitors Captopril (see Figure 17–2) and other drugs in this class inhibit the converting enzyme peptidyl dipeptidase that hydrolyzes angiotensin I to angiotensin II and (under the name plasma kininase) inactivates bradykinin, a potent vasodilator, which works at least in part by stimulating release of nitric oxide and prostacyclin. The hypotensive activity of captopril results both from an inhibitory action on the renin-angiotensin system and a stimulating action on the kallikrein-kinin system (Figure 11–6). The latter mechanism has been demonstrated by showing that an experimental bradykinin receptor antagonist, icatibant, blunts the blood pressure-lowering effect of captopril.
Enalapril (see Figure 17–2) is a prodrug that is converted by deesterification to a converting enzyme inhibitor, enalaprilat, with effects similar to those of captopril. Enalaprilat itself is available only for intravenous use, primarily for hypertensive emergencies. Lisinopril is a lysine derivative of enalaprilat. Benazepril, fosinopril, moexipril, perindopril, quinapril, ramipril, and trandolapril are other long-acting members of the class. All are prodrugs, like enalapril, and are converted to the active agents by hydrolysis, primarily in the liver. Angiotensin II inhibitors lower blood pressure principally by decreasing peripheral vascular resistance. Cardiac output and heart rate are not significantly changed. Unlike direct vasodilators, these agents do not result in reflex sympathetic activation and can be used safely in persons with ischemic heart disease. The absence of reflex tachycardia may be due to downward resetting of the baroreceptors or to enhanced parasympathetic activity. Although converting enzyme inhibitors are most effective in conditions associated with high plasma renin activity, there is no good correlation among subjects between plasma renin activity and antihypertensive response. Accordingly, renin profiling is unnecessary. ACE inhibitors have a particularly useful role in treating patients with diabetic nephropathy because they diminish proteinuria and stabilize renal function (even in the absence of lowering of blood pressure). These benefits probably result from improved intrarenal hemodynamics, with decreased glomerular efferent arteriolar resistance and a resulting reduction of intraglomerular capillary pressure. ACE inhibitors have also proved to be extremely useful in the treatment of heart failure, and after myocardial infarction (see Chapter 13: Drugs Used in Heart Failure). Pharmacokinetics & Dosage Captopril's pharmacokinetic parameters and dosing recommendations are set forth in Table 11–1. Peak concentrations of enalaprilat, the active metabolite, occur 3–4 hours after dosing with enalapril. The half-life of enalaprilat is about 11 hours. Typical doses of enalapril are 10–20 mg once or twice daily. Lisinopril has a half-life of 12 hours. Doses of 10–80 mg once daily are effective in most patients. All of the ACE inhibitors except fosinopril and moexipril are eliminated primarily by the kidneys; doses of these drugs should be reduced in patients with renal insufficiency. Toxicity Severe hypotension can occur after initial doses of any ACE inhibitor in patients who are hypovolemic due to diuretics, salt restriction, or gastrointestinal fluid loss. Other adverse effects common to all ACE inhibitors include acute renal failure (particularly in patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney), hyperkalemia, dry cough sometimes accompanied by wheezing, and angioedema. Hyperkalemia is more likely to occur in patients with renal insufficiency or diabetes. Bradykinin and substance P seem to be responsible for the cough and angioedema seen with ACE inhibition. The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy because of the risk of fetal hypotension, anuria, and renal failure, sometimes associated with fetal malformations or death. Captopril, particularly when given in high doses to patients with renal insufficiency, may cause neutropenia or proteinuria. Minor toxic effects seen more typically include
altered sense of taste, allergic skin rashes, and drug fever, which may occur in as many as 10% of patients. The incidence of these adverse effects may be lower with the long-acting ACE inhibitors. Important drug interactions include those with potassium supplements or potassium-sparing diuretics, which can result in hyperkalemia. Nonsteroidal anti-inflammatory drugs may impair the hypotensive effects of ACE inhibitors by blocking bradykinin-mediated vasodilation, which is at least in part, prostaglandin mediated. Angiotensin Receptor-Blocking Agents Losartan and valsartan were the first marketed blockers of the angiotensin II type 1 (AT1) receptor. More recently, candesartan, eprosartan, irbesartan, and telmisartan have been released. They have no effect on bradykinin metabolism and are therefore more selective blockers of angiotensin effects than ACE inhibitors. They also have the potential for more complete inhibition of angiotensin action compared with ACE inhibitors because there are enzymes other than ACE that are capable of generating angiotensin II. Losartan's pharmacokinetic parameters are listed in Table 11–1. The adverse effects are similar to those described for ACE inhibitors, including the hazard of use during pregnancy. Cough and angioedema can occur but are less common with angiotensin receptor blockers than with ACE inhibitors.
Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents > Monotherapy Versus Polypharmacy in Hypertension Monotherapy of hypertension (treatment with a single drug) has become more popular because compliance is likely to be better and because in some cases adverse effects are fewer. However, moderate to severe hypertension is still commonly treated by a combination of two or more drugs, each acting by a different mechanism (polypharmacy). The rationale for polypharmacy is that each of the drugs acts on one of a set of interacting, mutually compensatory regulatory mechanisms for maintaining blood pressure (see Figures 6–7 and 11–1). For example, because an adequate dose of hydralazine causes a significant decrease in peripheral vascular resistance, there will initially be a drop in mean arterial blood pressure, evoking a strong response in the form of compensatory tachycardia and salt and water retention (Figure 11–5). The result is an increase in cardiac output that is capable of almost completely reversing the effect of hydralazine. The addition of a -blocker prevents the tachycardia; addition of a diuretic (eg, hydrochlorothiazide) prevents the salt and water retention. In effect, all three drugs increase the sensitivity of the cardiovascular system to each other's actions. Thus, partial impairment of one regulatory mechanism (sympathetic discharge to the heart) increases the antihypertensive effect of impairing regulation by another mechanism (peripheral vascular resistance). Finally, in some circumstances, a normal compensatory response accounts for the toxicity of an antihypertensive agent, and the toxic effect can be prevented by administering a second type of drug. In the case of hydralazine, compensatory tachycardia and increased cardiac output may precipitate angina in patients with coronary atherosclerosis. Addition of the -blocker and diuretic can prevent this toxicity in many patients. In practice, when hypertension does not respond adequately to a regimen of one drug, a second drug from a different class with a different mechanism of action and different pattern of toxicity is added. If the response is still inadequate and compliance is known to be good, a third drug
may be added. The drugs least likely to be successful as monotherapy are the vasodilators hydralazine and minoxidil. It is not completely clear why other vasodilators such as calcium channel blockers cause less marked compensatory responses for the same amount of blood pressure lowering.
Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents > Clinical Pharmacology of Antihypertensive Agents Hypertension presents a unique problem in therapeutics. It is usually a lifelong disease that causes few symptoms until the advanced stage. For effective treatment, medicines that may be expensive and often produce adverse effects must be consumed daily. Thus, the physician must establish with certainty that hypertension is persistent and requires treatment and must exclude secondary causes of hypertension that might be treated by definitive surgical procedures. Persistence of hypertension, particularly in persons with mild elevation of blood pressure, should be established by finding an elevated blood pressure on at least three different office visits. Ambulatory blood pressure monitoring may be the best predictor of risk and therefore of need for therapy in mild hypertension. Isolated systolic hypertension and hypertension in the elderly also benefit from therapy. Once the presence of hypertension is established, the question of whether or not to treat and which drugs to use must be considered. The level of blood pressure, the age and sex of the patient, the severity of organ damage (if any) due to high blood pressure, and the presence of cardiovascular risk factors must all be considered. At this stage, the patient must be educated about the nature of hypertension and the importance of treatment so that he or she can make an informed decision regarding therapy. Once the decision is made to treat, a therapeutic regimen must be developed. Selection of drugs is dictated by the level of blood pressure, the presence and severity of end-organ damage, and the presence of other diseases. Severe high blood pressure with life-threatening complications requires more rapid treatment with more potent drugs. Most patients with essential hypertension, however, have had elevated blood pressure for months or years, and therapy is best initiated in a gradual fashion. Education about the natural history of hypertension and the importance of treatment compliance as well as potential side effects of drugs is essential. Follow-up visits should be frequent enough to convince the patient that the physician thinks the illness is serious. With each follow-up visit, the importance of treatment should be reinforced and questions particularly concerning dosing or side effects of medication encouraged. Other factors that may improve compliance are simplifying dosing regimens and having the patient monitor blood pressure at home. Outpatient Therapy of Hypertension The initial step in treating hypertension may be nonpharmacologic. As discussed previously, sodium restriction may be effective treatment for many patients with mild hypertension. The average American diet contains about 200 mEq of sodium per day. A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day, which can be achieved by not salting food
during or after cooking and by avoiding processed foods that contain large amounts of sodium. Weight reduction even without sodium restriction has been shown to normalize blood pressure in up to 75% of overweight patients with mild to moderate hypertension. Regular exercise has been shown in some but not all studies to lower blood pressure in hypertensive patients. For pharmacologic management of mild hypertension, blood pressure can be normalized in most patients with a single drug. Such "monotherapy" is also sufficient for some patients with moderate hypertension. Thiazide diuretics, -blockers, and ACE inhibitors have been shown to reduce morbidity and mortality and are recommended for initial drug therapy in such patients. There has been concern that diuretics, by adversely affecting the serum lipid profile or impairing glucose tolerance, may add to the risk of coronary disease, thereby offsetting the benefit of blood pressure reduction. However a recent large clinical trial comparing different classes of antihypertensive mediations for initial therapy found that chlorthalidone (a thiazide diuretic) was as effective as other agents in reducing coronary heart disease death and nonfatal myocardial infarction, and was superior to amlodipine in preventing heart failure and superior to lisinopril in preventing stroke (ALLHAT Collaborative Research Group, 2002). Alternative choices for initial monotherapy include angiotensin receptor blockers, calcium channel blockers, combination - and -blockers (labetalol or carvedilol), and central sympathoplegic agents (eg, clonidine). Alpha blockers should not be considered first-line therapy (ALLHAT, 2000). The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. For example, ACE inhibitors are particularly useful in diabetic patients with evidence of renal disease. Beta blockers or calcium channel blockers are useful in patients who also have angina; diuretics, ACE inhibitors, or -blockers in patients who also have heart failure; and 1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection: blacks respond better to diuretics and calcium channel blockers than to blockers and ACE inhibitors. Chinese are more sensitive to the effects of -blockers and may require lower doses. If a single drug does not adequately control blood pressure, drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity ("stepped care"). If a diuretic is not used initially, it is often selected as the second drug. If three drugs are required, combining a diuretic, a sympathoplegic agent or an ACE inhibitor, and a direct vasodilator (eg, hydralazine or a calcium channel blocker) is often effective. In the USA, fixed-dose drug combinations containing a -blocker plus a thiazide, an ACE inhibitor plus a thiazide, an angiotensin receptor blocker plus a diuretic, and a calcium channel blocker plus an ACE inhibitor are available. Fixed-dose combinations have the drawback of not allowing for titration of individual drug doses but have the advantage of allowing fewer pills to be taken, potentially enhancing compliance. Assessment of blood pressure during office visits should include measurement of recumbent, sitting, and standing pressures. An attempt should be made to normalize blood pressure in the posture or activity level that is customary for the patient. The recent large Hypertension Optimal Treatment study suggests that the optimal blood pressure end point is 138/83 mm Hg. Lowering blood pressure below this level produces no further benefit (Hansson et al, 1998). In diabetic patients, however, there is a continued reduction of event rates with progressively lower blood pressures. In addition to noncompliance with medication, causes of failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume (this can be measured directly), and drugs such as tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, over-the-counter sympathomimetics, abuse of stimulants (amphetamine or
cocaine), or excessive doses of caffeine and oral contraceptives that can interfere with actions of some antihypertensive drugs or directly raise blood pressure. Management of Hypertensive Emergencies Despite the large number of patients with chronic hypertension, hypertensive emergencies are relatively rare. Marked or sudden elevation of blood pressure may be a serious threat to life, however, and prompt control of blood pressure is indicated. Most commonly, hypertensive emergencies occur in patients whose hypertension is severe and poorly controlled and in those who suddenly discontinue antihypertensive medications. Clinical Presentation & Pathophysiology Hypertensive emergencies include hypertension associated with vascular damage (termed malignant hypertension) and hypertension associated with hemodynamic complications such as heart failure, stroke, or dissecting aneurysm. The underlying pathologic process in malignant hypertension is a progressive arteriopathy with inflammation and necrosis of arterioles. Vascular lesions occur in the kidney, which releases renin, which in turn stimulates production of angiotensin and aldosterone, which further increase blood pressure. Hypertensive encephalopathy is a classic feature of malignant hypertension. Its clinical presentation consists of severe headache, mental confusion, and apprehension. Blurred vision, nausea and vomiting, and focal neurologic deficits are common. If untreated, the syndrome may progress over a period of 12–48 hours to convulsions, stupor, coma, and even death. Treatment of Hypertensive Emergencies The general management of hypertensive emergencies requires monitoring the patient in an intensive care unit with continuous recording of arterial blood pressure. Fluid intake and output must be monitored carefully and body weight measured daily as an indicator of total body fluid volume during the course of therapy. Parenteral antihypertensive medications are used to lower blood pressure rapidly (within a few hours); as soon as reasonable blood pressure control is achieved, oral antihypertensive therapy should be substituted, because this allows smoother long-term management of hypertension. The goal of treatment in the first few hours or days is not complete normalization of blood pressure because chronic hypertension is associated with autoregulatory changes in cerebral blood flow. Thus, rapid normalization of blood pressure may lead to cerebral hypoperfusion and brain injury. Rather, blood pressure should be lowered by about 25%, maintaining diastolic blood pressure at no less than 100–110 mm Hg. Subsequently, blood pressure can be reduced to normal levels using oral medications over several weeks. The drug most commonly used to treat hypertensive emergencies is the vasodilator sodium nitroprusside. Other parenteral drugs that may be effective include fenoldopam, nitroglycerin, labetalol, calcium channel blockers, diazoxide, and hydralazine. Esmolol is often used to manage intraoperative and postoperative hypertension. Diuretics such as furosemide are administered to prevent the volume expansion that typically occurs during administration of powerful vasodilators. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents >
Preparations Available Beta Adrenoceptor Blockers Acebutolol(generic, Sectral) Oral: 200, 400 mg capsules Atenolol(generic, Tenormin) Oral: 25, 50, 100 mg tablets Parenteral: 0.5 mg/mL for injection Betaxolol(Kerlone) Oral: 10, 20 mg tablets Bisoprolol(Zebeta) Oral: 5, 10 mg tablets Carteolol(Cartrol) Oral: 2.5, 5 mg tablets Carvedilol(Coreg) Oral: 3.125, 6.25, 12.5, 25 mg tablets Esmolol (BreviBloc) Parenteral: 10, 250 mg/mL for injection Labetalol (generic, Normodyne, Trandate) Oral: 100, 200, 300 mg tablets Parenteral: 5 mg/mL for injection Metoprolol (generic, Lopressor) Oral: 50, 100 mg tablets Oral extended-release (Toprol-XL): 25, 50, 100, 200 mg tablets Parenteral: 1 mg/mL for injection Nadolol (generic, Corgard)
Oral: 20, 40, 80, 120, 160 mg tablets Penbutolol(Levatol) Oral: 20 mg tablets Pindolol(generic, Visken) Oral: 5, 10 mg tablets Propranolol(generic, Inderal) Oral: 10, 20, 40, 60, 80, 90 mg tablets; 4, 8 mg/mL oral solution; Intensol, 80 mg/mL solution Oral sustained-release (generic, Inderal LA): 60, 80, 120, 160 mg capsules Parenteral: 1 mg/mL for injection Timolol(generic, Blocadren) Oral: 5, 10, 20 mg tablets Centrally Acting Sympathoplegic Drugs Clonidine(generic, Catapres) Oral: 0.1, 0.2, 0.3 mg tablets Transdermal (Catapres-TTS): patches that release 0.1, 0.2, 0.3 mg/24 h Guanabenz (generic, Wytensin) Oral: 4, 8 mg tablets Guanfacine(Tenex) Oral: 1, 2 mg tablets Methyldopa(generic) Oral: 250, 500 mg tablets Parenteral: 50 mg/mL for injection Postganglionic Sympathetic Nerve Terminal Blockers Guanadrel (Hylorel) Oral: 10, 25 mg tablets
Guanethidine(Ismelin) Oral: 10, 25 mg tablets Reserpine (generic) Oral: 0.1, 0.25 mg tablets Alpha1 Selective Adrenoceptor Blockers Doxazosin(generic, Cardura) Oral: 1, 2, 4, 8 mg tablets Prazosin (generic, Minipress) Oral: 1, 2, 5 mg capsules Terazosin (generic, Hytrin) Oral: 1, 2, 5, 10 mg capsules and tablets Ganglion-Blocking Agents Mecamylamine (Inversine) Oral: 2.5 mg tablets Vasodilators Used in Hypertension Diazoxide (Hyperstat IV) Parenteral: 15 mg/mL ampule Oral (Proglycem): 50 mg capsule; 50 mg/mL oral suspension Fenoldopam(Corlopam) Parenteral: 10 mg/mL for IV infusion Hydralazine(generic, Apresoline) Oral: 10, 25, 50, 100 mg tablets Parenteral: 20 mg/mL for injection Minoxidil(generic, Loniten) Oral: 2.5, 10 mg tablets
Topical (Rogaine, etc): 2% lotion Nitroprusside(generic, Nitropress) Parenteral: 50 mg/vial Calcium Channel Blockers Amlodipine (Norvasc) Oral 2.5, 5, 10 mg tablets Diltiazem(generic, Cardizem) Oral: 30, 60, 90, 120 mg tablets (unlabeled in hypertension) Oral sustained-release (Cardizem CD, Cardizem SR, Dilacor XL): 60, 90, 120, 180, 240, 300, 360, 420 mg capsules Parenteral: 5 mg/mL for injection Felodipine (Plendil) Oral extended-release: 2.5, 5, 10 mg tablets Isradipine(DynaCirc) Oral: 2.5, 5 mg capsules; 5, 10 mg controlled-release tablets Nicardipine (generic, Cardene) Oral: 20, 30 mg capsules Oral sustained-release (Cardene SR): 30, 45, 60 mg capsules Parenteral (Cardene I.V.): 2.5 mg/mL for injection Nisoldipine (Sular) Oral: 10, 20, 30, 40 mg extended-release tablets Nifedipine(generic, Adalat, Procardia) Oral: 10, 20 mg capsules (unlabeled in hypertension) Oral extended-release (Adalat CC, Procardia-XL): 30, 60, 90 mg tablets Verapamil(generic, Calan, Isoptin) Oral: 40, 80, 120 mg tablets
Oral sustained-release (generic, Calan SR, Verelan): 120, 180, 240 mg tablets; 100, 120, 180, 200, 240, 300 mg capsules Parenteral: 2.5 mg/mL for injection Angiotensin-Converting Enzyme Inhibitors Benazepril(Lotensin) Oral: 5, 10, 20, 40, mg tablets Captopril (generic, Capoten) Oral: 12.5, 25, 50, 100 mg tablets Enalapril(Vasotec) Oral: 2.5, 5, 10, 20 mg tablets Parenteral (Enalaprilat): 1.25 mg/mL for injection Fosinopril(Monopril) Oral: 10, 20, 40 mg tablets Lisinopril(Prinivil, Zestril) Oral: 2.5, 5, 10, 20, 40 mg tablets Moexipril(Univasc) Oral: 7.5, 15 mg tablets Perindopril (Aceon) Oral: 2, 4, 8 mg tablets Quinapril(Accupril) Oral: 5, 10, 20, 40 mg tablets Ramipril (Altace) Oral: 1.25, 2.5, 5, 10 mg capsules Trandolapril(Mavik) Oral: 1, 2, 4 mg tablets Angiotensin Receptor Blockers
Candesartan (Atacand) Oral: 4, 8, 16, 32 mg tablets Eprosartan(Teveten) Oral: 400, 600 mg tablets Irbesartan (Avapro) Oral; 75, 150, 300 mg tablets Losartan (Cozaar) Oral: 25, 50, 100 mg tablets Olmisartan (Benicar) Oral: 5, 20, 40 mg tablets Telmisartan(Micardis) Oral: 20, 40, 80 mg tablets Valsartan (Diovan) Oral: 40, 80, 160, 320 mg tablet Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 11. Antihypertensive Agents >
Chapter 12. Vasodilators & the Treatment of Angina Pectoris Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris > Vasodilators & the Treatment of Angina Pectoris Angina pectoris is the most common condition involving tissue ischemia in which vasodilator drugs are used. Angina (pain) is caused by the accumulation of metabolites in striated muscle; angina pectoris is the severe chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by the heart. The organic nitrates, eg, nitroglycerin, are the mainstay of therapy for the immediate relief of angina. Another group of vasodilators, the calcium channel blockers, is also important, especially for prophylaxis, and the -blockers, which are not vasodilators, are also useful in prophylaxis. A new group of drugs (fatty acid oxidation inhibitors) that are not vasodilators but alter myocardial metabolism are under intense investigation.
Ischemic heart disease is the most common serious health problem in many Western societies. By far the most frequent cause of angina is atheromatous obstruction of the large coronary vessels (atherosclerotic angina, classic angina). However, transient spasm of localized portions of these vessels, which is usually associated with underlying atheromas, can also cause significant myocardial ischemia and pain (angiospastic or variant angina). The primary cause of angina pectoris is an imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels. In classic angina, the imbalance occurs when the myocardial oxygen requirement increases, as during exercise, and coronary blood flow does not increase proportionately. The resulting ischemia usually leads to pain. Classic angina is therefore "angina of effort." (In some individuals, the ischemia is not always accompanied by pain, resulting in "silent" or "ambulatory" ischemia.) In variant angina, oxygen delivery decreases as a result of reversible coronary vasospasm. Variant angina is also called vasospastic or Prinzmetal's angina. In theory, the imbalance between oxygen delivery and myocardial oxygen demand can be corrected by decreasing oxygen demand or by increasing delivery (by increasing coronary flow). Oxygen demand can be reduced by decreasing cardiac work or, according to recent studies, by shifting myocardial metabolism to substrates that require less oxygen per unit of ATP produced. In effort angina, acute reduction of demand has traditionally been achieved by means of organic nitrates— potent vasodilators—and several other classes of drugs, which decrease cardiac work. Increased delivery via increased coronary flow is difficult to achieve rapidly by pharmacologic means when flow is limited by fixed atheromatous plaques. In this situation, invasive measures (coronary bypass grafts or angioplasty) may be needed if reduction of oxygen demand does not control symptoms. In variant angina, on the other hand, spasm of coronary vessels can be reversed by nitrates or calcium channel blockers. It should be emphasized that not all vasodilators are effective in angina and, conversely, that some agents useful in angina (eg, propranolol) are not vasodilators. Lipid-lowering drugs, especially the "statins," have become extremely important in the long-term treatment of atherosclerotic disease (see Chapter 35: Agents Used in Hyperlipidemia). Unstable angina, an acute coronary syndrome, is said to be present when there are episodes of angina at rest and when there is a change in the character, frequency, and duration of chest pain as well as precipitating factors in patients with previously stable angina. Unstable angina is caused by episodes of increased epicardial coronary artery tone or small platelet clots occurring in the vicinity of an atherosclerotic plaque. In most cases, formation of labile nonocclusive thrombi at the site of a fissured or ulcerated plaque is the mechanism for reduction in flow. The course and the prognosis of unstable angina are variable, but this subset of acute coronary syndrome is associated with a high risk of myocardial infarction and death. Pathophysiology of Angina Determinants of Myocardial Oxygen Demand The major and minor determinants of myocardial oxygen requirement are set forth in Table 12–1. Unlike skeletal muscle, human cardiac muscle cannot develop an appreciable oxygen debt during stress and repay it later. As a consequence of its continuous activity, the heart's oxygen needs are relatively high, and it extracts approximately 75% of the available oxygen even under conditions of no stress. The myocardial oxygen requirement increases when there is an increase in heart rate, contractility, arterial pressure, or ventricular volume. These hemodynamic alterations frequently occur during physical exercise and sympathetic discharge, which often precipitate angina in patients with obstructive coronary artery disease. The relative contributions of basal metabolism and activation of contraction to the overall myocardial oxygen consumption appear to be small, but
under pathologic conditions these apparently minor determinants of myocardial oxygen consumption may become relevant. Table 12–1. Determinants of Myocardial Oxygen Consumption.
Major Wall stress Intraventricular pressure Ventricular radius (volume) Wall thickness Heart rate Contractility Minor Activation energy Resting metabolism
The heart favors fatty acids as a substrate for energy production. However, oxidation of fatty acids requires more oxygen per unit of ATP generated than oxidation of carbohydrates. Therefore, drugs that shift myocardial metabolism toward greater use of glucose (fatty acid oxidation inhibitors) have the potential of reducing the oxygen demand without altering hemodynamics. Experimental models suggest that ranolazine and trimetazidine may have this effect. Preliminary clinical trials have shown favorable results. Determinants of Coronary Blood Flow & Myocardial Oxygen Supply Increased myocardial demands for oxygen in the normal heart are met by augmenting coronary blood flow. Coronary blood flow is directly related to the perfusion pressure (aortic diastolic pressure) and the duration of diastole. Because coronary flow drops to negligible values during systole, the duration of diastole becomes a limiting factor for myocardial perfusion during tachycardia. Coronary blood flow is inversely proportional to coronary vascular bed resistance. Resistance is determined mainly by intrinsic factors, including metabolic products and autonomic activity; and by various pharmacologic agents. Damage to the endothelium of coronary vessels has been shown to alter their ability to dilate and to increase coronary vascular resistance. Determinants of Vascular Tone Arteriolar and venous tone (smooth muscle tension) both play a role in determining myocardial wall stress (Table 12–1). Arteriolar tone directly controls peripheral vascular resistance and thus arterial blood pressure. In systole, intraventricular pressure must exceed aortic pressure to eject blood; arterial blood pressure thus determines the systolic wall stress in an important way. Venous tone determines the capacity of the venous circulation and controls the amount of blood sequestered in the venous system versus the amount returned to the heart. Venous tone thereby determines the diastolic wall stress. The regulation of smooth muscle contraction and relaxation is shown schematically in Figure 12–1.
As shown in Figures 12–1 and 12–2, drugs may relax vascular smooth muscle in several ways: Figure 12–1.
Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown). Figure 12–1. Control of smooth muscle contraction and site of action of calcium channel-blocking drugs. Contraction is triggered by influx of calcium (which can be blocked by calcium channel blockers) through transmembrane calcium channels. The calcium combines with calmodulin to form a complex that converts the enzyme myosin light chain kinase to its active form (MLCK*). The latter phosphorylates the myosin light chains, thereby initiating the interaction of myosin with actin. Beta2 agonists (and other substances that increase cAMP) may cause relaxation in smooth muscle by accelerating the inactivation of MLCK (heavy arrows) and by facilitating the expulsion of calcium from the cell (not shown). 1. Increasing cGMP—As indicated in Figure 12–2, cGMP facilitates the dephosphorylation of myosin light chains, preventing the interaction of myosin with actin. Nitric oxide is an effective activator of soluble guanylyl cyclase and acts mainly through this mechanism. Important molecular donors of nitric oxide include nitroprusside (see Chapter 11: Antihypertensive Agents) and the organic nitrates used in angina. 2. Decreasing intracellular Ca2+—Calcium channel blockers predictably cause vasodilation because they reduce intracellular Ca2+, a major modulator of the activation of myosin light chain kinase. (Beta blockers and calcium channel blockers reduce Ca2+influx in cardiac muscle,
thereby reducing rate, contractility, and oxygen requirement unless reversed by compensatory responses.) 3. Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane—The membrane potential of excitable cells is stabilized near the resting potential by increasing potassium permeability. Potassium channel openers, such as minoxidil sulfate, (see Chapter 11: Antihypertensive Agents) increase the permeability of K+ channels, probably ATP-dependent K+ channels. Certain newer agents under investigation for use in angina (eg, nicorandil) may act, in part, by this mechanism. 4. Increasing cAMP in the vascular cells—As shown in Figure 12–1, an increase in cAMP increases the rate of inactivation of myosin light chain kinase, the enzyme responsible for triggering the interaction of actin with myosin in these cells. This appears to be the mechanism of vasodilation caused by 2-agonists, drugs that are not used in angina. Figure 12–2.
Mechanism of action of nitrates, nitrites, and other substances that increase the concentration of nitric oxide (NO) in smooth muscle cells. (MLCK*, activated myosin light chain kinase [see Figure 12–1]; guanylyl cyclase*, activated guanylyl cyclase; ?, unknown intermediate steps. Steps leading to relaxation are shown with heavy arrows.) Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris > Basic Pharmacology of Drugs Used to Treat Angina Drug Action in Angina All three of the drug groups currently approved for use in angina (organic nitrates, calcium channel blockers, and -blockers) decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure, and contractility). In some
patients, a redistribution of coronary flow may increase oxygen delivery to ischemic tissue. In variant angina, the nitrates and the calcium channel blockers may also increase myocardial oxygen delivery by reversing coronary arterial spasm. Nitrates & Nitrites Chemistry These agents are simple nitric and nitrous acid esters of polyalcohols. Nitroglycerin may be considered the prototype of the group. Although it is used in the manufacture of dynamite, the formulations of nitroglycerin used in medicine are not explosive. The conventional sublingual tablet form of nitroglycerin may lose potency when stored as a result of volatilization and adsorption to plastic surfaces. Therefore, it should be kept in tightly closed glass containers. It is not sensitive to light.
All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities. Therefore, pharmacokinetic factors govern the choice of agent and mode of therapy when using the nitrates. Pharmacokinetics The liver contains a high-capacity organic nitrate reductase that removes nitrate groups in a stepwise fashion from the parent molecule and ultimately inactivates the drug. Therefore, oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is very low (typically < 10–20%). The sublingual route, which avoids the first-pass effect, is therefore preferred for achieving a therapeutic blood level rapidly. Nitroglycerin and isosorbide dinitrate are both absorbed efficiently by this route and reach therapeutic blood levels within a few minutes. However, the total dose administered by this route must be limited to avoid excessive effect; therefore, the total duration of effect is brief (15–30 minutes). When much longer duration of action is needed, oral preparations can be given that contain an amount of drug sufficient to result in sustained systemic blood levels of the parent drug plus active metabolites. Other routes of administration available for nitroglycerin include transdermal and buccal absorption from slowrelease preparations; these are described below. Amyl nitrite and related nitrites are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering. The ampule can be crushed with the fingers, resulting in rapid release of inhalable vapors through the cloth covering. The inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and short duration of action, amyl nitrite is now obsolete for angina. Once absorbed, the unchanged nitrate compounds have half-lives of only 2–8 minutes. The partially denitrated metabolites have much longer half-lives (up to 3 hours). Of the nitroglycerin metabolites (two dinitroglycerins and two mononitro forms), the dinitro derivatives have significant vasodilator
efficacy; they probably provide most of the therapeutic effect of orally administered nitroglycerin. The 5-mononitrate metabolite of isosorbide dinitrate is an active metabolite of the latter drug and is available for clinical use as isosorbide mononitrate. It has a bioavailability of 100%. Excretion, primarily in the form of glucuronide derivatives of the denitrated metabolites, is largely by way of the kidney. Pharmacodynamics Mechanism of Action in Smooth Muscle Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite ion is released, which is then converted to nitric oxide (see Chapter 19: Nitric Oxide, Donors, & Inhibitors). A different unknown enzymatic reaction releases nitric oxide directly from the parent drug molecule. As shown in Figure 12–2, nitric oxide (or an S-nitrosothiol derivative) causes activation of guanylyl cyclase and an increase in cGMP, which are the first steps toward smooth muscle relaxation. The production of prostaglandin E or prostacyclin (PGI2) and membrane hyperpolarization may also be involved. There is no evidence that autonomic receptors are involved in the primary nitrate response (although autonomic reflex responses are evoked when hypotensive doses are given). As described below, tolerance is an important consideration in the use of nitrates. While tolerance may be caused in part by a decrease in tissue sulfhydryl groups, it can be only partially prevented or reversed with a sulfhydryl-regenerating agent. The site of this cellular tolerance may be in the unknown reaction responsible for the release of nitric oxide from the nitrate, since other agents, eg, acetylcholine, that cause vasodilation via release of nitric oxide from endogenous substrates do not show cross tolerance with the nitrates. Nicorandil and several other investigational antianginal agents appear to combine the activity of nitric oxide release with potassium channel-opening action, thus providing an additional mechanism for causing vasodilation. Organ System Effects Nitroglycerin relaxes all types of smooth muscle irrespective of the cause of the preexisting muscle tone (Figure 12–3). It has practically no direct effect on cardiac or skeletal muscle. Figure 12–3.
Effects of vasodilators on contractions of human vein segments studied in vitro. Panel A shows contractions induced by two vasoconstrictor agents, norepinephrine (NE) and potassium (K+). Panel B shows the relaxation induced by nitroglycerin (NTG), 4 mol/L. The relaxation is prompt. Panel C shows the relaxation induced by verapamil, 2.2 mol/L. The relaxation is slower but more sustained. (Modified and reproduced, with permission, from Mikkelsen E, Andersson KE, Bengtsson B: Effects of verapamil and nitroglycerin on contractile responses to potassium and noradrenaline in isolated human peripheral veins. Acta Pharmacol Toxicol 1978;42:14.) Vascular Smooth Muscle All segments of the vascular system from large arteries through large veins relax in response to nitroglycerin. Veins respond at the lowest concentrations, arteries at slightly higher ones. Arterioles and precapillary sphincters are dilated less than the large arteries and the veins, partly because of reflex responses and partly because different vessels vary in their ability to release nitric oxide (see The Coronary Steal Phenomenon). The primary direct result of an effective dose of nitroglycerin is marked relaxation of veins with increased venous capacitance and decreased ventricular preload. Pulmonary vascular pressures and heart size are significantly reduced. In the absence of heart failure, cardiac output is reduced. Because venous capacitance is increased, orthostatic hypotension may be marked and syncope can result. Dilation of some large arteries (including the aorta) may be significant because of their large increase in compliance. Temporal artery pulsations and a throbbing headache associated with meningeal artery pulsations are frequent effects of nitroglycerin and amyl nitrite. In heart failure, preload is often abnormally high; the nitrates and other vasodilators, by reducing preload, may have a beneficial effect on cardiac output in this condition (see Chapter 13: Drugs Used in Heart Failure). The indirect effects of nitroglycerin consist of those compensatory responses evoked by baroreceptors and hormonal mechanisms responding to decreased arterial pressure (see Figure 6–7); this consistently results in tachycardia and increased cardiac contractility. Retention of salt and water may also be significant, especially with intermediate- and long-acting nitrates. These compensatory responses contribute to the development of tolerance.
In normal subjects without coronary disease, nitroglycerin can induce a significant, if transient, increase in total coronary blood flow. In contrast, there is no evidence that total coronary flow is increased in patients with angina due to atherosclerotic obstructive coronary artery disease. However, some studies suggest that redistribution of coronary flow from normal to ischemic regions may play a role in nitroglycerin's therapeutic effect. Nitroglycerin also exerts a weak negative inotropic effect via nitric oxide. Other Smooth Muscle Organs Relaxation of smooth muscle of the bronchi, gastrointestinal tract (including biliary system), and genitourinary tract has been demonstrated experimentally. Because of their brief duration, these actions of the nitrates are rarely of any clinical value. During recent years, the use of amyl nitrite and isobutyl nitrite by inhalation as purported recreational (sex-enhancing) drugs has become popular with some segments of the population. Nitrites release nitric oxide in erectile tissue as well as vascular smooth muscle and activate guanylyl cyclase. The resulting increase in cGMP causes dephosphorylation of myosin light chains and relaxation (Figure 12–2), which enhances erection. Drugs used in the treatment of erectile dysfunction are discussed in the section, Drugs Used in the Treatment of Erectile Dysfunction. Action on Platelets Nitric oxide released from nitroglycerin stimulates guanylyl cyclase in platelets as in smooth muscle. The increase in cGMP that results is responsible for a decrease in platelet aggregation. Unfortunately, recent prospective trials have established no survival benefit when nitroglycerin is used in acute myocardial infarction. Other Effects Nitrite ion reacts with hemoglobin (which contains ferrous iron) to produce methemoglobin (which contains ferric iron). Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death. Fortunately, the plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults. However, sodium nitrite is used as a curing agent for meats. In nursing infants, the intestinal flora is capable of converting significant amounts of inorganic nitrate, eg, from well water, to nitrite ion. Thus, inadvertent exposure to large amounts of nitrite ion can occur and may produce serious toxicity. One therapeutic application of this otherwise toxic effect of nitrite has been discovered. Cyanide poisoning results from complexing of cytochrome iron by the CN- ion. Methemoglobin iron has a very high affinity for CN-; thus, administration of sodium nitrite (NaNO2) soon after cyanide exposure will regenerate active cytochrome. The cyanmethemoglobin produced can be further detoxified by the intravenous administration of sodium thiosulfate (Na2S2O3); this results in formation of thiocyanate ion (SCN-), a less toxic ion that is readily excreted. Methemoglobinemia, if excessive, can be treated by giving methylene blue intravenously. Toxicity & Tolerance Acute Adverse Effects The major acute toxicities of organic nitrates are direct extensions of therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache. Glaucoma, once thought to be a
contraindication, does not worsen, and nitrates can be used safely in the presence of increased intraocular pressure. Nitrates are contraindicated, however, if intracranial pressure is elevated. Tolerance With continuous exposure to nitrates, isolated smooth muscle may develop complete tolerance (tachyphylaxis), and the intact human becomes progressively more tolerant when long-acting preparations (oral, transdermal) or continuous intravenous infusions are used for more than a few hours without interruption. Continuous exposure to high levels of nitrates can occur in the chemical industry, especially where explosives are manufactured. When contamination of the workplace with volatile organic nitrate compounds is severe, workers find that upon starting their work week (Monday), they suffer headache and transient dizziness. After a day or so, these symptoms disappear owing to the development of tolerance. Over the weekend, when exposure to the chemicals is reduced, tolerance disappears, so symptoms recur each Monday. Other hazards of industrial exposure, including dependence, have been reported. There is no evidence that physical dependence develops as a result of the therapeutic use of short-acting nitrates for angina, even in large doses. The mechanisms by which tolerance develops are not completely understood. As noted above, diminished release of nitric oxide may be partly responsible for tolerance to nitroglycerin. Systemic compensation also plays a role in tolerance in the intact human. Initially, significant sympathetic discharge occurs and after one or more days of therapy with long-acting nitrates, retention of salt and water may reverse the favorable hemodynamic changes normally caused by nitroglycerin. Carcinogenicity of Nitrate and Nitrate Derivatives Nitrosamines are small molecules with the structure R2–N–NO formed from the combination of nitrates and nitrites with amines. Some nitrosamines are powerful carcinogens in animals, apparently through conversion to reactive derivatives. While there is no direct proof that these agents cause cancer in humans, there is a strong epidemiologic correlation between the incidence of esophageal and gastric carcinoma and the nitrate content of food in different cultures. Nitrosamines are also found in tobacco and in cigarette smoke. There is no evidence that the small doses of nitrates used in the treatment of angina result in significant body levels of nitrosamines. Mechanisms of Clinical Effect The beneficial and deleterious effects of nitrate-induced vasodilation are summarized in Table 12– 2. Table 12–2. Beneficial and Deleterious Effects of Nitrates in the Treatment of Angina.
Effect
Result
Potential beneficial effects Decreased ventricular volume Decreased arterial pressure Decreased ejection time
Decreased myocardial oxygen requirement
Vasodilation of epicardial coronary arteries
Relief of coronary artery spasm
Increased collateral flow
Improved perfusion to ischemic myocardium
Decreased left ventricular diastolic pressure
Improved subendocardial perfusion
Potential deleterious effects Reflex tachycardia
Increased myocardial oxygen requirement
Reflex increase in contractility Decreased diastolic perfusion time due to tachycardia
Decreased myocardial perfusion
Nitrate Effects in Angina of Effort Decreased venous return to the heart and the resulting reduction of intracardiac volume are the principal hemodynamic effects. Arterial pressure also decreases. Decreased intraventricular pressure and left ventricular volume are associated with decreased wall tension (Laplace relation) and decreased myocardial oxygen requirement. In rare instances, a paradoxical increase in myocardial oxygen demand may occur as a result of excessive reflex tachycardia and increased contractility. Intracoronary, intravenous, or sublingual nitrate administration consistently increases the caliber of the large epicardial coronary arteries. Coronary arteriolar resistance tends to decrease, although to a lesser extent. However, nitrates administered by the usual systemic routes also consistently decrease overall coronary blood flow and myocardial oxygen consumption. The reduction in oxygen consumption is the major mechanism for the relief of angina. Nitrate Effects in Variant Angina Nitrates benefit patients with variant angina by relaxing the smooth muscle of the epicardial coronary arteries and relieving coronary artery spasm. Nitrate Effects in Unstable Angina Nitrates are also useful in the treatment of this acute coronary syndrome, but the precise mechanism for their beneficial effects is not clear. Because both increased coronary vascular tone and increased myocardial oxygen demand can precipitate rest angina in these patients, nitrates may exert their beneficial effects both by dilating the epicardial coronary arteries and by simultaneously reducing myocardial oxygen demand. As noted above, nitroglycerin also decreases platelet aggregation, and this effect may be of importance in unstable angina. Clinical Use of Nitrates Some of the forms of nitroglycerin and its congeners are listed in Table 12–3. Because of its rapid onset of action (1–3 minutes), sublingual nitroglycerin is the most frequently used agent for the immediate treatment of angina. Because its duration of action is short (not exceeding 20–30 minutes), it is not suitable for maintenance therapy. The onset of action of intravenous nitroglycerin is also rapid (minutes), but its hemodynamic effects are quickly reversed by stopping its infusion. Clinical application of intravenous nitroglycerin, therefore, is restricted to the treatment of severe,
recurrent rest angina. Slowly absorbed preparations of nitroglycerin include a buccal form, oral preparations, and several transdermal forms. These formulations have been shown to provide blood concentrations for long periods but, as noted above, this leads to the development of tolerance. Table 12–3. Nitrate and Nitrite Drugs Used in the Treatment of Angina.
Drug
Dose
Duration of Action
Nitroglycerin, sublingual
0.15–1.2 mg
10–30 minutes
Isosorbide dinitrate, sublingual
2.5–5 mg
10–60 minutes
Amyl nitrite, inhalant
0.18–0.3 mL
3–5 minutes
6.5–13 mg per 6–8 hours
6–8 hours
1–1.5 inches per 4 hours
3–6 hours
1–2 mg per 4 hours
3–6 hours
10–25 mg per 24 hours (one patch per day)
8–10 hours
Isosorbide dinitrate, sublingual
2.5–10 mg per 2 hours
1.5–2 hours
Isosorbide dinitrate, oral
10–60 mg per 4–6 hours
4–6 hours
Isosorbide dinitrate, chewable oral
5–10 mg per 2–4 hours
2–3 hours
Isosorbide mononitrate oral
20 mg per 12 hours
6–10 hours
"Short-acting"
"Long-acting" Nitroglycerin, oral sustained-action Nitroglycerin, 2% ointment, transdermal Nitroglycerin, slow-release, buccal Nitroglycerin, slow-release patch, transdermal
The hemodynamic effects of sublingual or chewable isosorbide dinitrate and other organic nitrates are similar to those of nitroglycerin. The recommended dosage schedules for commonly used longacting nitrate preparations, along with their durations of action, are listed in Table 12–3. Although transdermal administration may provide blood levels of nitroglycerin for 24 hours or longer, the full hemodynamic effects usually do not persist for more than 6–8 hours. The clinical efficacy of slowrelease forms of nitroglycerin in maintenance therapy of angina is thus limited by the development of significant tolerance. Therefore, a nitrate-free period of at least 8 hours between doses should be observed to reduce or prevent tolerance. Calcium Channel-Blocking Drugs It has been known since the late 1800s that calcium influx was necessary for the contraction of smooth and cardiac muscle. The discovery of a calcium channel in cardiac muscle was followed by the finding of several different types of calcium channels in different tissues (Table 12–4). The discovery of these channels made possible the development of clinically useful blocking drugs. Although the successful therapeutic blockers developed to date have been exclusively L-type channel blockers, selective blockers of other types of calcium channels are under intensive investigation.
Table 12–4. Properties of Several Recognized Voltage-Activated Calcium Channels.
Type Where Found
Properties of the Calcium Current
Blocked By
L
Muscle, neurons
Long, large, high threshold
Verapamil, DHPs, Cd2+
T
Heart, neurons
Short, small, low threshold
sFTX, flunarizine1, Ni2+
N
Neurons
Short, high threshold
P
Cerebellar Purkinje neurons
Long, high threshold
-CTX-GVIA, Cd2+ -CTX-MVIIC, -AgaIVA
DHPs, dihydropyridines (eg, nifedipine); sFTX, synthetic funnel web spider toxin; -CTX, conotoxins extracted from several marine snails of the genus Conus; -Aga-IVA, a toxin of the funnel web spider, Agelenopsis aperta. 1
An organic calcium channel blocker.
Chemistry & Pharmacokinetics Verapamil, the first clinically useful member of this group, was the result of attempts to synthesize more active analogs of papaverine, a vasodilator alkaloid found in the opium poppy. Since then, dozens of agents of varying structure have been found to have the same fundamental pharmacologic action (Table 12–5). Three chemically dissimilar calcium channel blockers are shown in Figure 12– 4. Nifedipine is the prototype of the dihydropyridine family of calcium channel blockers; dozens of molecules in this family have been investigated, and eight are currently approved in the USA for angina and other indications. Nifedipine is the most extensively studied of this group, but the properties of the other dihydropyridines can be assumed to be similar to it unless otherwise noted. Table 12–5. Pharmacokinetics of Some Calcium Channel-Blocking Drugs.
Drug
Oral Onset of Action Plasma Disposition Bioavailability (route) Half-Life (hours)
Dihydropyridines Amlodipine
65–90%
No data available
30–50
> 90% bound to plasma proteins; extensively metabolized.
Felodipine
15–20%
2–5 hours (oral) 11–16
> 99% bound to plasma proteins; extensively metabolized.
Isradipine
15–25%
2 hours (oral)
95% bound to plasma protein; extensively metabolized.
8
Nicardipine
35%
20 minutes (oral)
2–4
95% bound; extensively metabolized in the liver.
Nifedipine
45–70%
< 1 minute (IV), 4 5–20 minutes (sublingual or oral)
About 90% bound to plasma protein; metabolized to an acid lactate. 80% of the drug and metabolites excreted in urine.
Nimodipine
13%
No data available
1–2
Extensively metabolized.
Nisoldipine
< 10%
No data available
6–12
Extensively metabolized.
Nitrendipine
10–30%
4 hours (oral)
5–12
98% bound; extensively metabolized.
Bepridil
60%
60 minutes (oral)
24–40
> 99% bound to plasma proteins; extensively metabolized.
Diltiazem
40–65%
< 3 minutes (IV), > 30 minutes (oral)
3–4
70–80% bound to plasma protein; extensively deacylated. Drug and metabolites excreted in feces.
Verapamil
20–35%
< 1.5 minutes 6 (IV), 30 minutes (oral)
Miscellaneous
Figure 12–4.
About 90% bound to plasma protein. 70% eliminated by kidney; 15% by gastrointestinal tract.
Chemical structures of several calcium channel-blocking drugs. The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein binding, and extensive metabolism. Verapamil and diltiazem are also used by the intravenous route. Pharmacodynamics Mechanism of Action The L-type calcium channel is the dominant type in cardiac and smooth muscle and is known to contain several drug receptors. It has been demonstrated that nifedipine and other dihydropyridines bind to one site, while verapamil and diltiazem appear to bind to closely related but not identical receptors in another region. Binding of a drug to the verapamil or diltiazem receptors also affects dihydropyridine binding. These receptor regions are stereoselective, since marked differences in both stereoisomer-binding affinity and pharmacologic potency are observed for enantiomers of verapamil, diltiazem, and optically active nifedipine congeners. Blockade by these drugs resembles that of sodium channel blockade by local anesthetics (see Chapters 14 and 26). The drugs act from the inner side of the membrane and bind more effectively to channels in depolarized membranes. Binding of the drug reduces the frequency of opening in response to depolarization. The result is a marked decrease in transmembrane calcium current associated in smooth muscle with a long-lasting relaxation (Figure 12–3) and in cardiac muscle with a reduction in contractility throughout the heart and decreases in sinus node pacemaker rate and in atrioventricular node conduction velocity.* *
At very low doses and under certain circumstances, some dihydropyridines increase calcium influx. Some special dihydropyridines, eg, Bay K 8644, actually increase calcium influx over most of their dose range.
Smooth muscle responses to calcium influx through receptor-operated calcium channels are also reduced by these drugs but not as markedly. The block can be partially reversed by elevating the concentration of calcium, although the levels of calcium required are not easily attainable. Block can also be partially reversed by the use of drugs that increase the transmembrane flux of calcium, such as sympathomimetics. Other types of calcium channels are less sensitive to blockade by these calcium channel blockers (Table 12–4). Therefore, tissues in which these channel types play a major role—neurons and most secretory glands—are much less affected by these drugs than are cardiac and smooth muscle. Organ System Effects Smooth Muscle Most types of smooth muscle are dependent on transmembrane calcium influx for normal resting tone and contractile responses. These cells are relaxed by the calcium channel blockers (Figure 12– 3). Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. In the vascular system, arterioles appear to be more sensitive than veins; orthostatic hypotension is not a common adverse effect. Blood pressure is reduced with all calcium channel blockers. Women may be more sensitive than men to the hypotensive action of diltiazem. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina of effort. Reduction of coronary arterial tone has been demonstrated in patients with variant angina. Important differences in vascular selectivity exist among the calcium channel blockers. In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do bepridil, diltiazem, and verapamil (Table 12–6). Furthermore, the dihydropyridines may differ in their potency in different vascular beds. For example, nimodipine is claimed to be particularly selective for cerebral blood vessels. Table 12–6. Vascular Selectivity and Clinical Properties of Some Calcium Channel-Blocking Drugs.
Drug
Vascular Selectivity1
Indications
Usual Dosage
Toxicity
Amlodipine
++
Angina, hypertension
5–10 mg orally once daily
Headache, peripheral edema
Felodipine
5.4
Hypertension, Raynaud's 5–10 mg phenomenon, congestive orally once heart failure daily
Dizziness, headache
Isradipine
7.4
Hypertension
2.5–10 mg orally every 12 hours
Headache, fatigue
Nicardipine
17.0
Angina, hypertension,
20–40 mg
Peripheral edema,
Dihydropyridines
congestive heart failure
orally every 8 dizziness, headache, hours flushing
Nifedipine
3.1
Angina, hypertension, migraine, cardiomyopathy, Raynaud's phenomenon
3–10 g/kg IV; 20–40 mg orally every 8 hours
Hypotension, dizziness, flushing, nausea, constipation, dependent edema
Nimodipine
++
Subarachnoid hemorrhage, migraine
60 mg orally Headache, diarrhea every 4 hours
Nisoldipine
++
Hypertension
20–40 mg orally once daily
Nitrendipine
14.4
Investigational for angina, hypertension
20 mg orally Probably similar to once or twice nifedipine daily
Bepridil
–
Angina
200–400 mg orally once daily
Diltiazem
0.3
Angina, hypertension, Raynaud's phenomenon
75–150 g/kg Hypotension, IV; 30–80 mg dizziness, flushing, orally every 6 bradycardia hours
Verapamil
1.3
Angina, hypertension, arrhythmias, migraine, cardiomyopathy
75–150 g/kg IV; 80–160 mg orally every 8 hours
Probably similar to nifedipine
Miscellaneous Arrhythmias, dizziness, nausea
Hypotension, myocardial depression, constipation, dependent edema
1
Numerical data (Spedding, 1990) give the ratio of vascular potency to cardiac potency; higher numbers mean greater vascular, less cardiac potency. Plus and minus signs reflect estimated ratio of vascular to cardiac potency: – = myocardial depression greater than vasodilation; ++ = significant degree of vasodilation greater than myocardial depression. 2. Cardiac muscle—Cardiac muscle is highly dependent upon calcium influx for normal function. Impulse generation in the sinoatrial node and conduction in the atrioventricular node—so-called slow response, or calcium-dependent, action potentials—may be reduced or blocked by all of the calcium channel blockers. Excitation-contraction coupling in all cardiac cells requires calcium influx, so these drugs reduce cardiac contractility in a dose-dependent fashion. In some cases, cardiac output may also decrease. This reduction in cardiac mechanical function is another mechanism by which the calcium channel blockers may reduce the oxygen requirement in patients with angina. Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Cardiac sodium channels are blocked by bepridil but somewhat less effectively than are calcium channels. Sodium channel block is modest with verapamil and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and
diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines; they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. (See Chapter 14: Agents Used in Cardiac Arrhythmias for additional details.) On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects; they are therefore less depressant on the heart than verapamil or diltiazem. Bepridil also has a significant potassium channel blocking effect in the heart. This results in prolongation of cardiac repolarization (see Chapter 14: Agents Used in Cardiac Arrhythmias) and a distinct risk of induction of arrhythmias. Skeletal Muscle Skeletal muscle is not depressed by the calcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require as much transmembrane calcium influx. Cerebral Vasospasm and Infarct Following Subarachnoid Hemorrhage Nimodipine, a member of the dihydropyridine group of calcium channel blockers, has a high affinity for cerebral blood vessels and appears to reduce morbidity following a subarachnoid hemorrhage. Nimodipine is therefore labeled for use in patients who have had a hemorrhagic stroke. Although evidence suggests that calcium channel blockers may also reduce cerebral damage following thromboembolic stroke in experimental animals, there is no evidence that this occurs in humans. Other Effects Calcium channel blockers minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channels in different tissues, as noted above. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina. A significant body of evidence suggests that the calcium channel blockers may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. Clinical studies have not established their role in human blood clotting and atherosclerosis. Verapamil has been shown to block the P170 glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells; other calcium channel blockers appear to have a similar effect. This action is not stereospecific. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results suggest similar effects in patients (see Chapter 55: Cancer Chemotherapy). Toxicity The most important toxic effects reported for the calcium channel blockers are direct extensions of their therapeutic action. Excessive inhibition of calcium influx can cause serious cardiac depression, including cardiac arrest, bradycardia, atrioventricular block, and heart failure. These effects have been rare in clinical use. Retrospective case control studies reported that immediate-acting nifedipine increased the risk of myocardial infarction in patients with hypertension (Psaty, 1995). Slow-release and long-acting
vasoselective calcium channel blockers are usually well tolerated. However, dihydropyridines, compared with angiotensin-converting enzyme inhibitors, have been reported to increase the risk of adverse cardiac events in patients with hypertension with or without diabetes (ABCD Trial, FACET Trial). These results suggest that relatively short-acting calcium channel blockers have the potential to enhance the risk of adverse cardiac events and should be avoided. Bepridil consistently prolongs the cardiac action potential and may cause a dangerous torsade de pointes arrhythmia in susceptible patients. It is contraindicated in patients with a history of serious arrhythmias or prolonged QT syndrome. Patients receiving -adrenoceptor-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel blockers. Minor toxicity (troublesome but not usually requiring discontinuance of therapy) includes flushing, dizziness, nausea, constipation, and peripheral edema (Table 12–6). Mechanisms of Clinical Effects Calcium channel blockers decrease myocardial contractile force, which reduces myocardial oxygen requirements. Inhibition of calcium entry into arterial smooth muscle is associated with decreased arteriolar tone and systemic vascular resistance, resulting in decreased arterial and intraventricular pressure. Some of these drugs (eg, verapamil) also possess a nonspecific antiadrenergic effect, which may contribute to peripheral vasodilation. As a result of all of these effects, left ventricular wall stress declines, which reduces myocardial oxygen requirements. Decreased heart rate with the use of verapamil, diltiazem, or bepridil causes a further decrease in myocardial oxygen demand. Calcium channel-blocking agents also relieve and prevent the primary cause of variant angina— focal coronary artery spasm. Use of these agents has thus emerged as the most effective prophylactic treatment for this form of angina pectoris. Sinoatrial and atrioventricular nodal tissues, which are mainly composed of slow response cells, are affected markedly by verapamil, moderately by diltiazem, and much less by dihydropyridines. Thus, verapamil and diltiazem decrease atrioventricular nodal conduction and are effective in the management of supraventricular reentry tachycardia and in decreasing ventricular responses in atrial fibrillation or flutter. Nifedipine does not affect atrioventricular conduction. Nonspecific sympathetic antagonism is most marked with diltiazem and much less with verapamil. Nifedipine does not appear to have this effect. Thus, significant reflex tachycardia in response to hypotension occurs most frequently with nifedipine and less so with verapamil. These differences in pharmacologic effects should be considered in selecting calcium channel-blocking agents for the management of angina. Clinical Uses of Calcium Channel-Blocking Drugs In addition to angina, calcium channel blockers have well-documented efficacy in hypertension (see Chapter 11: Antihypertensive Agents) and supraventricular tachyarrhythmias (see Chapter 14: Agents Used in Cardiac Arrhythmias). They also show promise in a wide variety of other conditions, including hypertrophic cardiomyopathy, migraine, and Raynaud's phenomenon. Approved and unlabeled indications and dosages for these drugs are set forth in Table 12–6. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely in the presence of atrioventricular conduction abnormalities. A combination of verapamil or diltiazem with -blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of heart failure as a result of their negative inotropic effect. Amlodipine, however, does not increase the mortality of patients
with heart failure due to left ventricular systolic dysfunction and can be used safely in these patients. In the presence of relatively low blood pressure, dihydropyridines can cause further deleterious lowering of pressure. Verapamil and diltiazem appear to produce less hypotension and may be better tolerated in these circumstances. In patients with a history of atrial tachycardia, flutter, and fibrillation, verapamil and diltiazem provide a distinct advantage because of their antiarrhythmic effects. In the patient receiving digitalis, verapamil should be used with caution, because it may increase digoxin blood levels through a pharmacokinetic interaction. Although increases in digoxin blood level have also been demonstrated with diltiazem and nifedipine, such interactions are less consistent than with verapamil. In patients with unstable angina, immediate-release short-acting calcium channel blockers can increase the risk of adverse cardiac events and therefore are contraindicated (see Toxicity, above). However, in patients with non-Q-wave myocardial infarction, diltiazem can decrease the frequency of postinfarction angina and may be used. Beta-Adrenoceptor-Blocking Drugs Although they are not vasodilators, -blocking drugs (see Chapter 10: Adrenoceptor Antagonist Drugs) are extremely useful in the management of angina pectoris associated with effort. The beneficial effects of -blocking agents are related primarily to their hemodynamic effects— decreased heart rate, blood pressure, and contractility—which decrease myocardial oxygen requirements at rest and during exercise. Lower heart rate is also associated with an increase in diastolic perfusion time that may increase myocardial perfusion. However, reduction of heart rate and blood pressure and consequently decreased myocardial oxygen consumption appear to be the most important mechanisms for relief of angina and improved exercise tolerance. Beta blockers may also be valuable in treating silent or ambulatory ischemia. Because this condition causes no pain, it is usually detected by the appearance of typical electrocardiographic signs of ischemia. The total amount of "ischemic time" per day is reduced by long-term therapy with a -blocker. Betablocking agents decrease mortality of patients with recent myocardial infarction and improve survival and prevent stroke in patients with hypertension. Randomized trials in patients with stable angina have shown better outcome and symptomatic improvement with -blockers compared with calcium channel blockers (Gibbons, 1999). Undesirable effects of -blocking agents in angina include an increase in end-diastolic volume and an increase in ejection time. Increased myocardial oxygen requirements associated with increased diastolic volume partially offset the beneficial effects of -blocking agents. These potentially deleterious effects of -blocking agents can be balanced by the concomitant use of nitrates as described below. The contraindications to the use of -blockers are asthma and other bronchospastic conditions, severe bradycardia, atrioventricular blockade, bradycardia-tachycardia syndrome, and severe unstable left ventricular failure. Potential complications include fatigue, impaired exercise tolerance, insomnia, unpleasant dreams, worsening of claudication, and erectile dysfunction. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris > The Coronary Steal Phenomenon The development of useful vasodilators for management of angina has been marked by frustrating episodes when pharmacologists found that new drugs that were extremely effective vasodilators in normal animals were ineffective or even caused increased anginal symptoms in patients. It is now
clear that potent arteriolar dilators (eg, hydralazine, dipyridamole) are generally ineffective in angina and may reduce perfusion of ischemic areas. In fact, dipyridamole is often used in imaging studies of the coronary circulation to demonstrate regions of poor perfusion. On the other hand, drugs that are more effective dilators of veins and large arteries and relatively ineffective dilators of resistance vessels (eg, nitrates) are very useful in angina. The reason for this apparent anomaly has been called the coronary steal phenomenon. Coronary steal occurs when two branches from a main coronary vessel have differing degrees of obstruction. For example, one branch may be relatively normal and capable of dilating and constricting in response to changes in oxygen demand, while the other branch is significantly obstructed and has significant arteriolar dilation even when cardiac oxygen demand is low, because of the accumulation of metabolites in the ischemic tissue. Perfusion in the obstructed region may be adequate at rest, because perfusion pressure is well maintained in the main coronary artery. If a powerful arteriolar dilator drug is administered, the arterioles in the unobstructed vessel will be forced to dilate, reducing the resistance in this area and greatly increasing flow through the already adequately perfused tissue. As a result of the reduction in resistance in the normal branch, perfusion pressure in the main coronary will diminish, flow through the obstructed branch will decrease, and angina may worsen. It has been suggested that the lesser potency of the nitrates in dilating arterioles is the result of a reduced ability of these vessels to release nitric oxide from the parent nitrate molecule. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris > Drugs Used in the Treatment of Erectile Dysfunction Erectile dysfunction in men has long been the subject of research (by both amateur and professional scientists). Among the substances used in the past and generally discredited are "Spanish Fly" (a bladder and urethral irritant), yohimbine (an 2-antagonist; see Chapter 10: Adrenoceptor Antagonist Drugs), nutmeg, and mixtures containing lead, arsenic, or strychnine. Substances currently favored by practitioners of herbal medicine include ginseng and kava (see Chapter 65: Botanicals ("Herbal Medications") & Nutritional Supplements). Scientific studies of the process have shown that erection requires relaxation of the nonvascular smooth muscle of the corpora cavernosa. This relaxation permits inflow of blood at nearly arterial pressure into the sinuses of the cavernosa, and it is the pressure of the blood that causes erection. Physiologic erection occurs in response to the release of nitric oxide from nonadrenergicnoncholinergic nerves (see Chapter 6: Introduction to Autonomic Pharmacology) associated with parasympathetic discharge. Thus, parasympathetic innervation must be intact and nitric oxide synthesis must be active. (It appears that a similar process occurs in female erectile tissues.) Certain other smooth muscle relaxants—eg, PGE1 analogs, -antagonists—if present in high enough concentration, can independently cause sufficient cavernosal relaxation to result in erection. As noted in the text, NO activates guanylyl cyclase, increases the concentration of cGMP, and the latter messenger stimulates the dephosphorylation of myosin light chains (see Figure 12–2) and relaxation of the smooth muscle. Thus, any drug that increases cGMP might be of value in erectile dysfunction if normal innervation is present. Sildenafil (Viagra) acts to increase cGMP by inhibiting its breakdown by phosphodiesterase isoform 5. The drug has been very successful in the marketplace because it can be taken orally. However, sildenafil is of little or no value in men with loss of potency due to cord injury or other damage to innervation and in men lacking libido. Furthermore, sildenafil potentiates the action of nitrates used for angina, and severe hypotension and a few myocardial infarctions have been reported in men taking both drugs. It is recommended that at least
6 hours pass between use of a nitrate and the ingestion of sildenafil. Sildenafil also has effects on color vision, causing difficulty in blue-green discrimination. Two similar PDE-5 inhibitors tadalafil and vardenafil, were released in 2003. The drug most commonly used in patients who do not respond to sildenafil is alprostadil, a PGE1 analog (see Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds) that can be injected directly into the cavernosa or placed in the urethra as a minisuppository, from which it diffuses into the cavernosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to sildenafil. Another oral drug, apomorphine, acts by releasing dopamine in the central nervous system and is under investigation for erectile dysfunction. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris > Clinical Pharmacology of Drugs Used to Treat Angina Principles of Therapy for Angina In addition to modification of the risk factors for coronary atherosclerosis (smoking, hypertension, hyperlipidemia), the treatment of angina and other manifestations of myocardial ischemia is based on reduction of myocardial oxygen demand and increase of coronary blood flow to the potentially ischemic myocardium to restore the balance between myocardial oxygen supply and demand. Pharmacologic therapy to prevent myocardial infarction and death is with antiplatelet agents (aspirin, clopidogrel) and lipid-lowering agents. Recently, angiotensin-converting enzyme inhibitors have also been reported to reduce the risk of adverse cardiac events in patients with high risk for coronary artery disease (Yusuf et al, 2000). In unstable angina and non-ST-segment elevation myocardial infarction, aggressive therapy with coronary stenting, antilipid drugs, heparin, and antiplatelet agents is recommended (Braunwald et al, 2000, 2002). Angina of Effort Many studies have demonstrated that nitrates, calcium channel blockers, and -blockers increase time to onset of angina and ST depression during treadmill tests in patients with angina of effort (Figure 12–5). Although exercise tolerance increases, there is usually no change in the angina threshold, ie, the rate-pressure product at which symptoms occur. Figure 12–5.
Effects of diltiazem on the double product (heart rate times systolic blood pressure) in a group of 20 patients with angina of effort. In a double-blind study using a standard protocol, patients were tested on a treadmill during treatment with placebo and three doses of the drug. Heart rate (HR) and systolic blood pressure (BP) were recorded at 180 seconds of exercise (midpoints of lines) and at the time of onset of anginal symptoms (rightmost points). Note that the drug treatment decreased the double product at all times during exercise and prolonged the time to appearance of symptoms. (Data from Lindenberg BS et al: Efficacy and safety of incremental doses of diltiazem for the treatment of angina. J Am Coll Cardiol 1983;2:1129. Used with permission of the American College of Cardiology.) For maintenance therapy of chronic stable angina, long-acting nitrates, calcium channel-blocking agents, or -blockers may be chosen; the best choice of drug will depend on the individual patient's response. In hypertensive patients, monotherapy with either slow-release or long-acting calcium channel blockers or -blockers may be adequate. In normotensive patients, long-acting nitrates may be suitable. The combination of a -blocker with a calcium channel blocker (eg, propranolol with nifedipine) or two different calcium channel blockers (eg, nifedipine and verapamil) has been shown to be more effective than individual drugs used alone. If response to a single drug is inadequate, a drug from a different class should be added to maximize the beneficial reduction of cardiac work while minimizing undesirable effects (Table 12–7). Some patients may require therapy with all three drug groups. Table 12–7. Effects of Nitrates Alone and with -Blockers or Calcium Channel Blockersin Angina Pectoris. (Undesirable Effects Are Shown in Italics.)
Nitrates Alone
Beta Blockers or Calcium Channel Blockers
Combined Nitrates With Beta Blockers or Calcium Channel Blockers
Heart rate
Reflex increase
Decrease1
Decrease
Arterial pressure
Decrease
Decrease
Decrease
End-diastolic volume
Decrease
Increase
None or decrease
Contractility
Reflex increase
Decrease
None
Ejection time
Decrease
Increase
None
1
Nifedipine may cause a reflex increase in heart rate and cardiac contractility.
Surgical revascularization (ie, coronary artery bypass grafting [CABG]) and catheter-based revascularization (ie, percutaneous coronary intervention [PCI]) are the primary methods for promptly restoring coronary blood flow and increasing oxygen supply to the myocardium. Major clinical trials suggest that coronary obstruction can also be decreased by vigorous antilipidemic therapy. Vasospastic Angina Nitrates and the calcium channel blockers are effective drugs for relieving and preventing ischemic episodes in patients with variant angina. In approximately 70% of patients treated with nitrates plus calcium channel blockers, angina attacks are completely abolished; in another 20%, marked reduction of frequency of anginal episodes is observed. Prevention of coronary artery spasm (in the presence or absence of fixed atherosclerotic coronary artery lesions) is the principal mechanism for this beneficial response. All presently available calcium channel blockers appear to be equally effective, and the choice of a particular drug should depend on the patient, as indicated above. Surgical revascularization and angioplasty are not indicated in patients with variant angina. Unstable Angina & Acute Coronary Syndromes In patients with unstable angina with recurrent ischemic episodes at rest, recurrent thrombotic occlusions of the offending coronary artery occur as the result of fissuring of atherosclerotic plaques and platelet aggregation. Anticoagulant and antiplatelet drugs play a major role in therapy (see Chapter 34: Drugs Used in Disorders of Coagulation). Aspirin has been shown to reduce the incidence of cardiac events in such patients. Intravenous heparin or subcutaneous low-molecularweight heparin is indicated in most patients. Antiplatelet agents (ticlopidine, clopidogrel, and GPIIb/IIIa antagonists) have been found to be effective in decreasing risk in unstable angina (Braunwald et al 2000, 2002). In addition, therapy with nitroglycerin and -blockers should be considered; calcium channel blockers should be added in refractory cases. Catheter-based or surgical myocardial revascularization is indicated in high-risk patients. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 12. Vasodilators & the Treatment of Angina Pectoris > Preparations Available Nitrates & Nitrites Amyl nitrite (generic, Aspirols, Vaporole)
Inhalant: 0.3 mL capsules Isosorbide dinitrate(generic, Isordil, Sorbitrate) Oral: 5, 10, 20, 30, 40 mg tablets; 5, 10 mg chewable tablets Oral sustained-release (generic, Sorbitrate SA, Iso-Bid): 40 mg tablets and capsules Sublingual: 2.5, 5, 10 mg sublingual tablets Isosorbide mononitrate(Ismo, others) Oral: 10, 20 mg tablets; extended-release 30, 60, 120 mg tablets Nitroglycerin Sublingual: 0.3, 0.4, 0.6 mg tablets; 0.4 mg/metered dose aerosol Oral sustained-release (generic, Nitrong): 2.6, 6.5, 9 mg tablets; 2.5, 6.5, 9, 13 mg capsules Buccal (Nitrogard): 2, 3 mg buccal tablets Parenteral (Nitro-Bid IV, Tridil, generic): 0.5, 5 mg/mL for IV administration Transdermal patches (Minitran, Nitro-Dur, Transderm-Nitro): to release at rates of 0.1, 0.2, 0.3, 0.4, 0.6, or 0.8 mg/h. Topical ointment (generic, Nitrol): 20 mg/mL ointment (1 inch, or 25 mm, of ointment contains about 15 mg nitroglycerin) Calcium Channel Blockers Amlodipine (Norvasc) Oral: 2.5, 5, 10 mg tablets Bepridil (Vascor) Oral: 200, 300 mg tablets Diltiazem(Cardizem, generic) Oral: 30, 60, 90, 120 mg tablets Oral sustained-release (Cardizem SR, Dilacor XL, others): 60, 90, 120, 180, 240, 300, 360, 420 mg capsules Parenteral: 5 mg/mL for injection Felodipine (Plendil)
Oral extended-release: 2.5, 5, 10 mg tablets Isradipine(DynaCirc) Oral: 2.5, 5 mg capsules Oral controlled release: 5, 10 mg tablets Nicardipine (Cardene, others) Oral: 20, 30 mg capsules Oral sustained-release (Cardene SR): 30, 45, 60 mg capsules) Parenteral (Cardene I.V.): 2.5 mg/mL Nifedipine (Adalat, Procardia, others) Oral: 10, 20 mg capsules Oral extended-release (Procardia XL, Adalat CC): 30, 60, 90 mg tablets Nimodipine(Nimotop) Oral: 30 mg capsules. (Labeled for use in subarachnoid hemorrhage, not angina.) Nisoldipine(Sular) Oral extended-release: 10, 20, 30, 40 mg tablets Verapamil(generic, Calan, Isoptin) Oral: 40, 80, 120 mg tablets Oral sustained-release: 100, 120, 180, 240 mg tablets or capsules Parenteral: 2.5 mg/mL for injection Beta Blockers See Chapter 10: Adrenoceptor Antagonist Drugs.
Chapter 13. Drugs Used in Heart Failure Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 13. Drugs Used in Heart Failure > Drugs Used in Heart Failure: Introduction
Heart failure occurs when the cardiac output is inadequate to provide the oxygen needed by the body. It is a highly lethal condition, with a 5-year mortality rate conventionally said to be about 50%. The most common cause of heart failure in the USA is coronary artery disease. In systolic failure, the mechanical pumping action (contractility) and the ejection fraction of the heart are reduced. In diastolic failure, stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejection fraction may be normal. Because other cardiovascular conditions are now being treated more effectively (especially myocardial infarction), more patients are surviving long enough for heart failure to develop, making this one of the cardiovascular conditions that is actually increasing in prevalence. Although it is believed that the primary defect in early heart failure resides in the excitationcontraction coupling machinery of the heart, the clinical condition also involves many other processes and organs, including the baroreceptor reflex, the sympathetic nervous system, the kidneys, angiotensin II and other peptides, and death of cardiac cells. Recognition of these factors has resulted in evolution of a variety of treatment strategies (Table 13–1). Table 13–1. Drug Groups Commonly Used in Heart Failure.
ACE inhibitors Beta blockers Angiotensin receptor blockers Cardiac glycosides Vasodilators Beta agonists, dopamine Bipyridines
ACE, angiotensin-converting enzyme. Clinical research has shown that therapy directed at noncardiac targets may be more valuable in the long-term treatment of heart failure than traditional positive inotropic agents (cardiac glycosides [digitalis]). Thus, drugs acting on the kidneys (diuretics) have long been considered at least as valuable as digitalis. Careful clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors, -blockers, and spironolactone (a potassium-sparing diuretic) are the only agents in current use that actually prolong life in patients with chronic heart failure. Positive inotropic drugs, on the other hand, can be very helpful in acute failure. They also reduce symptoms in chronic failure. Control of Normal Cardiac Contractility The vigor of contraction of heart muscle is determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere (Figure 13–1). Ultimately, contraction results from the interaction of calcium (during systole) with the actin-troponintropomyosin system, thereby releasing the actin-myosin interaction. This activator calcium is released from the sarcoplasmic reticulum (SR). The amount released depends on the amount stored in the SR and on the amount of trigger calcium that enters the cell during the plateau of the action potential.
Figure 13–1.
Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility (numbered structures). Site 1 is Na+/K+ ATPase, the sodium pump. Site 2 is the sodium/calcium exchanger. Site 3 is the voltage-gated calcium channel. Site 4 is a calcium transporter that pumps calcium into the sarcoplasmic reticulum (SR). Site 5 is a calcium channel in the membrane of the SR that is triggered to release stored calcium by activator calcium. Site 6 is the actin-troponin-tropomyosin complex at which activator calcium brings about the contractile interaction of actin and myosin. Sensitivity of the Contractile Proteins to Calcium The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect it in vitro. Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure. the Amount of Calcium Released from the Sarcoplasmic Reticulum A small rise in free cytoplasmic calcium, brought about by calcium influx during the action potential, triggers the opening of calcium channels in the membrane of the SR and the rapid release
of a large amount of the ion into the cytoplasm in the vicinity of the actin-troponin-tropomyosin complex. The amount released is proportional to the amount stored in the SR and the amount of trigger calcium that enters the cell through the cell membrane. Ryanodine is a potent negative inotropic plant alkaloid that interferes with the release of calcium through the SR channels. No drugs are available that increase the release of calcium through these channels. the Amount of Calcium Stored in the Sarcoplasmic Reticulum The SR membrane contains a very efficient calcium uptake transporter, which maintains free cytoplasmic calcium at very low levels during diastole by pumping calcium into the SR. The amount of calcium sequestered in the SR is thus determined, in part, by the amount accessible to this transporter. This in turn is dependent on the balance of calcium influx (primarily through the voltage-gated membrane calcium channels) and calcium efflux, the amount removed from the cell (primarily via the sodium-calcium exchanger, a transporter in the cell membrane). the Amount of Trigger Calcium The amount of trigger calcium that enters the cell depends on the availability of calcium channels (primarily the L type) and the duration of their opening. As described in Chapter 6: Introduction to Autonomic Pharmacology and Chapter 9: Adrenoceptor-Activating & Other Sympathomimetic Drugs, sympathomimetics cause an increase in calcium influx through an action on these channels. Conversely, the calcium channel blockers (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris) reduce this influx and depress contractility. Activity of the Sodium-Calcium Exchanger This antiporter uses the sodium gradient to move calcium against its concentration gradient from the cytoplasm to the extracellular space. Extracellular concentrations of these ions are much less labile than intracellular concentrations under physiologic conditions. The sodium-calcium exchanger's ability to carry out this transport is thus strongly dependent on the intracellular concentrations of both ions, especially sodium. Intracellular Sodium Concentration and Activity of Na+/K+ Atpase Na+/K+ ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell. The sodium influx through voltage-gated channels, which occurs as a normal part of almost all cardiac action potentials, is another determinant. As described below, Na+/K+ ATPase appears to be the primary target of cardiac glycosides. Pathophysiology of Heart Failure Heart failure is a syndrome with multiple causes that may involve the right ventricle, the left ventricle, or both. Cardiac output in heart failure is usually below the normal range. Systolic dysfunction, with reduced cardiac output and significantly reduced ejection fraction (less than 45%), is typical of acute failure, especially that resulting from myocardial infarction. Diastolic dysfunction often occurs as a result of hypertrophy and stiffening of the myocardium, and although cardiac output is reduced, ejection fraction may be normal. Heart failure due to diastolic dysfunction does not usually respond optimally to positive inotropic drugs. Rarely, "high-output" failure may occur. In this condition, the demands of the body are so great that even increased cardiac output is insufficient. High-output failure can result from hyperthyroidism,
beriberi, anemia, and arteriovenous shunts. This form of failure responds poorly to the drugs discussed in this chapter and should be treated by correcting the underlying cause. The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance and shortness of breath, peripheral and pulmonary edema, and cardiomegaly. Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect. Neurohumoral (extrinsic) compensation involves two major mechanisms previously presented in Figure 6–7: the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13–2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. While the increased preload, force, and heart rate initially increase cardiac output, increased arterial tone results in increased afterload and decreased ejection fraction, cardiac output, and renal perfusion. After a relatively short time, complex downregulatory changes in the 1-adrenoceptor-G protein-effector system take place that result in diminished stimulatory effects. Beta2 receptors are not down-regulated and may develop increased coupling to the IP3-DAG cascade. It has also been suggested that cardiac 3 receptors (which do not appear to be down-regulated in failure) may mediate negative inotropic effects. Increased angiotensin II production leads to increased aldosterone secretion (with sodium and water retention), to increased afterload, and to remodeling of both heart and vessels (discussed below). Other hormones may also be released, including natriuretic peptide and endothelin (see Chapter 17: Vasoactive Peptides). Figure 13–2.
Some compensatory responses that occur during congestive heart failure. In addition to the effects shown, angiotensin II increases sympathetic effects by facilitating norepinephrine release. The most important intrinsic compensatory mechanism is myocardial hypertrophy. This increase in muscle mass helps maintain cardiac performance. However, after an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling is the term applied to dilation (other than that due to passive stretch) and slow structural changes that occur in the stressed myocardium. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes. Ultimately, myocytes in the failing heart die at an accelerated rate through apoptosis, leaving the remaining myocytes subject to even greater overload. The severity of heart failure is usually described according to a scale devised by the New York Heart Association. Class I failure is associated with no limitations on ordinary activities and symptoms that occur only with greater than ordinary exercise. Class II is characterized by slight limitation of ordinary activities, which result in fatigue and palpitations. Class III results in no symptoms at rest, but fatigue, etc, with less than ordinary physical activity. Class IV is associated with symptoms even when the patient is at rest. Pathophysiology of Cardiac Performance Cardiac performance is a function of four primary factors: 1. Preload: When some measure of left ventricular performance such as stroke volume or stroke work is plotted as a function of left ventricular filling pressure, the resulting curve is termed the left ventricular function curve (Figure 13–3). The ascending limb (< 15 mm Hg filling pressure) represents the classic Frank-Starling relation. Beyond approximately 15 mm Hg, there is a plateau of performance. Preloads greater than 20–25 mm Hg result in pulmonary congestion. As noted above, preload is usually increased in heart failure because of increased blood volume and venous tone. Reduction of high filling pressure is the goal of salt restriction and diuretic therapy in heart failure. Venodilator drugs (eg, nitroglycerin) also reduce preload by redistributing blood away from the chest into peripheral veins. 2. Afterload: Afterload is the resistance against which the heart must pump blood and is represented by aortic impedance and systemic vascular resistance. As cardiac output falls in chronic failure, there is a reflex increase in systemic vascular resistance, mediated in part by increased sympathetic outflow and circulating catecholamines and in part by activation of the renin-angiotensin system. Endothelin, a potent vasoconstrictor peptide, may also be involved. This sets the stage for the use of drugs that reduce arteriolar tone in heart failure. 3. Contractility: Heart muscle obtained by biopsy from patients with chronic low-output failure demonstrates a reduction in intrinsic contractility. As contractility decreases in the patient, there is a reduction in the velocity of muscle shortening, the rate of intraventricular pressure development (dP/dt), and the stroke output achieved (Figure 13–3). However, the heart is still capable of some increase in all of these measures of contractility in response to inotropic drugs. 4. Heart rate: The heart rate is a major determinant of cardiac output. As the intrinsic function of the heart decreases in failure and stroke volume diminishes, an increase in heart rate— through sympathetic activation of adrenoceptors—is the first compensatory mechanism that comes into play to maintain cardiac output.
Figure 13–3.
Relation of left ventricular (LV) performance to filling pressure in patients with acute myocardial infarction, an important cause of heart failure. The upper line indicates the range for normal, healthy individuals. If acute heart failure occurs, function is shifted down and to the right. Similar depression is observed in patients with chronic heart failure. (Modified and reproduced with permission, from Swan HJC, Parmley WW: Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]. Pathologic Physiology. Saunders, 1979.) Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 13. Drugs Used in Heart Failure > Basic Pharmacology of Drugs Used in Heart Failure Although digitalis is rarely the first drug used in heart failure, we begin our discussion with this group because other drugs are discussed in more detail in Chapter 11: Antihypertensive Agents, Chapter 12: Vasodilators & the Treatment of Angina Pectoris, and Chapter 15: Diuretic Agents. Digitalis Digitalis is the genus name for the family of plants that provide most of the medically useful cardiac glycosides, eg, digoxin. Such plants have been known for thousands of years but were used erratically and with variable success until 1785, when William Withering, an English physician and botanist, published a monograph describing the clinical effects of an extract of the foxglove plant (Digitalis purpurea, a major source of these agents). Chemistry All of the cardiac glycosides, or cardenolides—of which digoxin is the prototype—combine a steroid nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon 3 of the
nucleus. Because they lack an easily ionizable group, their solubility is not pH-dependent.
Sources of these drugs include white and purple foxglove (Digitalis lanata and D purpurea) and numerous other temperate zone and tropical plants. Certain toads have skin glands capable of elaborating bufadienolides, which differ only slightly from the cardenolides. Pharmacokinetics Absorption and Distribution Cardenolides vary in their absorption, distribution, metabolism, and excretion, as shown by comparison of three representative agents: digoxin, digitoxin, and ouabain (Table 13–2). Of these three, digoxin is the only preparation used in the USA. Table 13–2. Properties of Three Typical Cardiac Glycosides.
Ouabain1 Digoxin Digitoxin1 Lipid solubility (oil/water coefficient)
Low
Medium High
Oral availability (percentage absorbed)
75
> 90
Half-life in body (hours)
21
40
168
Plasma protein binding (percentage bound) 0
20–40
> 90
Percentage metabolized
< 40
> 80
Volume of distribution (L/kg)
18
6.3
0.6
1
Ouabain and digitoxin are no longer in use in the USA.
Digoxin is fairly well absorbed after oral administration. However, about 10% of individuals harbor enteric bacteria that inactivate digoxin in the gut, greatly reducing bioavailability and requiring higher than average maintenance dosage. Treatment of such patients with antibiotics can result in a
glycosides is very narrow, even minor variations in bioavailability can cause serious toxicity or loss of effect. Once absorbed into the blood, all cardiac glycosides are widely distributed to tissues, including the central nervous system. Their volumes of distribution differ, however, depending on their tendency to bind to plasma proteins versus tissue proteins. Metabolism and Excretion Digoxin is not extensively metabolized in humans; almost two thirds is excreted unchanged by the kidneys. Its renal clearance is proportional to creatinine clearance. Equations and nomograms are available for adjusting digoxin dosage in patients with renal impairment. Digitoxin is metabolized in the liver and excreted into the gut via the bile. Cardioactive metabolites (which include digoxin) as well as unchanged digitoxin can then be reabsorbed from the intestine, thus establishing an enterohepatic circulation that contributes to the very long half-life of this agent. Renal impairment does not significantly prolong the half-life of digitoxin. Ouabain must be given parenterally and is excreted, mostly unchanged, in the urine. Pharmacodynamics Digitalis has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences. In addition, it has undesirable effects on the central nervous system and gut. At the molecular level, all therapeutically useful cardiac glycosides inhibit Na+/K+ ATPase, the membrane-bound transporter often called the sodium pump. This protein consists of and subunits. The binding sites for Na+, K+, ATP, and digitalis all appear to reside on the subunit. Different isoforms of the subunits have been identified, thus providing for different isoforms of the complete enzyme with differing affinities for cardiac glycosides in various tissues. Very low concentrations of these drugs have occasionally been reported to stimulate the enzyme. In contrast, inhibition over most of the dose range has been extensively documented in all tissues studied. It is probable that the inhibitory action is largely responsible for the therapeutic effect (positive inotropy) in the heart. Since the sodium pump is necessary for maintenance of normal resting potential in most excitable cells, it is likely that a major portion of the toxicity of digitalis is also caused by this enzymeinhibiting action. Other molecular-level effects of digitalis have been studied in the heart and are discussed below. The fact that the receptor for cardiac glycosides exists on the sodium pump has prompted some investigators to propose that an endogenous "digitalis-like" agent, possibly ouabain, must exist. Cardiac Effects Mechanical Effects Cardiac glycosides increase the intensity of the interaction of the actin and myosin filaments of the cardiac sarcomere (Figure 13–1) by increasing the free calcium concentration in the vicinity of the contractile proteins during systole. The increase in calcium concentration is the result of a two-step process: first, an increase of intracellular sodium concentration because of Na+/K+ ATPase inhibition (1 in Figure 13–1); and second, a relative reduction of calcium expulsion from the cell by the sodium-calcium exchanger (2 in Figure 13–1) caused by the increase in intracellular sodium. Other mechanisms have been proposed but are not well supported.
The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility (Figure 13–4, bottom trace). In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact animal or patient the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure. Figure 13–4.
Effects of a cardiac glycoside, ouabain, on isolated cardiac tissue. The top tracing shows action potentials evoked during the control period, early in the "therapeutic" phase, and later, when toxicity is present. The middle tracing shows the light (L) emitted by the calcium-detecting protein aequorin (relative to the maximum possible, Lmax) and is roughly proportionate to the free intracellular calcium concentration. The bottom tracing records the tension elicited by the action potentials. The early phase of ouabain action (A) shows a slight shortening of action potential and a marked increase in free intracellular calcium concentration and contractile tension. The toxic phase (B) is associated with depolarization of the resting potential, a marked shortening of the action potential, and the appearance of an oscillatory depolarization, calcium increment, and contraction (arrows). (Unpublished data kindly provided by P Hess and H Gil Wier.) Electrical Effects The effects of digitalis on the electrical properties of the heart are a mixture of direct and autonomic actions. Direct actions on the membranes of cardiac cells follow a well-defined progression: an early, brief prolongation of the action potential, followed by a protracted period of shortening (especially the plateau phase). The decrease in action potential duration is probably the result of increased potassium conductance that is caused by increased intracellular calcium (see Chapter 14: Agents Used in Cardiac Arrhythmias). All of these effects can be observed at therapeutic concentrations in the absence of overt toxicity. Shortening of the action potential contributes to the shortening of atrial and ventricular refractoriness (Table 13–3).
Table 13–3. Major Actions of Digitalis on Cardiac Electrical Functions.
Tissue Variable
Atrial Muscle
AV Node
Purkinje System, Ventricles
Effective refractory period
(PANS)
(PANS)
(Direct)
Conduction velocity
(PANS)
(PANS)
Negligible
Automaticity
(Direct)
(Direct)
(Direct)
Electrocardiogram Before arrhythmias Negligible
PR interval
During arrhythmias Atrial tachycardia, AV nodal atrial fibrillation tachycardia, AV blockade
QT interval; T wave inversion; ST segment depression Premature ventricular contractions, bigeminy, ventricular tachycardia, ventricular fibrillation
Key:
(PANS) = parasympathetic actions
(Direct) = direct membrane actions At higher concentrations, resting membrane potential is reduced (made less negative) as a result of inhibition of the sodium pump and reduced intracellular potassium. As toxicity progresses, oscillatory depolarizing afterpotentials appear following normally evoked action potentials (Figure 13–4, panel B). The afterpotentials (also known as delayed afterdepolarizations) are associated with overloading of the intracellular calcium stores and oscillations in the free intracellular calcium ion concentration. When below threshold, these afterpotentials may interfere with normal conduction because of the further reduction of resting potential. Eventually, an afterpotential may reach threshold, eliciting an action potential (premature depolarization or ectopic "beat") that is coupled to the preceding normal one. If afterpotentials in the Purkinje conducting system regularly reach threshold in this way, bigeminy will be recorded on the electrocardiogram (Figure 13–5). With further intoxication, each afterpotential-evoked action potential will itself elicit a suprathreshold afterpotential, and a self-sustaining tachycardia will be established. If allowed to progress, such a tachycardia may deteriorate into fibrillation; in the case of ventricular fibrillation, the arrhythmia will be rapidly fatal unless corrected. Figure 13–5.
Electrocardiographic record showing digitalis-induced bigeminy. The complexes marked NSR are normal sinus rhythm beats; an inverted T wave and depressed ST segment are present. The complexes marked PVB are premature ventricular beats and are the electrocardiographic manifestations of depolarizations evoked by delayed oscillatory afterpotentials as shown in Figure 13–4. (Modified and reproduced, with permission, from Goldman MJ: Principles of Clinical Electrocardiography, 12th ed. Lange, 1986.) Autonomic actions of cardiac glycosides on the heart involve both the parasympathetic and the sympathetic systems. In the lower portion of the dose range, cardioselective parasympathomimetic effects predominate. In fact, these atropine-blockable effects account for a significant portion of the early electrical effects of digitalis (Table 13–3). This action involves sensitization of the baroreceptors, central vagal stimulation, and facilitation of muscarinic transmission at the cardiac muscle cell. Because cholinergic innervation is much richer in the atria, these actions affect atrial and atrioventricular nodal function more than Purkinje or ventricular function. Some of the cholinomimetic effects are useful in the treatment of certain arrhythmias. At toxic levels, sympathetic outflow is increased by digitalis. This effect is not essential for typical cardenolide toxicity but sensitizes the myocardium and exaggerates all the toxic effects of the drug. The most common cardiac manifestations of glycoside toxicity include atrioventricular junctional rhythm, premature ventricular depolarizations, bigeminal rhythm, and second-degree atrioventricular blockade. However, it is claimed that digitalis can cause virtually every variety of arrhythmia. Effects on Other Organs Cardiac glycosides affect all excitable tissues, including smooth muscle and the central nervous system. Inhibition of Na+/K+ ATPase in these tissues depolarizes and increases spontaneous activity both in neurons and in smooth muscle cells. The gastrointestinal tract is the most common site of digitalis toxicity outside the heart. The effects include anorexia, nausea, vomiting, and diarrhea. This toxicity may be partially caused by direct effects on the gastrointestinal tract but is also the result of central nervous system actions, including chemoreceptor trigger zone stimulation. Central nervous system effects commonly include vagal and chemoreceptor zone stimulation. Much less often, disorientation and hallucinations—especially in the elderly—and visual disturbances are noted. The latter effect may include aberrations of color perception. Agitation and even convulsions are occasionally reported in patients taking digitalis. Gynecomastia is a rare effect reported in men taking digitalis; it is not certain whether this effect represents a peripheral estrogenic action of these steroid drugs or a manifestation of hypothalamic stimulation.
Interactions with Potassium, Calcium, and Magnesium Potassium and digitalis interact in two ways. First, they inhibit each other's binding to Na+/K+ ATPase; therefore, hyperkalemia reduces the enzyme-inhibiting actions of cardiac glycosides, whereas hypokalemia facilitates these actions. Second, abnormal cardiac automaticity is inhibited by hyperkalemia (see Chapter 14: Agents Used in Cardiac Arrhythmias). Moderately increased extracellular K+ therefore reduces the effects of digitalis, especially the toxic effects. Calcium ion facilitates the toxic actions of cardiac glycosides by accelerating the overloading of intracellular calcium stores that appears to be responsible for digitalis-induced abnormal automaticity. Hypercalcemia therefore increases the risk of a digitalis-induced arrhythmia. The effects of magnesium ion appear to be opposite to those of calcium. Hypomagnesemia is therefore a risk factor for arrhythmias. These interactions mandate careful evaluation of serum electrolytes in patients with digitalis-induced arrhythmias. Other Positive Inotropic Drugs Used in Heart Failure Drugs that inhibit phosphodiesterases, the family of enzymes that inactivate cAMP and cGMP, have long been used in therapy of heart failure. Although they have positive inotropic effects, most of their benefits appear to derive from vasodilation, as discussed below. Phosphodiesterase inhibitors have been intensively studied for several decades with mixed results. The bipyridines inamrinone and milrinone are the most successful of these agents found to date, but their usefulness is quite limited. Levosimendan, an investigational drug that sensitizes the troponin system to calcium, also appears to inhibit phosphodiesterase and cause some vasodilation in addition to its inotropic effects. Some early clinical trials suggest that this drug may be useful in patients with heart failure (Follath, et al, 2002). A group of -adrenoceptor stimulants have also been used as digitalis substitutes, but they may increase mortality (see below). Bipyridines Inamrinone (previously called amrinone) and milrinone are bipyridine compounds that inhibit phosphodiesterase. They are active orally as well as parenterally but are only available in parenteral forms. They have elimination half-lives of 3–6 hours, with 10–40% being excreted in the urine. Pharmacodynamics The bipyridines increase myocardial contractility by increasing inward calcium flux in the heart during the action potential; they may also alter the intracellular movements of calcium by influencing the sarcoplasmic reticulum. They also have an important vasodilating effect. These drugs are relatively selective for phosphodiesterase isozyme 3, a form found in cardiac and smooth muscle. Inhibition of this isozyme results in an increase in cAMP and the increase in contractility and vasodilation noted above. The toxicity of inamrinone includes nausea and vomiting; arrhythmias, thrombocytopenia, and liver enzyme changes have been reported in a significant number of patients. This drug has been withdrawn in some countries. Milrinone appears less likely to cause bone marrow and liver toxicity than inamrinone, but it does cause arrhythmias. Inamrinone and milrinone are now used only intravenously and only for acute heart failure or for an exacerbation of chronic heart failure. Beta Adrenoceptor Stimulants
The general pharmacology of these agents is discussed in Chapter 9: Adrenoceptor-Activating & Other Sympathomimetic Drugs. The selective 1-agonist that has been most widely used in patients with heart failure is dobutamine. This drug produces an increase in cardiac output together with a decrease in ventricular filling pressure. Some tachycardia and an increase in myocardial oxygen consumption have been reported. The potential for producing angina or arrhythmias in patients with coronary artery disease must be considered, as well as the tachyphylaxis that accompanies the use of any stimulant. Intermittent dobutamine infusion may benefit some patients with chronic heart failure. Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure. Drugs Without Positive Inotropic Effects Used in Heart Failure The drugs most commonly used in chronic heart failure are diuretics, ACE inhibitors, angiotensin receptor antagonists, and -blockers (Table 13–1). In acute failure, diuretics and vasodilators play important roles. Diuretics The diuretics are discussed in detail in Chapter 15: Diuretic Agents. Their major mechanism of action in heart failure is to reduce venous pressure and ventricular preload. These reductions have two useful effects: reduction of edema and its symptoms and reduction of cardiac size, which leads to improved pump efficiency. Spironolactone, the aldosterone antagonist diuretic (see Chapter 15: Diuretic Agents), has the additional benefit of decreasing morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy. One possible mechanism for this benefit lies in accumulating evidence that aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects. Angiotensin-Converting Enzyme Inhibitors, Angiotensin Receptor Antagonists, & Related Agents The ACE inhibitors such as captopril are introduced in Chapter 11: Antihypertensive Agents and discussed again in Chapter 17: Vasoactive Peptides. These versatile drugs reduce peripheral resistance and thereby reduce afterload; they also reduce salt and water retention (by reducing aldosterone secretion) and in that way reduce preload. The reduction in tissue angiotensin levels also reduces sympathetic activity, probably through diminution of angiotensin's presynaptic effects on norepinephrine release. Finally, these drugs reduce the long-term remodeling of the heart and vessels, an effect that may be responsible for the observed reduction in mortality and morbidity (see Clinical Pharmacology). Angiotensin AT1 receptor-blockers such as losartan (see Chapter 11: Antihypertensive Agents and Chapter 17: Vasoactive Peptides) appear to have similar but more limited beneficial effects, and clinical trials of these drugs in heart failure continue. A newer class of drugs that inhibit both ACE and neutral endopeptidase, an enzyme that inactivates bradykinin and natriuretic peptide (see below), has been introduced into clinical trials recently. Omapatrilat is the first of these agents and has been shown in early studies to increase exercise tolerance and to reduce morbidity and mortality. Unfortunately, it causes a significant incidence of angioedema. Vasodilators
The vasodilators are effective in acute heart failure because they provide a reduction in preload (through venodilation), or reduction in afterload (through arteriolar dilation), or both. Some evidence suggests that long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart. A synthetic form of the endogenous peptide brain natriuretic peptide (BNP) has recently been approved for use in acute cardiac failure as nesiritide. This recombinant product increases cGMP in smooth muscle cells and effectively reduces venous and arteriolar tone in experimental preparations. It also causes diuresis. The peptide has a short half-life of about 18 minutes and is administered as a bolus intravenous dose followed by continuous infusion. Excessive hypotension is the most common adverse effect. Measurement of endogenous BNP has been proposed as a diagnostic test because plasma concentrations rise in most patients with heart failure. Bosentan, an orally active competitive inhibitor of endothelin (see Chapter 17: Vasoactive Peptides), has been shown to have some benefits in experimental animal models of heart failure, but results in human trials have not been impressive. This drug is approved for use in pulmonary hypertension (see Chapter 11: Antihypertensive Agents). It has significant teratogenic and hepatotoxic effects. Beta Adrenoceptor Blockers Most patients with chronic heart failure respond favorably to certain -blockers in spite of the fact that these drugs can precipitate acute decompensation of cardiac function (see Chapter 10: Adrenoceptor Antagonist Drugs). Studies with bisoprolol, carvedilol, and metoprolol showed a reduction in mortality in patients with stable severe heart failure but this effect was not observed with another -blocker, bucindolol. A full understanding of the beneficial action of -blockade is lacking, but suggested mechanisms include attenuation of the adverse effects of high concentrations of catecholamines (including apoptosis), up-regulation of -receptors, decreased heart rate, and reduced remodeling through inhibition of the mitogenic activity of catecholamines. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 13. Drugs Used in Heart Failure > Clinical Pharmacology of Drugs Used in Heart Failure In the past, prescription of a diuretic plus digitalis was almost automatic in every case of chronic heart failure, and other drugs were rarely considered. At present, diuretics are still considered as first-line therapy, but digitalis is usually reserved for patients who do not respond adequately to diuretics, ACE inhibitors, and -blockers (Table 13–1). Management of Chronic Heart Failure The major steps in the management of patients with chronic heart failure are outlined in Table 13–4. Reduction of cardiac work is helpful in most cases. This can be accomplished by reducing activity and weight, and—especially important—control of hypertension. Table 13–4. Steps in the Treatment of Chronic Heart Failure.
1. Reduce workload of the heart
a. Limit activity level b. Reduce weight c. Control hypertension 2. Restrict sodium 3. Restrict water (rarely required) 4. Give diuretics 5. Give ACE inhibitor or angiotensin receptor blocker 6. Give digitalis if systolic dysfunction with 3rd heart sound or atrial fibrillation is present 7. Give -blockers to patients with stable class II–IV heart failure 8. Give vasodilators
Sodium Removal Sodium removal is the next important step—by dietary salt restriction or a diuretic—especially if edema is present. In mild failure, it is reasonable to start with a thiazide diuretic, switching to more powerful agents as required. Sodium loss causes secondary loss of potassium, which is particularly hazardous if the patient is to be given digitalis. Hypokalemia can be treated with potassium supplementation or through the addition of a potassium-sparing diuretic such as spironolactone. As noted above, spironolactone should probably be considered in all patients with moderate or severe heart failure since it appears to reduce both morbidity and mortality. ACE Inhibitors & Angiotensin Receptor Blockers In patients with left ventricular dysfunction but no edema, an ACE inhibitor should be used first. Several large studies have compared ACE inhibitors with digoxin or with other traditional therapies for chronic heart failure. The results show clearly that ACE inhibitors are superior to both placebo and to vasodilators and must be considered, along with diuretics, as first-line therapy for chronic failure. However, ACE inhibitors cannot replace digoxin in patients already receiving that drug because patients withdrawn from the cardiac glycoside while on ACE inhibitor therapy deteriorate. Additional studies suggest that ACE inhibitors are also valuable in asymptomatic patients with ventricular dysfunction. By reducing preload and afterload, these drugs appear to slow the rate of ventricular dilation and thus delay the onset of clinical heart failure. Thus, ACE inhibitors are beneficial in all subsets of patients, from those who are asymptomatic to those in severe chronic failure. It appears that all ACE inhibitors tested to date have beneficial effects in patients with chronic heart failure. Recent studies have documented these beneficial effects with enalapril, captopril, lisinopril, quinapril, and ramipril. Thus, this benefit appears to be a class effect. The angiotensin II receptor antagonists (eg, losartan, valsartan, etc) produce beneficial hemodynamic effects similar to those of the ACE inhibitors. However, large clinical trials suggest that the angiotensin receptor blockers should only be used in patients who are intolerant of ACE inhibitors (usually because of cough). Vasodilators
Vasodilator drugs can be divided into selective arteriolar dilators, venous dilators, and drugs with nonselective vasodilatory effects. For this purpose, the ACE inhibitors may be considered nonselective arteriolar and venous dilators. The choice of agent should be based on the patient's signs and symptoms and hemodynamic measurements. Thus, in patients with high filling pressures in whom the principal symptom is dyspnea, venous dilators such as long-acting nitrates will be most helpful in reducing filling pressures and the symptoms of pulmonary congestion. In patients in whom fatigue due to low left ventricular output is a primary symptom, an arteriolar dilator such as hydralazine may be helpful in increasing forward cardiac output. In most patients with severe chronic failure that responds poorly to other therapy, the problem usually involves both elevated filling pressures and reduced cardiac output. In these circumstances, dilation of both arterioles and veins is required. In one trial, combined therapy with hydralazine (arteriolar dilation) and isosorbide dinitrate (venous dilation) prolonged life more than placebo in patients already receiving digitalis and diuretics. Beta Blockers & Calcium Channel Blockers Many trials have evaluated the potential for -blocker therapy in patients with heart failure. The rationale is based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart contribute to the downward course of heart failure patients. However, such therapy must be initiated very cautiously at low doses, since acutely blocking the supportive effects of catecholamines can worsen heart failure. Several months of therapy may be required before improvement is noted; this usually consists of a slight rise in ejection fraction, slower heart rate, and reduction in symptoms. As noted above, bisoprolol, carvedilol, and metoprolol have been shown to reduce mortality. The calcium-blocking drugs appear to have no role in the treatment of patients with heart failure. Their depressant effects on the heart may worsen heart failure. Digitalis Digoxin is indicated in patients with heart failure and atrial fibrillation. It is also most helpful in patients with a dilated heart and third heart sound. It is usually given after ACE inhibitors. Only about 50% of patients with normal sinus rhythm (usually those with documented systolic dysfunction) will have documentable relief of heart failure from digitalis. Better results are obtained in patients with atrial fibrillation. If the decision is made to use a cardiac glycoside, digoxin is the one chosen in the great majority of cases (and the only one available in the USA). When symptoms are mild, slow loading (digitalization) (Table 13–3) is safer and just as effective as the rapid method. Determining the optimal level of digitalis effect may be difficult. In patients with atrial fibrillation, reduction of ventricular rate is the best measure of glycoside effect. In patients in normal sinus rhythm, symptomatic improvement and reductions in heart size, heart rate during exercise, venous pressure, or edema may signify optimum drug levels in the myocardium. Unfortunately, toxic effects may occur before the therapeutic end point is detected. If digitalis is being loaded slowly, simple omission of one dose and halving the maintenance dose will often bring the patient to the narrow range between suboptimal and toxic concentrations. Measurement of plasma digoxin levels is useful in patients who appear unusually resistant or sensitive; a level of 1.1 ng/mL or less is appropriate. Because it has a moderate but persistent positive inotropic effect, digitalis can, in theory, reverse the signs and symptoms of heart failure. In an appropriate patient, digitalis increases stroke work and
cardiac output. The increased output (and possibly a direct action resetting the sensitivity of the baroreceptors) eliminates the stimuli evoking increased sympathetic outflow, and both heart rate and vascular tone diminish. With decreased end-diastolic fiber tension (the result of increased systolic ejection and decreased filling pressure), heart size and oxygen demand decrease. Finally, increased renal blood flow improves glomerular filtration and reduces aldosterone-driven sodium reabsorption. Thus, edema fluid can be excreted, further reducing ventricular preload and the danger of pulmonary edema. Although digitalis had a neutral effect on mortality (Digitalis Investigation Group, 1997), it reduced hospitalization and deaths from progressive heart failure at the expense of an increase in sudden death. It is important to note that the mortality rate was reduced in patients with serum digoxin concentrations of 1 ng/mL or less but increased in those with digoxin levels greater than 1.5 ng/mL. Administration & Dosage Long-term treatment with digoxin requires careful attention to pharmacokinetics because of its long half-life. According to the rules set forth in Chapter 3: Pharmacokinetics & Pharmacodynamics: Rational Dosing & the Time Course of Drug Action, it will take three to four half-lives to approach steady-state total body load when given at a constant dosing rate, ie, approximately 1 week for digoxin. Typical doses used in adults are given in Table 13–5. A parenteral preparation of digoxin is available but is not used to achieve a faster onset of effect because the time to peak effect is determined mainly by time-dependent ion changes in the tissue. Thus, the parenteral preparation is only suitable for patients who cannot take drugs by mouth. Table 13–5. Clinical Use of Digoxin.1
Digoxin Therapeutic plasma concentration
0.5–1.5 ng/mL
Toxic plasma concentration
> 2 ng/mL
Daily dose (slow loading or maintenance) 0.25 (0.125–0.5) mg Rapid digitalizing dose (rarely used)
1
0.5–0.75 mg every 8 hours for three doses
These values are appropriate for adults with normal renal and hepatic function.
Interactions Patients are at risk for developing serious digitalis-induced cardiac arrhythmias if hypokalemia develops, as in diuretic therapy or diarrhea. Furthermore, patients taking digoxin are at risk if given quinidine, which displaces digoxin from tissue binding sites (a minor effect) and depresses renal digoxin clearance (a major effect). The plasma level of the glycoside may double within a few days after beginning quinidine therapy, and toxic effects may become manifest. As noted above, antibiotics that alter gastrointestinal flora may increase digoxin bioavailability in about 10% of patients. Finally, agents that release catecholamines may sensitize the myocardium to digitalisinduced arrhythmias. Other Clinical Uses of Digitalis Digitalis is useful in the management of atrial arrhythmias because of its cardioselective
parasympathomimetic effects. In atrial flutter, the depressant effect of the drug on atrioventricular conduction will help control an excessively high ventricular rate. The effects of the drug on the atrial musculature may convert flutter to fibrillation, with a further decrease in ventricular rate. In atrial fibrillation, the same vagomimetic action helps control ventricular rate, thereby improving ventricular filling and increasing cardiac output. Digitalis has also been used in the control of paroxysmal atrial and atrioventricular nodal tachycardia. At present, calcium channel blockers and adenosine are preferred for this application. Digitalis should be avoided in the therapy of arrhythmias associated with Wolff-Parkinson-White syndrome because it increases the probability of conduction of arrhythmic atrial impulses through the alternative rapidly conducting atrioventricular pathway. It is explicitly contraindicated in patients with Wolff-Parkinson-White syndrome and atrial fibrillation (see Chapter 14: Agents Used in Cardiac Arrhythmias). Toxicity In spite of its recognized hazards, digitalis is heavily used and toxicity is common. Therapy of toxicity manifested as visual changes or gastrointestinal disturbances generally requires no more than reducing the dose of the drug. If cardiac arrhythmia is present and can definitely be ascribed to digitalis, more vigorous therapy may be necessary. Serum digitalis and potassium levels and the ECG should be monitored during therapy of significant digitalis toxicity. Electrolyte status should be corrected if abnormal (see above). For patients who do not respond promptly (within one to two half-lives), calcium and magnesium as well as potassium levels should be checked. For occasional premature ventricular depolarizations or brief runs of bigeminy, oral potassium supplementation and withdrawal of the glycoside may be sufficient. If the arrhythmia is more serious, parenteral potassium and antiarrhythmic drugs may be required. Of the available antiarrhythmic agents, lidocaine is favored. In severe digitalis intoxication (which usually involves young children or suicidal overdose), serum potassium will already be elevated at the time of diagnosis (because of potassium loss from the intracellular compartment of skeletal muscle and other tissues). Furthermore, automaticity is usually depressed, and antiarrhythmic agents administered in this setting may lead to cardiac arrest. Such patients are best treated with insertion of a temporary cardiac pacemaker catheter and administration of digitalis antibodies (digoxin immune fab). These antibodies are produced in sheep, and although they are raised to digoxin they also recognize digitoxin and cardiac glycosides from many other plants. They are extremely useful in reversing severe intoxication with most glycosides. Digitalis-induced arrhythmias are frequently made worse by cardioversion; this therapy should be reserved for ventricular fibrillation if the arrhythmia is glycoside-induced. Management of Acute Heart Failure Acute heart failure occurs frequently in patients with chronic failure. Such episodes are usually associated with increased exertion, emotion, salt in the diet, noncompliance with medical therapy, or increased metabolic demand occasioned by fever, anemia, etc. A particularly common and important cause of acute failure—with or without chronic failure—is acute myocardial infarction. Patients with acute myocardial infarction are best treated with emergency revascularization with either coronary angioplasty and a stent or a thrombolytic agent. Even with revascularization, acute failure may develop in such patients. Many of the signs and symptoms of acute and chronic failure
are identical, but their therapies diverge because of the need for more rapid response and the relatively greater frequency and severity of pulmonary vascular congestion in the acute form. Measurements of arterial pressure, cardiac output, stroke work index, and pulmonary capillary wedge pressure are particularly useful in patients with acute myocardial infarction and acute heart failure. Such patients can be usefully characterized on the basis of three hemodynamic measurements: arterial pressure, left ventricular filling pressure, and cardiac index. One such classification and therapies that have proved most effective are set forth in Table 13–6. When filling pressure is greater than 15 mm Hg and stroke work index is less than 20 g-m/m2, the mortality rate is high (Figure 13–3). Intermediate levels of these two variables imply a much better prognosis. Table 13–6. Therapeutic Classification of Subsets in Acute Myocardial Infarction.1
Subset
Systolic Left Ventricular Arterial Filling Pressure Pressure (mm (mm Hg) Hg)
Cardiac Index (L/min/m2)
Therapy
1. Hypovolemia
< 100
< 10
< 2.5
Volume replacement
2. Pulmonary congestion
100–150
> 20
> 2.5
Diuretics
3. Peripheral vasodilation
< 100
10–20
> 2.5
None, or vasoactive drugs
4. Power failure
< 100
> 20
< 2.5
Vasodilators, inotropic drugs
5. Severe shock
< 90
> 20
< 2.0
Vasoactive drugs, inotropic drugs, vasodilators, circulatory assist
6. Right ventricular < 100 infarct
RVFP > 10
< 2.5
Provide volume replacement for LVFP, inotropic drugs. Avoid diuretics.
7. Mitral regurgitation, ventricular septal defect
> 20
< 2.5
Vasodilators, inotropic drugs, circulatory assist, surgery
< 100
LVFP < 15
1
The numerical values are intended to serve as general guidelines and not as absolute cutoff points. Arterial pressures apply to patients who were previously normotensive and should be adjusted upward for patients who were previously hypertensive. (RVFP and LVFP = right and left ventricular filling pressure.) Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 13. Drugs Used in Heart Failure >
Preparations Available (Diuretics: See Chapter 15: Diuretic Agents.) Digitalis Digoxin (generic, Lanoxicaps, Lanoxin) Oral: 0.125, 0.25 mg tablets; 0.05, 0.1, 0.2 mg capsules*; 0.05 mg/mL elixir Parenteral: 0.1, 0.25 mg/mL for injection Digitalis Antibody Digoxin immune fab (ovine) (digibind, digifab) Parenteral: 38 or 40 mg per vial with 75 mg sorbitol lyophilized powder to reconstitute for IV injection. Each vial will bind approximately 0.5 mg digoxin or digitoxin. Sympathomimetics Most Commonly Used in Congestive Heart Failure Dobutamine (generic, Dobutrex) Parenteral: 12.5 mg/mL for IV infusion Dopamine (generic, Intropin) Parenteral: 40, 80, 160 mg/mL for IV injection; 80, 160, 320 mg/dL in 5% dextrose for IV infusion Angiotensin-Converting Enzyme Inhibitors Labeled for Use in Congestive Heart Failure Captopril (generic, Capoten) Oral: 12.5, 25, 50, 100 mg tablets Enalapril (Vasotec, Vasotec I.V.) Oral: 2.5, 5, 10, 20 mg tablets Parenteral: 1.25 mg enalaprilat/mL Fosinopril (Monopril) Oral: 10, 20, 40 mg tablets Lisinopril (Prinivil, Zestril) Oral: 2.5, 5, 10, 20, 40 mg tablets Quinapril (Accupril)
Oral: 5, 10, 20, 40 mg tablets Ramipril (Altace) Oral: 1.25, 2.5, 5, 10 mg capsules Trandolapril (Mavik) Oral: 1, 2, 5 mg tablets Angiotensin Receptor Blockers Candesartan (Atacand) Oral: 4, 8, 16, 32 mg tablets Eprosartan (Teveten) Oral: 400, 800 mg tablets Irbesartan (Avapro) Oral: 75, 150, 300 mg tablets Losartan (Cozaar) Oral: 25, 50, 100 mg tablets Olmesartan (Benicar) Oral: 5, 20, 40 mg tablets Telmisartan (Micardis) Oral: 20, 40, 80 mg tablets Valsartan (Diovan) Oral: 40, 80, 160, 320 mg tablets Beta-Blockers That Have Reduced Mortality in Heart Failure Bisoprolol (Zebeta, unlabeled use) Oral: 5, 10 mg tablets Carvedilol (Coreg) Oral: 3.125, 6.25, 12.5, 25 mg tablets
Metoprolol (Lopressor, Toprol XL) Oral: 50, 100 mg tablets; 25, 50, 100, 200 mg extended-release tablets Parenteral: 1 mg/mL for IV injection Other Drugs Inamrinone Parenteral: 5 mg/mL for IV injection Milrinone (generic, Primacor) Parenteral: 1 mg/mL for IV injection; 200 g/mL premixed for IV infusion Nesiritide (Natrecor) Parenteral: 1.58 mg powder for IV injection Bosentan (Tracleer) Oral: 62.5, 125 mg tablets
Chapter 14. Agents Used in Cardiac Arrhythmias Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Agents Used in Cardiac Arrhythmias: Introduction *The authors acknowledge the contributions of the previous authors of this chapter, Drs L Hondeghem and D Roden. Cardiac arrhythmias are a frequent problem in clinical practice, occurring in up to 25% of patients treated with digitalis, 50% of anesthetized patients, and over 80% of patients with acute myocardial infarction. Arrhythmias may require treatment because rhythms that are too rapid, too slow, or asynchronous can reduce cardiac output. Some arrhythmias can precipitate more serious or even lethal rhythm disturbances—eg, early premature ventricular depolarizations can precipitate ventricular fibrillation. In such patients, antiarrhythmic drugs may be lifesaving. On the other hand, the hazards of antiarrhythmic drugs—and in particular the fact that they can precipitate lethal arrhythmias in some patients—has led to a reevaluation of their relative risks and benefits. In general, treatment of asymptomatic or minimally symptomatic arrhythmias should be avoided for this reason. Arrhythmias can be treated with the drugs discussed in this chapter and with nonpharmacologic therapies such as pacemakers, cardioversion, catheter ablation, and surgery. This chapter describes
the pharmacology of drugs that suppress arrhythmias by a direct action on the cardiac cell membrane. Other modes of therapy are discussed briefly. Electrophysiology of Normal Cardiac Rhythm The electrical impulse that triggers a normal cardiac contraction originates at regular intervals in the sinoatrial node (Figure 14–1), usually at a frequency of 60–100 beats per minute. This impulse spreads rapidly through the atria and enters the atrioventricular node, which is normally the only conduction pathway between the atria and ventricles. Conduction through the atrioventricular node is slow, requiring about 0.15 s. (This delay provides time for atrial contraction to propel blood into the ventricles.) The impulse then propagates over the His-Purkinje system and invades all parts of the ventricles. Ventricular activation is complete in less than 0.1 s; therefore, contraction of all of the ventricular muscle is synchronous and hemodynamically effective. Figure 14–1.
Schematic representation of the heart and normal cardiac electrical activity (intracellular recordings from areas indicated and ECG). Sinoatrial node, atrioventricular node, and Purkinje cells display pacemaker activity (phase 4 depolarization). The ECG is the body surface manifestation of the depolarization and repolarization waves of the heart. The P wave is generated by atrial depolarization, the QRS by ventricular muscle depolarization, and the T wave by ventricular repolarization. Thus, the PR interval is a measure of conduction time from atrium to ventricle, and the QRS duration indicates the time required for all of the ventricular cells to be activated (ie, the intraventricular conduction time). The QT interval reflects the duration of the ventricular action potential. Arrhythmias consist of cardiac depolarizations that deviate from the above description in one or more aspects– ie, there is an abnormality in the site of origin of the impulse, its rate or regularity, or its conduction.
Ionic Basis of Membrane Electrical Activity The transmembrane potential of cardiac cells is determined by the concentrations of several ions— chiefly sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl–)—on either side of the membrane and the permeability of the membrane to each ion. These water-soluble ions are unable to freely diffuse across the lipid cell membrane in response to their electrical and concentration gradients; they require aqueous channels (specific pore-forming proteins) for such diffusion. Thus, ions move across cell membranes in response to their gradients only at specific times during the cardiac cycle when these ion channels are open. The movements of these ions produce currents that form the basis of the cardiac action potential. Individual channels are relatively ion-specific, and the flux of ions through them is thought to be controlled by "gates" (probably flexible peptide chains or energy barriers). Each type of channel has its own type of gate (sodium, calcium, and some potassium channels are each thought to have two types of gates), and each type of gate is opened and closed by specific transmembrane voltage, ionic, or metabolic conditions. At rest, most cells are not significantly permeable to sodium, but at the start of each action potential, they become quite permeable (see below). Similarly, calcium enters and potassium leaves the cell with each action potential. Therefore, the cell must have a mechanism to maintain stable transmembrane ionic conditions by establishing and maintaining ion gradients. The most important of these active mechanisms is the sodium pump, Na+/K+ ATPase, described in Chapter 13: Drugs Used in Heart Failure. This pump and other active ion carriers contribute indirectly to the transmembrane potential by maintaining the gradients necessary for diffusion through channels. In addition, some pumps and exchangers produce net current flow (eg, by exchanging three Na+ for two K+ ions) and hence are termed "electrogenic." When the cardiac cell membrane becomes permeable to a specific ion (ie, when the channels selective for that ion are open), movement of that ion across the cell membrane is determined by Ohm's law: current = voltage ÷ resistance, or current = voltage x conductance. Conductance is determined by the properties of the individual ion channel protein. The voltage term is the difference between the actual membrane potential and the reversal potential for that ion (the membrane potential at which no current would flow even if channels were open). For example, in the case of sodium in a cardiac cell at rest, there is a substantial concentration gradient (140 mmol/L Na+ outside; 10–15 mmol/L Na+ inside) and electrical gradient (0 mV outside; –90 mV inside) that would drive Na+ into cells. Sodium does not enter the cell at rest because sodium channels are closed; when sodium channels open, the very large influx of Na+ ions accounts for phase 0 depolarization. The situation for K+ ions in the resting cardiac cell is quite different. Here, the concentration gradient (140 mmol/L inside; 4 mmol/L outside) would drive the ion out of the cell, but the electrical gradient would drive it in, ie, the inward gradient is in equilibrium with the outward gradient. In fact, certain potassium channels ("inward rectifier" channels) are open in the resting cell, but little current flows through them because of this balance. The equilibrium, or reversal potential, for ions is determined by the Nernst equation:
where Ce and Ci are the extracellular and intracellular concentrations, respectively, multiplied by their activity coefficients. Note that raising extracellular potassium makes EK less negative. When this occurs, the membrane depolarizes until EK is reached. Thus, extracellular potassium concentration and inward rectifier channel function are the major factors determining the membrane potential of the resting cardiac cell. The conditions required for application of the Nernst equation are approximated at the peak of the overshoot and during rest in most nonpacemaker cardiac cells.
If the permeability is significant for both potassium and sodium, the Nernst equation is not a good predictor of membrane potential, but the Goldman-Hodgkin-Katz equation may be used.
In pacemaker cells (whether normal or ectopic), spontaneous depolarization (the pacemaker potential) occurs during diastole (phase 4, Figure 14–1). This depolarization results from a gradual increase of depolarizing current through special hyperpolarization-activated ion channels in pacemaker cells. The effect of changing extracellular potassium is more complex in a pacemaker cell than it is in a nonpacemaker cell because the effect on permeability to potassium is much more important in a pacemaker (see Effects of Potassium). In a pacemaker—especially an ectopic one— the end result of an increase in extracellular potassium will usually be to slow or stop the pacemaker. Conversely, hypokalemia will often facilitate ectopic pacemakers. The Active Cell Membrane In normal atrial, Purkinje, and ventricular cells, the action potential upstroke (phase 0) is dependent on sodium current. From a functional point of view, it is convenient to describe the behavior of the sodium current in terms of three channel states (Figure 14–2). The cardiac sodium channel protein has been cloned, and it is now recognized that these channel states actually represent different protein conformations. In addition, regions of the protein that confer specific behaviors, such as voltage sensing, pore formation, and inactivation, are now being identified. The gates described below and in Figure 14–2 represent such regions. Figure 14–2.
A schematic representation of Na+ channels cycling through different conformational states during the cardiac action potential. Transitions between resting, activated, and inactivated states are dependent on membrane potential and time. The activation gate is shown as m and the inactivation
gate as h. Potentials typical for each state are shown under each channel schematic as a function of time. The dashed line indicates that part of the action potential during which most Na+ channels are completely or partially inactivated and unavailable for reactivation.
Depolarization to the threshold voltage results in opening of the activation (m) gates of sodium channels (Figure 14–2, middle). If the inactivation (h) gates of these channels have not already closed, the channels are now open or activated, and sodium permeability is markedly increased, greatly exceeding the permeability for any other ion. Extracellular sodium therefore diffuses down its electrochemical gradient into the cell, and the membrane potential very rapidly approaches the sodium equilibrium potential, ENa (about +70 mV when Nae = 140 mmol/L and Nai = 10 mmol/L). This intense sodium current is very brief because opening of the m gates upon depolarization is promptly followed by closure of the h gates and inactivation of the sodium channels (Figure 14–2, right). Most calcium channels become activated and inactivated in what appears to be the same way as sodium channels, but in the case of the most common type of cardiac calcium channel (the "L" type), the transitions occur more slowly and at more positive potentials. The action potential plateau (phases 1 and 2) reflects the turning off of most of the sodium current, the waxing and waning of calcium current, and the slow development of a repolarizing potassium current. Final repolarization (phase 3) of the action potential results from completion of sodium and calcium channel inactivation and the growth of potassium permeability, so that the membrane potential once again approaches the potassium equilibrium potential. The major potassium currents involved in phase 3 repolarization include a rapidly activating potassium current (IKr) and a slowly activating potassium current (IKs). These processes are diagrammed in Figure 14–3. Figure 14–3.
Schematic diagram of the ion permeability changes and transport processes that occur during an action potential and the diastolic period following it. The size and weight of the arrows indicate approximate magnitudes of the ion channel currents; arrows pointing down indicate inward (depolarizing) membrane currents, arrows pointing up indicate outward (repolarizing) membrane currents. Multiple subtypes of potassium and calcium currents, with different sensitivities to blocking drugs, have been identified. Chloride currents (dotted arrows) produce both inward and outward membrane currents during the cardiac action potential. The Effect of Resting Potential on Action Potentials A key factor in the pathophysiology of arrhythmias and the actions of antiarrhythmic drugs is the relationship between the resting potential of a cell and the action potentials that can be evoked in it (Figure 14–4, left panel). Because the inactivation gates of sodium channels in the resting membrane close over the potential range –75 to –55 mV, fewer sodium channels are "available" for diffusion of sodium ions when an action potential is evoked from a resting potential of –60 mV than when it is evoked from a resting potential of –80 mV. Important consequences of the reduction in peak sodium permeability include reduced upstroke velocity (called max, for maximum rate of change of membrane voltage), reduced action potential amplitude, reduced excitability, and reduced conduction velocity. Figure 14–4.
Dependence of sodium channel function on the membrane potential preceding the stimulus. Left: The fraction of sodium channels available for opening in response to a stimulus is determined by the membrane potential immediately preceding the stimulus. The decrease in the fraction available when the resting potential is depolarized in the absence of a drug (control curve) results from the voltage-dependent closure of h gates in the channels. The curve labeled Drug illustrates the effect of a typical local anesthetic antiarrhythmic drug. Most sodium channels are inactivated during the plateau of the action potential. Right: The time constant for recovery from inactivation after repolarization also depends on the resting potential. In the absence of drug, recovery occurs in less than 10 ms at normal resting potentials (–85 to –95 mV). Depolarized cells recover more slowly (note logarithmic scale). In the presence of a sodium channel-blocking drug, the time constant of recovery is increased, but the increase is far greater at depolarized potentials than at more negative ones. During the plateau of the action potential, most sodium channels are inactivated. Upon repolarization, recovery from inactivation takes place (in the terminology of Figure 14–2, the h gates reopen), making the channels again available for excitation. The time between phase 0 and sufficient recovery of sodium channels in phase 3 to permit a new propagated response to external stimulus is the refractory period. Changes in refractoriness (determined by either altered recovery from inactivation or altered action potential duration) can be important in the genesis or suppression of certain arrhythmias. Another important effect of less negative resting potential is prolongation of this recovery time, as shown in Figure 14–4 (right panel). The prolongation of recovery time is reflected in an increase in the effective refractory period. A brief depolarizing stimulus, whether caused by a propagating action potential or by an external electrode arrangement, causes the opening of large numbers of activation gates before a significant number of inactivation gates can close. In contrast, slow reduction (depolarization) of the resting potential, whether brought about by hyperkalemia, sodium pump blockade, or ischemic cell damage, results in depressed sodium currents during the upstrokes of action potentials. Depolarization of the resting potential to levels positive to –55 mV abolishes sodium currents, since all sodium channels are inactivated. However, such severely depolarized cells have been found to support special action potentials under circumstances that increase calcium permeability or decrease potassium permeability. These "slow responses"—slow upstroke velocity and slow conduction— depend on a calcium inward current and constitute the normal electrical activity in the sinoatrial and atrioventricular nodes, since these tissues have a normal resting potential in the range of –50 to –70 mV. Slow responses may also be important for certain arrhythmias. Modern techniques of
molecular biology and electrophysiology can identify multiple subtypes of calcium and potassium channels. One way in which such subtypes may differ is in sensitivity to drug effects, so drugs targeting specific channel subtypes may be developed in the future. Mechanisms of Arrhythmias Many factors can precipitate or exacerbate arrhythmias: ischemia, hypoxia, acidosis or alkalosis, electrolyte abnormalities, excessive catecholamine exposure, autonomic influences, drug toxicity (eg, digitalis or antiarrhythmic drugs), overstretching of cardiac fibers, and the presence of scarred or otherwise diseased tissue. However, all arrhythmias result from (1) disturbances in impulse formation, (2) disturbances in impulse conduction, or (3) both. Disturbances of Impulse Formation The interval between depolarizations of a pacemaker cell is the sum of the duration of the action potential and the duration of the diastolic interval. Shortening of either duration results in an increase in pacemaker rate. The more important of the two, diastolic interval, is determined primarily by the slope of phase 4 depolarization (pacemaker potential). Vagal discharge and receptor-blocking drugs slow normal pacemaker rate by reducing the phase 4 slope (acetylcholine also makes the maximum diastolic potential more negative). Acceleration of pacemaker discharge is often brought about by increased phase 4 depolarization slope, which can be caused by hypokalemia, -adrenoceptor stimulation, positive chronotropic drugs, fiber stretch, acidosis, and partial depolarization by currents of injury. Latent pacemakers (cells that show slow phase 4 depolarization even under normal conditions, eg, some Purkinje fibers) are particularly prone to acceleration by the above mechanisms. However, all cardiac cells, including normally quiescent atrial and ventricular cells, may show repetitive pacemaker activity when depolarized under appropriate conditions, especially if hypokalemia is also present. Afterdepolarizations (Figure 14–5) are depolarizations that interrupt phase 3 (early afterdepolarizations, EADs) or phase 4 (delayed afterdepolarizations, DADs). DADs, discussed in Chapter 13: Drugs Used in Heart Failure, often occur when intracellular calcium is increased. They are exacerbated by fast heart rates and are thought to be responsible for some arrhythmias related to digitalis excess, to catecholamines, and to myocardial ischemia. EADs, on the other hand, are usually exacerbated at slow heart rates and are thought to contribute to the development of long QTrelated arrhythmias (see Molecular & Genetic Bases of Cardiac Arrhythmias). Figure 14–5.
Two forms of abnormal activity, early (top) and delayed afterdepolarizations (bottom). In both cases, abnormal depolarizations arise during or after a normally evoked action potential. They are therefore often referred to as "triggered" automaticity, ie, they require a normal action potential for their initiation. Disturbances of Impulse Conduction Severely depressed conduction may result in simple block, eg, atrioventricular nodal block or bundle branch block. Because parasympathetic control of atrioventricular conduction is significant, partial atrioventricular block is sometimes relieved by atropine. Another common abnormality of conduction is reentry (also known as "circus movement"), in which one impulse reenters and excites areas of the heart more than once (Figure 14–6). The path of the reentering impulse may be confined to very small areas, eg, within or near the atrioventricular node, or it may involve large portions of the atrial or ventricular walls. Some forms of reentry are strictly anatomically determined; for example, in the Wolff-Parkinson-White syndrome, the reentry circuit consists of atrial tissue, the AV node, ventricular tissue, and an accessory atrioventricular connection (a "bypass tract"). In other cases (eg, atrial or ventricular fibrillation), multiple reentry circuits, determined by the properties of the cardiac tissue, may meander through the heart in apparently random paths. Furthermore, the circulating impulse often gives off "daughter impulses" that can spread to the rest of the heart. Depending on how many round trips through the pathway the impulse makes before dying out, the arrhythmia may be manifest as one or a few extra beats or as a sustained tachycardia. Figure 14–6.
Schematic diagram of a reentry circuit that might occur in small bifurcating branches of the Purkinje system where they enter the ventricular wall. A: Normally, electrical excitation branches around the circuit, is transmitted to the ventricular branches, and becomes extinguished at the other end of the circuit due to collision of impulses. B: An area of unidirectional block develops in one of the branches, preventing anterograde impulse transmission at the site of block, but the retrograde impulse may be propagated through the site of block if the impulse finds excitable tissue, ie, the refractory period is shorter than the conduction time. This impulse will then reexcite tissue it had previously passed through, and a reentry arrhythmia will be established. In order for reentry to occur, three conditions must coexist, as indicated in Figure 14–6: (1) There must be an obstacle (anatomic or physiologic) to homogeneous conduction, thus establishing a circuit around which the reentrant wavefront can propagate; (2) there must be unidirectional block at some point in the circuit, ie, conduction must die out in one direction but continue in the opposite direction (as shown in Figure 14–6, the impulse can gradually decrease as it invades progressively more depolarized tissue until it finally blocks—a process known as decremental conduction); and (3) conduction time around the circuit must be long enough so that the retrograde impulse does not enter refractory tissue as it travels around the obstacle, ie, the conduction time must exceed the effective refractory period. Importantly, reentry depends on conduction that has been depressed by some critical amount, usually as a result of injury or ischemia. If conduction velocity is too slow,
conduction may fail, or the impulse may arrive so late that it collides with the next regular impulse. On the other hand, if conduction is too rapid, ie, almost normal, bidirectional conduction rather than unidirectional block will occur. Even in the presence of unidirectional block, if the impulse travels around the obstacle too rapidly, it will reach tissue that is still refractory. Slowing of conduction may be due to depression of sodium current, depression of calcium current (the latter especially in the atrioventricular node), or both. Drugs that abolish reentry usually work by further slowing depressed conduction (by blocking the sodium or calcium current) and causing bidirectional block. In theory, accelerating conduction (by increasing sodium or calcium current) would also be effective, but only under very unusual circumstances does this mechanism explain the action of any available drug. Lengthening (or shortening) of the refractory period may also make reentry less likely. The longer the refractory period in tissue near the site of block, the greater the chance that the tissue will still be refractory when reentry is attempted. (Alternatively, the shorter the refractory period in the depressed region, the less likely it is that unidirectional block will occur.) Thus, increased dispersion of refractoriness is one contributor to reentry, and drugs may suppress arrhythmias by reducing such dispersion. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Effects of Potassium The effects of changes in serum potassium on cardiac action potential duration, pacemaker rate, and arrhythmias can appear somewhat paradoxical if changes are predicted based solely on a consideration of changes in the potassium electrochemical gradient. In the heart, however, changes in serum potassium concentration have an additional effect to alter potassium conductance (increased extracellular potassium increases potassium conductance) independent of simple changes in electrochemical driving force, and this effect often predominates. As a result, the actual observed effects of hyperkalemia include reduced action potential duration, slowed conduction, decreased pacemaker rate, and decreased pacemaker arrhythmogenesis. Conversely, the actual observed effects of hypokalemia include prolonged action potential duration, increased pacemaker rate, and increased pacemaker arrhythmogenesis. Furthermore, pacemaker rate and arrhythmias involving ectopic pacemaker cells appear to be more sensitive to changes in serum potassium concentration, compared with cells of the sinoatrial node. These effects of serum potassium on the heart probably contribute to the observed increased sensitivity to potassium channel-blocking antiarrhythmic agents (quinidine or sotalol) during hypokalemia, eg, accentuated action potential prolongation and tendency to cause torsade de pointes. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Basic Pharmacology of the Antiarrhythmic Agents Mechanisms of Action Arrhythmias are caused by abnormal pacemaker activity or abnormal impulse propagation. Thus, the aim of therapy of the arrhythmias is to reduce ectopic pacemaker activity and modify conduction or refractoriness in reentry circuits to disable circus movement. The major mechanisms currently available for accomplishing these goals are (1) sodium channel blockade, (2) blockade of sympathetic autonomic effects in the heart, (3) prolongation of the effective refractory period, and
(4) calcium channel blockade. Antiarrhythmic drugs decrease the automaticity of ectopic pacemakers more than that of the sinoatrial node. They also reduce conduction and excitability and increase the refractory period to a greater extent in depolarized tissue than in normally polarized tissue. This is accomplished chiefly by selectively blocking the sodium or calcium channels of depolarized cells (Figure 14–8). Therapeutically useful channel-blocking drugs have a high affinity for activated channels (ie, during phase 0) or inactivated channels (ie, during phase 2) but very low affinity for rested channels. Therefore, these drugs block electrical activity when there is a fast tachycardia (many channel activations and inactivations per unit time) or when there is significant loss of resting potential (many inactivated channels during rest). This type of drug action is often described as usedependent or state-dependent, ie, channels that are being used frequently, or in an inactivated state, are more susceptible to block. Channels in normal cells that become blocked by a drug during normal activation-inactivation cycles will rapidly lose the drug from the receptors during the resting portion of the cycle (Figure 14–8). Channels in myocardium that is chronically depolarized (ie, has a resting potential more positive than –75 mV) will recover from block very slowly if at all (see also right panel, Figure 14–4). Figure 14–8.
Diagram of a mechanism for the selective depressant action of antiarrhythmic drugs on sodium channels. The upper portion of the figure shows the population of channels moving through a cycle of activity during an action potential in the absence of drugs: R (rested) A (activated) I (inactivated). Recovery takes place via the I R pathway. Antiarrhythmic drugs (D) that act by blocking sodium channels can bind to their receptors in the channels, as shown by the vertical arrows, to form drug-channel complexes, indicated as R-D, A-D, and I-D. Affinity of the drugs for the receptor varies with the state of the channel, as indicated by the separate rate constants (k and l) for the R R-D, A A-D, and I I-D steps. The data available for a variety of sodium channel blockers indicate that the affinity of the drugs for the active and inactivated channel receptor is much higher than the affinity for the rested channel. Furthermore, recovery from the I-D state to the R-D state is much slower than from I to R. As a result, rapid activity (more activations and inactivations) and depolarization of the resting potential (more channels in the I state) will favor blockade of the channels and selectively suppress arrhythmic cells. In cells with abnormal automaticity, most of these drugs reduce the phase 4 slope by blocking either sodium or calcium channels and thereby reducing the ratio of sodium (or calcium) permeability to potassium permeability. As a result, the membrane potential during phase 4 stabilizes closer to the potassium equilibrium potential. In addition, some agents may increase the threshold (make it more positive). Beta-adrenoceptor-blocking drugs indirectly reduce the phase 4 slope by blocking the positive chronotropic action of norepinephrine in the heart.
In reentry arrhythmias, which depend on critically depressed conduction, most antiarrhythmic agents slow conduction further by one or both of two mechanisms: (1) steady-state reduction in the number of available unblocked channels, which reduces the excitatory currents to a level below that required for propagation (Figure 14–4, left); and (2) prolongation of recovery time of the channels still able to reach the rested and available state, which increases the effective refractory period (Figure 14–4, right). As a result, early extrasystoles are unable to propagate at all; later impulses propagate more slowly and are subject to bidirectional conduction block. By these mechanisms, antiarrhythmic drugs can suppress ectopic automaticity and abnormal conduction occurring in depolarized cells—rendering them electrically silent—while minimally affecting the electrical activity in normally polarized parts of the heart. However, as dosage is increased, these agents also depress conduction in normal tissue, eventually resulting in druginduced arrhythmias. Furthermore, a drug concentration that is therapeutic (antiarrhythmic) under the initial circumstances of treatment may become "proarrhythmic" (arrhythmogenic) during fast heart rates (more development of block), acidosis (slower recovery from block for most drugs), hyperkalemia, or ischemia. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Molecular & Genetic Basis of Cardiac Arrhythmias During the past decade, molecular biologic, genetic, and biophysical approaches have provided remarkable new insights into the molecular basis of several congenital and acquired cardiac arrhythmias. The best example is the polymorphic ventricular tachycardia known as torsade de pointes (shown in Figure 14–7), which is associated with syncope and sudden death. The electrocardiographic hallmark of both the acquired and congenital syndromes is prolongation of the QT interval, especially at the onset of the tachycardia. As can be inferred from Figure 14–1, this must represent prolongation of the action potential of at least some ventricular cells. This effect can, in theory, be attributed either to increased inward current (gain of function) or decreased outward current (loss of function) during the plateau of the action potential. In fact, recent molecular genetic studies have identified up to 300 different mutations in at least five ion channel genes that produce the congenital long QT (LQT) syndrome (Table 14–1), and each mutation may have different clinical implications. Loss of function mutations in potassium channel genes produce decreases in outward repolarizing current and are responsible for LQT subtypes 1, 2, 5, and 6. HERG and KCNE2 (MiRP1) genes encode subunits of the the rapid delayed rectifer potassium curent (IKr), whereas KCNQ1 and KCNE1 (minK) encode subunits of the slow delayed rectifier potassium current (IKs). In contrast, gain of function mutations in the sodium channel gene (SCN5A) cause increases in inward plateau current and are responsible for LQT subtype 3. Figure 14–7.
Electrocardiogram from a patient with the long QT syndrome during two episodes of torsade de pointes. The polymorphic ventricular tachycardia is seen at the start of this tracing and spontaneously halts at the middle of the panel. A single normal sinus beat (NSB) with an extremely prolonged QT interval follows, succeeded immediately by another episode of ventricular tachycardia of the torsade type. The usual symptoms would be dizziness or transient loss of consciousness. Table 14–1. Molecular and Genetic Basis of Some Cardiac Arrhythmias.
Type
Chromosome Involved
Defective Gene
Ion Channel or Proteins Affected
Result1
LQT-12
11
KCNQ1
IKs
LF
LQT-2
7
HERG
IKr
LF
LQT-3
3
SCN5A
INa
GF
LQT-4
4
Ankyrin-B
3
LF
LQT-5
21
KCNE1 (minK)
IKs
LF
LQT-6
21
KCNE2 (MiRP1)
IKr
LF
Brugada syndrome
3
SCN5A
INa
LF
PCCD4
3
SCN5A
INa
LF
Familial atrial
11
KCNQ1
IKs
GF
fibrillation
1
LF, loss of function; GF, gain of function.
2
LQT, long QT syndrome.
3
Ankyrins are intracellular proteins that associate with a variety of transport proteins including Na+ channels, Na+/K+ ATPase, Na+/Ca2+ exchange, Ca2+ release channels. 4
PCCD, progressive cardiac conduction disorder.
Molecular genetic studies have identified the reason why congenital and acquired cases of torsades de pointes can be so strikingly similar. The potassium channel gene (HERG) that encodes IKr, is blocked or modified by many drugs (eg, quinidine, sotalol) or electrolyte abnormalities (hypokalemia, hypomagnesemia, hypocalcemia) that also produce torsades de pointes. Thus, the identification of the precise molecular mechanisms underlying various forms of the long QT syndromes now raises the possibility that specific therapies may be developed for individuals with defined molecular abnormalities. Indeed, preliminary reports suggest that the sodium channel blocker mexiletine can correct the clinical manifestations of congenital long QT subtype 3 syndrome. In vitro and clinical data demonstrate that most available action potential-prolonging drugs exert greater effects at slow rates (where torsade de pointes is a risk) than at fast rates (where arrhythmia suppression would occur). This "reverse use-dependent" action potential prolongation seems to be absent with amiodarone, which may help explain that drug's apparently greater clinical efficacy with its low rate of torsade de pointes. It is likely that torsade de pointes originates from triggered upstrokes arising from early afterdepolarizations (Figure 14–5). Thus, therapy is directed at correcting hypokalemia, eliminating triggered upstrokes (eg, by using -blockers or magnesium), or shortening the action potential (eg, by increasing heart rate with isoproterenol or pacing)—or all of these. The molecular basis of several other congenital cardiac arrhythmias associated with sudden death has also recently been identified. The Brugada syndrome, which is characterized by ventricular fibrillation associated with persistent ST-segment elevation and progressive cardiac conduction disorder (PCCD), characterized by impaired conduction in the His-Purkinje system and right or left bundle block leading to complete atrioventricular block, have both been linked to several loss-offunction mutations in the sodium channel gene, SCN5A. At least one form of familial atrial fibrillation is caused by a gain-of-function mutation in the potassium channel gene, KCNQ1. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Specific Antiarrhythmic Agents The most widely used scheme for the classification of antiarrhythmic drug actions recognizes four classes: 1. Class 1 action is sodium channel blockade. Subclasses of this action reflect effects on the action potential duration (APD) and the kinetics of sodium channel blockade. Drugs with class 1A action prolong the APD and dissociate from the channel with intermediate kinetics; drugs with class 1B action have no significant effects on the APD and dissociate from the channel with rapid kinetics; and drugs with class 1C action have minimal effects on the APD and
dissociate from the channel with slow kinetics. 2. Class 2 action is sympatholytic. Drugs with this action reduce -adrenergic activity in the heart. 3. Class 3 action is manifest by prolongation of the APD. Most drugs with this action block the rapid component of the delayed rectifier potassium current, IKr. 4. Class 4 action is blockade of the cardiac calcium current. This action slows conduction in regions where the action potential upstroke is calcium dependent, eg, the sinoatrial and atrioventricular nodes. A given drug may have multiple classes of action. For example, amiodarone shares all four classes of action. Drugs are usually discussed according to the predominant class of action. Certain antiarrhythmic agents, eg, adenosine and magnesium, do not fit readily into this scheme and are described separately. See Table 14–2 and Table 14–3. Table 14–2. Membrane Actions of Antiarrhythmic Drugs.
Block of Sodium Channels
Refractory Period
Drug
Norma Depolarize Norma Depolarize Calcium Effect on Sympatholyti l Cells d Cells l Cells d Cells Channel Pacemake c Action Blockad r Activity e
Adenosine
Amiodarone +
+++
+
Bretylium
Diltiazem
Disopyramid + e
+++
Dofetilide
Esmolol
+
Flecainide
+
+++
Ibutilide
Lidocaine
+++
Mexiletine
+++
Moricizine
+
Procainamide +
+ + 1
++
+++
+
?
NA2
+++
?
++
+++
+
Propafenone +
++
+
+
Propranolol
+
+++
Quinidine
+
++
+
Sotalol
++
Tocainide
+++
Verapamil
+
+++
+
1
Bretylium may transiently increase pacemaker rate by causing catecholamine release.
2
Data not available. Table 14–3. Clinical Pharmacologic Properties of Antiarrhythmic Drugs.
Usefulness in Arrhythmias Drug
Effec t on SA Noda l Rate
Adenosine
Little
Amiodarone
1
Bretylium
2
Effect on PR QRS QT Supraventricul Ventricula HalfAV Nodal Interva Duratio Interva ar r Life Refractor l n l y Period
2
Diltiazem 1,3
Disopyrami de Dofetilide
(?)
3
Lidocaine
None None
+++
(weeks ) 4h
+++
–
4–8 h
+
+++
6–8 h
++
None
7h
+
+
10 min
++++
20 h
+++
+
0 0
< 10 s
None (?)
?
Ibutilide
++++
3
Esmolol Flecainide
+
4
++
?
6h
5
+++
1–2 h
None
None6
+++
12 h
None
+++
2–6 h6
+
+++
3–4 h
1
Mexiletine
None None 1
Moricizine Procainamid
None None 1
3
3
e Propafenone 0 Propranolol
0 1,3
Quinidine
3
+
+++
5–7 h
+
+
8h
+
+++
6h
+++
7h
+++
12 h
–
7h
3
Sotalol Tocainide
0 None None
+++
None
+++
5
1
Verapamil
1
May suppress diseased sinus nodes.
2
Initial stimulation by release of endogenous norepinephrine followed by depression.
3
Anticholinergic effect and direct depressant action.
4
Especially in Wolff-Parkinson-White syndrome.
5
May be effective in atrial arrhythmias caused by digitalis.
6
Half-life of active metabolites much longer.
Sodium Channel-Blocking Drugs (Class 1) Quinidine (Subgroup 1a) Cardiac Effects Quinidine slows the upstroke of the action potential and conduction, and prolongs the QRS duration of the ECG, by blockade of activated sodium channels. Recovery from block occurs with intermediate kinetics and is slowed further in partially depolarized cells. Sodium channel-blocking concentrations of quinidine also prolong the action potential duration as a result of potassium channel blockade. This action is relatively nonspecific as most types of potassium channels are blocked by therapeutic concentrations of quinidine although the resting potential is not altered. The action potential prolonging action is greatest at slow rates. Its major cardiac effects are excessive QT interval prolongation and induction of torsade de pointes arrhythmia, and syncope. Toxic concentrations of quinidine also produce excessive sodium channel blockade with slowed conduction throughout the heart, increased PR interval, and further QRS duration prolongation.
Extracardiac Effects Gastrointestinal side effects of diarrhea, nausea, and vomiting are observed in one third to half of patients. A syndrome of headache, dizziness, and tinnitus (cinchonism) is observed at toxic drug concentrations. Idiosyncratic reactions including thrombocytopenia, hepatitis, angioneurotic edema, and fever are observed rarely. Pharmacokinetics Quinidine is 70–80% bioavailable following oral administration. It is 80% bound to albumin and 1-acid glycoprotein. It is eliminated primarily by hepatic metabolism. The principal metabolite, 3hydroxy quinidine is biologically active with half the activity of the parent compound. Twenty percent of the quinidine dose appears in the unchanged form in the urine. The elimination half-life is 6–8 hours. Quinidine is usually administered in a slow release formulation, eg, that of the gluconate salt. Therapeutic Use Quinidine is used for the maintenance of normal sinus rhythm in patients with atrial flutter or fibrillation. It is also used occasionally to treat patients with ventricular tachycardia. Because of its cardiac and extracardiac side effects, its use has decreased considerably in recent years and is now largely restricted to patients with normal (but arrhythmic) hearts. In randomized, controlled clinical trials, quinidine-treated patients are twice as likely to remain in normal sinus rhythm compared with controls. However, drug treatment was associated with a twofold to threefold increase in mortality. Procainamide (Subgroup 1a) Cardiac Effects The electrophysiologic effects of procainamide are similar to those of quinidine. The drug may be somewhat less effective in suppressing abnormal ectopic pacemaker activity but more effective in blocking sodium channels in depolarized cells.
Perhaps the most important difference between quinidine and procainamide is the less prominent
antimuscarinic action of procainamide. Therefore, the directly depressant actions of procainamide on sinoatrial and atrioventricular nodes are not as effectively counterbalanced by drug-induced vagal block as in the case of quinidine. Extracardiac Effects Procainamide has ganglion-blocking properties. This action reduces peripheral vascular resistance and can cause hypotension, particularly with intravenous use. However, in therapeutic concentrations, its peripheral vascular effects are less prominent than those of quinidine. Hypotension is usually associated with excessively rapid procainamide infusion or the presence of severe underlying left ventricular dysfunction. Toxicity Cardiac Procainamide's cardiotoxic effects are similar to those of quinidine. Antimuscarinic and direct depressant effects may occur. New arrhythmias may be precipitated. Extracardiac The most troublesome adverse effect of long-term procainamide therapy is a syndrome resembling lupus erythematosus and usually consisting of arthralgia and arthritis. In some patients, pleuritis, pericarditis, or parenchymal pulmonary disease also occurs. Renal lupus is rarely induced by procainamide. During long-term therapy, serologic abnormalities (eg, increased antinuclear antibody titer) occur in nearly all patients, and in the absence of symptoms these are not an indication to stop drug therapy. Approximately one third of patients receiving long-term procainamide therapy develop these reversible lupus-related symptoms. Other adverse effects include nausea and diarrhea (about 10% of cases), rash, fever, hepatitis (< 5%), and agranulocytosis (approximately 0.2%). Pharmacokinetics & Dosage Procainamide can be administered safely by the intravenous and intramuscular routes and is well absorbed orally, with 75% systemic bioavailability. The major metabolite is N-acetylprocainamide (NAPA), which has class III activity. Excessive accumulation of NAPA has been implicated in torsade de pointes during procainamide therapy, especially in patients with renal failure. Some individuals rapidly acetylate procainamide and develop high levels of NAPA. The lupus syndrome appears to be less common in these patients. Procainamide is eliminated by hepatic metabolism to NAPA and by renal elimination. Its half-life is only 3–4 hours, which necessitates frequent dosing or use of a slow-release formulation (the usual practice). NAPA is eliminated by the kidneys. Thus, procainamide dosage must be reduced in patients with renal failure. The reduced volume of distribution and renal clearance associated with heart failure also require reduction in dosage. The half-life of NAPA is considerably longer than that of procainamide, and it therefore accumulates more slowly. Thus, it is important to measure plasma levels of both procainamide and NAPA, especially in patients with circulatory or renal impairment. If a rapid procainamide effect is needed, an intravenous loading dose of up to 12 mg/kg can be
given at a rate of 0.3 mg/kg/min or less rapidly. This dose is followed by a maintenance dosage of 2–5 mg/min, with careful monitoring of plasma levels. The risk of gastrointestinal or cardiac toxicity rises at plasma concentrations greater than 8 g/mL or NAPA concentrations greater than 20 g/mL. In order to control ventricular arrhythmias, a total procainamide dosage of 2–5 g/d is usually required. In an occasional patient who accumulates high levels of NAPA, less frequent dosing may be possible. This is also possible in renal disease, where procainamide elimination is slowed. Therapeutic Use Like quinidine, procainamide is effective against most atrial and ventricular arrhythmias. However, many clinicians attempt to avoid long-term therapy because of the requirement for frequent dosing and the common occurrence of lupus-related effects. Procainamide is the drug of second choice (after lidocaine) in most coronary care units for the treatment of sustained ventricular arrhythmias associated with acute myocardial infarction. Disopyramide (Subgroup 1a) Cardiac Effects The effects of disopyramide are very similar to those of quinidine. Its cardiac antimuscarinic effects are even more marked than those of quinidine. Therefore, a drug that slows atrioventricular conduction should be administered with disopyramide when treating atrial flutter or fibrillation.
Toxicity Cardiac Toxic concentrations of disopyramide can precipitate all of the electrophysiologic disturbances described under quinidine. As a result of its negative inotropic effect, disopyramide may precipitate heart failure de novo or in patients with preexisting depression of left ventricular function. Because of this effect, disopyramide is not used as a first-line antiarrhythmic agent in the USA. It should not be used in patients with heart failure. Extracardiac Disopyramide's atropine-like activity accounts for most of its symptomatic adverse effects: urinary retention (most often, but not exclusively, in male patients with prostatic hyperplasia), dry mouth,
blurred vision, constipation, and worsening of preexisting glaucoma. These effects may require discontinuation of the drug. Pharmacokinetics & Dosage In the USA, disopyramide is only available for oral use. The usual oral dosage of disopyramide is 150 mg three times a day, but as much as 1 g/d has been used. In patients with renal impairment, dosage must be reduced. Because of the danger of precipitating heart failure, the use of loading doses is not recommended. Therapeutic Use Although disopyramide has been shown to be effective in a variety of supraventricular arrhythmias, in the USA it is approved only for the treatment of ventricular arrhythmias. Lidocaine (Subgroup 1b) Lidocaine has a low incidence of toxicity and a high degree of effectiveness in arrhythmias associated with acute myocardial infarction. It is used only by the intravenous route.
Cardiac Effects Lidocaine blocks activated and inactivated sodium channels with rapid kinetics (Figure 14–9); the inactivated state block ensures greater effects on cells with long action potentials such as Purkinje and ventricular cells, compared with atrial cells. The rapid kinetics at normal resting potentials result in recovery from block between action potentials and no effect on conduction. The increased inactivation and slower unbinding kinetics result in the selective depression of conduction in depolarized cells. Figure 14–9.
Effect of resting membrane potential on the blocking and unblocking of sodium channels by lidocaine. Upper tracing: Action potentials in a ventricular muscle cell. Lower tracing: Percentage of channels blocked by the drug. As the membrane depolarizes through –80, –75, –70 and –65 mV, an 800 ms time segment is shown. Extra passage of time is indicated by breaks in the traces. Left side: At the normal resting potential of –85 mV, the drug combines with open (activated) and inactivated channels during each action potential, but block is rapidly reversed during diastole because the affinity of the drug for its receptor is so low when the channel recovers to the resting state at –85 mV. Middle: Metabolic injury has occurred, eg, ischemia due to coronary occlusion, that causes gradual depolarization over time. With subsequent action potentials arising from more depolarized potentials, the fraction of channels blocked increases because more channels remain in the inactivated state at less negative potentials (Figure 14–4, left), and the time constant for unblocking during diastole rapidly increases at less negative resting potentials (Figure 14–4, right). Right: Because of marked drug binding, conduction block and loss of excitability in this tissue result, ie, the "sick" (depolarized) tissue is selectively suppressed. Toxicity Cardiac Lidocaine is one of the least cardiotoxic of the currently used sodium channel blockers. Proarrhythmic effects, including sinoatrial node arrest, worsening of impaired conduction, and ventricular arrhythmias are uncommon with lidocaine use. In large doses, especially in patients with preexisting heart failure, lidocaine may cause hypotension—partly by depressing myocardial contractility. Extracardiac Lidocaine's most common adverse effects—like those of other local anesthetics—are neurologic: paresthesias, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions. These occur most commonly in elderly or otherwise vulnerable patients or when a bolus of the drug is given too rapidly. The effects are dose-related and usually short-lived; seizures respond to intravenous diazepam. In general, if plasma levels above 9 g/mL are avoided, lidocaine is well tolerated.
Pharmacokinetics & Dosage Because of its very extensive first-pass hepatic metabolism, only 3% of orally administered lidocaine appears in the plasma. Thus, lidocaine must be given parenterally. Lidocaine has a halflife of 1–2 hours. In adults, a loading dose of 150–200 mg administered over about 15 minutes (as a single infusion or as a series of slow boluses) should be followed by a maintenance infusion of 2–4 mg/min to achieve a therapeutic plasma level of 2–6 g/mL. Determination of lidocaine plasma levels is of great value in adjusting the infusion rate. Occasional patients with myocardial infarction or other acute illness require (and tolerate) higher concentrations. This may be due to increased plasma 1-acid glycoprotein, an acute phase reactant protein that binds lidocaine, making less free drug available to exert its pharmacologic effects. In patients with heart failure, lidocaine's volume of distribution and total body clearance may both be decreased. Thus, both loading and maintenance doses should be decreased. Since these effects counterbalance each other, the half-life may not be increased as much as predicted from clearance changes alone. In patients with liver disease, plasma clearance is markedly reduced and the volume of distribution is often increased; the elimination half-life in such cases may be increased threefold or more. In liver disease, the maintenance dose should be decreased, but usual loading doses can be given. Elimination half-life determines the time to steady state. Thus, while steady-state concentrations may be achieved in 8–10 hours in normal patients and patients with heart failure, 24–36 hours may be required in those with liver disease. Drugs that decrease liver blood flow (eg, propranolol, cimetidine) reduce lidocaine clearance and so increase the risk of toxicity unless infusion rates are decreased. With infusions lasting more than 24 hours, clearance falls and plasma concentrations rise. Renal disease has no major effect on lidocaine disposition. Therapeutic Use Lidocaine is the agent of choice for termination of ventricular tachycardia and prevention of ventricular fibrillation after cardioversion in the setting of acute ischemia. However, routine prophylactic use of lidocaine in this setting may actually increase total mortality, possibly by increasing the incidence of asystole and is not the standard of care. Most physicians administer lidocaine only to patients with arrhythmias. Mexiletine (Subgroup 1b) Mexiletine is a congener of lidocaine that is resistant to first-pass hepatic metabolism and is effective by the oral route. Its electrophysiologic and antiarrhythmic actions are similar to those of lidocaine. (The anticonvulsant phenytoin [see Chapter 24: Antiseizure Drugs] also exerts similar electrophysiologic effects and has been used as an antiarrhythmic.) Mexiletine is used in the treatment of ventricular arrhythmias. The elimination half-life is 8–20 hours and permits administration two or three times a day. The usual daily dosage of mexiletine is 600–1200 mg/d. Dose-related adverse effects are seen frequently at therapeutic dosage. These are predominantly neurologic, including tremor, blurred vision, and lethargy. Nausea is also a common effect.
Mexiletine has also shown significant efficacy in relieving chronic pain, especially pain due to diabetic neuropathy and nerve injury. The usual dosage is 450–750 mg/d orally. This application is unlabeled. Flecainide (Subgroup 1c) Flecainide is a potent blocker of sodium and potassium channels with slow unblocking kinetics. (Note that although it does block certain potassium channels, it does not prolong the action potential or the QT interval.) It is currently used for patients with otherwise normal hearts who have supraventricular arrhythmias. It has no antimuscarinic effects.
Flecainide is very effective in suppressing premature ventricular contractions. However, it may cause severe exacerbation of arrhythmia even when normal doses are administered to patients with preexisting ventricular tachyarrhythmias and those with a previous myocardial infarction and ventricular ectopy (see The Cardiac Arrhythmia Suppression Trial). The drug is well absorbed and has a half-life of approximately 20 hours. Elimination is both by hepatic metabolism and by the kidney. The usual dosage of flecainide is 100–200 mg twice a day. Propafenone (Subgroup 1c) Propafenone has some structural similarities to propranolol and possesses weak -blocking activity. Its spectrum of action is very similar to that of quinidine. Its sodium channel blocking kinetics are similar to that of flecainide. Propafenone is metabolized in the liver, with an average elimination of 5–7 hours except in poor metabolizers (7% of whites), in whom it is as much as 17 hours. The usual daily dosage of propafenone is 450–900 mg in three doses. The drug is used primarily for supraventricular arrhythmias. The most common adverse effects are a metallic taste and constipation; arrhythmia exacerbation can occur. Moricizine (Subgroup 1c) Moricizine is an antiarrhythmic phenothiazine derivative that is used for treatment of ventricular arrhythmias. It is a relatively potent sodium channel blocker that does not prolong action potential duration. Moricizine has multiple metabolites, some of which are probably active and have long half-lives. Its most common adverse effects are dizziness and nausea. Like other potent sodium channel blockers, it can exacerbate arrhythmias. The usual dosage of moricizine is 200–300 mg by mouth three times a day. Beta-Adrenoceptor-Blocking Drugs (Class 2) Cardiac Effects
Propranolol and similar drugs have antiarrhythmic properties by virtue of their -receptor–blocking action and direct membrane effects. As described in Chapter 10: Adrenoceptor Antagonist Drugs, some of these drugs have selectivity for cardiac 1-receptors; some have intrinsic sympathomimetic activity; some have marked direct membrane effects; and some prolong the cardiac action potential. The relative contributions of the -blocking and direct membrane effects to the antiarrhythmic effects of these drugs are not fully known. Although -blockers are fairly well tolerated, their efficacy for suppression of ventricular ectopic depolarizations is lower than that of sodium channel blockers. However, there is good evidence that these agents can prevent recurrent infarction and sudden death in patients recovering from acute myocardial infarction (see Chapter 10: Adrenoceptor Antagonist Drugs). Esmolol is a short-acting blocker used primarily as an antiarrhythmic drug for intraoperative and other acute arrhythmias. See Chapter 10: Adrenoceptor Antagonist Drugs for more information. Sotalol is a nonselective -blocking drug that prolongs the action potential (class 3 action). Drugs That Prolong Effective Refractory Period by Prolonging Action Potential (Class 3) These drugs prolong action potentials, usually by blocking potassium channels in cardiac muscle or by enhancing inward current, eg, through sodium channels. Action potential prolongation by most of these drugs often exhibits the undesirable property of "reverse use-dependence": action potential prolongation is least marked at fast rates (where it is desirable) and most marked at slow rates, where it can contribute to the risk of torsade de pointes. Amiodarone In the USA, amiodarone is approved for oral and intravenous use to treat serious ventricular arrhythmias. However, the drug is also highly effective for the treatment of supraventricular arrhythmias such as atrial fibrillation. Amiodarone has a broad spectrum of cardiac actions, unusual pharmacokinetics, and important extracardiac side effects.
Cardiac Effects Amiodarone markedly prolongs the action potential duration (and the QT interval on the ECG) by blockade of IKr. During chronic administration, IKs is also blocked. The action potential duration is prolonged uniformly over a wide range of heart rates, ie, the drug does not have reverse usedependent action. In spite of its present classification as a class 3 agent, amiodarone also significantly blocks inactivated sodium channels. Its action potential prolonging action reinforces this effect. Amiodarone also has weak adrenergic and calcium channel blocking actions. Consequences of these actions include slowing of the heart rate and atrioventricular node conduction. The broad spectrum of actions may account for its relatively high efficacy and low incidence of torsade de pointes despite significant QT interval prolongation. Extracardiac Effects
Amiodarone causes peripheral vasodilation. This action is prominent following intravenous administration and may be related to the action of the solvent. Toxicity Cardiac Amiodarone may produce symptomatic bradycardia and heart block in patients with preexisting sinus or atrioventricular node disease. Extracardiac Amiodarone accumulates in many tissues, including the heart (10–50 times greater than plasma), lung, liver, and skin, and is concentrated in tears. Dose-related pulmonary toxicity is the most important adverse effect. Even on a low dose of 200 mg/d, fatal pulmonary fibrosis may be observed in 1% of patients. Abnormal liver function tests and hepatitis may develop during amiodarone treatment. The skin deposits result in a photodermatitis and a gray-blue skin discoloration in sun-exposed areas, eg, the malar regions. After a few weeks of treatment, asymptomatic corneal microdeposits are present in virtually all patients treated with amiodarone. Halos develop in the peripheral visual fields of some patients. Drug discontinuation is usually not required. Rarely, an optic neuritis may progress to blindness. Amiodarone blocks the peripheral conversion of thyroxine (T4) to triiodothyronine (T3). It is also a potential source of large amounts of inorganic iodine. Amiodarone may result in hypothyroidism or hyperthyroidism. Thyroid function should be evaluated prior to initiation of treatment and monitored periodically. Because effects have been described in virtually every organ system, amiodarone treatment should be reevaluated whenever new symptoms develop in a patient, including arrhythmia aggravation. Pharmacokinetics Amiodarone is variably absorbed with a bioavailability of 35–65%. It undergoes hepatic metabolism, and the major metabolite, desethylamiodarone, is bioactive. The elimination half-life is complex, with a rapid component of 3–10 days (50% of the drug) and a slower component of several weeks. Following discontinuation of the drug, effects are maintained for 1–3 months. Measurable tissue levels may be observed up to 1 year after dosing. A total loading dose of 10 g is usually achieved with 0.8–1.2 g daily doses. The maintenance dose is 200–400 mg daily. Pharmacologic effects may be achieved rapidly by IV loading. QT-prolonging effect is modest with this route of administration, whereas bradycardia and atrioventricular block may be significant. Amiodarone has many important drug interactions and all medications should be reviewed during drug initiation or dose adjustments. Amiodarone is a substrate for the liver cytochrome metabolizing enzyme CYP3A4 and its levels are increased by drugs that inhibit this enzyme, eg, the histamine H2 blocker cimetidine. Drugs that induce CYP3A4, eg, rifampin, decrease amiodarone concentration when coadministered. Amiodarone inhibits the other liver cytochrome metabolizing enzymes and may result in high levels of drugs that are substrates for these enzymes eg, digoxin and warfarin. Therapeutic Use Low doses (100–200 mg/d) of amiodarone are effective in maintaining normal sinus rhythm in
patients with atrial fibrillation. The drug is effective in the prevention of recurrent ventricular tachycardia. Its use is not associated with an increase in mortality in patients with coronary artery disease or heart failure. The implanted cardioverter-defibrillator (ICD) has succeeded drug therapy as the primary treatment modality for ventricular tachycardia, but amiodarone may be used for ventricular tachycardia as adjuvant therapy to decrease the frequency of uncomfortable ICD discharges. The drug increases the pacing and defibrillation threshold and these devices require retesting after a maintenance dose has been achieved. Bretylium Bretylium was first introduced as an antihypertensive agent. It interferes with the neuronal release of catecholamines but also has direct antiarrhythmic properties. Cardiac Effects Bretylium lengthens the ventricular (but not the atrial) action potential duration and effective refractory period. This effect is most pronounced in ischemic cells, which have shortened action potential durations. Thus, bretylium may reverse the shortening of action potential duration caused by ischemia. Since bretylium causes an initial release of catecholamines, it has some positive inotropic actions when first administered. This action may also precipitate ventricular arrhythmias and must be watched for at the onset of therapy with the drug. Extracardiac Effects These result from the drug's sympathoplegic actions. The major adverse effect is postural hypotension. This effect can be almost totally prevented by concomitant administration of a tricyclic antidepressant agent such as protriptyline. Nausea and vomiting may occur after the intravenous administration of a bolus of bretylium. Pharmacokinetics & Dosage Bretylium is available only for intravenous use in the USA. In adults, an intravenous bolus of bretylium tosylate, 5 mg/kg, is administered over a 10-minute period. This dosage may be repeated after 30 minutes. Maintenance therapy is achieved by a similar bolus every 4–6 hours or by a constant infusion of 0.5–2 mg/min. Therapeutic Use Bretylium is usually used in an emergency setting, often during attempted resuscitation from ventricular fibrillation when lidocaine and cardioversion have failed. Sotalol Sotalol has both -adrenergic receptor-blocking (class 2) and action potential prolonging (class 3) actions. The drug is formulated as a racemic mixture of d- and l-sotalol. All the beta-adrenergic blocking activity resides in the l-isomer; the d- and l-isomers share action potential prolonging actions. Beta-adrenergic action is noncardioselective and is maximal at doses below those required for action potential prolongation.
Sotalol is well absorbed orally with bioavailability of approximately 100%. It is not metabolized in the liver and it is not bound to plasma proteins. Excretion is predominantly by the kidneys in the unchanged form with a half-life of approximately 12 hours. Because of its relatively simple pharmacokinetics, it exhibits few direct drug interactions. Its most significant cardiac adverse effect is an extension of its pharmacologic action: a dose-related incidence of torsade de pointes that approaches 6% at the highest recommended daily dose. Patients with overt heart failure may experience further depression of left ventricular function during treatment with sotalol. Sotalol is approved for the treatment of life-threatening ventricular arrhythmias and the maintenance of sinus rhythm in patients with atrial fibrillation. It is also approved for treatment of supraventricular and ventricular arrhythmias in the pediatric age group. Sotalol decreases the threshold for cardiac defibrillation. Dofetilide Dofetilide has class 3 action potential prolonging action. This action is effected by a dosedependent blockade of the rapid component of the delayed rectifier potassium current, IKr. Dofetilide block of IKr increases in hypokalemia. Dofetilide produces no relevant blockade of the other potassium channels or the sodium channel. Because of the slow rate of recovery from blockade, the extent of blockade shows little dependence on stimulation frequency. However, dofetilide does show less action potential prolongation at rapid rates because of the increased importance of other potassium channels such as IKs at rapid rates. Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged; the remainder is eliminated by the kidneys as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QTprolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dose must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the QTC and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 beats/min, and hypokalemia are relative contraindications to its use. Dofetilide is approved for the maintenance of normal sinus rhythm in patients with atrial fibrillation. It is also effective in restoring normal sinus rhythm in patients with atrial fibrillation. Ibutilide Ibutilide slows cardiac repolarization by blockade of the rapid component of the delayed rectifier potassium current. Activation of slow inward sodium current has also been suggested as an additional mechanism of action. After intravenous administration, ibutilide is rapidly cleared from the plasma by hepatic metabolism. The metabolites are excreted by the kidney. The elimination half-life averages 6 hours. Intravenous ibutilide is used for the acute conversion of atrial flutter and atrial fibrillation to normal
sinus rhythm. The drug is more effective in atrial flutter than fibrillation, with a mean time to termination of 20 minutes. The most important adverse effect is excessive QT interval prolongation and torsade de pointes. Patients require continuous ECG monitoring for 4 hours following ibutilide infusion or until QTC returns to baseline. Calcium Channel-Blocking Drugs (Class 4) These drugs, of which verapamil is the prototype, were first introduced as antianginal agents and are discussed in greater detail in Chapter 12: Vasodilators & the Treatment of Angina Pectoris. Verapamil, diltiazem, and bepridil also have antiarrhythmic effects. Verapamil Cardiac Effects Verapamil blocks both activated and inactivated L-type calcium channels. Thus, its effect is more marked in tissues that fire frequently, those that are less completely polarized at rest, and those in which activation depends exclusively on the calcium current, such as the sinoatrial and atrioventricular nodes. Atrioventricular nodal conduction and effective refractory period are invariably prolonged by therapeutic concentrations. Verapamil usually slows the sinoatrial node by its direct action, but its hypotensive action may occasionally result in a small reflex increase of sinoatrial nodal rate. Verapamil can suppress both early and delayed afterdepolarizations and may antagonize slow responses arising in severely depolarized tissue. Extracardiac Effects Verapamil causes peripheral vasodilation, which may be beneficial in hypertension and peripheral vasospastic disorders. Its effects upon smooth muscle produce a number of extracardiac effects (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris). Toxicity Cardiac Verapamil's cardiotoxic effects are dose-related and usually avoidable. A common error has been to administer intravenous verapamil to a patient with ventricular tachycardia misdiagnosed as supraventricular tachycardia. In this setting, hypotension and ventricular fibrillation can occur. Verapamil's negative inotropic effects may limit its clinical usefulness in diseased hearts (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris). Verapamil can lead to atrioventricular block when used in large doses or in patients with atrio-ventricular nodal disease. This block can be treated with atropine and -receptor stimulants. In patients with sinus node disease, verapamil can precipitate sinus arrest. Extracardiac Adverse effects include constipation, lassitude, nervousness, and peripheral edema. Pharmacokinetics & Dosage
The half-life of verapamil is approximately 7 hours. It is extensively metabolized by the liver; after oral administration, its bioavailability is only about 20%. Therefore, verapamil must be administered with caution in patients with hepatic dysfunction. In adult patients without heart failure or sinoatrial or atrioventricular nodal disease, parenteral verapamil can be used to terminate supraventricular tachycardia, although adenosine has become the agent of first choice. Verapamil dosage is an initial bolus of 5 mg administered over 2–5 minutes, followed a few minutes later by a second 5 mg bolus if needed. Thereafter, doses of 5–10 mg can be administered every 4–6 hours, or a constant infusion of 0.4 g/kg/min may be used. Effective oral dosages are higher than with intravenous drug because of first-pass metabolism and range from 120 to 640 mg daily, divided into three or four doses. Therapeutic Use Supraventricular tachycardia is the major arrhythmia indication for verapamil. Adenosine or verapamil are preferred over older treatments (propranolol, digoxin, edrophonium, vasoconstrictor agents, and cardioversion) for termination. Verapamil can also reduce the ventricular rate in atrial fibrillation and flutter. It only rarely converts atrial flutter and fibrillation to sinus rhythm. Verapamil is occasionally useful in ventricular arrhythmias. However, the use of intravenous verapamil in a patient with sustained ventricular tachycardia can cause hemodynamic collapse. Diltiazem & Bepridil These agents appear to be similar in efficacy to verapamil in the management of supraventricular arrhythmias, including rate control in atrial fibrillation. An intravenous form of diltiazem is available for the latter indication and causes hypotension or bradyarrhythmias relatively infrequently. Bepridil also has action potential- and QT-prolonging actions that theoretically may make it more useful in some ventricular arrhythmias but also create the risk of torsade de pointes. Bepridil is only rarely used, primarily to control refractory angina. Miscellaneous Antiarrhythmic Agents Certain agents used for the treatment of arrhythmias do not fit the conventional class 1–4 organization. These include digitalis (already discussed in Chapter 13: Drugs Used in Heart Failure), adenosine, magnesium, and potassium. Adenosine Mechanism & Clinical Use Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Its mechanism of action involves activation of an inward rectifier K+ current and inhibition of calcium current. The results of these actions are marked hyperpolarization and suppression of calcium-dependent action potentials. When given as a bolus dose, adenosine directly inhibits atrioventricular nodal conduction and increases the atrioventricular nodal refractory period but has lesser effects on sinoatrial node. Adenosine is currently the drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm because of its high efficacy (90–95%) and very short duration of action. It is usually given in a bolus dose of 6 mg followed, if necessary, by a dose of 12 mg. An uncommon variant of ventricular tachycardia is adenosine sensitive. It is less effective in the presence of adenosine receptor blockers such as theophylline or
caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole. Toxicity Adenosine causes flushing in about 20% of patients and shortness of breath or chest burning (perhaps related to bronchospasm) in over 10%. Induction of high-grade atrioventricular block may occur but is very short-lived. Atrial fibrillation may occur. Less common toxicities include headache, hypotension, nausea, and paresthesias. Magnesium Originally used for patients with digitalis-induced arrhythmias who were hypomagnesemic, magnesium infusion has been found to have antiarrhythmic effects in some patients with normal serum magnesium levels. The mechanisms of these effects are not known, but magnesium is recognized to influence Na+/K+ ATPase, sodium channels, certain potassium channels, and calcium channels. Magnesium therapy appears to be indicated in patients with digitalis-induced arrhythmias if hypomagnesemia is present; it is also indicated in some patients with torsade de pointes even if serum magnesium is normal. The usual dosage is 1 g (as sulfate) given intravenously over 20 minutes and repeated once if necessary. A full understanding of the action and indications of magnesium as an antiarrhythmic drug awaits further investigation. Potassium The significance of the potassium ion concentrations inside and outside the cardiac cell membrane has been discussed earlier in this chapter. The effects of increasing serum K+ can be summarized as (1) a resting potential depolarizing action and (2) a membrane potential stabilizing action, caused by increased potassium permeability. Hypokalemia results in an increased risk of early and delayed afterdepolarizations, and ectopic pacemaker activity, especially in the presence of digitalis; hyperkalemia depresses ectopic pacemakers (severe hyperkalemia is required to suppress the sinoatrial node) and slows conduction. Because both insufficient and excess potassium are potentially arrhythmogenic, potassium therapy is directed toward normalizing potassium gradients and pools in the body. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > The Cardiac Arrhythmia Suppression Trial Premature ventricular contractions (PVCs) are commonly recorded in patients convalescing from myocardial infarction. Since such arrhythmias have been associated with an increased risk of sudden cardiac death, it had been the empiric practice of many physicians to treat PVCs, even if asymp-tomatic, in such patients. In CAST (Cardiac Arrhythmia Suppression Trial [CAST], Echt et al, 1991), an attempt was made to document the efficacy of such therapy in a controlled clinical trial. The effects of several antiarrhythmic drugs on arrhythmia frequency were first evaluated in an open-label fashion. Then, patients in whom antiarrhythmic therapy suppressed PVCs were randomly assigned, in a double-blind fashion, to continue that therapy or its corresponding placebo. The results showed that mortality among patients treated with the drugs flecainide and encainide (the latter is no longer available) was increased more than twofold compared with those treated with placebo. The mechanism underlying this effect is not known, although an interaction between conduction depression by sodium channel block and chronic or acute myocardial ischemia seems likely. Indirect evidence suggests that other sodium channel blockers may produce a similar effect.
Whatever the mechanism, the important lesson reinforced by CAST was that the decision to initiate any form of drug therapy (antiarrhythmic or otherwise) should be predicated on the knowledge (or at least a reasonable assumption) that any risk is outweighed by real or potential benefit. Large trials suggest that amiodarone (unlike flecainide) has a slightly beneficial effect on survival of patients with advanced heart disease, while many studies indicate a prominent beneficial effect of blockade. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Principles in the Clinical Use of Antiarrhythmic Agents The margin between efficacy and toxicity is particularly narrow for antiarrhythmic drugs. Therefore, individuals prescribing antiarrhythmic drugs must be thoroughly familiar with the indications, contraindications, risks, and clinical pharmacologic characteristics of each compound they use. Pretreatment Evaluation Several important determinations must be made prior to initiation of any antiarrhythmic therapy: (1) Precipitating factors must be recognized and eliminated if possible. These include not only abnormalities of internal homeostasis, such as hypoxia or electrolyte abnormalities (especially hypokalemia or hypomagnesemia), but also drug therapy and underlying disease states such as hyperthyroidism or underlying cardiac disease. It is important to separate this abnormal substrate from triggering factors, such as myocardial ischemia or acute cardiac dilation, which may be treatable and reversible. (2) A firm arrhythmia diagnosis should be established. For example, the misuse of verapamil in patients with ventricular tachycardia mistakenly diagnosed as supraventricular tachycardia can lead to catastrophic hypotension and cardiac arrest. As increasingly sophisticated methods to characterize underlying arrhythmia mechanisms become available and are validated, it may be possible to direct certain drugs (or other therapies—see The Nonpharmacologic Therapy of Cardiac Arrhythmias) toward specific arrhythmia mechanisms. (3) It is important to establish a reliable baseline upon which to judge the efficacy of any subsequent antiarrhythmic intervention. A number of methods are now available for such baseline quantitation. These include prolonged ambulatory monitoring, electrophysiologic studies that reproduce a target arrhythmia, reproduction of a target arrhythmia by treadmill exercise, or the use of transtelephonic monitoring for recording of sporadic but symptomatic arrhythmias. (4) The mere identification of an abnormality of cardiac rhythm does not necessarily require that the arrhythmia be treated. An excellent justification for conservative treatment was provided by the Cardiac Arrhythmia Suppression Trial (CAST) referred to earlier. Benefits & Risks The benefits of antiarrhythmic therapy are actually relatively difficult to establish. Two types of benefits can be envisioned: reduction of arrhythmia-related symptoms, such as palpitations, syncope, or cardiac arrest; or reduction in long-term mortality in asymptomatic patients. Among drugs discussed here, only -blockers have been definitely associated with reduction of mortality in
relatively asymptomatic patients, and the mechanism underlying this effect is not established (see Chapter 10: Adrenoceptor Antagonist Drugs). Antiarrhythmic therapy carries with it a number of risks. In some cases, the risk of an adverse reaction is clearly related to high dosages or plasma concentrations. Examples include lidocaineinduced tremor or quinidine-induced cinchonism. In other cases, adverse reactions are unrelated to high plasma concentrations (eg, procainamide-induced agranulocytosis). For many serious adverse reactions to antiarrhythmic drugs, the combination of drug therapy and the underlying heart disease appears important. Several specific syndromes of arrhythmia provocation by antiarrhythmic drugs have also been identified, each with its underlying pathophysiologic mechanism and risk factors. Drugs such as quinidine, sotalol, ibutilide, and dofetilide, which act—at least in part—by slowing repolarization and prolonging cardiac action potentials, can result in marked QT prolongation and torsade de pointes. Treatment of torsade de pointes requires recognition of the arrhythmia, withdrawal of any offending agent, correction of hypokalemia, and treatment with maneuvers to increase heart rate (pacing or isoproterenol); intravenous magnesium also appears effective, even in patients with normal magnesium levels. Drugs that markedly slow conduction, such as flecainide, or high concentrations of quinidine, can result in an increased frequency of reentry arrhythmias, notably ventricular tachycardia in patients with prior myocardial infarction in whom a potential reentry circuit may be present. Treatment here consists of recognition, withdrawal of the offending agent, and intravenous sodium. Some patients with this form of arrhythmia aggravation cannot be resuscitated, and deaths have been reported. Conduct of Antiarrhythmic Therapy The urgency of the clinical situation determines the route and rate of drug initiation. When immediate drug action is required, the intravenous route is preferred. Therapeutic drug levels can be achieved by administration of multiple intravenous boluses. Drug therapy can be considered effective when the target arrhythmia is suppressed (according to the measure used to quantify at baseline) and toxicities are absent. Conversely, drug therapy should not be considered ineffective unless toxicities occur at a time when arrhythmias are not suppressed. Occasionally, arrhythmias may recur at a time when plasma drug concentrations are relatively high but toxicities have not recurred. Under these conditions, the prescriber must decide whether a judicious increase in dose might suppress the arrhythmia and still leave the patient free of toxicity. Monitoring plasma drug concentrations can be a useful adjunct to managing antiarrhythmic therapy. Plasma drug concentrations are also important in establishing compliance during long-term therapy as well as in detecting drug interactions that may result in very high concentrations at low drug dosages or very low concentrations at high dosages. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > The Nonpharmacologic Therapy of Cardiac Arrhythmias It was recognized at the start of the 20th century that reentry in simple in vitro models (eg, rings of conducting tissues) was permanently interrupted by transecting the reentry circuit. This concept has now been applied to treat clinical arrhythmias that occur as a result of reentry in anatomically delineated pathways. For example, interruption of accessory atrio-ventricular connections can permanently cure arrhythmias in patients with the Wolff-Parkinson-White syndrome. Such
interruption was originally performed at open heart surgery but is now readily accomplished by delivery of radiofrequency energy through an appropriately positioned intracardiac catheter. Since the procedure carries only minimal morbidity, it is being increasingly applied to other reentry arrhythmias with defined pathways, such as atrioventricular nodal reentry, atrial flutter, and some forms of ventricular tachycardia. Another form of nonpharmacologic therapy is the implantable cardioverter-defibrillator (ICD), a device that can automatically detect and treat potentially fatal arrhythmias such as ventricular fibrillation. ICDs are now widely used in patients who have been resuscitated from such arrhythmias, and several trials have suggested that they should be used in patients with advanced heart disease who have not yet had such arrhythmias but are judged to be at high risk. The increasing use of nonpharmacologic antiarrhythmic therapies reflects both advances in the relevant technologies and an increasing appreciation of the dangers of long-term therapy with currently available drugs. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias > Preparations Available Sodium Channel Blockers Disopyramide (generic, Norpace) Oral: 100, 150 mg capsules Oral controlled-release (generic, Norpace CR): 100, 150 capsules Flecainide (Tambocor) Oral: 50, 100, 150 mg tablets Lidocaine (generic, Xylocaine) Parenteral: 100 mg/mL for IM injection; 10, 20 mg/mL for IV injection; 40, 100, 200 mg/mL for IV admixtures; 2, 4, 8 mg/mL premixed IV (5% D/W) solution Mexiletine (Mexitil) Oral: 150, 200, 250 mg capsules Moricizine (Ethmozine) Oral: 200, 250, 300 mg tablets Procainamide (generic, Pronestyl, others) Oral: 250, 375, 500 mg tablets and capsules Oral sustained-release (generic, Procan-SR): 250, 500, 750, 1000 mg tablets
Parenteral: 100, 500 mg/mL for injection Propafenone (Rythmol) Oral: 150, 225, 300 mg tablets Quinidine sulfate [83% quinidine base] (generic) Oral: 200, 300 mg tablets Oral sustained-release (Quinidex Extentabs): 300 mg tablets Quinidine gluconate [62% quinidine base] (generic) Oral sustained-release: 324 mg tablets Parenteral: 80 mg/mL for injection Quinidine polygalacturonate [60% quinidine base] (Cardioquin) Oral: 275 mg tablets -Blockers Labeled for Use As Antiarrhythmics Acebutolol (generic, Sectral) Oral: 200, 400 mg capsules Esmolol (Brevibloc) Parenteral: 10 mg/mL, 250 mg/mL for IV injection Propranolol (generic, Inderal) Oral: 10, 20, 40, 60, 80, 90 mg tablets Oral sustained-release: 60, 80, 120, 160 mg capsules Oral solution: 4, 8 mg/mL Parenteral: 1 mg/mL for injection Action Potential-Prolonging Agents Amiodarone (Cordarone) Oral: 200, 400 mg tablets Parenteral: 150 mg/3 mL for intravenous infusion
Bretylium (generic) Parenteral: 2, 4, 50 mg/mL for injection Dofetilide (Tikosyn) Oral: 125, 250, 500 g capsules Ibutilide (Corvert) Parenteral: 0.1 g/mL solution for IV infusion Sotalol (generic, Betapace) Oral: 80, 120, 160, 240 mg capsules Calcium Channel Blockers Bepridil (Vascor; not labeled for use in arrhythmias) Oral: 200, 300 mg tablets Diltiazem (generic, Cardizem, Dilacor) Oral: 30, 60, 90, 120 mg tablets; 60, 90, 120, 180, 240, 300, 340, 420 mg extended- or sustainedrelease capsules (not labeled for use in arrhythmias) Parenteral: 5 mg/mL for intravenous injection Verapamil (generic, Calan, Isoptin) Oral: 40, 80, 120 mg tablets; Oral sustained-release (Calan SR, Isoptin SR): 100, 120, 180, 240 mg capsules Parenteral: 5 mg/2 mL for injection Miscellaneous Adenosine (Adenocard) Parenteral: 3 mg/mL for injection Magnesium sulfate Parenteral: 125, 500 mg/mL for intravenous infusion Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 14. Agents Used in Cardiac Arrhythmias >
Chapter 15. Diuretic Agents Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 15. Diuretic Agents > Diuretic Agents: Introduction Abnormalities in fluid volume and electrolyte composition are common and important clinical problems. Drugs that block the transport functions of the renal tubules are valuable clinical tools in the treatment of these disorders. Although various agents that increase urine flow have been described since antiquity, it was not until 1957 that a practical and powerful diuretic agent (chlorothiazide) became available for widespread use. Technically, the term "diuresis" signifies an increase in urine volume, while "natriuresis" denotes an increase in renal sodium excretion. Because natriuretic drugs almost always also increase water excretion, they are usually called diuretics. Many diuretic agents (loop diuretics, thiazides, amiloride, and triamterene) exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (spironolactone). Most diuretics act upon a single anatomic segment of the nephron (Figure 15–1). Because these segments have distinctive transport functions, the first section of this chapter is devoted to a review of those features of renal tubule physiology that are relevant to diuretic action. The second section is devoted to the basic pharmacology of diuretics, and the third section discusses the clinical applications of these drugs. Figure 15–1.
Tubule transport systems and sites of action of diuretics. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 15. Diuretic Agents > Renal Tubule Transport Mechanisms Proximal Tubule Sodium bicarbonate, sodium chloride, glucose, amino acids, and other organic solutes are reabsorbed via specific transport systems in the early proximal tubule. Water is reabsorbed passively so as to maintain nearly constant osmolality of proximal tubular fluid. As tubule fluid is processed along the length of the proximal tubule, the luminal concentrations of the solutes decrease relative to the concentration of inulin, an experimental marker that is neither secreted nor absorbed by renal tubules (Figure 15–2). Approximately 85% of the filtered sodium bicarbonate, 40% of the sodium chloride, 60% of the water, and virtually all of the filtered organic solutes are reabsorbed in the proximal tubule.
Figure 15–2.
Reabsorption of various solutes in the proximal tubule in relation to tubule length. (TF/P, tubular fluid to plasma concentration ratio; PD, potential difference across the tubule.) (Reproduced, with permission, from Ganong WF: Review of Medical Physiology, 17th ed. Lange, 1993.)
Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are sodium bicarbonate and sodium chloride. Of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHCO3 reabsorption) acts predominantly in the proximal tubule. In view of the large quantity of sodium chloride absorbed in the proximal tubule, a drug that specifically blocked reabsorption of this salt at this site might be a particularly powerful diuretic agent. No such drug is currently available. Sodium bicarbonate reabsorption by the proximal tubule is initiated by the action of a Na+/H+ exchanger located in the luminal membrane of the proximal tubule epithelial cell (Figure 15–3). This transport system allows sodium to enter the cell from the tubular lumen in exchange for a proton from inside the cell. As in all portions of the nephron, Na+/K+ ATPase in the basolateral
membrane pumps the reabsorbed Na+ into the interstitium so as to maintain the normal intracellular concentration of this ion. Protons secreted into the lumen combine with bicarbonate to form carbonic acid, H2CO3. Carbonic acid is rapidly dehydrated to CO2 and H2O by carbonic anhydrase. CO2 produced by dehydration of H2CO3 enters the proximal tubule cell by simple diffusion where it is then rehydrated back to H2CO3. After dissociation of H2CO3, the H+ is available for transport by the Na+/H+ exchanger, and the bicarbonate is transported out of the cell by a basolateral membrane transporter (Figure 15–3). Bicarbonate reabsorption by the proximal tubule is thus dependent on carbonic anhydrase. This enzyme can be inhibited by acetazolamide and related agents. Figure 15–3.
Apical membrane Na+/H+ exchange and bicarbonate reabsorption in the proximal convoluted tubule cell. Na+/K+ ATPase is present in the basolateral membrane to maintain intracellular sodium and potassium levels within the normal range. Because of rapid equilibration, concentrations of the solutes shown are approximately equal in the interstitial fluid and the blood. Carbonic anhydrase (CA) is found in other locations in addition to the brush border of the luminal membrane. In the late proximal tubule, as bicarbonate and organic solutes have been largely removed from the tubular fluid, the residual luminal fluid contains predominantly NaCl. Under these conditions, Na+ reabsorption continues, but the protons secreted by the Na+/H+ exchanger can no longer bind to bicarbonate. Free H+ causes luminal pH to fall, activating a still poorly defined Cl-/base exchanger (Figure 15–3). The net effect of parallel Na+/H+ exchange and Cl-/base exchange is NaCl reabsorption. As yet, there are no diuretic agents that are known to act on this conjoint process. Because of the high water permeability of the proximal tubule, water is reabsorbed in direct proportion to salt reabsorption in this segment. Thus, luminal fluid osmolality and sodium concentration remain nearly constant along the length of the proximal tubule (Figure 15–2). An experimental impermeant solute like inulin will rise in concentration as water is reabsorbed (Figure 15–2). If large amounts of an impermeant solute such as mannitol are present in the tubular fluid,
water reabsorption will cause the concentration of the solute to rise to a point at which further water reabsorption is prevented. This is the mechanism by which osmotic diuretics act (see below). Organic acid secretory systems are located in the middle third of the proximal tubule (S2 segment). These systems secrete a variety of organic acids (uric acid, nonsteroidal anti-inflammatory drugs NSAIDs, diuretics, antibiotics, etc) into the luminal fluid from the blood. These systems thus help deliver diuretics to the luminal side of the tubule, where most of them act. Organic base secretory systems (creatinine, choline, etc) are also present, in the early (S1) and middle (S2) segments of the proximal tubule. Loop of Henle At the boundary between the inner and outer stripes of the outer medulla, the thin limb of Henle's loop begins. Water is extracted from the thin descending limb of the loop of Henle by osmotic forces created in the hypertonic medullary interstitium. As in the proximal tubule, impermeant luminal solutes such as mannitol oppose water extraction. The thick ascending limb of the loop of Henle actively reabsorbs NaCl from the lumen (about 35% of the filtered sodium), but unlike the proximal tubule and the thin limb, it is nearly impermeable to water. Salt reabsorption in the thick ascending limb therefore dilutes the tubular fluid, leading to its designation as a "diluting segment." Medullary portions of the thick ascending limb contribute to medullary hypertonicity and thereby also play an important role in concentration of urine. The NaCl transport system in the luminal membrane of the thick ascending limb is a Na+/K+/2Clcotransporter (Figure 15–4). This transporter is selectively blocked by diuretic agents known as "loop" diuretics (see below). Although the Na+/K+/2Cl- transporter is itself electrically neutral (two cations and two anions are cotransported), the action of the transporter contributes to excess K+ accumulation within the cell. This results in back diffusion of K+ into the tubular lumen and development of a lumen-positive electrical potential. This electrical potential provides the driving force for reabsorption of cations—including Mg2+ and Ca2+—via the paracellular pathway (between the cells). Thus, inhibition of salt transport in the thick ascending limb by loop diuretics causes an increase in urinary excretion of divalent cations in addition to NaCl. Figure 15–4.
Ion transport pathways across the luminal and basolateral membranes of the thick ascending limb cell. The lumen positive electrical potential created by K+ back diffusion drives divalent cation reabsorption via the paracellular pathway. Distal Convoluted Tubule Only about 10% of the filtered NaCl is reabsorbed in the distal convoluted tubule. Like the thick ascending limb, this segment is relatively impermeable to water, and the NaCl reabsorption therefore further dilutes the tubular fluid. The mechanism of NaCl transport in the distal convoluted tubule is electrically neutral Na+ and Cl- cotransport (Figure 15–5). This NaCl transporter is blocked by diuretics of the thiazide class. Figure 15–5.
Ion transport pathways across the luminal and basolateral membranes of the distal convoluted tubule cell. As in all tubular cells, Na+/K+ ATPase is present in the basolateral membrane. (R, PTH receptor.)
Because K+ does not recycle across the apical membrane of the distal convoluted tubule as it does in the loop of Henle, there is no lumen-positive potential in this segment, and Ca2+ and Mg2+ are not driven out of the tubular lumen by electrical forces. However, Ca2+ is actively reabsorbed by the distal convoluted tubule epithelial cell via an apical Ca2+ channel and basolateral Na+/Ca2+ exchanger (Figure 15–5). This process is regulated by parathyroid hormone. As will be seen below, the differences in the mechanism of Ca2+ transport in the distal convoluted tubule and in the loop of Henle have important implications for the effects of various diuretics on Ca2+ transport. Collecting Tubule The collecting tubule is responsible for only 2–5% of NaCl reabsorption by the kidney. Despite this small contribution, the collecting tubule plays an important role in renal physiology and in diuretic action. As the final site of NaCl reabsorption, the collecting tubule is responsible for volume regulation and for determining the final Na+ concentration of the urine. Furthermore, the collecting tubule is a site at which mineralocorticoids exert a significant influence. Lastly, the collecting tubule is the major site of potassium secretion by the kidney and the site at which virtually all diuretic-induced changes in potassium balance occur. The mechanism of NaCl reabsorption in the collecting tubule is distinct from the mechanisms found in other tubule segments. The principal cells are the major sites of Na+, K+, and H2O transport (Figure 15–6), and the intercalated cells are the primary sites of proton secretion. Unlike cells in other nephron segments, the principal cells do not contain cotransport systems for Na+ and other ions in their apical membranes. Rather, principal cell membranes exhibit separate ion channels for Na+ and K+. Since these channels exclude anions, transport of Na+ or K+ leads to a net movement of charge across the membrane. Because the driving force for Na+ entry into the principal cell greatly exceeds that for K+ exit, Na+ reabsorption predominates, and a 10–50 mV lumen-negative electrical potential develops. Na+ that enters the principal cell from the urine is then transported back to the blood via the basolateral Na+/K+ ATPase (Figure 15–6). The lumen-negative electrical potential drives the transport of Cl- back to the blood via the paracellular pathway and also pulls K+ out of the cell through the apical membrane K+ channel. Thus, there is an important relationship between Na+ delivery to the collecting tubule and the resulting secretion of K+. Diuretics that act upstream of the collecting tubule will increase Na+ delivery to this site and will enhance K+ secretion. If the Na+ is delivered with an anion which cannot be reabsorbed as readily as Cl- (eg, bicarbonate), the lumennegative potential is increased, and K+ secretion will be enhanced. This mechanism, combined with enhanced aldosterone secretion due to volume depletion, is the basis for most diuretic-induced K+ wasting. Figure 15–6.
Ion and H2O transport pathways across the luminal and basolateral membranes of collecting tubule and collecting duct cells. Inward diffusion of Na+ leaves a lumen-negative potential, which drives reabsorption of Cl- and efflux of K+. (R, aldosterone or ADH receptor.) Reabsorption of Na+ via the epithelial Na channel (ENaC) and its coupled secretion of K+ is regulated by aldosterone. This steroid hormone, through its actions on gene transcription, increases the activity of both apical membrane channels and the basolateral N+/K+ ATPase. This leads to an increase in the transepithelial electrical potential and a dramatic increase in both Na+ reabsorption and K+ secretion. A key determinant of the final urine concentration is antidiuretic hormone (ADH; also called vasopressin). In the absence of ADH, the collecting tubule (and duct) is impermeable to water, and dilute urine is produced. However, membrane water permeability of principal cells can be increased by ADH-induced fusion of vesicles containing preformed water channels with the apical membranes (Figure 15–6). ADH secretion is regulated by serum osmolality and by volume status. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 15. Diuretic Agents > Basic Pharmacology of Diuretic Agents Carbonic Anhydrase Inhibitors Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the luminal membrane of the proximal tubule cells (Figure 15–3), where it catalyzes the dehydration of H2CO3, a critical step in the reabsorption of bicarbonate. By blocking carbonic
anhydrase, inhibitors block sodium bicarbonate reabsorption and cause diuresis. The carbonic anhydrase inhibitors were the forerunners of modern diuretics. They are unsubstituted sulfonamide derivatives and were discovered when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is acetazolamide. Pharmacokinetics The carbonic anhydrase inhibitors are well absorbed after oral administration. An increase in urine pH from the bicarbonate diuresis is apparent within 30 minutes, maximal at 2 hours, and persists for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule S2 segment. Therefore, dosing must be reduced in renal insufficiency. Pharmacodynamics Inhibition of carbonic anhydrase activity profoundly depresses bicarbonate reabsorption in the proximal tubule. At its maximal safely administered dosage, 85% of the bicarbonate reabsorptive capacity of the superficial proximal tubule is inhibited. Some bicarbonate can still be absorbed at other nephron sites by carbonic anhydrase–independent mechanisms, and the overall effect of maximal acetazolamide dosage is about 45% inhibition of whole kidney bicarbonate reabsorption. Nevertheless, carbonic anhydrase inhibition causes significant bicarbonate losses and hyperchloremic metabolic acidosis. Because of this and the fact that HCO3- depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days. The major clinical applications of acetazolamide involve carbonic anhydrase–dependent bicarbonate transport at sites other than the kidney. The ciliary body of the eye secretes bicarbonate from the blood into the aqueous humor. Likewise, formation of cerebrospinal fluid by the choroid plexus involves bicarbonate secretion into the cerebrospinal fluid. Although these processes remove bicarbonate from the blood (the direction opposite to that in the proximal tubule), they are significantly inhibited by carbonic anhydrase inhibitors, which in both cases dramatically alter the pH and quantity of fluid produced. Clinical Indications & Dosage See Table 15–1. Table 15–1. Carbonic Anhydrase Inhibitors Used Orally in Treatment of Glaucoma.
Drug
Usual Oral Dose (1–4 Times Daily)
Acetazolamide
250 mg
Dichlorphenamide
50 mg
Methazolamide
50 mg
Glaucoma The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. This effect is valuable in the management of severe forms of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active carbonic anhydrase inhibitors (dorzolamide, brinzolamide) are also available. These topical compounds reduce intraocular pressure, but plasma levels are undetectable. Thus, diuretic and systemic metabolic effects are eliminated. Urinary Alkalinization Uric acid, cystine, and some other weak acids are relatively insoluble in, and easily reabsorbed from, acidic urine. Renal excretion of these compounds can be enhanced by increasing urinary pH with carbonic anhydrase inhibitors. In the absence of continuous bicarbonate administration, these effects of acetazolamide are of relatively short duration (2–3 days). Prolonged therapy requires bicarbonate administration. Metabolic Alkalosis Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid levels. However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, saline administration may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for the correction of heart failure. Acetazolamide has also been used to rapidly correct the metabolic alkalosis that may develop in the setting of respiratory acidosis. Acute Mountain Sickness Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. The symptoms are usually mild and last for a few days. In more serious cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. By decreasing cerebrospinal fluid formation and by decreasing the pH of the cerebrospinal fluid and brain, acetazolamide can enhance performance status and diminish symptoms of mountain sickness. Other Uses Carbonic anhydrase inhibitors have been used as adjuvants for the treatment of epilepsy, in some forms of hypokalemic periodic paralysis, and to increase urinary phosphate excretion during severe hyperphosphatemia. Toxicity Hyperchloremic Metabolic Acidosis Acidosis predictably results from chronic reduction of body bicarbonate stores by carbonic anhydrase inhibitors and limits the diuretic efficacy of these drugs to 2 or 3 days. Renal Stones
Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use. Calcium salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced. Renal Potassium Wasting Potassium wasting can occur because NaHCO3 presented to the collecting tubule increases the lumen-negative electrical potential in that segment and enhances K+ secretion. This effect can be counteracted by simultaneous administration of KCl. Other Toxicities Drowsiness and paresthesias are common following large doses. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur. Contraindications Carbonic anhydrase inhibitor-induced alkalinization of the urine will decrease urinary excretion of NH4+ and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis. Loop Diuretics Loop diuretics selectively inhibit NaCl reabsorption in the thick ascending limb of the loop of Henle. Due to the large NaCl absorptive capacity of this segment and the fact that diuresis is not limited by development of acidosis, as it is with the carbonic anhydrase inhibitors, these drugs are the most efficacious diuretic agents available. Chemistry The two prototypical drugs of this group are furosemide and ethacrynic acid. The structures of several loop diuretics are shown in Figure 15–7. Like the carbonic anhydrase inhibitors, furosemide, bumetanide, and torsemide are sulfonamide derivatives. Figure 15–7.
Some loop diuretics. The shaded methylene group on ethacrynic acid is reactive and may combine with free sulfhydryl groups. Ethacrynic acid—not a sulfonamide derivative—is a phenoxyacetic acid derivative containing an adjacent ketone and methylene group (Figure 15–7). The methylene group (shaded) forms an adduct with the free sulfhydryl group of cysteine. The cysteine adduct appears to be an active form of the drug. Organic mercurial diuretics also inhibit salt transport in the thick ascending limb but are no longer used because of their high toxicity. Pharmacokinetics The loop diuretics are rapidly absorbed. They are eliminated by tubular secretion as well as by glomerular filtration. Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2–3 hours) and is nearly as complete as with intravenous administration. Diuretic response is extremely rapid following intravenous injection. The duration of effect for furosemide is usually 2– 3 hours and that of torsemide is 4–6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they have any diuretic activity. Torsemide has at least one active metabolite with a
half-life considerably longer than that of the parent compound. Pharmacodynamics These drugs inhibit the luminal Na+/K+/2Cl- transporter in the thick ascending limb of Henle's loop. By inhibiting this transporter, the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that derives from K+ recycling (Figure 15–4). This electrical potential normally drives divalent cation reabsorption in the loop, and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since Ca2+ is actively reabsorbed in the distal convoluted tubule, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia, Ca2+ excretion can be greatly enhanced by combining loop agents with saline infusions. Loop diuretics induce renal prostaglandin synthesis, and these prostaglandins participate in the renal actions of these drugs. NSAIDs (eg, indomethacin) can interfere with the actions of the loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis. In addition to their diuretic activity, loop agents appear to have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow. Furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs, and in anephric patients. Clinical Indications & Dosage The most important indications for the use of the loop diuretics include acute pulmonary edema, other edematous conditions, and acute hypercalcemia (Table 15–2). The use of loop diuretics in these conditions is discussed in Clinical Pharmacology. Other indications for loop diuretics include hyperkalemia, acute renal failure, and anion disease. Table 15–2. Loop Diuretics: Dosages.
Drug
Daily Oral Dose1
Bumetanide
0.5–2 mg
Ethacrynic acid
50–200 mg
Furosemide
20–80 mg
Torsemide
2.5–20 mg
1
As single dose or in two divided doses.
Hyperkalemia In mild hyperkalemia—or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K+. This response is enhanced by
simultaneous NaCl and water administration. Acute Renal Failure Loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. However, they do not seem to shorten the duration of renal failure. If a large pigment load has precipitated acute renal failure or threatens to do so, loop agents may help flush out intratubular casts and ameliorate intratubular obstruction. On the other hand, loop agents can theoretically worsen cast formation in myeloma and light chain nephropathy. Anion Overdose Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the thick ascending limb. Saline solution must be administered to replace urinary losses of Na+ and to provide Cl-, so as to avoid extracellular fluid volume depletion. Toxicity Hypokalemic Metabolic Alkalosis Loop diuretics increase delivery of salt and water to the collecting duct and thus enhance the renal secretion of K+ and H+, causing hypokalemic metabolic alkalosis. This toxicity is a function of the magnitude of the diuretic effect and can be reversed by K+ replacement and correction of hypovolemia. Ototoxicity Loop diuretics can cause dose-related hearing loss that is usually reversible. It is most common in patients who have diminished renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics. Hyperuricemia Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. It may be avoided by using lower doses. Hypomagnesemia Magnesium depletion is a predictable consequence of the chronic use of loop agents and occurs most often in patients with dietary magnesium deficiency. It can be reversed by administration of oral magnesium preparations. Allergic Reactions Skin rash, eosinophilia and, less often, interstitial nephritis are occasional side effects of furosemide, bumetanide, and torsemide therapy. These usually resolve rapidly after drug withdrawal. Allergic reactions are much less common with ethacrynic acid. Other Toxicities
Even more than other diuretics, loop agents can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become severely hyponatremic with loop agents. Loop agents are known for their calciuric effect, but hypercalcemia can occur in patients who have another— previously occult—cause for hypercalcemia, such as an oat cell carcinoma of the lung if they become severely volume-depleted. Contraindications Furosemide, bumetanide, and torsemide may demonstrate cross-reactivity in patients who are sensitive to other sulfonamides. Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure (see below). Thiazides The thiazide diuretics emerged from efforts to synthesize more potent carbonic anhydrase inhibitors. It subsequently became clear that the thiazides inhibit NaCl transport predominantly in the distal convoluted tubule. However, some members of this group retain significant carbonic anhydrase inhibitory activity. The prototypical thiazide is hydrochlorothiazide. Chemistry & Pharmacokinetics Similar to the carbonic anhydrase inhibitors, all of the thiazides have an unsubstituted sulfonamide group (Figure 15–8). Figure 15–8.
Hydrochlorothiazide and related agents. All of the thiazides can be administered orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. Chlorthalidone is slowly absorbed and has a longer duration of action. Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the distal convoluted tubule. All of the thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result, uric acid secretion may be reduced, with an elevation in serum uric acid level. Pharmacodynamics Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the distal convoluted tubule by blocking the Na+/Cl- transporter. In contrast to the situation in the loop of Henle, where loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption in the distal convoluted tubule. This enhancement has been postulated to result from a lowering of intracellular Na+ upon blockade of Na+ entry by thiazides. The lower cell Na+ would enhance Na+/Ca2+ exchange in the basolateral membrane (Figure 15–5), increasing overall reabsorption of Ca2+. While thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask
hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria. The action of thiazides depends in part on renal prostaglandin production. As described above for the loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions. Clinical Indications & Dosage The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes insipidus (Table 15– 3). Use of the thiazides in each of these conditions is described below in the section on clinical pharmacology. Table 15–3. Thiazides and Related Diuretics: Dosages.
Drug
Daily Oral Dose
Frequency of Dosage
Bendroflumethiazide
2.5–10 mg
As single dose
Benzthiazide
25–100 mg
In two divided doses
Chlorothiazide
0.5–1 g
In two divided doses
Chlorthalidone1
50–100 mg
As single dose
Hydrochlorothiazide
25–100 mg
As single dose
Hydroflumethiazide
25–100 mg
In two divided doses
2.5–10 mg
As single dose
2.5–10 mg
As single dose
2.5–10 mg
As single dose
1–4 mg
As single dose
50–100 mg
As single dose
2–8 mg
As single dose
1
Indapamide
Methyclothiazide Metolazone
1
Polythiazide Quinethazone
1
Trichlormethiazide
1
Not a thiazide but a sulfonamide qualitatively similar to the thiazides.
Toxicity Hypokalemic Metabolic Alkalosis and Hyperuricemia These toxicities are similar to those observed with loop diuretics (see above). Impaired Carbohydrate Tolerance
Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. The effect is due both to impaired pancreatic release of insulin and to diminished tissue utilization of glucose. Hyperglycemia may be partially reversible with correction of hypokalemia. Hyperlipidemia Thiazides cause a 5–15% increase in serum cholesterol and increased low-density lipoproteins (LDL). These levels may return toward baseline after prolonged use. Hyponatremia Hyponatremia is an important adverse effect of thiazide diuretics. It is due to a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. Allergic Reactions The thiazides are sulfonamides and share cross-reactivity with other members of this chemical group. Photosensitivity or generalized dermatitis occurs rarely. Serious allergic reactions are extremely rare but do include hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis. Other Toxicities Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase inhibitors may occur. Impotence has been reported but is probably related to volume depletion. Contraindications Excessive use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure (see below). Potassium-Sparing Diuretics These diuretics antagonize the effects of aldosterone at the late distal tubule and cortical collecting tubule. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene). Chemistry & Pharmacokinetics Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Its onset and duration of action are determined by the kinetics of the aldosterone response in the target tissue. Substantial inactivation of spironolactone occurs in the liver. Overall, spironolactone has a rather slow onset of action, requiring several days before full therapeutic effect is achieved. Eplerenone, a new spironolactone analog with greater selectivity for the aldosterone receptor, has recently been approved for the treatment of hypertension. Amiloride is excreted unchanged in the urine. Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Because
triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride. The structures of spironolactone, triamterene, and amiloride are shown in Figure 15–9. Figure 15–9.
Aldosterone antagonists. Pharmacodynamics Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts. Na+ absorption (and K+ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H+ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists. Spironolactone and eplerenone bind to aldosterone receptors and may also reduce the intracellular formation of active metabolites of aldosterone. Triamterene and amiloride do not block the aldosterone receptor but instead directly interfere with Na+ entry through the sodium-selective (ENaC) ion channels in the apical membrane of the collecting tubule. Since K+ secretion is coupled
with Na+ entry in this segment, these agents are also effective potassium-sparing diuretics. The actions of triamterene and spironolactone depend on renal prostaglandin production. As described above for loop diuretics and thiazides, the actions of triamterene and spironolactone can also be inhibited by NSAIDs under certain conditions. Clinical Indications & Dosage These agents are most useful in states of mineralocorticoid excess, due either to primary hypersecretion (Conn's syndrome, ectopic ACTH production) or to secondary aldosteronism (from heart failure, hepatic cirrhosis, nephrotic syndrome, and other conditions associated with diminished effective intravascular volume) (Table 15–4). Use of other diuretics, like thiazides or loop agents, can cause or exacerbate volume contraction and thus intensify secondary aldosteronism. In the setting of enhanced mineralocorticoid secretion and continuing delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response. Table 15–4. Potassium-Sparing Diuretics and Combination Preparations.
Trade Name
Potassium-Sparing Agent Hydrochlorothiazide Frequency of Dosage
Aldactazide
Spironolactone 25 mg
25 mg
1–4 times daily
Aldactone
Spironolactone 25 mg
...
1–4 times daily
Dyazide
Triamterene 50 mg
25 mg
1–4 times daily
Dyrenium
Triamterene 50 mg
...
1–3 times daily
Inspra1
Eplerenone 25, 50 mg
...
Once or twice daily
Maxzide
Triamterene 75 mg
50 mg
Once daily
Maxzide-25 mg Triamterene 27.5 mg
25 mg
Once daily
Midamor
Amiloride 5 mg
...
Once daily
Moduretic
Amiloride 5 mg
50 mg
Once or twice daily
1
Eplerenone is currently approved for use only in hypertension.
Toxicity Hyperkalemia Unlike other diuretics, these agents can cause mild, moderate, or even life-threatening hyperkalemia. The risk of this complication is greatly increased in the presence of renal disease or of other drugs that reduce renin ( -blockers, NSAIDs) or angiotensin II activity (angiotensinconverting enzyme [ACE] inhibitors, angiotensin receptor inhibitors). Since most other diuretic agents lead to K+ losses, hyperkalemia is more common when aldosterone antagonists are used as the sole diuretic agent, especially in patients with renal insufficiency. With fixed-dosage combinations of potassium-sparing and thiazide diuretics, the thiazide-induced hypokalemia and metabolic alkalosis are ameliorated by the aldosterone antagonist. However, owing to variations in
the bioavailability of the components of fixed-dosage forms, the thiazide-associated adverse effects may predominate. Therefore, it is generally preferable to adjust the doses of the two drugs separately. Hyperchloremic Metabolic Acidosis By inhibiting H+ secretion in parallel with K+ secretion, the potassium-sparing diuretics can cause acidosis similar to that seen with type IV renal tubular acidosis. Gynecomastia Synthetic steroids may cause endocrine abnormalities by effects on other steroid receptors. Gynecomastia, impotence, and benign prostatic hyperplasia have all been reported with spironolactone. Such effects have not been reported with eplerenone. Acute Renal Failure The combination of triamterene with indomethacin has been reported to cause acute renal failure. This has not been reported with other potassium-sparing agents. Kidney Stones Triamterene is poorly soluble and may precipitate in the urine, causing kidney stones. Contraindications These agents can cause severe, even fatal hyperkalemia in susceptible patients. Oral K+ administration should be discontinued if aldosterone antagonists are administered. Patients with chronic renal insufficiency are especially vulnerable and should rarely be treated with aldosterone antagonists. Concomitant use of other agents that blunt the renin-angiotensin system ( -blockers or ACE inhibitors) increases the likelihood of hyperkalemia. Patients with liver disease may have impaired metabolism of triamterene and spironolactone, and dosing must be carefully adjusted. Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole) can markedly increase blood levels of eplerenone. Agents That Alter Water Excretion Osmotic Diuretics The proximal tubule and descending limb of Henle's loop are freely permeable to water. An osmotic agent that is not reabsorbed causes water to be retained in these segments and promotes a water diuresis. Such agents can be used to reduce increased intracranial pressure and to promote prompt removal of renal toxins. The prototypic osmotic diuretic is mannitol. Pharmacokinetics Osmotic diuretics are poorly absorbed, which means that they must be given parenterally. If administered orally, mannitol causes osmotic diarrhea. Mannitol is not metabolized and is excreted primarily by glomerular filtration within 30–60 minutes, without any important tubular reabsorption or secretion.
Pharmacodynamics Osmotic diuretics have their major effect in those segments of the nephron that are freely permeable to water: the proximal tubule and the descending limb of the loop of Henle. They also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow rate decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ reabsorption. However, the resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to hypernatremia. Clinical Indications & Dosage to Increase Urine Volume Osmotic diuretics are used to increase water excretion in preference to sodium excretion. This effect can be useful when avid Na+ retention limits the response to conventional agents. It can be used to maintain urine volume and to prevent anuria that might otherwise result from presentation of large pigment loads to the kidney (eg, from hemolysis or rhabdomyolysis). Some oliguric patients do not respond to an osmotic diuretic. Therefore, a test dose of mannitol (12.5 g intravenously) should be given prior to starting a continuous infusion. Mannitol should not be continued unless there is an increase in urine flow rate to more than 50 mL/h during the 3 hours following the test dose. Mannitol (12.5–25 g) can be repeated every 1–2 hours to maintain urine flow rate greater than 100 mL/h. Prolonged use of mannitol is not advised. Reduction of Intracranial and Intraocular Pressure Osmotic diuretics alter Starling forces so that water leaves cells and reduces intracellular volume. This effect is used to reduce intracranial pressure in neurologic conditions and to reduce intraocular pressure before ophthalmologic procedures. A dose of 1–2 g/kg mannitol is administered intravenously. Intracranial pressure, which must be monitored, should fall in 60–90 minutes. Toxicity Extracellular Volume Expansion Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This effect can complicate heart failure and may produce florid pulmonary edema. Headache, nausea, and vomiting are commonly observed in patients treated with osmotic diuretics. Dehydration and Hypernatremia Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, and hypernatremia. These complications can be avoided by careful attention to serum ion composition and fluid balance. Antidiuretic Hormone (ADH) Agonists Vasopressin and desmopressin are used in the treatment of pituitary diabetes insipidus. They are discussed in Chapter 37: Hypothalamic & Pituitary Hormones.
Antidiuretic Hormone (ADH) Antagonists A variety of medical conditions cause water retention as the result of ADH excess. Unfortunately, specific ADH antagonists are available only for investigational purposes. Two nonselective agents, lithium and demeclocycline (a tetracycline derivative), are of limited use in some situations. Pharmacokinetics Both lithium and demeclocycline are orally active. Lithium is excreted by the kidney, and demeclocycline is metabolized in the liver. Pharmacodynamics ADH antagonists inhibit the effects of ADH in the collecting tubule. Both lithium and demeclocycline appear to reduce the formation of cyclic adenosine monophospate (cAMP) in response to ADH and also to interfere with the actions of cAMP in the collecting tubule cells. Clinical Indications & Dosage Syndrome of Inappropriate ADH Secretion (SIADH) ADH antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. This generally occurs in the outpatient setting, where water restriction cannot be enforced, or in the hospital when large quantities of intravenous fluid are administered with drugs. Lithium carbonate has been used to treat this syndrome, but the response is unpredictable. Serum levels of lithium must be monitored closely, as serum concentrations greater than 1 mmol/L are toxic. Demeclocycline, in dosages of 600–1200 mg/d, yields a more predictable result and is less toxic. Appropriate plasma levels (2 g/mL) should be maintained by monitoring. Other Causes of Elevated Antidiuretic Hormone (ADH) ADH is also elevated in response to diminished effective circulating blood volume. When treatment by volume replacement is not possible, as in heart failure or liver disease, hyponatremia may result. As for SIADH, water restriction is the treatment of choice, but if it is not successful, demeclocycline may be used. Toxicity Nephrogenic Diabetes Insipidus If serum Na+ is not monitored closely, ADH antagonists can cause severe hypernatremia and nephrogenic diabetes insipidus. If lithium is being used for an affective disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride (see below). Renal Failure Both lithium and demeclocycline have been reported to cause acute renal failure. Long-term lithium therapy may also cause chronic interstitial nephritis. Other
Adverse effects associated with lithium therapy include tremulousness, mental obtundation, cardiotoxicity, thyroid dysfunction, and leukocytosis (see Chapter 29: Antipsychotic Agents & Lithium). Demeclocycline should be avoided in patients with liver disease (see Chapter 44: Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, & Streptogramins) and in children younger than 12 years. Diuretic Combinations Loop Agents & Thiazides Some patients are refractory to the usual dose of loop diuretics or become refractory after an initial response. Since these agents have a short half-life, refractoriness may be due to an excessively long interval between doses. Renal Na+ retention is enhanced during the time period when the drug is no longer active. After the dosing interval for loop agents is minimized or the dose is maximized, the use of two drugs acting at different nephron sites may exhibit synergy. Loop agents and thiazides in combination will often produce diuresis when neither agent acting alone is even minimally effective. There are several reasons for this phenomenon. First, salt and water reabsorption in either the thick ascending limb or the distal convoluted tubule can increase when the other is blocked. Inhibition of both can therefore produce more than an additive diuretic response. Second, thiazide diuretics may produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the thick ascending limb. The combination of loop diuretics and thiazides will therefore blunt Na+ reabsorption, to some extent, from all three segments. Metolazone is the usual choice of thiazide-like drug in patients refractory to loop agents alone, but it is likely that other thiazides would be as effective as metolazone. Moreover, metolazone is available only in an oral preparation, while chlorothiazide can be given parenterally. The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Therefore, close hemodynamic monitoring is essential. Routine outpatient use is not recommended. Furthermore, K+-wasting is extremely common and may require parenteral K+ administration with careful monitoring of fluid and electrolyte status. Potassium-Sparing Diuretics & Loop Agents or Thiazides Hypokalemia eventually develops in many patients who are placed on loop diuretics or thiazides. This can often be managed with dietary NaCl restriction. When hypokalemia cannot be managed in this way, or with dietary KCl supplements, the addition of a potassium-sparing diuretic can significantly lower potassium excretion. While this approach is generally safe, it should be avoided in patients with renal insufficiency in whom life-threatening hyperkalemia can develop in response to potassium-sparing diuretics. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 15. Diuretic Agents > Clinical Pharmacology of Diuretic Agents This section discusses the clinical use of diuretic agents in edematous and nonedematous states. The effects of these agents on urinary electrolyte excretion are shown in Table 15–5.
Table 15–5. Changes in Urinary Electrolyte Patterns in Response to Diuretic Drugs.
Urinary Electrolyte Patterns Agent
NaCl
NaHCO3
K+
Carbonic anhydrase inhibitors
+
+++
+
Loop agents
++++
–
+
Thiazides
++
±
+
Loop agents plus thiazides
+++++
+
++
+
–
–
+
K -sparing agents
+, increase; –, decrease. Edematous States The most common reason for diuretic use is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases, or abnormalities in the blood oncotic pressure. Salt and water retention with edema formation often occurs when diminished blood delivery to the kidney is sensed as insufficient "effective" arterial blood volume. Judicious use of diuretics can mobilize interstitial edema fluid without significant reductions in plasma volume. However, excessive diuretic therapy in this setting may lead to further compromise of the effective arterial blood volume with reduction in perfusion of vital organs. Therefore, the use of diuretics to mobilize edema requires careful monitoring of the patient's hemodynamic status and an understanding of the pathophysiology of the underlying condition. Heart Failure When cardiac output is reduced by disease, the resultant changes in blood pressure and blood flow to the kidney are sensed as hypovolemia and thus induce renal retention of salt and water. This physiologic response initially expands the intravascular volume and venous return to the heart and may partially restore the cardiac output toward normal (see Chapter 13: Drugs Used in Heart Failure). If the underlying disease causes cardiac function to deteriorate despite expansion of plasma volume, the kidney continues to retain salt and water, which then leaks from the vasculature and becomes interstitial or pulmonary edema. At this point, diuretic use becomes necessary to reduce the accumulation of edema, particularly that which is in the lungs. Reduction of pulmonary vascular congestion with diuretics may actually improve oxygenation and thereby improve myocardial function. Edema associated with heart failure is generally managed with loop diuretics. In some instances, salt and water retention may become so severe that a combination of thiazides and loop diuretics is necessary. In treating the heart failure patient with diuretics, it must always be remembered that cardiac output in these patients is being maintained in part by high filling pressures and that excessive use of diuretics may diminish venous return and thereby impair cardiac output. This issue is especially
critical in right ventricular failure. Systemic rather than pulmonary vascular congestion is the hallmark of this disorder. Diuretic-induced volume contraction will predictably reduce venous return and can severely compromise cardiac output if left ventricular filling pressure is reduced below 15 mm Hg. Diuretic-induced metabolic alkalosis is another adverse effect that may further compromise cardiac function. While this effect is generally treated with replacement of potassium and restoration of intravascular volume with saline, severe heart failure may preclude the use of saline even in patients who have received too much diuretic. In these cases, adjunctive use of acetazolamide can help correct the alkalosis. Another serious toxicity of diuretic use, particularly in the cardiac patient, is hypokalemia. Hypokalemia can exacerbate underlying cardiac arrhythmias and contribute to digitalis toxicity. This can often be avoided by having the patient reduce sodium intake, thus decreasing sodium delivery to the K+-secreting collecting tubule. Patients who are noncompliant with a low sodium diet must take oral KCl supplements or a potassium-sparing diuretic or must stop using the thiazide diuretic. Finally, it should be kept in mind that diuretics can never correct the underlying cardiac disease. Drugs that improve myocardial contractility or reduce peripheral vascular resistance are more direct approaches to the basic problem. Kidney Disease A variety of renal diseases may interfere with the kidney's critical role in volume homeostasis. Although renal disorders will occasionally cause salt wasting, most kidney diseases cause retention of salt and water. When loss of renal function is severe, diuretic agents are of little benefit, because there is insufficient glomerular filtration to sustain a natriuretic response. However, a large number of patients with milder degrees of renal insufficiency can be treated with diuretics when they retain sodium. Many primary and secondary glomerular diseases, such as those associated with diabetes mellitus or systemic lupus erythematosus, exhibit renal retention of salt and water. The cause of this sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation and tubular function through release of vasoconstrictors, prostaglandins, cytokines, and other mediators. When edema or hypertension develops in these patients, diuretic therapy can be very effective. If heart failure is also present, see the warnings mentioned above. Certain forms of renal disease, particularly diabetic nephropathy, are frequently associated with development of hyperkalemia at a relatively early stage of renal failure. In these cases, a thiazide or loop diuretic will enhance K+ excretion by increasing delivery of salt to the K+-secreting collecting tubule. Patients with renal diseases leading to the nephrotic syndrome often present complex problems in volume management. These patients may have reduced plasma volume in conjunction with reduced plasma oncotic pressures, especially those with "minimal change" nephropathy. In these patients, diuretic use may cause further reductions in plasma volume that can impair glomerular filtration rate and may lead to orthostatic hypotension. However, most other causes of nephrotic syndrome are associated with a primary retention of salt and water by the kidney, leading to expanded plasma volume and hypertension despite the low plasma oncotic pressure. In these cases, diuretic therapy may be beneficial in controlling the volume-dependent component of hypertension. In choosing a
diuretic for the patient with kidney disease, there are a number of important limitations. Acetazolamide and potassium-sparing diuretics must usually be avoided because of their tendency to exacerbate acidosis and hyperkalemia, respectively. Thiazide diuretics are generally ineffective when glomerular filtration rate falls below 30 mL/min. Thus, loop diuretics are often the best choice in treating edema associated with kidney failure. Lastly, excessive use of diuretics will cause renal function to decline in all patients, but the consequences are more serious in those with underlying renal disease. Hepatic Cirrhosis Liver disease is often associated with edema and ascites in conjunction with elevated portal hydrostatic pressures and reduced plasma oncotic pressures. The mechanisms for retention of sodium by the kidney are complex. They probably involve a combination of factors, including diminished renal perfusion resulting from systemic vascular alterations, diminished plasma volume as the result of ascites formation, and diminished oncotic pressure from hypoalbuminemia. In addition, there may be primary sodium retention by the kidney. Plasma aldosterone levels are usually high in response to the reduction in effective circulating volume. When ascites and edema become severe, diuretic therapy can be useful in initiating and maintaining diuresis. Cirrhotic patients are often resistant to loop diuretics, in part because of a decrease in secretion of the drug into the tubular fluid and in part because of high aldosterone levels leading to enhanced collecting duct salt reabsorption. In contrast, cirrhotic edema is unusually responsive to spironolactone. The combination of loop diuretics and spironolactone may be useful in some patients. However, even more than in heart failure, overly aggressive use of diuretics in this setting can be disastrous. Vigorous diuretic therapy can cause marked depletion of intravascular volume, hypokalemia, and metabolic alkalosis. Hepatorenal syndrome and hepatic encephalopathy are the unfortunate consequences of excessive diuretic use in the cirrhotic patient. Idiopathic Edema Despite intensive study, the pathophysiology of this disorder (fluctuating salt retention and edema) remains obscure. Some studies suggest that intermittent diuretic use may actually contribute to the syndrome. Therefore, idiopathic edema should be managed with mild salt restriction alone if possible. Nonedematous States Hypertension The diuretic and mild vasodilator actions of the thiazides are useful in treating virtually all patients with essential hypertension, and may be completely sufficient in two thirds. Moderate restriction of dietary Na+ intake (60–100 meq/d) has been shown to potentiate the effects of diuretics in essential hypertension and to lessen renal K+ wasting. A recent very large study (over 30,000 participants) has shown that inexpensive diuretics are similar or superior in outcomes to ACE inhibitor or calcium channel blocker therapy (ALLHAT, 2002). This important result reinforces the importance of thiazide therapy in hypertension. Diuretics also play an important role in patients who require multiple drugs to control blood pressure. Diuretics enhance the efficacy of many agents, particularly the ACE inhibitors. Patients being treated with powerful vasodilators such as hydralazine or minoxidil usually require diuretics
simultaneously because the vasodilators cause significant salt and water retention. Nephrolithiasis Approximately two thirds of all renal stones contain calcium phosphate or calcium oxalate. Many patients with such stones exhibit a renal defect in calcium reabsorption that causes hypercalciuria. This can be treated with thiazide diuretics, which enhance calcium reabsorption in the distal convoluted tubule and thus reduce the urinary calcium concentration. Salt intake must be reduced in this setting, as excess dietary NaCl will overwhelm the hypocalciuric effect of thiazides. Calcium stones may also be caused by increased intestinal absorption of calcium, or they may be idiopathic. In these situations, thiazides are also effective, but should be used as adjunctive therapy with decreased calcium intake and other measures. Hypercalcemia Hypercalcemia can be a medical emergency. Since the loop of Henle is an important site of calcium reabsorption, loop diuretics can be quite effective in promoting calcium diuresis. However, loop diuretics alone can cause marked volume contraction. If this occurs, loop diuretics are ineffective (and potentially counterproductive) because calcium reabsorption in the proximal tubule is enhanced. Thus, saline must be administered simultaneously with loop diuretics if an effective calcium diuresis is to be achieved. The usual approach is to infuse normal saline and furosemide (80–120 mg) intravenously. Once the diuresis begins, the rate of saline infusion can be matched with the urine flow rate to avoid volume depletion. Potassium may be added to the saline infusion as needed. Diabetes Insipidus Thiazide diuretics can reduce polyuria and polydipsia in patients who are not responsive to ADH. This seemingly paradoxic beneficial effect is mediated through plasma volume reduction, with an associated fall in glomerular filtration rate, enhanced proximal reabsorption of NaCl and water, and decreased delivery of fluid to the diluting segments. Thus, the maximum volume of dilute urine that can be produced is lowered and thiazides can significantly reduce urine flow in the polyuric patient. Dietary sodium restriction can potentiate the beneficial effects of thiazides on urine volume in this setting. Lithium, used in the treatment of manic-depressive disorder, is a common cause of druginduced diabetes insipidus, and thiazide diuretics have been found to be helpful in treating it. Serum lithium levels must be carefully monitored in this situation, since diuretics may reduce renal clearance of lithium and raise plasma lithium levels into the toxic range (see Chapter 29: Antipsychotic Agents & Lithium). Lithium polyuria can also be partially reversed by amiloride, which appears to block lithium entry into collecting duct cells, much as it blocks Na+ entry. Katzung PHARMACOLOGY, 9e > Section III. Cardiovascular-Renal Drugs > Chapter 15. Diuretic Agents > Preparations Available Acetazolamide(generic, Diamox) Oral: 125, 250 mg tablets Oral sustained-release: 500 mg capsules
Parenteral: 500 mg powder for injection Amiloride(generic, Midamor, combination drugs) Oral: 5 mg tablets Bendroflumethiazide (Naturetin) Oral: 5, 10 mg tablets Benzthiazide (Exna, combination drugs) Oral: 50 mg tablets Brinzolamide(Azopt) Ophthalmic: 1% suspension Bumetanide(generic, Bumex) Oral: 0.5, 1, 2 mg tablets Parenteral: 0.5 mg/2 mL ampule for IV or IM injection Chlorothiazide (generic, Diuril, others) Oral: 250, 500 mg tablets; 250 mg/5 mL oral suspension Parenteral: 500 mg for injection Chlorthalidone(generic, Thalitone, combination drugs) Oral: 15, 25, 50, 100 mg tablets Demeclocycline(Declomycin) Oral: 150 mg tablets and capsules; 300 mg tablets Dichlorphenamide (Daranide) Oral: 50 mg tablets Dorzolamide(Trusopt) Ophthalmic: 2% solution Eplerenone (Inspra) Oral: 25, 50, 100 mg tablets
Ethacrynic acid(Edecrin) Oral: 25, 50 mg tablets Parenteral: 50 mg IV injection Furosemide(generic, Lasix, others) Oral: 20, 40, 80 mg tablets; 8 mg/mL solutions Parenteral: 10 mg/mL for IM or IV injection Hydrochlorothiazide (generic, Microzide, Hydro-DIURIL, combination drugs) Oral: 12.5 mg capsules; 25, 50, 100 mg tablets; 10 mg/mL solution Hydroflumethiazide (generic, Diucardin) Oral: 50 mg tablets Indapamide(generic, Lozol) Oral: 1.25, 2.5 mg tablets Mannitol(generic, Osmitrol) Parenteral: 5, 10, 15, 20, 25% for injection Methazolamide (generic, Neptazane) Oral: 25, 50 mg tablets Methyclothiazide (generic, Aquatensen) Oral: 2.5, 5 mg tablets Metolazone (Mykrox, Zaroxolyn) (Note: BioAvailability of Mykrox is greater than that of Zaroxolyn.) Oral: 0.5 (Mykrox); 2.5, 5, 10 mg (Zaroxolyn) tablets Polythiazide (Renese) Oral: 1, 2, 4 mg tablets Quinethazone (Hydromox) Oral: 50 mg tablets
Spironolactone(generic, Aldactone) Oral: 25, 50, 100 mg tablets Torsemide(Demadex) Oral: 5, 10, 20, 100 mg tablets Parenteral: 10 mg/mL for injection Triamterene(Dyrenium) Oral: 50, 100 mg capsules Trichlormethiazide (generic, Diurese, others) Oral: 2, 4 mg tablets
Section IV. Drugs with Important Actions on Smooth Muscle Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Histamine, Serotonin, & the Ergot Alkaloids: Introduction Histamine and serotonin (5-hydroxytryptamine) are biologically active amines that are found in many tissues, have complex physiologic and pathologic effects through multiple receptor subtypes, and are often released locally. Together with endogenous peptides (see Chapter 17: Vasoactive Peptides), prostaglandins and leukotrienes (see Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds), and cytokines (see Chapter 56: Immunopharmacology), they are sometimes called autacoids (Gk "self-remedy") or local hormones in recognition of these properties. Because of their broad and largely undesirable effects, neither histamine nor serotonin has any clinical application in the treatment of disease. However, compounds that selectively activate certain receptor subtypes or selectively antagonize the actions of these amines are of considerable clinical usefulness. This chapter therefore emphasizes the basic pharmacology of the agonist amines and the clinical pharmacology of the more selective agonist and antagonist drugs. The ergot alkaloids, compounds with partial agonist activity at serotonin and several other receptors, are discussed at the end of the chapter. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Histamine Histamine was synthesized in 1907 and later isolated from mammalian tissues. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between histamine's actions and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic and
inflammatory reactions; has an important role in gastric acid secretion; and functions as a neurotransmitter and neuromodulator. New evidence indicates that histamine also plays a role in chemotaxis of white blood cells. Basic Pharmacology of Histamine Chemistry & Pharmacokinetics Histamine occurs in plants as well as in animal tissues and is a component of some venoms and stinging secretions. Histamine is formed by decarboxylation of the amino acid L-histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged. The major inactivation pathways involve conversion to methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid. Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites.
Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or basophils; the histamine content of many tissues is directly related to their mast cell content. The bound form of histamine is biologically inactive, but many stimuli, as noted below, can trigger the release of mast cell histamine, allowing the free amine to exert its actions on surrounding tissues. Mast cells are especially rich at sites of potential tissue injury—nose, mouth, and feet; internal body surfaces; and blood vessels, particularly at pressure points and bifurcations. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter (see Chapter 21: Introduction to the Pharmacology of CNS Drugs). Endogenous neurotransmitter histamine may play a role in many brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and arousal. A second important nonneuronal site of histamine storage and release is the enterochromaffin-like (ECL) cell of the fundus of the stomach. These cells release histamine, one of the primary acid secretagogues, to activate the acid-producing parietal cells of the mucosa (see Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases). Storage & Release of Histamine The stores of histamine in mast cells can be released through several mechanisms. Immunologic Release The important pathophysiologic mechanism of mast cell and basophil histamine release is immunologic. These cells, if sensitized by IgE antibodies attached to their surface membranes, degranulate when exposed to the appropriate antigen (see Figure 56–5, effector phase). This type of
release also requires energy and calcium. Degranulation leads to the simultaneous release of histamine, ATP, and other mediators that are stored together in the granules. Histamine released by this mechanism is a mediator in immediate (type I) allergic reactions. Substances released during IgG- or IgM-mediated immune reactions that activate the complement cascade also release histamine from mast cells and basophils. By a negative feedback control mechanism mediated by H2 receptors, histamine appears to modulate its own release and that of other mediators from sensitized mast cells in some tissues. In humans, mast cells in skin and basophils show this negative feedback mechanism; lung mast cells do not. Thus, histamine may act to limit the intensity of the allergic reaction in the skin and blood. Endogenous histamine has a modulating role in a variety of inflammatory and immune responses. Upon injury to a tissue, released histamine causes local vasodilation and leakage of plasma containing mediators of acute inflammation (complement, C-reactive protein), and antibodies. Histamine has an active chemotactic attraction for inflammatory cells (neutrophils, eosinophils, basophils, monocytes, and lymphocytes). Histamine inhibits the release of lysosome contents and several T and B lymphocyte functions. Most of these actions are mediated by H2 or H4 receptors acting through increased intracellular cAMP. Release of peptides from nerves in response to inflammation is also probably modulated by histamine, in this case acting through presynaptic H3 receptors. Chemical and Mechanical Release Certain amines, including drugs such as morphine and tubocurarine, can displace histamine from the heparin-protein complex within cells. This type of release does not require energy and is not associated with mast cell injury or degranulation. Loss of granules from the mast cell will also release histamine, since sodium ions in the extracellular fluid rapidly displace the amine from the complex. Chemical and mechanical mast cell injury causes degranulation and histamine release. Compound 48/80, an experimental diamine polymer, specifically releases histamine from tissue mast cells by an exocytotic degranulation process requiring energy and calcium. Pharmacodynamics Mechanism of Action Histamine exerts its biologic actions by combining with specific cellular receptors located on the surface membrane. The four different histamine receptors thus far characterized are designated H1– H4 and are described in Table 16–1. Unlike the other amine transmitter receptors discussed previously, no subfamilies have been found within these major types. Table 16–1. Histamine Receptor Subtypes.
Receptor Subtype
Distribution
H1
Smooth muscle, endothelium, brain
Postreceptor Mechanism
Partially Selective Agonists
IP3, DAG (Gq) 2-(m-Fluorophenyl)histamine1
Partially Selective Antagonists Mepyramine, triprolidine
H2
Gastric mucosa, cardiac muscle, mast cells, brain
H3
Presynaptic: brain, myenteric plexus, other neurons
cAMP, Cai2+ (Gi)
R- -Methylhistamine, Thioperamide, imetit, immepip iodophenpropit, clobenpropit
H4
Eosinophils, neutrophils, CD4 T cells
cAMP, Cai2+ (Gi)
Clobenpropit, imetit, clozapine
1
cAMP (Gs)
Dimaprit, impromidine, amthamine
Ranitidine, tiotidine
Thioperamide
Partial agonist.
All four receptor types have been cloned and belong to the large superfamily of receptors having seven membrane-spanning regions and intracellular association with G proteins. The structures of the H1 and H2 receptors differ significantly and appear to be more closely related to muscarinic and 5-HT1 receptors, respectively, than to each other. The H4 receptor has about 40% homology with the H3 receptor but does not seem to be closely related to any other histamine receptor. In the brain, H1 and H2 receptors are located on postsynaptic membranes, while H3 receptors are predominantly presynaptic. Activation of H1 receptors, which are present in endothelium, smooth muscle cells, and nerve endings, usually elicits an increase in phosphoinositol hydrolysis and an increase in intracellular calcium. Activation of H2 receptors, present in gastric mucosa, cardiac muscle cells, and some immune cells, increases intracellular cAMP. Like the 2 adrenoceptor, under certain circumstances the H2 receptor may couple to Gq, activating the IP3-DAG cascade. Activation of H3 receptors decreases transmitter release from histaminergic and other neurons, probably mediated by a decrease in calcium influx through N-type calcium channels in nerve endings. H4 receptors are mainly found on blood cells in the bone marrow and circulating blood. They may modulate production of these cell types and they may mediate, in part, the previously recognized effects of histamine on cytokine production. Tissue and Organ System Effects of Histamine Histamine exerts powerful effects on smooth and cardiac muscle, on certain endothelial and nerve cells, and on the secretory cells of the stomach. However, sensitivity to histamine varies greatly among species. Humans, guinea pigs, dogs, and cats are quite sensitive, while mice and rats are much less so. Nervous System Histamine is a powerful stimulant of sensory nerve endings, especially those mediating pain and itching. This H1-mediated effect is an important component of the urticarial response and reactions to insect and nettle stings. Some evidence suggests that local high concentrations can also depolarize efferent (axonal) nerve endings (see ¶ 8, below). In the mouse, and probably in humans, respiratory neurons signaling inspiration and expiration are modulated by H1 receptors. Presynaptic H3 receptors play important roles in modulating transmitter release in the nervous system. H3 agonists reduce the release of acetylcholine, amine, and peptide transmitters in various areas of the brain and in peripheral nerves. Cardiovascular System
In humans, injection or infusion of histamine causes a decrease in systolic and diastolic blood pressure and an increase in heart rate (Figure 16–1). The blood pressure changes are caused by the direct vasodilator action of histamine on arterioles and precapillary sphincters; the increase in heart rate involves both stimulatory actions of histamine on the heart and a reflex tachycardia. Flushing, a sense of warmth, and headache may also occur during histamine administration, consistent with the vasodilation. Histamine-induced vasodilation is mediated primarily by release of nitric oxide (see Chapter 19: Nitric Oxide, Donors, & Inhibitors). Studies with histamine receptor antagonists show that both H1 and H2 receptors are involved in these cardiovascular responses to high doses. However, in humans, the cardiovascular effects of small doses of histamine can usually be antagonized by H1 receptor antagonists alone. Figure 16–1.
Effects of histamine on blood pressure and heart rate in humans. Histamine was infused at 40 g/kg/h for 5 minutes as shown at the top of the panel. (Modified and reproduced, with permission, from Torsoli A, Lucchelli PE, Brimblecombe RW [editors]: H-Antagonists: H2 Receptor Antagonists in Peptic Ulcer Disease and Progress in Histamine Research. Excerpta Medica, 1980.) Histamine-induced edema results from the action of the amine on H1 receptors in the vessels of the microcirculation, especially the postcapillary vessels. The effect is associated with the separation of the endothelial cells, which permits the transudation of fluid and molecules as large as small proteins into the perivascular tissue. This effect is responsible for the urticaria (hives) that signals the release of histamine in the skin. Studies of endothelial cells suggest that actin and myosin within these cells contract, resulting in separation of the endothelial cells and increased permeability. Direct cardiac effects of histamine include both increased contractility and increased pacemaker rate. These effects are mediated chiefly by H2 receptors. In human atrial muscle, histamine can also decrease contractility; this effect is mediated by H1 receptors. The physiologic significance of these
cardiac actions is not clear. Some of the cardiovascular signs and symptoms of anaphylaxis are due to released histamine, though several other mediators are involved and appear to be more important than histamine in humans. Bronchiolar Smooth Muscle In both humans and guinea pigs, histamine causes bronchoconstriction mediated by H1 receptors. In the guinea pig, this effect is the cause of death from histamine toxicity, but in normal humans, bronchoconstriction following small doses of histamine is not marked. However, patients with asthma are very sensitive to histamine. The bronchoconstriction induced in these patients probably represents a hyperactive neural response, since such patients also respond excessively to many other stimuli, and the response to histamine can be blocked by autonomic blocking drugs such as ganglionic blocking agents as well as by H1 receptor antagonists (see Chapter 20: Drugs Used in Asthma). Provocative tests using increasing doses of inhaled histamine are of diagnostic value for bronchial hyperreactivity in patients with suspected asthma or cystic fibrosis. Such individuals may be 100- to 1000-fold more sensitive to histamine than are normal subjects. Curiously, a few species (eg, rabbit) respond to histamine with bronchodilation, reflecting the dominance of the H2 receptor in their airways. Gastrointestinal Tract Smooth Muscle Histamine causes contraction of intestinal smooth muscle, and histamine-induced contraction of guinea pig ileum is a standard bioassay for this amine. The human gut is not as sensitive as that of the guinea pig, but large doses of histamine may cause diarrhea, partly as a result of this effect. This action of histamine is mediated by H1 receptors. Other Smooth Muscle Organs In humans, histamine generally has insignificant effects on the smooth muscle of the eye and genitourinary tract. However, pregnant women suffering anaphylactic reactions may abort as a result of histamine-induced contractions, and in some species the sensitivity of the uterus is sufficient to form the basis for a bioassay. Secretory Tissue Histamine has long been recognized as a powerful stimulant of gastric acid secretion and, to a lesser extent, of gastric pepsin and intrinsic factor production. The effect is caused by activation of H2 receptors on gastric parietal cells and is associated with increased adenylyl cyclase activity, cAMP concentration, and intracellular Ca2+ concentration. Other stimulants of gastric acid secretion such as acetylcholine and gastrin do not increase cAMP even though their maximal effects on acid output can be reduced—but not abolished—by H2-receptor antagonists. These actions are discussed in detail in Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. Histamine also stimulates secretion in the small and large intestine. In contrast, H3-selective histamine agonists inhibit acid secretion stimulated by food or pentagastrin in several species. Histamine has much smaller effects on the activity of other glandular tissue at ordinary concentrations. Very high concentrations can cause adrenal medullary discharge. Metabolic Effects Recent studies of H3 receptor knockout mice demonstrate that absence of this receptor results in
animals with increased food intake, decreased energy expenditure, and obesity. They also show insulin resistance and increased blood levels of leptin and insulin. It is not yet known whether the H3 receptor has a similar role in humans. The "Triple Response" Intradermal injection of histamine causes a characteristic wheal-and-flare response that was first described over 60 years ago. The effect involves three separate cell types: smooth muscle in the microcirculation, capillary or venular endothelium, and sensory nerve endings. At the site of injection, a reddening appears owing to dilation of small vessels, followed soon by an edematous wheal at the injection site and a red irregular flare surrounding the wheal. The flare is said to be caused by an axon reflex. The sensation of itch may also accompany the appearance of these effects. The wheal is due to local edema. Similar local effects may be produced by injecting histamine liberators (compound 48/80, morphine, etc) intradermally or by applying the appropriate antigens to the skin of a sensitized person. Although most of these local effects can be blocked by prior administration of an H1 receptor-blocking agent, H2 and H3 receptors may also be involved. Other Effects Possibly Mediated by Histamine Receptors In addition to the local stimulation of peripheral pain nerve endings via H3 and H1 receptors, histamine may play a role in nociception in the central nervous system. Burimamide, an early candidate for H2 blocking action, and improgran, a newer analog with no effect on H1, H2, or H3 receptors, have been shown to have significant analgesic action in rodents when administered into the central nervous system. The analgesia is said to be comparable to that produced by opioids, but tolerance, respiratory depression, and constipation have not been reported. Although the mechanism of this action is not known, these compounds may represent an important new class of analgesics. Other Histamine Agonists Small substitutions on the imidazole ring of histamine significantly modify the selectivity of the compounds for the histamine receptor subtypes. Some of these are listed in Table 16–1. Clinical Pharmacology of Histamine Clinical Uses In pulmonary function laboratories, histamine aerosol (in addition to other agents) is sometimes used as a provocative test of bronchial hyperreactivity. Histamine has no other current clinical applications. Toxicity & Contraindications Adverse effects of histamine release, like those following administration of histamine, are doserelated. Flushing, hypotension, tachycardia, headache, wheals, bronchoconstriction, and gastrointestinal upset are noted. These effects are also observed after the ingestion of spoiled fish (scombroid fish poisoning), and there is evidence that histamine produced by bacterial action in the flesh of the fish is the major causative agent. Histamine should not be given to asthmatics (except as part of a carefully monitored test of
pulmonary function) or to patients with active ulcer disease or gastrointestinal bleeding. Histamine Antagonists The effects of histamine released in the body can be reduced in several ways. Physiologic antagonists, especially epinephrine, have smooth muscle actions opposite to those of histamine, but they act at different receptors. This is important clinically because injection of epinephrine can be lifesaving in systemic anaphylaxis and in other conditions in which massive release of histamine— and other mediators—occurs. Release inhibitors reduce the degranulation of mast cells that results from immunologic triggering by antigen-IgE interaction. Cromolyn and nedocromil appear to have this effect (see Chapter 20: Drugs Used in Asthma) and are used in the treatment of asthma, though the molecular mechanism underlying their action is presently unknown. Beta2 adrenoceptor agonists also appear capable of reducing histamine release. Histamine receptor antagonists represent a third approach to the reduction of histamine-mediated responses. For over 60 years, compounds have been available that competitively antagonize many of the actions of histamine on smooth muscle. However, not until the H2 receptor antagonist burimamide was described in 1972 was it possible to antagonize the gastric acid-stimulating activity of histamine. The development of selective H2 receptor antagonists has led not only to more precise definition of histamine's actions in terms of receptors involved but also to more effective therapy for peptic ulcer. Selective H3 antagonists are not yet available for clinical use. However, potent and selective experimental H3 receptor antagonists, thioperamide and clobenpropit, have been developed. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > H1 Receptor Antagonists Compounds that competitively block histamine at H1 receptors have been used clinically for many years, and many H1 antagonists are currently marketed in the USA. Many are available without prescription, both alone and in combination formulations such as "cold pills" and sleep aids (see Chapter 64: Therapeutic & Toxic Potential of Over-the-Counter Agents). Basic Pharmacology of H1 Receptor Antagonists Chemistry & Pharmacokinetics The H1 antagonists are conveniently divided into first-generation and second-generation agents. These groups are distinguished by the relatively strong sedative effects of most of the firstgeneration drugs. The first-generation agents are also more likely to block autonomic receptors. The relatively less sedating characteristic of the second-generation H1 blockers is due in part to their less complete distribution into the central nervous system. All of the H1 antagonists are stable amines with the general structure illustrated in Figure 16–2. There are several chemical subgroups, and the structures of compounds representing different subgroups are shown in the figure. Doses of some of these drugs are given in Table 16–2.
Figure 16–2.
General structure of H1 antagonist drugs and examples of the major subgroups.
Table 16–2. Some H1 Antihistaminic Drugs in Past or Current Clinical Use.
Drugs
Usual Adult Dose
Anticholinergic Activity
Comments
FIRST-GENERATION ANTIHISTAMINES Ethanolamines Carbinoxamine (Clistin)
4–8 mg
+++
Slight to moderate sedation
50 mg
+++
Marked sedation; anti-motion sickness activity
Diphenhydramine (Benadryl, etc) 25–50 mg +++
Marked sedation; anti-motion sickness activity
Doxylamine
Marked sedation; now available only in OTC "sleep aids"
Dimenhydrinate (salt of diphenhydramine) (Dramamine)
1.25–25 mg
nd
Ethylaminediamines Pyrilamine (Neo-Antergan)
25–50 mg +
Moderate sedation; component of OTC "sleep aids"
Tripelennamine (PBZ, etc)
25–50 mg +
Moderate sedation
Hydroxyzine (Atarax, etc)
15–100 mg
Marked sedation
Cyclizine (Marezine)
25–50 mg –
Slight sedation; anti-motion sickness activity
Meclizine (Bonine, etc)
25–50 mg –
Slight sedation; anti-motion sickness activity
Brompheniramine (Dimetane, etc)
4–8 mg
+
Slight sedation
Chlorpheniramine (ChlorTrimeton, etc)
4–8 mg
+
Slight sedation; common component of OTC "cold" medication
Piperazine derivatives nd
Alkylamines
Phenothiazine derivatives Promethazine (Phenergan, etc)
10–25 mg +++
Marked sedation; antiemetic
4 mg
Moderate sedation; also has antiserotonin activity
Miscellaneous Cyproheptadine (Periactin, etc)
+
SECOND-GENERATION ANTIHISTAMINES Piperidines Fexofenadine (Allegra)
60 mg
–
Lower risk of arrhythmia
Miscellaneous Loratadine (Claritin)
10 mg
–
Cetirizine (Zyrtec)
5–10 mg
–
Longer action
Nd, no data found. These agents are rapidly absorbed following oral administration, with peak blood concentrations occurring in 1–2 hours. They are widely distributed throughout the body, and the first-generation drugs enter the central nervous system readily. Some of them are extensively metabolized, primarily by microsomal systems in the liver. Several of the second-generation agents are metabolized by the CYP3A4 system and thus are subject to important interactions when other drugs (such as ketoconazole) inhibit this subtype of P450 enzymes. Most of the drugs have an effective duration of action of 4–6 hours following a single dose, but meclizine and several second-generation agents are longer-acting, with a duration of action of 12–24 hours. The newer agents also are considerably less lipid-soluble and enter the central nervous system with difficulty or not at all. Many H1 antagonists have active metabolites. The active metabolites of hydroxyzine, terfenadine, and loratadine are available as drugs (cetirizine, fexofenadine, and desloratadine, respectively). Pharmacodynamics Histamine Receptor Blockade H1 receptor antagonists block the actions of histamine by reversible competitive antagonism at the H1 receptor. They have negligible potency at the H2 receptor and little at the H3 receptor. For example, histamine-induced contraction of bronchiolar or gastrointestinal smooth muscle can be completely blocked by these agents, but the effects on gastric acid secretion and the heart are unmodified. Actions Not Caused by Histamine Receptor Blockade The first-generation H1 receptor antagonists have many actions not ascribable to blockade of the actions of histamine. The large number of these actions probably results from the similarity of the general structure (Figure 16–2) to the structure of drugs that have effects at muscarinic cholinoceptor, -adrenoceptor, serotonin, and local anesthetic receptor sites. Some of these actions are of therapeutic value and some are undesirable. Sedation A common effect of first-generation H1 antagonists is sedation, but the intensity of this effect varies among chemical subgroups (Table 16–2) and among patients as well. The effect is sufficiently prominent with some agents to make them useful as "sleep aids" (see Chapter 64: Therapeutic & Toxic Potential of Over-the-Counter Agents) and unsuitable for daytime use. The effect resembles that of some antimuscarinic drugs and is considered very unlike the disinhibited sedation produced by sedative-hypnotic drugs. Compulsive use has not been reported. At ordinary dosages, children occasionally (and adults rarely) manifest excitation rather than sedation. At very high toxic dose levels, marked stimulation, agitation, and even convulsions may precede coma. Second-generation H1 antagonists have little or no sedative or stimulant actions. These drugs (or their active metabolites) also have far fewer autonomic effects than the first-generation antihistamines.
Antinausea and Antiemetic Actions Several first-generation H1 antagonists have significant activity in preventing motion sickness (Table 16–2). They are less effective against an episode of motion sickness already present. Certain H1 antagonists, notably doxylamine (in Bendectin), were used widely in the past in the treatment of nausea and vomiting of pregnancy (see below). Antiparkinsonism Effects Perhaps because of their anticholinergic effects (cf benztropine, Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders), some of the H1 antagonists have significant acute suppressant effects on the parkinsonism symptoms associated with certain antipsychotic drugs. Anticholinoceptor Actions Many of the first-generation agents, especially those of the ethanolamine and ethylenediamine subgroups, have significant atropine-like effects on peripheral muscarinic receptors. This action may be responsible for some of the (uncertain) benefits reported for nonallergic rhinorrhea but may also cause urinary retention and blurred vision. Adrenoceptor-Blocking Actions Alpha receptor-blocking effects can be demonstrated for many H1 antagonists, especially those in the phenothiazine subgroup, eg, promethazine. This action may cause orthostatic hypotension in susceptible individuals. Beta receptor blockade is not observed. Serotonin-Blocking Action Strong blocking effects at serotonin receptors have been demonstrated for some first-generation H1 antagonists, notably cyproheptadine. This drug is promoted as an antiserotonin agent and is discussed with that drug group. Nevertheless, its structure resembles that of the phenothiazine antihistamines, and it is a potent H1 blocking agent. Local Anesthesia Many first-generation H1 antagonists are potent local anesthetics. They block sodium channels in excitable membranes in the same fashion as procaine and lidocaine. Diphenhydramine and promethazine are actually more potent than procaine as local anesthetics. They are occasionally used to produce local anesthesia in patients allergic to the conventional local anesthetic drugs. A small number of these agents also block potassium channels; this action is discussed below (see Toxicity). Other Actions Certain H1 antagonists, eg, cetirizine, inhibit mast cell release of histamine and some other mediators of inflammation. This action is not due to H1 receptor blockade. The mechanism is not understood but could play a role in the beneficial effects of these drugs in the treatment of allergies such as rhinitis. A few H1 antagonists (eg, terfenadine, acrivastine) have been shown to inhibit the P-glycoprotein transporter found in cancer cells, the epithelium of the gut, and the capillaries of the brain. The significance of this effect is not known.
Clinical Pharmacology of H1 Receptor Antagonists Clinical Uses Allergic Reactions The H1 antihistaminic agents are often the first drugs used to prevent or treat the symptoms of allergic reactions. In allergic rhinitis and urticaria, in which histamine is the primary mediator, the H1 antagonists are the drugs of choice and are often quite effective. However, in bronchial asthma, which involves several mediators, the H1 antagonists are largely ineffective. Angioedema may be precipitated by histamine release but appears to be maintained by peptide kinins that are not affected by antihistaminic agents. For atopic dermatitis, antihistaminic drugs such as diphenhydramine are used mostly for their sedative side effects and for some control of the itching. The H1 antihistamines used for treating allergic conditions such as hay fever are usually selected with the goal of minimizing sedative effects; in the USA, the drugs in widest use are the alkylamines and the second-generation nonsedating agents. However, the sedative effect and the therapeutic efficacy of different agents vary widely among individuals. In addition, the clinical effectiveness of one group may diminish with continued use, and switching to another group may restore drug effectiveness for as yet unexplained reasons. The second-generation H1 antagonists are used mainly for the treatment of allergic rhinitis and chronic urticaria. Several double-blind comparisons with older agents (such as chlorpheniramine) indicated about equal therapeutic efficacy. However, sedation and interference with safe operation of machinery, which occur in about 50% of subjects taking first-generation antihistamines, occurred in only about 7% of subjects taking second generation agents. The newer drugs are much more expensive. Motion Sickness and Vestibular Disturbances Scopolamine and certain first-generation H1 antagonists are the most effective agents available for the prevention of motion sickness. The antihistaminic drugs with the greatest effectiveness in this application are diphenhydramine and promethazine. Dimenhydrinate, which is promoted for the treatment of motion sickness, is a salt of diphenhydramine. The piperazines (cyclizine and meclizine) also have significant activity in preventing motion sickness and are less sedative in most patients. Dosage is the same as that recommended for allergic disorders (Table 16–2). Both scopolamine and the H1 antagonists are more effective in preventing motion sickness when combined with ephedrine or amphetamine. It has been claimed that the antihistaminic agents effective in prophylaxis of motion sickness are also useful in Meniere's syndrome, but efficacy in the latter application is not well established. Nausea and Vomiting of Pregnancy Several H1 antagonist drugs have been studied for possible use in treating "morning sickness." The piperazine derivatives were withdrawn from such use when it was demonstrated that they have teratogenic effects in rodents. Doxylamine, an ethanolamine H1 antagonist, was promoted for this application as a component of Bendectin, a prescription medication that also contained pyridoxine. Possible teratogenic effects of doxylamine were widely publicized in the lay press after 1978 as a
result of a few case reports of fetal malformation associated with maternal ingestion of Bendectin. However, several large prospective studies involving over 60,000 pregnancies, of which more than 3000 involved maternal Bendectin ingestion, disclosed no increase in the incidence of birth defects. However, because of the continuing controversy, adverse publicity, and lawsuits, the manufacturer of Bendectin withdrew the product from the market. Doxylamine is still available over-the-counter as a sleep aid. Toxicity The wide spectrum of adverse effects of the H1 antihistamines is described above. Several of these effects (sedation, antimuscarinic action) have been used for therapeutic purposes, especially in OTC remedies (see Chapter 64: Therapeutic & Toxic Potential of Over-the-Counter Agents). Nevertheless, these two effects constitute the most common undesirable actions when these drugs are used to block histamine receptors. Less common toxic effects of systemic use include excitation and convulsions in children, postural hypotension, and allergic responses. Drug allergy is relatively common after topical use of H1 antagonists. The effects of severe systemic overdosage of the older agents resemble those of atropine overdosage and are treated in the same way (see Chapter 8: Cholinoceptor-Blocking Drugs and Chapter 59: Management of the Poisoned Patient). Overdosage of astemizole or terfenadine may induce cardiac arrhythmias, but these drugs are no longer marketed in the USA; the same effect may be caused by interaction with enzyme inhibitors (see Drug Interactions, below). Drug Interactions Lethal ventricular arrhythmias occurred in several patients taking either of the early secondgeneration agents, terfenadine or astemizole, in combination with ketoconazole, itraconazole, or macrolide antibiotics such as erythromycin. These antimicrobial drugs inhibit the metabolism of many drugs by CYP3A4 and cause significant increases in blood concentrations of the antihistamines. The mechanism of this toxicity involves blockade of the potassium channels in the heart that are responsible for repolarization of the action potential, the IK channels (see Chapter 14: Agents Used in Cardiac Arrhythmias). The result is prolongation of the action potential, and excessive prolongation leads to arrhythmias. Both terfenadine and astemizole were withdrawn from the United States market in recognition of these problems. Where still available, terfenadine and astemizole should be considered to be contraindicated in patients taking ketoconazole, itraconazole, or macrolides and in patients with liver disease. Grapefruit juice also inhibits CYP3A4 and has been shown to increase terfenadine's blood levels significantly. For those H1 antagonists that cause significant sedation, concurrent use of other drugs that cause central nervous system depression produces additive effects and is contraindicated while driving or operating machinery. Similarly, the autonomic blocking effects of older antihistamines are additive with those of muscarinic and -blocking drugs. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > H2 Receptor Antagonists The development of H2 receptor antagonists was based on the observation that H1 antagonists had no effect on histamine-induced acid secretion in the stomach. Molecular manipulation of the histamine molecule resulted in a compound that blocked rather than stimulated acid production and
then a series of drugs with progressive increases in the acid secretion-blocking action and reduction in irrelevant effects. This development led to renewed interest in possible physiologic roles for histamine and to a classification of effects of both agonists and antagonists based upon histamine receptor subtypes. The high incidence of peptic ulcer disease and related gastrointestinal complaints created great interest in the therapeutic potential of H2 receptor antagonists. Because of the ability of this class of drugs to reduce gastric acid secretion and their low toxicity, they are now among the most frequently used drugs in the USA and have become OTC items. These drugs are discussed in Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Serotonin (5-Hydroxy-Tryptamine) Before the identification of 5-hydroxytryptamine (5-HT), it was known that when blood is allowed to clot, a vasoconstrictor (tonic) substance is released from the clot into the serum; this substance was called serotonin. Independent studies established the existence of a smooth muscle stimulant in intestinal mucosa; this was called enteramine. The synthesis of 5-hydroxytryptamine in 1951 permitted the identification of serotonin and enteramine as the same metabolite of 5hydroxytryptophan. Serotonin is thought to play a role in migraine headache. Serotonin is also one of the mediators of the signs and symptoms of carcinoid syndrome, an unusual manifestation of carcinoid tumor, a neoplasm of enterochromaffin cells. In patients whose tumor is not operable, serotonin antagonists may constitute the best treatment. Basic Pharmacology of Serotonin Chemistry & Pharmacokinetics Like histamine, serotonin is widely distributed in nature, being found in plant and animal tissues, venoms, and stings. It is an indoleethylamine formed in biologic systems from the amino acid Ltryptophan by hydroxylation of the indole ring followed by decarboxylation of the amino acid (Figure 16–3). Hydroxylation at C5 is the rate-limiting step and can be blocked by pchlorophenylalanine (PCPA; fenclonine) and by p-chloroamphetamine. These agents have been used experimentally to reduce serotonin synthesis in carcinoid syndrome. Figure 16–3.
Structures of serotonin and two 5-HT-receptor blockers. After synthesis, the free amine is stored or is rapidly inactivated, usually by oxidation catalyzed by the enzyme monoamine oxidase. In the pineal gland, serotonin serves as a precursor of melatonin, a melanocyte-stimulating hormone. In mammals (including humans), over 90% of the serotonin in the body is found in enterochromaffin cells in the gastrointestinal tract. In the blood, serotonin is found in platelets, which are able to concentrate the amine by means of an active carrier mechanism similar to that in the vesicles of noradrenergic and serotonergic nerve endings. Serotonin is also found in the raphe nuclei of the brain stem, which contain cell bodies of serotonergic neurons that synthesize, store, and release serotonin as a transmitter. Brain serotonergic neurons are involved in various functions such as mood, sleep, appetite, temperature regulation, the perception of pain, the regulation of blood pressure, and vomiting (see Chapter 21: Introduction to the Pharmacology of CNS Drugs). Serotonin also appears to be involved in conditions such as depression, anxiety, and migraine. Serotonergic neurons are also found in the enteric nervous system of the gastrointestinal tract and around blood vessels. In rodents (but not in humans), serotonin is found in mast cells. The function of serotonin in enterochromaffin cells is not clear. These cells synthesize serotonin, store the amine in a complex with ATP and with other substances in granules, and can release serotonin in response to mechanical and neuronal stimuli. Some of the released serotonin diffuses into blood vessels and is taken up and stored in platelets. Stored serotonin can be depleted by reserpine in much the same manner as this drug depletes catecholamines from vesicles in adrenergic nerves (see Chapter 6: Introduction to Autonomic Pharmacology).
Serotonin is metabolized by monoamine oxidase, and the intermediate product, 5hydroxyindoleacetaldehyde, is further oxidized by aldehyde dehydrogenase to 5hydroxyindoleacetic acid (5-HIAA). In humans consuming a normal diet, the excretion of 5-HIAA is a measure of serotonin synthesis. Therefore, the 24-hour excretion of 5-HIAA can be used as a diagnostic test for tumors that synthesize excessive quantities of serotonin, especially carcinoid tumor. A few foods (eg, bananas) contain large amounts of serotonin or its precursors and must be prohibited during such diagnostic tests. Pharmacodynamics Mechanisms of Action Serotonin exerts many actions and, like histamine, has many species differences, making generalizations difficult. The actions of serotonin are mediated through a remarkably large number of cell membrane receptors. The serotonin receptors that have been characterized thus far are described in Table 16–3. Seven families of 5-HT-receptor subtypes (those given numeric subscripts 1 through 7) have been identified, six involving G protein-coupled receptors and one a ligand-gated ion channel. Among these receptor subtypes, several lack any recognized physiologic function. Discovery of these functions awaits the development of subtype-selective drugs or the mutation or deletion of genes encoding these receptors from the mouse genome. Table 16–3. Serotonin Receptor Subtypes.
Receptor Subtype
Distribution
Postreceptor Mechanism
Partially Selective Agonists
Partially Selective Antagonists
5-HT1A
Raphe nuclei, hippocampus
Multiple, Gi coupling dominates
8-OH-DPAT
WAY100635
5-HT1B
Substantia nigra, globus pallidus, basal ganglia
Gi , cAMP
CP93129
5-HT1Da,b
Brain
Gi , cAMP
Sumatriptan
5-HT1E
Cortex, putamen
Gi , cAMP
5-HT1F
Cortex, hippocampus
Gi , cAMP
5-HT1P
Enteric nervous system
Go; slow EPSP
5-HT2A
Platelets, smooth muscle, cerebral cortex, skeletal muscle
Gq , IP3
5-Hydroxyindalpine -Methyl-5-HT
Renzapride Ketanserin
5-HT2B
Stomach fundus
Gq , IP3
-Methyl-5-HT
SB204741
5-HT2C
Choroid, hippocampus, substantia nigra
Gq , IP3
-Methyl-5-HT
Mesulergine
5-HT3
Area postrema, sensory and enteric nerves
Receptor is a Na+-K+ ion channel
5-HT4
CNS and myenteric Gs , cAMP neurons, smooth muscle
5-HT5A,B
Brain
5-HT6,7
Brain
2-Methyl-5-HT, mchlorophenylbiguanide
Tropisetron, ondansetron, granisetron
5-Methoxytryptamine, renzapride, metoclopramide
cAMP Gs , cAMP
Clozapine (5HT7)
8-OH-DPAT = 8-Hydroxy-2-(di-n-propylamine)tetralin; CP93129 = 5-Hydroxy-3(4-1,2,5,6tetrahydropyridyl)-4-azaindole; SB204741 = N-(1-methyl-5-indolyl)-N'-(3-methyl-5isothiazolyl)urea; WAY100635 = N-tert-Butyl 3-4-(2-methoxyphenyl) piperazin-1-yl-2phenylpropanamide Tissue and Organ System Effects Nervous System Serotonin is present in a variety of sites in the brain. Its role as a neurotransmitter and its relation to the actions of drugs acting in the central nervous system are discussed in Chapters 21 and 30. Serotonin is also a precursor of melatonin (see Chapter 65: Botanicals ("Herbal Medications") & Nutritional Supplements). 5-HT3 receptors in the gastrointestinal tract and in the vomiting center of the medulla participate in the vomiting reflex (see Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases). They are particularly important in vomiting caused by chemical triggers such as cancer chemotherapy drugs. 5-HT1P and 5-HT4 receptors also play a role in enteric nervous system function. Like histamine, serotonin is a potent stimulant of pain and itch sensory nerve endings and is responsible for some of the symptoms caused by insect and plant stings. In addition, serotonin is a powerful activator of chemosensitive endings located in the coronary vascular bed. Activation of 5HT3 receptors on these afferent vagal nerve endings is associated with the chemoreceptor reflex (also known as the Bezold-Jarisch reflex). The reflex response consists of marked bradycardia and hypotension. The bradycardia is mediated by vagal outflow to the heart and can be blocked by atropine. The hypotension is a consequence of the decrease in cardiac output that results from bradycardia. A variety of other agents can activate the chemoreceptor reflex. These include nicotinic cholinoceptor agonists and some cardiac glycosides, eg, ouabain.
Airways Serotonin has a small direct stimulant effect on bronchiolar smooth muscle in normal humans. It also appears to facilitate acetylcholine release from bronchial vagal nerve endings. In patients with carcinoid syndrome, episodes of bronchoconstriction occur in response to elevated levels of the amine or peptides released from the tumor. Serotonin may also cause hyperventilation as a result of the chemoreceptor reflex or stimulation of bronchial sensory nerve endings. Cardiovascular System Serotonin directly causes the contraction of vascular smooth muscle, mainly through 5-HT2 receptors. In humans, serotonin is a powerful vasoconstrictor except in skeletal muscle and heart, where it dilates blood vessels. At least part of this 5-HT-induced vasodilation requires the presence of vascular endothelial cells. When the endothelium is damaged, coronary vessels constrict. As noted previously, serotonin can also elicit reflex bradycardia by activation of 5-HT3 receptors on chemoreceptor nerve endings. A triphasic blood pressure response is often seen following injection of serotonin. Initially, there is a decrease in heart rate, cardiac output, and blood pressure caused by the chemoreceptor response. Following this decrease, blood pressure increases as a result of vasoconstriction. The third phase is again a decrease in blood pressure attributed to vasodilation in vessels supplying skeletal muscle. Pulmonary and renal vessels seem especially sensitive to the vasoconstrictor action of serotonin. Serotonin also constricts veins, and venoconstriction with a resulting increased capillary filling appears responsible for the flush that is observed following serotonin administration. Serotonin has small direct positive chronotropic and inotropic effects on the heart that are probably of no clinical significance. However, prolonged elevation of the blood level of serotonin (which occurs in carcinoid syndrome) is associated with pathologic alterations in the endocardium (subendocardial fibroplasia) that may result in valvular or electrical malfunction. Serotonin causes blood platelets to aggregate by activating surface 5-HT2 receptors. This response, in contrast to aggregation induced during clot formation, is not accompanied by the release of serotonin stored in the platelets. The physiologic role of this effect is unclear. Gastrointestinal Tract Serotonin is a powerful stimulant of gastrointestinal smooth muscle, increasing tone and facilitating peristalsis. This action is caused by the direct action of serotonin on 5-HT2 smooth muscle receptors plus a stimulating action on ganglion cells located in the enteric nervous system (see Chapter 6: Introduction to Autonomic Pharmacology). Activation of 5-HT4 receptors in the ENS causes increased acetylcholine release and thereby mediates a motility-enhancing or "prokinetic" effect of selective serotonin agonists such as cisapride. These agents are useful in several gastrointestinal disorders (see Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases). Overproduction of serotonin (and other substances) in carcinoid tumor is associated with severe diarrhea. Serotonin has little effect on secretions, and what effects it has are generally inhibitory. Skeletal Muscle 5-HT2 receptors are present on skeletal muscle membranes, but their physiologic role is not understood. Malignant hyperthermia is a condition precipitated by certain anesthetic and neuromuscular agents that results in severe hyperthermia due to skeletal muscle overactivity and metabolic and autonomic instability. In a genetic porcine model of this condition, administration of
serotonin or serotonin agonists can precipitate a typical attack. 5-HT2 blockers such as ketanserin can reduce or prevent many manifestations of the condition when evoked in this way. However, malignant hyperthermia provoked by anesthetic agents in these animals is not effectively prevented by 5-HT2 antagonists. Serotonin syndrome is a similar but not identical condition precipitated when MAO inhibitors are given with serotonin agonists, especially antidepressants of the selective serotonin reuptake inhibitor class (SSRIs). Clinical Pharmacology of Serotonin Serotonin Agonists Serotonin has no clinical applications as a drug. However, several receptor subtype-selective agonists have proved to be of value. Buspirone, a 5-HT1A agonist, has received wide attention for its utility as an effective nonbenzodiazepine anxiolytic (see Chapter 22: Sedative-Hypnotic Drugs). Dexfenfluramine, another selective 5-HT agonist, was widely used as an appetite suppressant (see Appetite Control Through Serotonin?) but was withdrawn because of toxicity. Sumatriptan and its congeners are agonists effective in the treatment of acute migraine and cluster headache attacks (see below). 5-HT1D Agonists Sumatriptan and several other "triptans" are selective agonists for 5-HT1D and 5-HT1B receptors. These receptor types are found in cerebral and meningeal vessels and mediate vasoconstriction. They are also found on neurons and probably function as presynaptic inhibitory receptors. These drugs have proved to be very effective in the treatment of acute migraine headache. The mechanism of action is discussed in more detail below under Clinical Pharmacology of Ergot Alkaloids. The bioavailability of sumatriptan is only about 15%, but the other agents in the group have availabilities of 40–80%. Sumatriptan, almotriptan, eletriptan, rizatriptan, and zolmitriptan have half-lives of 2–3 hours, while the half-life of naratriptan is 6 hours and that of frovatriptan more than 25 hours. Sumatriptan can be administered subcutaneously by self-injection, as a nasal spray, or orally. The other members of the group are available only for oral administration. The efficacy of 5-HT1 agonists in migraine is equal to or greater than that of other drug treatments, eg, parenteral or oral ergot alkaloids. Most adverse effects are mild and include altered sensations (tingling, warmth, etc), dizziness, muscle weakness, neck pain, and injection site reactions. Chest discomfort occurs in 1–5% of patients, and chest pain has been reported, probably because of the ability of these drugs to cause coronary vasospasm. They are therefore contraindicated in patients with coronary artery disease and in patients with angina. Another disadvantage is the fact that their duration of effect (especially that of almotriptan, sumatriptan, rizatriptan, and zolmitriptan) is often shorter than the duration of the headache. As a result, several doses may be required during a prolonged migraine attack. In addition, these drugs are extremely expensive at present. Naratriptan and eletriptan are contraindicated in patients with severe hepatic or renal impairment or peripheral vascular syndromes; frovatriptan in patients with peripheral vascular disease; and zolmitriptan in patients with Wolff-Parkinson-White syndrome. Other Serotonin Agonists in Clinical Use Cisapride, a 5-HT4 agonist, was used in the treatment of gastroesophageal reflux and motility disorders. Because of toxicity, it is now available only for compassionate use in the USA. Tegaserod, a newer 5-HT4 partial agonist, is used for irritable bowel syndrome with constipation.
These drugs are discussed in Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. Compounds such as fluoxetine and other serotonin-selective reuptake inhibitors, which modulate serotonergic transmission by blocking reuptake of the transmitter, are among the most widely prescribed drugs for the management of depression and other behavioral disorders. These drugs are discussed in Chapter 30: Antidepressant Agents. Serotonin Antagonists The actions of serotonin, like those of histamine, can be antagonized in several different ways. Such antagonism is clearly desirable in those rare patients who have carcinoid tumor and may also be valuable in certain other conditions. As noted above, serotonin synthesis can be inhibited by p-chlorophenylalanine and pchloroamphetamine. However, these agents are too toxic for general use. Storage of serotonin can be inhibited by the use of reserpine, but the sympatholytic effects of this drug (see Chapter 11: Antihypertensive Agents) and the high levels of circulating serotonin that result from release prevent its use in carcinoid. Therefore, receptor blockade is the major approach to therapeutic limitation of serotonin effects. Serotonin Receptor Antagonists A wide variety of drugs with actions at other receptors ( adrenoceptors, H1 histamine receptors, etc) are also serotonin receptor-blocking agents. Phenoxybenzamine (see Chapter 10: Adrenoceptor Antagonist Drugs) has a long-lasting blocking action at 5-HT2 receptors. In addition, the ergot alkaloids discussed in the last portion of the chapter are partial agonists at serotonin receptors. Cyproheptadine resembles the phenothiazine antihistaminic agents in chemical structure and has potent H1 receptor-blocking as well as 5-HT2-blocking actions. The actions of cyproheptadine are predictable from its H1 histamine and serotonin receptor affinities. It prevents the smooth muscle effects of both amines but has no effect on the gastric secretion stimulated by histamine. It has significant antimuscarinic effects and causes sedation. The major clinical applications of cyproheptadine are in the treatment of the smooth muscle manifestations of carcinoid tumor and in the postgastrectomy dumping syndrome. It is also the preferred drug in cold-induced urticaria. The usual dosage in adults is 12–16 mg/d in three or four divided doses. Ketanserin (Figure 16–3) blocks 5-HT1c and 5-HT2 receptors and has little or no reported antagonist activity at other 5-HT or H1 receptors. However, this drug potently blocks vascular 1 adrenoceptors. The drug blocks 5-HT2 receptors on platelets and antagonizes platelet aggregation promoted by serotonin. The mechanism involved in ketanserin's hypotensive action is not clear but probably involves 1 adrenoceptors more than 5-HT2 receptors. Ketanserin is available in Europe for the treatment of hypertension and vasospastic conditions but has not been approved in the USA. Ritanserin, another 5-HT2 antagonist, has little or no -blocking action. It has been reported to alter bleeding time and to reduce thromboxane formation, presumably by altering platelet function. Ondansetron (Figure 16–3) is the prototypical 5-HT3 antagonist. This drug and its analogs are very important in the prevention of nausea and vomiting associated with surgery and cancer
chemotherapy. They are discussed in Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. Considering the diverse effects attributed to serotonin and the heterogeneous nature of 5-HT receptors, other selective 5-HT antagonists may prove to be clinically useful. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Appetite Control Through Serotonin? As noted in the text, serotonin appears to be related to several general behaviors such as sleep, emotion, sex, and appetite, and early studies with the amine suggested that it could reduce food intake in animals, an anorexigenic effect. Fenfluramine, a racemic chemical more closely related to amphetamine than to serotonin, affects brain levels of serotonin and its metabolites at relatively low doses. It was introduced as an anorexigenic drug almost 20 years ago. Its d- isomer, d-fenfluramine (dexfenfluramine, Redux) was about twice as potent as fenfluramine. After several controlled clinical trials demonstrated that dexfenfluramine could help patients maintain weight loss for at least a year, it was quickly introduced into the market in the USA and became a best-selling drug overnight. Dexfenfluramine caused serotonin release and inhibited reuptake at moderately low concentrations. It also stimulated 5-HT receptors at relatively low concentrations. Metergoline, an ergot derivative with high affinity for 5-HT receptors, completely blocked the anorexiant effect of dexfenfluramine, further suggesting a serotonergic action. Unfortunately, after the introduction of the drug, several cases of fatal and nonfatal pulmonary hypertension were reported in individuals with no known risk factor for this devastating condition other than consumption of dexfenfluramine. These reports were followed by reports of valvular lesions appearing in young women with a similar lack of risk factors other than the consumption of weight-loss products. Assignment of causality was somewhat slowed by the fact that dexfenfluramine was usually used in combination with a much older amphetamine-like anorexiant, phentermine. (This combination was known as "Fen-Phen.") It soon became clear that the valvular lesions fell into the same class of drug-induced pathology as that caused by chronic ergot treatment for migraine (endocardial fibroplasia, retroperitoneal fibroplasia). These effects appear to be associated with 5-HT agonist action. Dexfenfluramine was withdrawn but not before multiple lawsuits had been filed against the manufacturer. Unfortunately, some weight loss clinics now recommend the combination of the antidepressant fluoxetine (Prozac) with phentermine, a combination known as "Phen-Pro." Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > The Ergot Alkaloids Ergot alkaloids are produced by Claviceps purpurea, a fungus that infects grain—especially rye— under damp growing or storage conditions. This fungus synthesizes histamine, acetylcholine, tyramine, and other biologically active products in addition to a score or more of unique ergot alkaloids. These alkaloids affect adrenoceptors, dopamine receptors, 5-HT receptors, and perhaps
other receptor types. Similar alkaloids are produced by fungi parasitic to a number of other grasslike plants. The accidental ingestion of ergot alkaloids in contaminated grain can be traced back more than 2000 years from descriptions of epidemics of ergot poisoning (ergotism). The most dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion. In medieval times, ergot poisoning was called St. Anthony's fire after the saint whose help was sought in relieving the burning pain of vasospastic ischemia. Identifiable epidemics have occurred sporadically up to modern times (see Ergot Poisoning: Not Just an Ancient Disease) and mandate continuous surveillance of all grains used for food. Poisoning of grazing animals is common in many areas because the same and related fungi may grow on pasture grasses. In addition to the effects noted above, the ergot alkaloids produce a variety of other central nervous system and peripheral effects. Detailed structure-activity analysis and appropriate semisynthetic modifications have yielded a large number of agents with documented or potential clinical value. Basic Pharmacology of Ergot Alkaloids Chemistry & Pharmacokinetics Two major families of compounds that incorporate the tetracyclic ergoline nucleus may be identified; the amine alkaloids and the peptide alkaloids (Table 16–4). Drugs of therapeutic and toxicologic importance are found in both groups. Table 16–4. Major Ergoline Derivatives (Ergot Alkaloids).
1
Dihydroergotamine lacks the double bond between carbons 9 and 10.
The ergot alkaloids are variably absorbed from the gastrointestinal tract. The oral dose of ergotamine is about ten times larger than the intramuscular dose, but the speed of absorption and peak blood levels after oral administration can be improved by administration with caffeine (see below). The amine alkaloids are also absorbed from the rectum and the buccal cavity and after administration by aerosol inhaler. Absorption after intramuscular injection is slow but usually reliable. Bromocriptine and the amine derivative cabergoline are well absorbed from the gastrointestinal tract. The ergot alkaloids are extensively metabolized in the body. The primary metabolites are hydroxylated in the A ring, and peptide alkaloids are also modified in the peptide moiety. Pharmacodynamics Mechanism of Action
As suggested above, the ergot alkaloids act on several types of receptors. Their effects include agonist, partial agonist, and antagonist actions at adrenoceptors and serotonin receptors (especially 5-HT1A and 5-HT1D; less for 5-HT1C, 5-HT2, and 5-HT3); and agonist or partial agonist actions at central nervous system dopamine receptors (Table 16–5). Furthermore, some members of the ergot family have a high affinity for presynaptic receptors, while others are more selective for postjunctional receptors. There is a powerful stimulant effect on the uterus that seems to be most closely associated with agonist or partial agonist effects at 5-HT2 receptors. Structural variations increase the selectivity of certain members of the family for specific receptor types. Table 16–5. Effects of Ergot Alkaloids at Several Receptors.1
Ergot Alkaloid
Adrenoceptor
Dopamine Receptor
Serotonin Receptor (5HT2)
Uterine Smooth Muscle Stimulation
Bromocriptine
–
+++
–
Ergonovine
+
+
– (PA)
+++
Ergotamine
– – (PA)
+ (PA)
+++
Lysergic acid diethylamide (LSD)
+++
– –, ++ in CNS
+
Methysergide
+/0
+/0
– – – (PA)
+/0
1
Agonist effects are indicated by +, antagonist by –, no effect by 0. Relative affinity for the receptor is indicated by the number of + or – signs. PA means partial agonist (both agonist and antagonist effects can be detected). Organ System Effects Central Nervous System As indicated by traditional descriptions of ergotism, certain of the naturally occurring alkaloids are powerful hallucinogens. Lysergic acid diethylamide (LSD; "acid") is a synthetic ergot compound that clearly demonstrates this action. The drug has been used in the laboratory as a potent peripheral 5-HT2 antagonist, but good evidence suggests that its behavioral effects are mediated by agonist effects at prejunctional or postjunctional 5-HT2 receptors in the central nervous system. In spite of extensive research, no clinical value has been discovered for LSD's dramatic effects. Abuse of this drug has waxed and waned but is still widespread. It is discussed in Chapter 32: Drugs of Abuse. Dopamine receptors in the central nervous system play important roles in extrapyramidal motor control and the regulation of prolactin release. The actions of the peptide ergoline bromocriptine on the extrapyramidal system are discussed in Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders. Of all the currently available ergot derivatives, bromocriptine, cabergoline, and pergolide have the highest selectivity for the pituitary dopamine receptors. These drugs directly suppress prolactin secretion from pituitary cells by activating regulatory dopamine receptors (Chapter 37: Hypothalamic & Pituitary Hormones). They compete for binding to these sites with dopamine itself and with other dopamine agonists such as
apomorphine. Vascular Smooth Muscle The action of ergot alkaloids on vascular smooth muscle is drug-, species-, and vessel-dependent, so few generalizations are possible. Ergotamine and related compounds constrict most human blood vessels in a predictable, prolonged, and potent manner (Figure 16–4). This response is partially blocked by conventional -blocking agents. However, ergotamine's effect is also associated with "epinephrine reversal" (see Chapter 10: Adrenoceptor Antagonist Drugs) and with blockade of the response to other agonists. This dual effect represents partial agonist action (Table 16–5). Because ergotamine dissociates very slowly from the receptor, it produces very long-lasting agonist and antagonist effects at this receptor. There is little or no effect at adrenoceptors. Figure 16–4.
Effects of ergot derivatives on contraction of isolated segments of human basilar artery strips removed at surgery. All of the ergot derivatives are partial agonists, and all are more potent than the full agonists, norepinephrine and serotonin. (NE, norepinephrine; 5-HT, serotonin; ERG, ergotamine; MT, methylergometrine; DHE, dihydroergotamine; MS, methysergide.) (Modified and reproduced, with permission, from Müller-Schweinitzer E in: 5-Hydroxytryptamine Mechanisms in Primary Headaches. Oleson J, Saxena PR [editors]. Raven Press, 1992.) While much of the vasoconstriction elicited by ergot alkaloids can be ascribed to partial agonist effects at adrenoceptors, some may be the result of effects at 5-HT receptors. Ergotamine, ergonovine, and methysergide all have partial agonist effects at 5-HT2 vascular receptors. The remarkably specific antimigraine action of the ergot derivatives was originally thought to be related to their actions on vascular serotonin receptors. Current hypotheses, however, emphasize their action on prejunctional neuronal 5-HT receptors. After overdosage with ergotamine and similar agents, vasospasm is severe and prolonged (see Toxicity, below). This vasospasm is not easily reversed by antagonists, serotonin antagonists, or combinations of both.
Ergotamine is typical of the ergot alkaloids that have a strong vasoconstrictor spectrum of action. The hydrogenation of ergot alkaloids at the 9 and 10 positions (Table 16–4) yields dihydro derivatives that have reduced serotonin partial agonist effects and increased selective receptorblocking actions. Uterine Smooth Muscle The stimulant action of ergot alkaloids on the uterus, as on vascular smooth muscle, appears to combine agonist, serotonin, and other effects. Furthermore, the sensitivity of the uterus to the stimulant effects of ergot changes dramatically during pregnancy, perhaps because of increasing dominance of 1 receptors as pregnancy progresses. As a result, the uterus at term is more sensitive than earlier in pregnancy and far more sensitive than the nonpregnant organ. In very small doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus. At higher concentrations, these drugs induce powerful and prolonged contracture. Ergonovine is more selective than other ergot alkaloids in affecting the uterus and is the agent of choice in obstetric applications of these drugs. Other Smooth Muscle Organs In most patients, the ergot alkaloids have no significant effect on bronchiolar smooth muscle. The gastrointestinal tract, on the other hand, is quite sensitive in most patients. Nausea, vomiting, and diarrhea may be induced even by low doses in some patients. The effect is consistent with action on the central nervous system emetic center and on gastrointestinal serotonin receptors. Clinical Pharmacology of Ergot Alkaloids Clinical Uses Migraine Migraine headache in its "classic" form is characterized by a brief aura that may involve visual scotomas or even hemianopia and speech abnormalities, followed by a severe throbbing unilateral headache that lasts for a few hours to 1–2 days. "Common" migraine lacks the aura phase, but the headache is similar. Although the symptom pattern varies among patients, the severity of migraine headache justifies vigorous therapy in the great majority of cases. Migraine involves the trigeminal nerve distribution to intracranial (and possibly extracranial) arteries. These nerves appear to release peptide neurotransmitters, especially calcitonin generelated peptide (CGRP; see Chapter 17: Vasoactive Peptides), an extremely powerful vasodilator. Substance P and neurokinin A may also be involved. Extravasation of plasma and plasma proteins into the perivascular space appears to be a common feature of animal migraine models and biopsy specimens from migraine patients and probably represents the effect of the neuropeptides on the vessels. The mechanical stretching caused by this perivascular edema may be the immediate cause of activation of pain nerve endings in the dura. The onset of headache is sometimes associated with a marked increase in amplitude of temporal artery pulsations, and relief of pain by administration of ergotamine is sometimes accompanied by diminution of the arterial pulsations. The mechanisms of action of drugs used in migraine are poorly understood because they include such a wide variety of drug groups and actions. These include ergot alkaloids and synthetic 5-HT agonists (triptans), nonsteroidal anti-inflammatory analgesic agents, -adrenoceptor blockers,
tricyclic and serotonin-selective reuptake-inhibiting antidepressants, and several antiseizure agents. Furthermore, some of these drug groups are effective only for prophylaxis and not for the acute attack. Two primary hypotheses have been proposed to explain the actions of these drugs. First, 5-HT agonists, such as ergot alkaloids, the triptans, and antidepressants may activate 5-HT1 receptors on presynaptic trigeminal nerve endings to inhibit the release of vasodilating peptides, and antiseizure agents may suppress excessive firing of these nerve endings. Second, the vasoconstrictor actions of direct 5-HT agonists (ergot and the triptans) may prevent vasodilation and stretching of the pain endings. It is possible that both mechanisms contribute in the case of some drugs. Sumatriptan and its congeners, discussed above, are currently first-line therapy for acute severe migraine attacks in most patients. However, they should not be used in patients at risk for coronary artery disease. Antiinflammatory analgesics such as aspirin and ibuprofen are often helpful in controlling the pain of migraine. Rarely, parenteral opioids may be needed in refractory cases. For patients with very severe nausea and vomiting, parenteral metoclopramide may be helpful. Ergot derivatives are highly specific for migraine pain; they are not analgesic for any other condition. Although the triptan drugs discussed above are preferred by most clinicians and patients, traditional therapy with ergotamine can also be quite effective when given during the prodrome of an attack; it becomes progressively less effective if delayed. Ergotamine tartrate is available for oral, sublingual, rectal suppository, and inhaler use. It is often combined with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate) to facilitate absorption of the ergot alkaloid. The vasoconstriction induced by ergotamine is long-lasting and cumulative when the drug is taken repeatedly, as in a severe migraine attack. Therefore, patients must be carefully informed that no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per week. For very severe attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intravenously or intramuscularly. Dihydroergotamine, 0.5–1 mg intravenously, is favored by some clinicians for treatment of intractable migraine. Intranasal dihydroergotamine may also be effective. Because of the cumulative toxicity of ergotamine, safer agents useful for the prophylaxis of migraine have been sought. Methysergide, a derivative of the amine subgroup (Table 16–5), was shown to be effective in this application in about 60% of patients. Unfortunately, significant toxicity (discussed below) occurred in almost 40% of patients. Furthermore, methysergide was relatively ineffective in treatment of impending or active episodes of migraine. Although relatively free of the rapidly cumulative vasospastic toxicity of ergotamine, chronic use of methysergide was sometimes associated with retroperitoneal fibroplasia and subendocardial fibrosis, possibly through its vascular effects. Propranolol and amitriptyline have also been found to be effective for the prophylaxis of migraine in some patients. Like methysergide, they are of no value in the treatment of acute migraine. The anticonvulsant valproic acid in the form of divalproex (see Chapter 24: Antiseizure Drugs) has recently been found to have good prophylactic efficacy in many migraine patients. Flunarizine, a calcium channel blocker used in Europe, has been reported in clinical trials to effectively reduce the severity of the acute attack and to prevent recurrences. Verapamil appears to have modest efficacy as prophylaxis against migraine. Hyperprolactinemia Increased serum levels of the anterior pituitary hormone prolactin are associated with secreting tumors of the gland and also with the use of centrally acting dopamine antagonists, especially the
antipsychotic drugs. Because of negative feedback effects, hyperprolactinemia is associated with amenorrhea and infertility in women as well as galactorrhea in both sexes. Bromocriptine is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases. The usual dosage of bromocriptine is 2.5 mg two or three times daily. Cabergoline is similar but more potent. Bromocriptine has also been used in the same dosage to suppress physiologic lactation. However, serious postpartum cardiovascular toxicity has been reported in association with the latter use of bromocriptine or pergolide, and this application is discouraged (Chapter 37: Hypothalamic & Pituitary Hormones). Postpartum Hemorrhage The uterus at term is extremely sensitive to the stimulant action of ergot, and even moderate doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor. This was not appreciated when the drugs were introduced into obstetrics in the 18th century. Their use at that time to accelerate labor caused a dramatic increase in fetal and maternal mortality rates. Therefore, ergot derivatives are useful only for control of late uterine bleeding and should never be given before delivery. Oxytocin is the preferred agent for control of postpartum hemorrhage, but if this peptide agent is ineffective, ergonovine maleate, 0.2 mg usually given intramuscularly, can be tried. It is usually effective within 1–5 minutes and is less toxic than other ergot derivatives for this application. It is given at the time of delivery of the placenta or immediately afterward if bleeding is significant. Diagnosis of Variant Angina Ergonovine produces prompt vasoconstriction during coronary angiography to diagnose variant angina. Senile Cerebral Insufficiency Dihydroergotoxine, a mixture of dihydro- -ergocryptine and three similar dihydrogenated peptide ergot alkaloids (ergoloid mesylates), has been promoted for many years for the relief of senility and more recently for the treatment of Alzheimer's dementia. There is no evidence of significant benefit. Toxicity & Contraindications The most common toxic effects of the ergot derivatives are gastrointestinal disturbances, including diarrhea, nausea, and vomiting. Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors is involved. Since migraine attacks are often associated with these symptoms before therapy is begun, these adverse effects are rarely contraindications to the use of ergot. A more dangerous toxic effect of overdosage with agents like ergotamine and ergonovine is prolonged vasospasm. As described above, this sign of vascular smooth muscle stimulation may result in gangrene and require amputation. Most cases involve the circulation to the arms and legs. However, bowel infarction resulting from mesenteric artery vasospasm has also been reported. Peripheral vascular vasospasm caused by ergot is refractory to most vasodilators, but infusions of large doses of nitroprusside or nitroglycerin have been successful in some cases. Chronic therapy with methysergide was associated with connective tissue proliferation in the
retroperitoneal space, the pleural cavity, and the endocardial tissue of the heart. These changes occurred insidiously over months and presented as hydronephrosis (from obstruction of the ureters) or a cardiac murmur (from distortion of the valves of the heart). In some cases, valve damage required surgical replacement. As a result, this drug was withdrawn. Other toxic effects of the ergot alkaloids include drowsiness and, in the case of methysergide, occasional instances of central stimulation and hallucinations. In fact, methysergide was sometimes used as a substitute for LSD by members of the "drug culture." Contraindications to the use of ergot derivatives consist of the obstructive vascular diseases and collagen diseases. There is no evidence that ordinary use of ergotamine for migraine is hazardous in pregnancy. However, most clinicians counsel restraint in the use of the ergot derivatives by pregnant patients. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Ergot Poisoning: Not Just an Ancient Disease As noted in the text, epidemics of ergotism, or poisoning by ergot-contaminated grain, are known to have occurred sporadically in ancient times and through the Middle Ages. It is easy to imagine the social chaos that might result if fiery pain, gangrene, hallucinations, convulsions, and abortions occurred simultaneously throughout a community in which all or most of the people believed in witchcraft, demonic possession, and the visitation of supernatural punishments upon humans for their misdeeds. Such beliefs are uncommon in most cultures today. However, ergotism has not disappeared. A most convincing demonstration of ergotism occurred in the small French village of Pont-Saint-Esprit in 1951. It was described in the British Medical Journal in 1951 (Gabbai et al, 1951) and in a later book-length narrative account (Fuller, 1968). Several hundred individuals suffered symptoms of hallucinations, convulsions, and ischemia—and several died—after eating bread made from contaminated flour. Similar events have occurred even more recently when poverty, famine, or incompetence resulted in the consumption of contaminated grain. Iatrogenic ergot toxicity caused by excessive use of medical ergot preparations is still frequently reported. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids > Preparations Available Antihistamines (H1 Blockers)* Azelastine (Astelin) Nasal: 137 g/puff nasal spray Ophthalmic: 0.5 mg/mL solution
Brompheniramine (Brovex) Oral: 12 mg tablets; 12 mg/5 mL suspension Buclizine (Bucladin-S Softabs) Oral: 50 mg tablets Carbinoxamine (Histex, Pediatex) Oral: 8 mg timed-release tablets; 1.75, 4 mg/5 mL liquid Cetirizine (Zyrtec) Oral: 5, 10 mg tablets; 5 mg/5 mL syrup Chlorpheniramine (generic, Chlor-Trimeton, Teldrin, others) Oral: 2 mg chewable tablets; 4 mg tablets; 2 mg/5 mL syrup Oral sustained-release: 8, 12, 16 mg tablets; 8, 12 mg capsules Clemastine (generic, Tavist) Oral: 1.34, 2.68 mg tablets; 0.67 mg/5 mL syrup Cyclizine (Marezine) Oral: 50 mg tablets Cyproheptadine (generic) Oral: 4 mg tablets; 2 mg/5 mL syrup Desloratadine (Clarinex) Oral: 5 mg regular or rapidly disintegrating tablets Dimenhydrinate (Dramamine, others) Oral: 50 mg tablets; 50 mg chewable tablets; 12.5/5 mL, 12.5 mg/4 mL, 15.62 mg/5 mL liquid Diphenhydramine (generic, Benadryl) Oral: 12.5 mg chewable tablets; 25, 50 mg capsules; 25, 50 mg tablets; 12.5 mg/5 mL elixir and syrup Parenteral: 50 mg/mL for injection Emedastine (Emadine)
Ophthalmic: 0.05% solution Fexofenadine (Allegra) Oral: 30, 60, 180 mg tablets; 60 mg capsules Hydroxyzine (generic, Atarax, Vistaril) Oral: 10, 25, 50, 100 mg tablets; 25, 50, 100 mg capsules; 10 mg/5 mL syrup; 25 mg/5 mL suspension Parenteral: 25, 50 mg/mL for injection Ketotifen (Zaditor) Ophthalmic: 0.025% solution Levocabastine (Livostin) Ophthalmic: 0.05% solution Loratadine (Claritin) Oral: 10 mg tablets; 10 mg rapidly disintegrating tablets; 1 mg/mL syrup Meclizine (generic, Antivert, others) Oral: 12.5, 25, 50 mg tablets; 25, 30 mg capsules; 25 mg chewable tablets Olopatadine (Patanol) Ophthalmic: 0.1% solution Phenindamine (Nolahist) Oral: 25 mg tablets Promethazine (generic, Phenergan, others) Oral: 12.5, 25, 50 mg tablets; 6.25 mg/5 mL syrups Parenteral: 25 mg/mL for injection; 50 mg/mL for IM injection Rectal: 12.5, 25, 50 mg suppositories H2 Blockers See Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. 5-HT Agonists
Almotriptan (Axert) Oral: 6.25, 12.5 mg tablets Eletriptan (Relpax) Oral: 24.2, 48.5 mg tablets Frovatriptan (Frova) Oral: 2.5 mg tablets Naratriptan (Amerge) Oral: 1, 2.5 mg tablets Rizatriptan Oral: 5, 10 mg tablets (Maxalt); 5, 10 mg orally disintegrating tablets (Maxalt-MLT) Sumatriptan (Imitrex) Oral: 25, 50, 100 mg tablets Nasal: 5, 20 mg unit dose spray devices Parenteral: 6 mg/0.5 mL in SELFdose autoinjection units for subcutaneous injection Zolmitriptan (Zomig) Oral: 2.5, 5 mg tablets; 2.5 mg orally disintegrating tablets 5-HT Antagonists See Chapter 63: Drugs Used in the Treatment of Gastrointestinal Diseases. Ergot Alkaloids Dihydroergotamine Nasal (Migranal): 4 mg/mL nasal spray Parenteral (D.H.E. 45): 1 mg/mL for injection Ergonovine (Ergotrate maleate) Parenteral: 0.2 mg/mL for injection Ergotamine [mixtures] (generic, Cafergot, others)
Oral: 1 mg ergotamine/100 mg caffeine tablets Rectal: 2 mg ergotamine/100 mg caffeine suppositories Ergotamine tartrate (Ergomar) Sublingual: 2 mg sublingual tablets Methylergonovine (Methergine) Oral: 0.2 mg tablets Parenteral: 0.2 mg/mL for injection * Several other antihistamines are available only in combination products with, for example, pseudoephedrine. Dimenhydrinate is the chlorotheophylline salt of diphenhydramine. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 16. Histamine, Serotonin, & the Ergot Alkaloids >
Chapter 17. Vasoactive Peptides Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Vasoactive Peptides: Introduction Peptides are used by most tissues for cell-to-cell communication. As noted in Chapters 6 and 21, they play important roles in the autonomic and central nervous systems. Several peptides exert important direct effects on vascular and other smooth muscles. These peptides include vasoconstrictors (angiotensin II, vasopressin, endothelins, neuropeptide Y, and urotensin) and vasodilators (bradykinin and related kinins, natriuretic peptides, vasoactive intestinal peptide, substance P, neurotensin, calcitonin gene-related peptide, and adrenomedullin). This chapter focuses on the smooth muscle actions of the peptides.
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Angiotensin Biosynthesis of Angiotensin The pathway for the formation and metabolism of angiotensin II is summarized in Figure 17–1. The principal steps include enzymatic cleavage of angiotensin I from angiotensinogen by renin, conversion of angiotensin I to angiotensin II by converting enzyme, and degradation of angiotensin
II by several peptidases. Figure 17–1.
Chemistry of the renin-angiotensin system. The amino acid sequence of the amino terminal of human angiotensinogen is shown. R denotes the remainder of the protein molecule. Renin & Factors Controlling Renin Secretion Renin is an aspartyl protease that specifically catalyzes the hydrolytic release of the decapeptide angiotensin I from angiotensinogen. It is synthesized as a preprohormone that is processed to prorenin, which is inactive, and then to active renin, a glycoprotein consisting of 340 amino acids. Renin in the circulation originates in the kidneys. Enzymes with renin-like activity are present in several extrarenal tissues, including blood vessels, uterus, salivary glands, and adrenal cortex, but no physiologic role for these enzymes has been established. Within the kidney, renin is synthesized and stored in the juxtaglomerular apparatus of the nephron. Specialized granular cells called juxtaglomerular cells are the site of synthesis, storage, and release of renin. The macula densa is a specialized tubular segment closely associated with the vascular components of the juxtaglomerular apparatus. The vascular and tubular components of the juxtaglomerular apparatus, including the
juxtaglomerular cells, are innervated by noradrenergic neurons. The rate at which renin is secreted by the kidney is the primary determinant of activity of the reninangiotensin system. Renin secretion is controlled by a variety of factors, including a renal vascular receptor, the macula densa, the sympathetic nervous system, and angiotensin II. Renal Vascular Receptor The renal vascular receptor functions as a stretch receptor, decreased stretch leading to increased renin release and vice versa. The receptor is apparently located in the afferent arteriole, possibly in the juxtaglomerular cells. Stretch-induced changes in renin release are mediated by changes in Ca2+ concentration in the juxtaglomerular cells. Macula Densa The macula densa contains a different type of receptor, sensitive to changes in the rate of delivery of sodium or chloride to the distal tubule. Decreases in distal delivery result in stimulation of renin secretion and vice versa. Potential candidates for signal transmission between the macula densa and the juxtaglomerular cells include adenosine, prostaglandins, and nitric oxide. Sympathetic Nervous System Maneuvers that increase renal nerve activity cause stimulation of renin secretion, while renal denervation results in suppression of renin secretion. Norepinephrine stimulates renin secretion by a direct action on the juxtaglomerular cells. In humans, this effect is mediated by 1 adrenoceptors. Circulating epinephrine and norepinephrine may act via the same mechanisms as the norepinephrine released locally from the renal sympathetic nerves, but there is evidence that a major component of the renin secretory response to circulating catecholamines is mediated by extrarenal receptors. Angiotensin Angiotensin II inhibits renin secretion. The inhibition, which results from a direct action of the peptide on the juxtaglomerular cells, forms the basis of a short-loop negative feedback mechanism controlling renin secretion. Interruption of this feedback with inhibitors of the renin-angiotensin system (see below) results in stimulation of renin secretion. Pharmacologic Alteration of Renin Release The release of renin is altered by a wide variety of pharmacologic agents. Renin release is stimulated by vasodilators (hydralazine, minoxidil, nitroprusside), -adrenoceptor agonists (isoproterenol), -adrenoceptor antagonists, phosphodiesterase inhibitors (theophylline, milrinone, rolipram), and most diuretics and anesthetics. This stimulation can be accounted for by the control mechanisms just described. Drugs that inhibit renin release are discussed below in the section on inhibition of the renin-angiotensin system. Angiotensinogen Angiotensinogen is the circulating protein substrate from which renin cleaves angiotensin I. It is synthesized in the liver. Human angiotensinogen is a glycoprotein with a molecular weight of approximately 57,000. The 14 amino acids at the amino terminal of the molecule are shown in
Figure 17–1. In humans, the concentration of angiotensinogen in the circulation is less than the Km of the renin-angiotensinogen reaction and is therefore an important determinant of the rate of formation of angiotensin. The production of angiotensinogen is increased by corticosteroids, estrogens, thyroid hormones, and angiotensin II. It is also elevated during pregnancy and in women taking estrogen-containing oral contraceptives. The increased plasma angiotensinogen concentration is thought to contribute to the hypertension that may occur in these situations. There is also evidence for a genetic linkage between the angiotensinogen gene and essential hypertension (Lalouel et al, 2001). Angiotensin I Although angiotensin I contains the peptide sequences necessary for all of the actions of the reninangiotensin system, it has little or no biologic activity. Instead, it must be converted to angiotensin II by converting enzyme (Figure 17–1). Angiotensin I may also be acted on by plasma or tissue aminopeptidases to form [des-Asp1]angiotensin I; this in turn is converted to [des-Asp1]angiotensin II (commonly known as angiotensin III) by converting enzyme. Converting Enzyme (Peptidyl Dipeptidase [PDP], Kininase II) Converting enzyme is a dipeptidyl carboxypeptidase that catalyzes the cleavage of dipeptides from the carboxyl terminal of certain peptides. Its most important substrates are angiotensin I, which it converts to angiotensin II, and bradykinin, which it inactivates (see below). It also cleaves enkephalins and substance P, but the physiologic significance of these effects has not been established. The action of converting enzyme is prevented by a penultimate prolyl residue, and angiotensin II is therefore not hydrolyzed by converting enzyme. Converting enzyme is distributed widely in the body. In most tissues, converting enzyme is located on the luminal surface of vascular endothelial cells and is thus in close contact with the circulation. Angiotensinase Angiotensin II, which has a plasma half-life of 15–60 seconds, is removed rapidly from the circulation by a variety of peptidases collectively referred to as angiotensinase. It is metabolized during passage through most vascular beds (a notable exception being the lung). Most metabolites of angiotensin II are biologically inactive, but the initial product of aminopeptidase action—[desAsp1]angiotensin II—retains considerable biologic activity. Actions of Angiotensin II Angiotensin II exerts important actions at several sites in the body, including vascular smooth muscle, adrenal cortex, kidney, and brain. Through these actions, the renin-angiotensin system plays a key role in the regulation of fluid and electrolyte balance and arterial blood pressure. Excessive activity of the renin-angiotensin system can result in hypertension and disorders of fluid and electrolyte homeostasis. Blood Pressure Angiotensin II is a very potent pressor agent—on a molar basis, approximately 40 times more potent than norepinephrine. The pressor response to intravenous angiotensin II is rapid in onset (10– 15 seconds) and sustained during long-term infusions of the peptide. A large component of the pressor response to intravenous angiotensin II is due to direct contraction of vascular—especially
arteriolar—smooth muscle. In addition, however, angiotensin II can also increase blood pressure through actions on the brain and autonomic nervous system. The pressor response to angiotensin is usually accompanied by little or no reflex bradycardia because the peptide acts on the brain to reset the baroreceptor reflex control of heart rate to a higher pressure. Angiotensin II also interacts with the autonomic nervous system. It stimulates autonomic ganglia, increases the release of epinephrine and norepinephrine from the adrenal medulla, and—what is most important—facilitates sympathetic transmission by an action at adrenergic nerve terminals. The latter effect involves both increased release and reduced reuptake of norepinephrine. Angiotensin II also has a less important direct positive inotropic action on the heart. Adrenal Cortex Angiotensin II acts directly on the zona glomerulosa of the adrenal cortex to stimulate aldosterone biosynthesis. At higher concentrations, angiotensin II also stimulates glucocorticoid biosynthesis. Kidney Angiotensin II acts on the kidney to cause renal vasoconstriction, increase proximal tubular sodium reabsorption, and inhibit the secretion of renin. Central Nervous System In addition to its central effects on blood pressure, angiotensin II acts on the central nervous system to stimulate drinking (dipsogenic effect) and increase the secretion of vasopressin and adrenocorticotropic hormone (ACTH). The physiologic significance of the effects of angiotensin II on drinking and pituitary hormone secretion is not known. Cell Growth Angiotensin II is mitogenic for vascular and cardiac muscle cells and may contribute to the development of cardiovascular hypertrophy. Considerable evidence now indicates that angiotensinconverting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (see below) slow or prevent morphologic changes (remodeling) following myocardial infarction that would otherwise lead to heart failure. Angiotensin Receptors & Mechanism of Action Angiotensin II receptors are widely distributed in the body. Like the receptors for other peptide hormones, angiotensin II receptors are located on the plasma membrane of target cells, and this permits rapid onset of the various actions of angiotensin II. Two distinct subtypes of angiotensin II receptors, termed AT1 and AT2, have been identified on the basis of their differential affinity for antagonists, and their sensitivity to sulfhydryl-reducing agents. AT1 receptors have a high affinity for losartan and a low affinity for PD 123177 (an experimental nonpeptide antagonist), while AT2 receptors have a high affinity for PD 123177 and a low affinity for losartan. Angiotensin II and saralasin (see below) bind equally to both subtypes. The relative proportion of the two subtypes varies from tissue to tissue: AT1 receptors predominate in vascular smooth muscle. Most of the known actions of angiotensin II are mediated by the AT1 receptor, a G protein-coupled
receptor. Binding of angiotensin II to AT1 receptors in vascular smooth muscle results in activation of phospholipase C and generation of inositol trisphosphate and diacylglycerol (see Chapter 2: Drug Receptors & Pharmacodynamics). These events, which occur within seconds, result in smooth muscle contraction. The stimulation of vascular and cardiac growth by angiotensin II is mediated by other pathways, probably receptor and nonreceptor tyrosine kinases such as the Janus tyrosine kinase Jak2 and increased transcription of specific genes (see Chapter 2: Drug Receptors & Pharmacodynamics). The AT2 receptor has a structure and affinity for angiotensin II similar to those of the AT1 receptor. However, signal transduction by the AT2 receptor differs from transduction by the AT1 receptor, and current evidence suggests that serine and tyrosine phosphatases, phospholipase A2, nitric oxide, and cyclic guanosine monophosphate (cGMP) are involved. AT2 receptors are present at high density in all tissues during fetal development, but they are much less abundant in the adult where they are expressed at high concentration only in the adrenal medulla, reproductive tissues, vascular endothelium and parts of the brain. AT2 receptors are upregulated in pathologic conditions including heart failure and myocardial infarction. The functions of the AT2 receptor appear to include fetal tissue development, inhibition of growth and proliferation, cell differentiation, apoptosis, and possibly, vasodilation. Inhibition of the Renin-Angiotensin System A wide variety of agents are now available that block the formation or actions of angiotensin II. These drugs may block renin secretion, the enzymatic action of renin, the conversion of angiotensin I to angiotensin II, or angiotensin II receptors. Drugs That Block Renin Secretion Several drugs that interfere with the sympathetic nervous system inhibit the secretion of renin. Examples are clonidine and propranolol. Clonidine inhibits renin secretion by causing a centrally mediated reduction in renal sympathetic nerve activity, and it may also exert a direct intrarenal action. Propranolol and other -adrenoceptor-blocking drugs act by blocking the intrarenal and extrarenal receptors involved in the neural control of renin secretion. Renin Inhibitors Several orally active renin inhibitors have been developed. Two inhibitors that have been tested in humans are remikiren and enalkiren. They have a high specificity for renin, cause marked suppression of plasma renin activity and plasma angiotensin II concentration, and lower blood pressure in hypertensive patients. However, the bioavailability of these inhibitors is generally poor, mainly because of poor absorption and a considerable first pass effect. They also increase plasma renin concentrations because of interruption of the negative feedback effect of angiotensin II on renin secretion, and this further limits the reduction in plasma renin activity that can be achieved. Renin inhibitors have the potential to be as effective as converting enzyme inhibitors in inhibiting the renin-angiotensin system, but further improvement of their bioavailability and efficacy is needed. Converting Enzyme Inhibitors An important class of orally active ACE inhibitors, directed against the active site of ACE, is now extensively used. Captopril and enalapril (Figure 17–2) are examples of the many potent ACE
inhibitors that are available. These drugs differ in their structure and pharmacokinetics, but in clinical use, they are interchangeable. ACE inhibitors decrease systemic vascular resistance without increasing heart rate, and they promote natriuresis. As described in Chapter 11: Antihypertensive Agents and Chapter 13: Drugs Used in Heart Failure, they are effective in the treatment of hypertension, decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction, and delay the progression of diabetic nephropathy. Figure 17–2.
Two orally active converting enzyme inhibitors. Enalapril is a prodrug ethyl ester that is hydrolyzed in the body. ACE inhibitors not only block the conversion of angiotensin I to angiotensin II but also inhibit the degradation of other substances, including bradykinin, substance P, and enkephalins. The action of ACE inhibitors to inhibit bradykinin metabolism contributes significantly to their hypotensive action (Figure 11–6) and is apparently responsible for some adverse side effects, including cough and angioedema. Angiotensin Antagonists Substitution of certain amino acids, especially sarcosine, for the phenylalanine in position 8 of angiotensin II results in the formation of potent peptide antagonists of the action of angiotensin II. The best-known of these antagonists is saralasin. Saralasin exhibits some agonist activity and may elicit pressor responses, particularly when circulating angiotensin II levels are low. Saralasin must be administered intravenously, and this severely restricts its use as an antihypertensive agent. However, it has been used for the detection of renin-dependent hypertension and other hyperreninemic states. The nonpeptide angiotensin II antagonists are of much greater interest. Losartan, valsartan (Figure 17–3), eprosartan, irbesartan, candesartan, and telmesartan are orally active, potent, and specific competitive antagonists of angiotensin AT1 receptors. The blood pressure-lowering efficacy of these drugs is similar to that of enalapril, a typical ACE inhibitor, but associated with a lower
incidence of cough. Like the ACE inhibitors, they are well tolerated but should not be used by patients with nondiabetic renal disease or in pregnancy. Figure 17–3.
Structures of two angiotensin AT1 receptor antagonists. The current angiotensin II receptor antagonists are selective for the AT1 receptor. Since prolonged treatment with the drugs disinhibits renin secretion and increases circulating angiotensin II levels, there may be increased stimulation of AT2 receptors. This may be significant in view of the evidence that activation of the AT2 receptor causes vasodilation and other beneficial effects. AT2 receptor antagonists such as PD 123177 are available for research but have no clinical applications at this time. The clinical benefits of AT1 receptor antagonists are similar to those of ACE inhibitors, and it is currently not clear if one group of drugs has significant advantages over the other. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Kinins Biosynthesis of Kinins Kinins are a group of potent vasodilator peptides. They are formed enzymatically by the action of enzymes known as kallikreins or kininogenases acting on protein substrates called kininogens. From the biochemical point of view, the kallikrein-kinin system has several features in common with the renin-angiotensin system. Kallikreins
Kallikreins are glycoprotein enzymes produced in the liver as prekallikreins and present in plasma and in several tissues, including the kidneys, pancreas, intestine, sweat glands, and salivary glands. They are serine proteases with active sites and catalytic properties similar to those of enzymes such as trypsin, chymotrypsin, elastase, thrombin, plasmin, and other serine proteases. Plasma prekallikrein can be activated to kallikrein by trypsin, Hageman factor, and possibly kallikrein itself. In general, the biochemical properties of glandular kallikreins are quite different from those of plasma kallikreins. Kallikreins can convert prorenin to active renin, but the physiologic significance of this action has not been established. Kininogens Kininogens—the precursors of kinins and substrates of kallikreins—are present in plasma, lymph, and interstitial fluid. Two kininogens are known to be present in plasma: a low-molecular-weight form (LMW kininogen) and a high-molecular-weight form (HMW kininogen). About 15–20% of the total plasma kininogen is in the HMW form. It is thought that LMW kininogen crosses capillary walls and serves as the substrate for tissue kallikreins, while HMW kininogen is confined to the bloodstream and serves as the substrate for plasma kallikrein. Formation of Kinins in Plasma & Tissues The pathway for the formation and metabolism of kinins is shown in Figure 17–4. Three kinins have been identified in mammals: bradykinin, lysylbradykinin (also known as kallidin), and methionyllysylbradykinin. Their structures are shown below:
Figure 17–4.
The kallikrein-kinin system. Kininase II is identical to converting enzyme peptidyl dipeptidase. Note that each kinin contains bradykinin in its structure. Each kinin is formed from a kininogen by the action of a different enzyme. Bradykinin is released by plasma kallikrein, lysylbradykinin by glandular kallikrein, and methionyllysylbradykinin by pepsin and pepsin-like enzymes. The three kinins have been found in plasma and urine. Bradykinin is the predominant kinin in plasma, while lysylbradykinin is the major urinary form. Actions of Kinins Effects on the Cardiovascular System Kinins produce marked vasodilation in several vascular beds, including the heart, kidney, intestine, skeletal muscle, and liver. In this respect, kinins are approximately 10 times more potent on a molar basis than histamine. The vasodilation may result from a direct inhibitory effect of kinins on arteriolar smooth muscle or may be mediated by the release of endothelium-derived relaxing factor (EDRF, nitric oxide) or vasodilator prostaglandins such as PGE2 and PGI2. In contrast, the predominant effect of kinins on veins is contraction; again, this may result from direct stimulation of venous smooth muscle or from the release of venoconstrictor prostaglandins such as PGF2a. Kinins also produce contraction of most visceral smooth muscle. When injected intravenously, kinins produce a rapid fall in blood pressure that is due to their arteriolar vasodilator action. The hypotensive response to bradykinin is of very brief duration. Intravenous infusions of the peptide fail to produce a sustained decrease in blood pressure; prolonged hypotension can only be produced by progressively increasing the rate of infusion. The rapid reversibility of the hypotensive response to kinins is due primarily to reflex increases in heart rate, myocardial contractility, and cardiac output. In some species, bradykinin produces a biphasic change in blood pressure—an initial hypotensive response followed by an increase above the preinjection level. The increase in blood pressure may be due to a reflex activation of the sympathetic nervous system, but under some conditions, bradykinin can directly release catecholamines from the adrenal medulla and stimulate sympathetic ganglia. Bradykinin also increases blood pressure when injected into the central nervous system, but the physiologic significance of this effect is not clear, since it is unlikely that kinins cross the blood-brain barrier.
Kinins have no consistent effect on sympathetic or parasympathetic nerve endings. The arteriolar dilation produced by kinins causes an increase in pressure and flow in the capillary bed, thus favoring efflux of fluid from blood to tissues. This effect may be facilitated by increased capillary permeability resulting from contraction of endothelial cells and widening of intercellular junctions, and by increased venous pressure secondary to constriction of veins. As a result of these changes, water and solutes pass from the blood to the extracellular fluid, lymph flow increases, and edema may result. Effects on Endocrine & Exocrine Glands As noted earlier, prekallikreins and kallikreins are present in several glands, including the pancreas, kidney, intestine, salivary glands, and sweat glands, and can be released into the secretory fluids of these glands. The function of the enzymes in these tissues is not known. The enzymes (or active kinins) may diffuse from the organs to the blood and act as local modulators of blood flow. Since kinins have such marked effects on smooth muscle, they may also modulate the tone of salivary and pancreatic ducts and help regulate gastrointestinal motility. Kinins also influence the transepithelial transport of water, electrolytes, glucose, and amino acids, and may regulate the transport of these substances in the gastrointestinal tract and kidney. Finally, kallikreins may play a role in the physiologic activation of various prohormones, including proinsulin and prorenin. Role in Inflammation Kinins play an important role in the inflammatory process. Kallikreins and kinins can produce redness, local heat, swelling, and pain, and the production of kinins is increased in inflammatory lesions produced by a variety of methods. Effects on Sensory Nerves Kinins are potent pain-producing substances when applied to a blister base or injected intradermally. They elicit pain by stimulating nociceptive afferents in the skin and viscera. Kinin Receptors & Mechanisms of Action The biologic actions of kinins are mediated by specific receptors located on the membranes of the target tissues. Two types of kinin receptors, termed B1 and B2, have been defined based on the rank orders of agonist potencies: for B1 receptors, [des-Arg9]bradykinin > [Tyr(Me)8] bradykinin > bradykinin. For B2 receptors, [Tyr(Me)8] bradykinin > bradykinin > [des-Arg9]bradykinin. (Note that B here stands for bradykinin, not for -adrenoceptor.) Bradykinin displays the highest affinity in most B2 receptor systems, followed by Lys-bradykinin and then by Met-Lys-bradykinin. One exception is the B2 receptor that mediates contraction of venous smooth muscle; this appears to be most sensitive to Lys-bradykinin. Recent evidence suggests the existence of two B2 receptor subtypes, which have been termed B2A and B2B. B1 receptors appear to have a very limited distribution in mammalian tissues. Known functional roles for B1 receptors are limited. Studies with knockout mice that lack functional B1 receptors have provided evidence that these receptors participate in the inflammatory response (Pesquero, 2000). B1 receptors may also be important in long-lasting kinin effects such as collagen synthesis and cell multiplication. By contrast, B2 receptors have a widespread distribution that is consistent with the multitude of biologic effects that are mediated by this receptor type. B2 receptors belong to the G protein–coupled family of receptors. Receptor binding sets in motion multiple signal transduction
events, including calcium mobilization, chloride transport, formation of nitric oxide, and activation of phospholipase C, phospholipase A2, and adenylyl cyclase. Metabolism of Kinins Kinins are metabolized rapidly (half-life < 15 seconds) by nonspecific exopeptidases or endopeptidases, commonly referred to as kininases. Two plasma kininases have been well characterized. Kininase I, apparently synthesized in the liver, is a carboxypeptidase that releases the carboxyl terminal arginine residue. Kininase II is present in plasma and vascular endothelial cells throughout the body. It is identical to angiotensin-converting enzyme (ACE, peptidyl dipeptidase), discussed above. Kininase II inactivates kinins by cleaving the carboxyl terminal dipeptide phenylalanyl-arginine. Like angiotensin I, bradykinin is almost completely hydrolyzed during a single passage through the pulmonary vascular bed. Drugs Affecting the Kallikrein-Kinin System Drugs that modify the activity of the kallikrein-kinin system are available, though none are in wide clinical use. Considerable effort has been directed toward developing kinin receptor antagonists, since such drugs have considerable therapeutic potential as anti-inflammatory and antinociceptive agents. Competitive antagonists of both B1 and B2 receptors are available for research use. Examples of B1 receptor antagonists are the peptides [Leu8-des-Arg9]bradykinin and Lys[Leu8-des Arg9]bradykinin. Nonpeptide B1 receptor antagonists are not yet available. The first B2 receptor antagonists to be discovered were also peptide derivatives of bradykinin. These first-generation antagonists were used extensively in animal studies of kinin receptor pharmacology. However, their half-life is short, and they are almost inactive on the human B2 receptor. Icatibant is a second generation B2 receptor antagonist. It is orally active, potent, and selective, has a long duration of action (> 60 minutes), and displays high B2 receptor affinity in humans and all other species in which it has been tested. Icatibant has been used extensively in animal studies to block exogenous and endogenous bradykinin and in human studies to evaluate the role of kinins in pain, hyperalgesia, and inflammation. Recently, a third generation of B2 receptor antagonists was developed; examples are FR 173657, FR 172357, and NPC 18884. These antagonists block both human and animal B2 receptors and are orally active. They have been reported to inhibit bradykinin-induced bronchoconstriction in guinea pigs, carrageenin-induced inflammatory responses in rats, and capsaicin-induced nociception in mice. The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. There is evidence that by acting on B2 receptors, bradykinin may play a beneficial, protective role in cardiovascular disease. Selective B2 agonists are available and have been shown to be effective in some animal models of human cardiovascular disease. These drugs may have potential for the treatment of hypertension and myocardial hypertrophy. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides >
Vasopressin Vasopressin (antidiuretic hormone, ADH) plays an important role in the long-term control of blood pressure through its action on the kidney to increase water reabsorption. This and other aspects of the physiology of vasopressin are discussed in Chapter 15: Diuretic Agents and Chapter 37: Hypothalamic & Pituitary Hormones and will not be reviewed here. Vasopressin also plays an important role in the short-term regulation of arterial pressure by its vasoconstrictor action. It increases total peripheral resistance when infused in doses less than those required to produce maximum urine concentration. Such doses do not normally increase arterial pressure because the vasopressor activity of the peptide is buffered by a reflex decrease in cardiac output. When the influence of this reflex is removed, eg, in shock, pressor sensitivity to vasopressin is greatly increased. Pressor sensitivity to vasopressin is also enhanced in patients with idiopathic orthostatic hypotension. Higher doses of vasopressin increase blood pressure even when baroreceptor reflexes are intact. Vasopressin Receptors & Antagonists Three subtypes of vasopressin receptors have been identified. V1a receptors mediate the vasoconstrictor action of vasopressin; V1b receptors potentiate the release of ACTH by pituitary corticotropes; and V2 receptors mediate the antidiuretic action. V1a effects are mediated by activation of phospholipase C, formation of inositol trisphosphate, and increased intracellular calcium concentration. V2 effects are mediated by activation of adenylyl cyclase. Vasopressin-like peptides selective for either vasoconstrictor or antidiuretic activity have been synthesized. The most specific V1 vasoconstrictor agonist synthesized to date is [Phe2, Ile3, Orn8]vasotocin. Selective V2 antidiuretic analogs include 1-deamino[D-Arg8]arginine vasopressin (dDAVP) and 1-deamino[Val4,D-Arg8]arginine vasopressin (dVDAVP). Specific antagonists of the vasoconstrictor action of vasopressin are also available. The peptide antagonist [1-( -mercapto- , -cyclopentamethylenepropionic acid)-2-(O-methyl)tyrosine] arginine vasopressin also has antioxytocic activity but does not antagonize the antidiuretic action of vasopressin. Recently, nonpeptide, orally active V1a receptor antagonists have been discovered, examples being OPC-21268 and SR-49059 (Thibonnier et al, 2001). The vasopressor antagonists have been particularly useful in revealing the important role that vasopressin plays in blood pressure regulation in situations such as dehydration and hemorrhage. They have potential for the treatment of hypertension and heart failure. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Natriuretic Peptides Synthesis & Structure The atria and other tissues of mammals contain a family of peptides with natriuretic, diuretic, vasorelaxant and other properties. The family consists of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The structures of the three peptides are similar (Figure 17–5), but there are differences in their biologic effects. ANP is derived from the
carboxyl terminal end of a common precursor termed preproANP which, in humans, is a 151amino-acid peptide. ANP is synthesized primarily in cardiac atrial cells, but small amounts are synthesized in ventricular cells. It is also synthesized by neurons in the central and peripheral nervous systems and in the lungs. ANP circulates as a 28-amino-acid peptide with a single disulfide bridge that forms a 17-residue ring. Figure 17–5.
Structures of the atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Sequences common to the peptides are indicated in blue. Several factors increase the release of ANP from the heart, but the most important one appears to be atrial stretch via mechanosensitive ion channels (Thibault et al, 1999). ANP release is also increased by volume expansion, head-out water immersion, changing from the standing to the supine position, and exercise. In each case, the increase in ANP release is probably due to increased atrial stretch. ANP release can also be increased by sympathetic stimulation via 1A-adrenoceptors, endothelins (see below) via the ETA receptor subtype, glucocorticoids, and vasopressin. Finally, plasma ANP concentration increases in various pathologic states, including heart failure, primary aldosteronism, chronic renal failure, and inappropriate ADH secretion syndrome.
Administration of ANP produces prompt and marked increases in sodium excretion and urine flow. Glomerular filtration rate increases, with little or no change in renal blood flow, so that the filtration fraction increases. The ANP-induced natriuresis is apparently due to both the increase in glomerular filtration rate and a decrease in proximal tubular sodium reabsorption. ANP also inhibits the secretion of renin, aldosterone, and vasopressin; these changes may also increase sodium and water excretion. Finally, ANP decreases arterial blood pressure. This hypotensive action is due to vasodilation, which results from stimulated particulate guanylyl cyclase activity, increased cGMP levels, and decreased cytosolic free calcium concentration. ANP also reduces sympathetic tone to the peripheral vasculature and antagonizes the vasoconstrictor action of angiotensin II and other vasoconstrictors. These actions may contribute to the hypotensive action of the peptide. There is considerable evidence that ANP participates in the physiologic regulation of sodium excretion and blood pressure. For example, suppression of ANP production or blockade of its action impairs the natriuretic response to volume expansion, and increases blood pressure. BNP was originally isolated from porcine brain but, like ANP, it is synthesized primarily in the heart. It exists in two forms, having either 26 or 32 amino acids (Figure 17–5). Like ANP, the release of BNP appears to be volume-related; indeed, the two peptides may be co-secreted. BNP exhibits natriuretic, diuretic, and hypotensive activities similar to those of ANP but circulates at a lower concentration. CNP consists of 22 amino acids (Figure 17–5). It is located predominantly in the central nervous system but is also present in several tissues including the vascular endothelium, kidneys, and intestine. It has not been found in significant concentrations in the circulation. CNP has less natriuretic and diuretic activity than ANP and BNP but is a potent vasodilator. Its physiologic role is unclear. Pharmacodynamics & Pharmacokinetics The biologic actions of the natriuretic peptides are mediated through association with specific highaffinity receptors located on the surface of the target cells. Three receptor subtypes termed ANPA, ANPB, and ANPC have been identified. The ANPA receptor consists of a 120 kDa protein; its primary ligands are ANP and BNP. The ANPB receptor is similar in structure to the ANPA receptor, but its primary ligand appears to be CNP. The ANPA and ANPB receptors, but not the ANPC receptor, are coupled to guanylyl cyclase. The natriuretic peptides have a short half-life in the circulation. They are metabolized in the kidneys, liver, and lungs by the neutral endopeptidase NEP 24.11. Inhibition of this endopeptidase results in increases in circulating levels of the natriuretic peptides, natriuresis, and diuresis. The peptides are also removed from the circulation by binding to ANPC receptors in the vascular endothelium. This receptor binds the three natriuretic peptides with equal affinity. The receptor and bound peptide are internalized, the peptide is degraded enzymatically, and the receptor is returned to the cell surface. Administration of BNP as nesiritide (see Chapter 13: Drugs Used in Heart Failure) in patients with severe heart failure increases sodium excretion and improves hemodynamics. However, the peptide has to be given by constant intravenous infusion. A more promising approach may be the use of drugs that inhibit the neutral endopeptidase responsible for the breakdown of ANP. This is discussed below under Vasopeptidase Inhibitors. Pathophysiology
Patients with heart failure have high plasma levels of ANP and BNP, which have emerged as important diagnostic and prognostic markers in this condition. Thus, plasma ANP concentration has been shown to be closely correlated with the New York Heart Association functional class of symptomatic heart failure (Boomsma, 2001). Through the actions described above, the peptides reduce salt and water retention. However, renal responsiveness to the peptides decreases as heart failure worsens. The natriuretic peptides may also play a role in preventing the development of hypertension. For example, studies in experimental animals have identified an important role of the peptides in helping prevent mineralocorticoid-induced and salt-induced hypertension. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Vasopeptidase Inhibitors Vasopeptidase inhibitors are a new class of cardiovascular drugs that inhibit two metalloprotease enzymes, NEP 24.11 and ACE. They thus simultaneously increase the levels of natriuretic peptides and decrease the formation of angiotensin II. As a result, they enhance vasodilation, reduce vasoconstriction, and increase sodium excretion, in turn reducing peripheral vascular resistance and blood pressure. Recently developed vasopeptidase inhibitors include omapatrilat, sampatrilat, and fasidotrilat. Of these, omapatrilat is at the most advanced stage of clinical development. It lowers blood pressure in animal models of hypertension as well as in hypertensive patients and improves cardiac function in patients with heart failure. Unfortunately, omapatrilat causes a significant incidence of angioedema in addition to cough and dizziness. Nevertheless, combined inhibition of neutral endopeptidase NEP 24.11 and ACE with this new class of drugs may be a promising approach to treat cardiovascular disease and further clinical trials are underway. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Endothelins The endothelium is the source of a variety of substances with vasodilator (PGI2 and nitric oxide) and vasoconstrictor activities. The latter include the endothelin family, potent vasoconstrictor peptides that were first isolated from aortic endothelial cells. Biosynthesis, Structure, & Clearance Three isoforms of endothelin have been identified: the originally described endothelin (ET-1) and two similar peptides, ET-2 and ET-3. Each isoform is a product of a different gene and is synthesized as a prepro form that is processed to a propeptide and then to the mature peptide. Processing to the mature peptides occurs through the action of endothelin-converting enzyme. Each endothelin is a 21-amino-acid peptide containing two disulfide bridges (Figure 17–6). Figure 17–6.
Structures of the endothelin peptides endothelin-1, endothelin-2, and endothelin-3. Sequences different in the three peptides are shown in blue. Endothelins are widely distributed in the body. ET-1 is the predominant endothelin secreted by the vascular endothelium. It is also produced by neurons and astrocytes in the central nervous system and in endometrial, renal mesangial, Sertoli, breast epithelial, and other cells. ET-2 is produced predominantly in the kidneys and intestine, while ET-3 is found in highest concentration in the brain but is also present in the gastrointestinal tract, lungs, and kidneys. Endothelins are present in the blood but in low concentration; they apparently act locally in a paracrine or autocrine fashion rather than as circulating hormones. The expression of the ET-1 gene is increased by growth factors and cytokines, including transforming growth factor- (TGF- ) and interleukin 1 (IL-1), vasoactive substances including angiotensin II and vasopressin, and mechanical stress. Expression is inhibited by nitric oxide, prostacyclin, and atrial natriuretic peptide. Clearance of endothelins from the circulation is rapid, and involves both enzymatic degradation by NEP 24.11 and clearance by the ETB receptor. Actions Endothelins exert widespread actions in the body. In particular, they cause dose-dependent vasoconstriction in most vascular beds. Intravenous administration of ET-1 causes a rapid and transient decrease in arterial blood pressure followed by a prolonged increase. The depressor response results from release of prostacyclin and nitric oxide from the vascular endothelium, while the pressor response is due to direct constriction of vascular smooth muscle. Endothelins also exert direct positive inotropic and chronotropic actions on the heart and are potent coronary vasoconstrictors. They act on the kidneys to cause vasoconstriction and decrease glomerular
filtration rate and sodium and water excretion. In the respiratory system, they cause potent constriction of tracheal and bronchial smooth muscle. Endothelins interact with several endocrine systems, increasing the secretion of renin, aldosterone, vasopressin, and atrial natriuretic peptide. They exert a variety of actions on the central and peripheral nervous systems, the gastrointestinal system, the liver, the urinary tract, the male and female reproductive systems, the eye, the skeletal system, and the skin. Finally, ET-1 is a potent mitogen for vascular smooth muscle cells, cardiac myocytes, and glomerular mesangial cells. Endothelin receptors are present in many tissues and organs, including the blood vessel wall, cardiac muscle, central nervous system, lung, kidney, adrenal, spleen, and intestine. Two receptor subtypes, termed ETA and ETB, have been cloned and sequenced. ETA receptors have a high affinity for ET-1 and a low affinity for ET-3 and are located on smooth muscle cells, where they mediate vasoconstriction. ETB receptors have approximately equal affinities for ET-1 and ET-3 and are located on vascular endothelial cells, where they mediate release of PGI2 and nitric oxide. Both receptor subtypes belong to the G protein-coupled seven-transmembrane domain family of receptors. The signal transduction mechanisms triggered by binding of ET-1 to its receptors are summarized in Figure 17–7. Major effects include stimulation of phospholipase C, formation of inositol trisphosphate, and release of calcium from the endoplasmic reticulum, which results in vasoconstriction. Stimulation of PGI2 and nitric oxide synthesis results in decreased intracellular calcium concentration and vasodilation. Figure 17–7.
Signal transduction mechanisms mediating the effects of ET-1 on vascular smooth muscle.
Inhibitors of Endothelin Synthesis & Action The endothelin system can be blocked with receptor antagonists and drugs that block endothelinconverting enzyme. Endothelin ETA or ETB receptors can be blocked selectively, or both can be blocked with nonselective ETA-ETB antagonists. An example of a nonselective antagonist is bosentan. This drug is active both intravenously and orally, and blocks both the initial transient depressor (ETB) and the prolonged pressor (ETA) responses to intravenous endothelin. Many orally active endothelin receptor antagonists with increased selectivity have been developed and are available for research use. The formation of endothelins can be blocked by inhibiting endothelin-converting enzyme with phosphoramidon. This compound is not specific for endothelin-converting enzyme, but several potent and more selective inhibitors are now available. The therapeutic potential of these drugs may be similar to that of the endothelin receptor antagonists (see below).
Physiologic & Pathologic Roles of Endothelin: Effects of Endothelin Antagonists Systemic administration of endothelin receptor antagonists or endothelin-converting enzyme inhibitors causes vasodilation and decreases arterial pressure in humans and experimental animals. Intra-arterial administration of the drugs also causes slow-onset forearm vasodilation in humans. These observations provide evidence that the endothelin system participates in the regulation of vascular tone, even under resting conditions. There is increasing evidence that endothelins participate in a variety of cardiovascular diseases, including hypertension, cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease, and myocardial infarction. Endothelins have also been implicated in pulmonary diseases, including asthma and pulmonary hypertension, as well as in several renal diseases. This evidence includes findings of increased endothelin levels in the blood, increased expression of endothelin mRNA in endothelial or vascular smooth muscle cells, and the responses to administration of endothelin antagonists. Endothelin antagonists have considerable potential in the treatment of these diseases. In clinical trials, bosentan and other nonselective antagonists as well as ETA-selective antagonists have produced beneficial effects on hemodynamics and other symptoms in heart failure, pulmonary
hypertension, and essential hypertension. Bosentan is currently approved for use in pulmonary hypertension (see Chapter 11: Antihypertensive Agents). Endothelin antagonists occasionally cause systemic hypotension, increased heart rate, facial flushing or edema, and headaches. Potential gastrointestinal effects include nausea, vomiting, and constipation. Because of their teratogenic effects, ET antagonists are contraindicated in pregnancy. Thus, despite their considerable potential, additional research is needed before these drugs can be considered safe for more extensive clinical use. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Vasoactive Intestinal Peptide Vasoactive intestinal peptide (VIP) is a 28-amino-acid peptide related structurally to secretin and glucagon. Its structure is shown below.
VIP is widely distributed in the central and peripheral nervous systems where it functions as a neurotransmitter or neuromodulator. It is also present in several organs including the gastrointestinal tract, heart, lungs, kidneys, and thyroid gland. Many blood vessels are innervated by VIP neurons. VIP is present in the circulation but does not appear to function as a hormone. VIP exerts marked effects on the cardiovascular system. It produces marked vasodilation in most vascular beds and in this regard is more potent on a molar basis than acetylcholine. In the heart, VIP causes coronary vasodilation and exerts positive inotropic and chronotropic effects. It may thus participate in the regulation of coronary blood flow, cardiac contraction, and heart rate. The effects of VIP are mediated by G protein-coupled receptors, of which two subtypes termed VPAC1 and VPAC2 have been cloned from human tissues. Both subtypes are widely distributed in the central nervous system and in the heart, blood vessels, and other tissues. Binding of VIP to its receptors results in activation of adenylyl cyclase and formation of cAMP, which is responsible for the vasodilation and many other effects of the peptide. Other actions may be mediated by nitric oxide and cGMP. Specific VIP receptor agonists and antagonists are currently available for research use. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Substance P Substance P belongs to the tachykinin family of peptides, which share the common carboxyl terminal sequence Phe-X-Gly-Leu-Met. Other members of this family are neurokinin A and neurokinin B. Substance P is an undecapeptide, while neurokinins A and B are decapeptides. They have the following structures:
The amino terminal of substance P is not essential for biologic activity, but the carboxyl terminal is. The minimum fragment of substance P with significant activity is the carboxyl terminal hexapeptide. Substance P is present in the central nervous system, where it is a neurotransmitter (see Chapter 21: Introduction to the Pharmacology of CNS Drugs), and in the gastrointestinal tract, where it may play a role as a transmitter in the enteric nervous system and as a local hormone (see Chapter 6: Introduction to Autonomic Pharmacology). Substance P exerts a variety of incompletely understood central actions that implicate the peptide in behavior, anxiety, depression, nausea, and emesis. It is a potent vasodilator, producing marked hypotension in humans and several animal species. The vasodilation is mediated by release of nitric oxide from the endothelium. Conversely, substance P causes contraction of venous, intestinal, and bronchial smooth muscle. It also stimulates secretion by the salivary glands and causes diuresis and natriuresis by the kidneys. The actions of substance P and neurokinins A and B are mediated by three G protein-coupled receptors designated NK1, NK2, and NK3. Substance P is the preferred ligand for the NK1 receptor, the predominant tachykinin receptor in the human brain. However, neurokinins A and B also possess considerable affinity for this receptor. In humans, the majority of the central and peripheral effects of substance P are mediated by NK1 receptors. Several nonpeptide NK1 receptor antagonists have been developed. These compounds are highly selective, orally active, and enter the brain. Recent clinical trials have shown that these antagonists may be useful in treating depression and other disorders, and in preventing chemotherapy-induced emesis. The first of these to be approved for the prevention of chemotherapy-induced nausea and vomiting is aprepitant. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Neurotensin Neurotensin is a tridecapeptide that was first isolated from the central nervous system but subsequently was found to be present in the gastrointestinal tract and in the circulation. It is synthesized as part of a larger precursor that also contains neuromedin N, a six-amino-acid neurotensin-like peptide. Neurotensin and neuromedin N have the following structures:
In the brain, processing of the precursor leads primarily to the formation of neurotensin and neuromedin N; these are released together from nerve endings. In the gut, processing leads mainly to the formation of neurotensin and a larger peptide that contains the neuromedin N sequence at the carboxyl terminal. Both peptides are secreted into the circulation after ingestion of food. Like many other neuropeptides, neurotensin serves a dual function as a neurotransmitter or neuromodulator in the central nervous system and as a local hormone in the periphery. When administered centrally, neurotensin exerts potent effects including hypothermia, antinociception and modulation of dopamine neurotransmission. When administered into the peripheral circulation, it causes vasodilation, hypotension, increased vascular permeability, increased secretion of several anterior pituitary hormones, hyperglycemia, inhibition of gastric acid and pepsin secretion, and inhibition of gastric motility. Three subtypes of neurotensin receptors designated NT1, NT2, and NT3 have been cloned. NT1 and NT2 receptors belong to the G protein-coupled superfamily; NT3 receptors are structurally different. Neurotensin agonists that cross the blood-brain barrier have been developed and have potential as potential therapeutic agents for diseases such as schizophrenia and Parkinson's disease (McMahon, 2002). Neurotensin receptors can be blocked with the nonpeptide antagonists SR142948A and SR48692. SR142948A is a potent antagonist of the hypothermia and analgesia produced by centrally administered neurotensin. It also blocks the cardiovascular effects of systemic neurotensin. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Calcitonin Gene-Related Peptide Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides, which also includes calcitonin, adrenomedullin (see below) and amylin. CGRP consists of 37 amino acids and displays approximately 30% structural homology with salmon calcitonin. Like calcitonin, CGRP is present in large quantities in the C cells of the thyroid gland. It is also distributed widely in the central and peripheral nervous systems, in the cardiovascular system, the gastrointestinal tract, and the urogenital system. CGRP is found with substance P (see above) in some of these regions and with acetylcholine in others. When CGRP is injected into the central nervous system, it produces a variety of effects, including hypertension and suppression of feeding. When injected into the systemic circulation, the peptide causes hypotension and tachycardia. The hypotensive action of CGRP results from the potent vasodilator action of the peptide; indeed, CGRP is the most potent vasodilator yet discovered. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides >
Adrenomedullin Adrenomedullin is a 52-amino-acid peptide that was discovered in human adrenal medullary pheochromocytoma tissue. Like CGRP, it is a member of the calcitonin family of peptides. Adrenomedullin is present in several organs including the adrenals, lungs, heart, vascular tissue, and kidneys. It also circulates in the blood. In animals, adrenomedullin dilates resistance vessels in the kidney, brain, lung, hind limbs, and mesentery, resulting in a marked, long-lasting hypotension. The hypotension in turn causes reflex increases in heart rate and cardiac output. Adrenomedullin also acts on the kidneys to increase sodium excretion, and exerts several endocrine effects including inhibition of aldosterone and insulin secretion. Finally it acts on the central nervous system to increase sympathetic outflow. These diverse actions of adrenomedullin are mediated both by CGRP receptors and unique adrenomedullin receptors, the properties of which are incompletely defined. The major second messenger for both receptors is cAMP. Circulating adrenomedullin levels increase during intense exercise. Levels are also elevated in patients with hypertension, as well as in patients with renal failure, heart failure, and septic shock. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Neuropeptide Y Neuropeptide Y is a member of the family that also includes peptide YY and pancreatic polypeptide. Each peptide consists of 36 amino acids. The amino acid sequence of neuropeptide Y is shown below.
Neuropeptide Y is one of the most abundant neuropeptides in both the central and peripheral nervous systems. In the sympathetic nervous system, neuropeptide Y is frequently localized in noradrenergic neurons and apparently functions both as a vasoconstrictor and as a cotransmitter with norepinephrine. Peptide YY and pancreatic polypeptide are both gut endocrine peptides. Neuropeptide Y produces a variety of central nervous system effects, including increased feeding (it is one of the most potent orexigenic molecules in the brain), hypotension, hypothermia, and respiratory depression. Other effects include vasoconstriction of cerebral blood vessels, positive chronotropic and inotropic actions on the heart, and hypertension. The peptide is a potent renal vasoconstrictor and suppresses renin secretion, but can cause diuresis and natriuresis. Prejunctional actions include inhibition of transmitter release from sympathetic and parasympathetic nerves; vascular actions include direct vasoconstriction, potentiation of the action of vasoconstrictors, and inhibition of the action of vasodilators. These diverse effects are mediated by multiple receptors designated Y1 through Y6. All receptors except Y3 have been cloned and shown to be G protein-coupled receptors coupled to mobilization of Ca2+ and inhibition of adenylyl cyclase. Y1 and Y2 receptors are of major importance in the
cardiovascular and other peripheral effects of the peptide. Y4 receptors have a high affinity for pancreatic polypeptide and may be a receptor for this peptide rather than for neuropeptide Y. Y5 receptors are found mainly in the central nervous system and may be involved in the control of food intake. Y6 receptors do not appear to contribute significantly to the physiologic effects of neuropeptide Y in humans. Selective nonpeptide neuropeptide Y receptor antagonists are now available. The first nonpeptide Y1 receptor antagonist, BIBP3226, is also the most thoroughly studied. In animal models, it blocks the vasoconstrictor and pressor responses to neuropeptide Y. It has a short half-life in vivo. Structurally related Y1 antagonists include BIB03304 and H 409/22, which has been tested in humans. SR120107A and SR120819A are orally active Y1 antagonists and have a long duration of action. BIIE0246 is the first nonpeptide antagonist selective for the Y2 receptor. These antagonists have been useful in analyzing the role of neuropeptide Y in cardiovascular regulation. It now appears that the peptide is not important in the regulation of hemodynamics under resting conditions, but may be of increased importance in cardiovascular disorders including hypertension and heart failure. Other studies have implicated neuropeptide Y in feeding disorders, seizures, anxiety, and diabetes, and Y1 and Y5 receptor antagonists have potential as anti-obesity agents (Parker, 2002). Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Urotensin Urotensin II was originally identified in fish, but isoforms are now known to be present in mammalian species including the mouse, rat, pig, and human. The structure of human urotensin II is shown below.
There are species differences in the structure of urotensin II but the cyclic hexapeptide is conserved in all known isoforms. Major sites of urotensin II expression in humans are the brain, spinal cord, and kidneys. The kidneys may be the major source of circulating urotensin II. In vitro, urotensin II is a potent constrictor of vascular smooth muscle; its activity depends on the type of blood vessel and the species from which it was obtained. Vasoconstriction occurs primarily in arterial vessels, where urotensin II can be more potent than endothelin 1, making it the most potent known vasoconstrictor. In vivo, urotensin II has complex hemodynamic effects, the most prominent being regional vasoconstriction and cardiac depression. The extent to which the peptide is involved in the regulation of vascular tone and blood pressure in humans is not clear; recent studies have produced conflicting results. The actions of urotensin II are mediated by G proteincoupled receptors that are widely distributed in the brain, spinal cord, heart, vascular smooth muscle, skeletal muscle, and pancreas. Some effects of the peptide including vasoconstriction are mediated by the phospholipase C/IP3/DAG signal transduction pathway. It has been reported that the expression of urotensin II is upregulated in the heart of humans with end-stage heart failure, but it is not clear if the increase was a cause or consequence of the disease.
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides > Preparations Available1 Aprepitant (Emend) Oral: 80, 125 mg capsules Bosentan (Tracleer) Oral: 62.5, 125 mg tablets 1
Preparations of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists are found in Chapter 11: Antihypertensive Agents; preparations of vasopressin are found in Chapter 37: Hypothalamic & Pituitary Hormones. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 17. Vasoactive Peptides >
Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds > The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds: Introduction The eicosanoids are oxygenation products of polyunsaturated long chain fatty acids. They are ubiquitous in the animal kingdom and are also found—together with their precursor oils—in a variety of plants. They constitute a very large family of compounds that are not only highly potent but also display an extraordinarily wide spectrum of biologic activity. Because of their biologic activity, the eicosanoids, their specific receptor and enzyme inhibitors, and their plant and fish oil precursors have great therapeutic potential. Their short half-lives—seconds to minutes—make special delivery systems or synthesis of stable analogs mandatory for their clinical use. Arachidonic Acid & Other Polyunsaturated Precursors Arachidonic acid is the most abundant and the most important of the precursors of the eicosanoids. Arachidonic acid is a 20-carbon (C20) fatty acid that contains four double bonds beginning at the omega-6 position to yield a 5,8,11,14-eicosatetraenoic acid (designated C20:4–6). For eicosanoid synthesis to occur, arachidonate must first be released or mobilized from membrane phospholipids by one or more lipases of the phospholipase A2 (PLA2) type (Figure 18–1). At least three phospholipases mediate arachidonate release from membrane lipids: cardiac PLA2 (cPLA2), cytosolic PLA2, and secretory PLA2. In addition, arachidonate is also released by a combination of phospholipase C and diglyceride lipase. These lipase pathways are interdicted by corticosteroids. The precise mechanisms are still conjectural.
Figure 18–1.
Pathways of arachidonic acid release and metabolism. Following mobilization, arachidonic acid is oxygenated by four separate routes: the cyclooxygenase (COX), lipoxygenase, P450 epoxygenase, and isoprostane pathways (Figure 18–1). A number of factors determine the type of eicosanoid synthesized: (1) the species, (2) the type of cell, and (3) the cell's particular phenotype. The pattern of eicosanoids synthesized also frequently reflects (4) the manner in which the cell is stimulated. Finally, an important factor governing the pattern of eicosanoid release is (5) the nature of the precursor polyunsaturated fatty acid that has been esterified in specific membrane phospholipids. For example, homo- -linoleic acid (C20:3–6), which is trienoic, yields products that differ from those derived from arachidonate (C20:4–6), which has four double bonds. Similarly, the products derived from eicosapentaenoic acid (C20:5–3), which has five double bonds, are also quantitatively different. This is the basis for using as nutritional supplements in humans the structurally different fatty acids obtained from cold water fish or from plants. An example of the significance of the polyunsaturated fatty acid precursors is evident when one considers thromboxane A (TXA) derived from the COX pathway. TXA2 is synthesized from arachidonate, a tetraenoic acid and is a powerful vasoconstrictor and aggregator of platelets. However 5,8,11,14,17-eicosapentaenoic acid yields TXA3, which is relatively inactive. In theory, dietary eicosapentaenoate substitution for arachidonate should minimize thrombotic events due to the displacement of tetraenoic arachidonate in the membrane by a pentaenoic acid.
Synthesis of Eicosanoids Products of Prostaglandin Endoperoxide Synthases (Cyclooxygenases) Two unique COX isozymes convert arachidonic acid into prostaglandin endoperoxide. PGH synthase-1 (COX-1) is constitutively expressed, ie, it is always present. In contrast, PGH synthase-2 (COX-2) is inducible, ie, its expression varies markedly depending on the stimulus. The two isozymes also differ in function in that COX-1 is widely distributed and has "housekeeping" functions, eg, gastric cytoprotection. Two-fold to four-fold increases occur following humoral stimulation. In contrast, COX-2 is an immediate early response gene product in inflammatory and immune cells and expression is stimulated ten-fold to eighteen-fold by growth factors, tumor promoters, and cytokines. Lipopolysaccharide (endotoxin) is particularly potent in this respect. However, COX-2 is also involved in normal renal development and vascular prostacyclin production. Several additional COX isoforms have been described recently (Chandrasekharan, 2002). The synthases are important because it is at this step that the nonsteroidal anti-inflammatory drugs (NSAIDs) exert their therapeutic effects (see Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout). Indomethacin and sulindac are slightly selective for COX-1. Meclofenamate and ibuprofen are approximately equipotent on COX-1 and COX-2, while celecoxib and rofecoxib preferentially inhibit COX-2. The steroidal anti-inflammatory drugs such as dexamethasone can inhibit COX-2 gene expression. Aspirin acetylates and inhibits both enzymes to different extents. Both COXs promote the uptake of two molecules of oxygen by cyclization of arachidonic acid to yield a C9–C11 endoperoxide C15 hydroperoxide (Figure 18–2). This product is PGG2, which is then rapidly modified by the peroxidase moiety of the COX enzyme to add a 15-hydroxyl group that is essential for biologic activity. This product is PGH2. Both endoperoxides are highly unstable. Analogous families—PGH1 and PGH3 and all their subsequent products—are derived from homo- linolenic acid and eicosapentaenoic acid, respectively. Figure 18–2.
Prostaglandin and thromboxane biosynthesis. Compound names are enclosed in boxes. The asterisks indicate that both cyclooxygenase and peroxidase steps are catalyzed by the single enzyme prostaglandin endoperoxide (PGH) synthase. PGH2 then yields the prostaglandins, thromboxane, and prostacyclin by separate pathways. The prostaglandins differ from each other in two ways: (1) in the substituents of the pentane ring (indicated by the last letter, eg, E and F in PGE and PGF) and (2) in the number of double bonds in the side chains (indicated by the subscript, eg, PGE1, PGE2). Several products of the arachidonate series are of current clinical importance. Alprostadil (PGE1) is used for its smooth muscle relaxing
ulcer and in combination with mifepristone for terminating early pregnancies. PGE2 and PGF2 are used in obstetrics. Latanoprost and several similar compounds are topically active PGF2 derivatives used in ophthalmology. Prostacyclin (PGI2, epoprostenol) is synthesized mainly by the vascular endothelium and is a powerful vasodilator and inhibitor of platelet aggregation. In contrast, thromboxane (TXA2) has undesirable properties (aggregation of platelets, vasoconstriction). Therefore TXA2 receptor antagonists and synthesis inhibitors are developed for cardiovascular indications. All the naturally occurring COX products rapidly undergo metabolism by -oxidation, -oxidation, and oxidation of the key 15-hydroxyl group to the corresponding ketone. These inactive metabolites can be determined in blood and urine by immunoassay or mass spectrometry as a measure of the in vivo synthesis of their parent compounds. Products of Lipoxygenase The metabolism of arachidonic acid by the 5-, 12-, and 15-lipoxygenases results in the production of hydroperoxyeicosatetraenoic acids (HPETEs), which rapidly convert to hydroxy derivatives (HETEs) and leukotrienes (Figure 18–3). The most actively investigated leukotrienes are those produced by the 5-lipoxygenase present in inflammatory cells (PMNs, basophils, mast cells, eosinophils, macrophages). This pathway is of great interest since it is associated with asthma and anaphylactic shock. Stimulation of these cells elevates intracellular Ca2+, and releases arachidonate; incorporation of molecular oxygen by 5-lipoxygenase then yields the unstable epoxide leukotriene A4 (LTA4). This intermediate either converts to the dihydroxy leukotriene B4 (LTB4) or conjugates with glutathione to yield leukotriene C4 (LTC4), which undergoes sequential degradation of the glutathione moiety by peptidases to yield LTD4 and LTE4. These three products are called cysteinyl leukotrienes or peptidoleukotrienes. Figure 18–3.
Leukotriene biosynthesis. The asterisks indicate that both the lipoxygenase and dehydrase reactions are driven by the single enzyme 5-lipoxygenase. (GGTP, -glutamyltranspeptidase.) LTC4 and LTD4 are potent bronchoconstrictors and are recognized as the primary components of the slow-reacting substance of anaphylaxis (SRS-A) that is secreted in asthma and anaphylaxis. There are four current approaches to anti-leukotriene drug development: 5-lipoxygenase enzyme inhibitors, leukotriene receptor antagonists, inhibitors of an important membrane-bound 5lipoxygenase activating protein (FLAP), and phospholipase A2 inhibitors. Two selective leukotriene receptor antagonists are currently used for treatment of asthma.
Another group of 5-lipoxygenase products are the lipoxins LXA and LXB. Their biologic roles are still to be defined. Epoxygenase Products Specific isozymes of microsomal P450 monooxygenases convert arachidonic acid to four epoxyeicosatrienoic acids (EETs) (Figure 18–1). These are the 5,6-, 6,9-, 11,12-, and 14,15-oxido products. Each EET has two stereoisomers. These epoxides are unstable and rapidly form the corresponding dihydroxyeicosatrienoic (DHET) acid, eg, 5,6-DHET. Unlike the prostaglan-dins, both the EETs and the DHETs can be incorporated into phospholipids that then act as storage sites. The epoxygenase products are active on smooth muscle cells and in cell signaling pathways and are thought to have important roles in renal function. Isoprostanes The generation of isoprostanes from arachidonic acid is another potentially important pathway. The isoprostanes are prostaglandin stereoisomers. Because prostaglandins have many asymmetric centers, they have a large number of potential stereoisomers. Prostaglandin synthase (COX) is not needed for the formation of the isoprostanes, and aspirin and other nonsteroidal inhibitors of COX should not affect the isoprostane pathway. The primary epimerization mechanism is peroxidation of arachidonate by free radicals. Peroxidation occurs while arachidonic acid is still esterified to the membrane phospholipids. Thus, unlike prostaglandins, these stereoisomers are "stored" as part of the membrane. The importance of the isoprostane pathway lies in the relatively large amounts of these products (ten-fold greater in blood and urine than the COX-derived prostaglandins) and their potent vasoconstrictor effects in the renal and other vascular beds. It has been proposed that isoprostanes play an important role in the hepatorenal syndrome. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds > Basic Pharmacology of Eicosanoids Mechanisms & Effects of Eicosanoids Receptor Mechanisms The eicosanoids act in an autocrine and paracrine fashion. These ligands bind to receptors on the cell surface, and pharmacologic specificity is determined by receptor density and type on different cells. A number of the membrane receptors and their subtypes have been cloned. All of these receptors appear to be G protein-linked; properties of the best-studied receptors are listed in Table 18–1. Table 18–1. Some Properties of Prostanoid Membrane Receptors.
Receptor Type
Endogenous Agonist
G protein, Second Smooth Messenger Muscle Tone
Result of Receptor Knockout
DP
PGD2
Gs, inc cAMP
Dec allergic bronchial responses
+/–
EP1
PGE2
Gq, inc IP3, DAG
+
Dec response to colon carcinogens
EP2
PGE2
Gs, inc cAMP
–
Impaired ovulation and fertilization; salt-sensitive HTN, dec bronchodilation to EP2
EP3
PGE2
Gi, Gs, Gq, inc or dec cAMP, IP3, DAG
+/–
Dec febrile response; inc hypotensive response to PGE2
EP4
PGE2
Gs, inc cAMP
–
Patent ductus; dec bone inflammatory resorption response
FP
PGF2
Gq, inc IP3, DAG
+
Loss of labor, delivery
IP
PGI2
Gs, inc cAMP
–
Inc thrombosis, dec pain responses to chemical stimuli
TP
TXA2
Gq, inc IP3, DAG
+
Inc bleeding; dec thrombosis
inc, increased; dec, decreased; HTN, hypertension. Binding of PGI2, PGE1, and PGD2 to their platelet receptors inhibits platelet aggregation by activating adenylyl cyclase. This leads to increased intracellular cAMP levels, which in turn activates specific protein kinases. These kinases phosphorylate internal calcium pump proteins, an action that decreases free intracellular calcium concentration. In contrast, the binding of TXA2 to its specific receptors activates phosphatidylinositol metabolism, leading to the formation of IP3. IP3 causes mobilization of Ca2+ stores and an increase of free intracellular calcium. LTB4 also generates IP3 release and causes activation, degranulation, and superoxide anion generation in polymorphonuclear leukocytes. Subtypes are described for PGE2 receptors (EP1, EP2, EP3, and EP4), each of which activates distinct signaling pathways. EP1 is coupled to activation of phospholipase C, EP2 and EP4 to stimulation of adenylyl cyclase. EP3 appears to have multiple effects depending on concentration. The recent description of isoforms of receptor subtypes with coupling to different G proteins makes the issue of second messenger activation more complex. However this multiplicity of pathways may help clarify seemingly paradoxical experimental results. The contractile effects of eicosanoids on smooth muscle are mediated by the release of calcium, while their relaxing effects are mediated by the generation of cAMP. The effects of eicosanoids on many target systems, including the immune system, can be similarly explained (see below). Many of the eicosanoids' contractile effects on smooth muscle can be inhibited by lowering extracellular calcium or by using calcium channel blocking drugs. Action on nuclear PPAR receptors has also been proposed but the physiologic role of this interaction has not been determined. Effects of Prostaglandins & Thromboxanes
The prostaglandins and thromboxanes have major effects on four types of smooth muscle: airway, gastrointestinal, reproductive, and vascular. Other important targets include platelets and monocytes, kidneys, the central nervous system, autonomic presynaptic nerve terminals, sensory nerve endings, endocrine organs, adipose tissue, and the eye (the effects on the eye may involve smooth muscle). Smooth Muscle Vascular TXA2 is a smooth muscle cell mitogen and is the only eicosanoid that has convincingly been shown to have this effect. The mitogenic effect is potentiated by exposure of smooth muscle cells to testosterone, which up-regulates smooth muscle cell TXA2 receptors. In addition to its mitogenic effect, TXA2 is a potent vasoconstrictor. PGF2 is also a vasoconstrictor (via FP receptors) but is not a mitogen for smooth muscle cells. Another potent vasoconstrictor is 8-epi-PGF2 . In patients with cirrhosis, it is produced in large amounts in the liver and is thought to play a pathophysiologic role as an important vasoconstrictor substance in the hepatorenal syndrome. Vasodilator prostaglandins, especially PGI2 and PGE2, promote vasodilation by increasing cAMP and decreasing smooth muscle intracellular calcium, primarily via IP and EP4 receptors. Vascular prostacyclin is synthesized by both smooth muscle and endothelial cells, with the latter as the major contributor. PGI2 undergoes rapid metabolism in a few seconds to more stable but inactive products. In the microcirculation, PGE2 is an endothelial vasodilator product. Gastrointestinal Tract Most of the prostaglandins and thromboxanes activate gastrointestinal smooth muscle. Longitudinal muscle is contracted by PGE2 (via EP3) and PGF2 (via FP), while circular muscle is contracted strongly by PGF2 and weakly by PGI2, and relaxed by PGE2 (via EP4). Administration of either PGE2 or PGF2 results in colicky cramps (see Clinical Pharmacology of Eicosanoids, below). Airways Respiratory smooth muscle is relaxed by PGD2, PGE1, PGE2, and PGI2 and contracted by TXA2 and PGF2 . Although PGD2 is less well-studied than the other prostaglandins, studies of PGD2 receptor knockout mice suggest an important role of this receptor in asthma. Platelets and Blood Cells Platelet aggregation is markedly affected by eicosanoids. PGE1 and especially PGI2 effectively inhibit aggregation, while TXA2 is a potent platelet aggregator. Platelets release TXA2 during activation and aggregation, suggesting that thrombotic events such as myocardial infarction may result in the release of TXA2. In fact, urinary metabolites of TXA2 increase in patients experiencing a myocardial infarction even if they are receiving low-dosage aspirin. At this aspirin dosage, thromboxane synthesis is significantly inhibited only in platelets. This suggests that other cells may contribute to the increase in TXA2; these other cells may be monocytes, since monocytes have a high capacity for sustained release of TXA2. Neutrophils and lymphocytes synthesize little if any prostaglandins, while monocytes have a substantial capacity for prostaglandin and thromboxane synthesis through both constitutive and inducible COXs. Human eosinophils also seem to have a high capacity for prostaglandin and thromboxane synthesis.
Kidney Both the renal medulla and the renal cortex synthesize prostaglandins, the medulla substantially more than the cortex. The kidney also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides. These compounds play important autoregulatory roles in renal function by modifying renal hemodynamics and glomerular and tubular function. This regulatory role is especially important in marginally functioning kidneys, as shown by the decline in kidney function caused by COX inhibitors in elderly patients and those with renal disease. The major eicosanoid products of the renal cortex are PGE2 and PGI2. Both compounds increase renin release; normally, however, renin release is more directly under 1 adrenoceptor control. The glomeruli synthesize small amounts of TXA2 but this potent vasoconstrictor does not appear to be responsible for regulating glomerular function in healthy humans. PGE1, PGE2, and PGI2 increase glomerular filtration through their vasodilating effects. These prostaglandins also increase water and sodium excretion. The increase in water clearance probably results from an attenuation of the action of antidiuretic hormone on adenylyl cyclase. It is uncertain whether the natriuretic effect is caused by the direct inhibition of sodium resorption in the distal tubule or by increased medullary blood flow. Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity. In the normal kidney, this increases the synthesis of the vasodilator prostaglandins. Therefore, patient response to a loop diuretic will be diminished if a COX inhibitor is administered concurrently (see Chapter 15: Diuretic Agents). TXA2 causes intrarenal vasoconstriction (and perhaps an ADH-like effect), resulting in a decline in renal function. The normal kidney synthesizes only small amounts of TXA2. However, in renal conditions involving inflammatory cell infiltration (such as glomerulonephritis and renal transplant rejection), the inflammatory cells (monocyte-macrophages) release substantial amounts of TXA2. Theoretically, TXA2 synthase inhibitors or receptor antagonists should improve renal function in these patients, but no such drug is clinically available. Hypertension is associated with increased TXA2 and decreased PGE2 and PGI2 synthesis in some animal models, eg, the Goldblatt kidney model. It is not known whether these changes are primary contributing factors or secondary responses. Similarly, increased TXA2 formation has been reported in cyclosporine-induced nephrotoxicity, but no causal relationship has been established. PGE2 may also be involved in renal phosphate excretion, because exogenous PGE2 antagonizes the inhibition of phosphate resorption by parathyroid hormone in the proximal tubule. However, the physiologic role of this eicosanoid may be limited because the proximal tubule, the major site for phosphate transport, produces few prostaglandins. Reproductive Organs Female Reproductive Organs The effects of prostaglandins on uterine function are of great clinical importance. They are discussed below. (See Clinical Pharmacology of Eicosanoids.) Male Reproductive Organs The role of prostaglandins in semen is still conjectural. The major source of these prostaglandins is
the seminal vesicle; the prostate and the testes synthesize only small amounts. Thus, the term prostaglandin (referring to the prostate gland) is now known to be a misnomer. Semen from fertile men contains about 400 g/mL of PGE and PGF and their 19-hydroxy metabolites. There is about 20 times more PGE than PGF in fertile semen, although this ratio varies greatly among individuals. However, within individuals, this ratio remains fairly constant as long as the sperm characteristics are unchanged. The factors that regulate the concentration of prostaglandins in human seminal plasma are not known in detail, but testosterone does promote prostaglandin production. Thromboxane and leukotrienes have not been found in seminal plasma. Men with a low seminal fluid concentration of prostaglandins are relatively infertile. Large doses of aspirin reduce the prostaglandin content of seminal plasma. Smooth muscle–relaxing prostaglandins such as PGE1 enhance penile erection by relaxing the smooth muscle of the corpora cavernosa. (See Clinical Pharmacology of Eicosanoids.) Central and Peripheral Nervous Systems Fever PGE1 and PGE2 increase body temperature, probably via EP3 receptors, especially when administered into the cerebral ventricles. Pyrogens release interleukin-1, which in turn promotes the synthesis and release of PGE2. This synthesis is blocked by aspirin and other antipyretic compounds. Sleep When infused into the cerebral ventricles, PGD2 induces natural sleep (as determined by electroencephalographic analysis) in a number of species, including primates. Neurotransmission PGE compounds inhibit the release of norepinephrine from postganglionic sympathetic nerve endings. Moreover, NSAIDs increase norepinephrine release in vivo, suggesting that the prostaglandins play a physiologic role in this process. Thus, vasoconstriction observed during treatment with COX inhibitors may be due to increased release of norepinephrine as well as to inhibition of the endothelial synthesis of the vasodilators PGE2 and PGI2. Neuroendocrine Organs Both in vitro and in vivo tests have shown that some of the eicosanoids affect the secretion of anterior pituitary hormones. PGE compounds promote the release of growth hormone, prolactin, TSH, ACTH, FSH, and LH. However, endocrine changes reflecting significant release of these hormones have not been reported in patients receiving PGE compounds. LTC4 and LTD4 stimulate LHRH and LH secretion (see below). Bone Metabolism Prostaglandins are abundant in skeletal tissue and are produced by the osteoblasts and the adjacent hematopoietic cells. The major effect of prostaglandins (especially PGE2, acting on EP4 receptors) in vivo is to increase bone turnover, ie, stimulation of bone resorption and formation. Prostaglandins may mediate the effects of mechanical forces on bones and some of the changes that occur in bones with inflammation. Finally, prostaglandins may play a role in the bone loss that
occurs at menopause. Eye PGE and PGF derivatives lower the intraocular pressure. The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway (see Clinical Pharmacology of the Eicosanoids). Effects of Lipoxygenase & Cytochrome P450-Derived Metabolites The actions of lipoxygenases generate compounds that can regulate specific cellular responses important in inflammation and immunity. Cytochrome P450-derived metabolites affect nephron transport functions either directly or via metabolism to active compounds (see below). The biologic functions of the various forms of hydroxy- and hydroperoxyeicosaenoic acids are largely unknown, but their pharmacologic potency is impressive. Blood Cells and Inflammation LTB4 is a potent chemoattractant for neutrophils; LTC4 and LTD4 are potent chemoattractants for eosinophils. These leukotrienes also promote eosinophil adherence, degranulation, and oxygen radical formation. The leukotrienes have been strongly implicated in the pathogenesis of inflammation, especially in chronic diseases such as asthma and inflammatory bowel disease. Lipoxin A seems to exert effects similar to those of LTB4 on neutrophils. Lymphocyte proliferation and differentiation are modified by LTB4. Both lipoxin A and lipoxin B inhibit natural killer cell cytotoxicity. Heart and Smooth Muscle Cardiovascular—1 2(S)-HETE is a potent chemoattractant for smooth muscle cells, causing migration at concentrations as low as 1 fmol/L; it may play a role in myointimal proliferation that occurs after vascular injury such as that caused by angioplasty. Its stereoisomer, 12(R)-HETE, is not a chemoattractant but is a potent inhibitor of the Na+/K+ ATPase in the cornea. LTC4 and LTD4 reduce myocardial contractility and coronary blood flow, leading to cardiac depression. Lipoxin A and lipoxin B seem to exert coronary vasoconstrictor effects. Gastrointestinal Human colonic epithelial cells synthesize LTB4, a chemoattractant for neutrophils. The colonic mucosa of patients with inflammatory bowel disease contains substantially increased amounts of LTB4. Airways The peptidoleukotrienes, particularly LTC4 and LTD4, are potent bronchoconstrictors and cause increased microvascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC4-specific receptors have not been found in human lung tissue, whereas both high- and low-affinity LTD4 receptors are present.
Renal System The roles of leukotrienes and cytochrome P450 products in the human kidney are currently speculative. Recently, the 5,6-epoxide has been shown to be a powerful vasodilator in animal experiments. Another recent discovery is that free radicals attack arachidonic acid-containing phospholipids to yield an 8-epi-PGF2 that has powerful thromboxane-like properties. Synthesis is not blocked by COX inhibitors but can be blocked by antioxidants. This vasoconstrictor, which is present in humans, is thought to be another important mediator causing renal failure in the hepatorenal syndrome. Miscellaneous The effects of these products on the reproductive organs remain to be elucidated. Similarly, actions on the nervous system have been suggested (recent data indicate that 12-HPETE acts as a neurotransmitter in Aplysia neurons), but this has not been confirmed in higher organisms. Very low concentrations of LTC4 increase and higher concentrations of arachidonate-derived epoxides augment LH and LHRH release from isolated rat anterior pituitary cells. Inhibition of Eicosanoid Synthesis Corticosteroids block all the known pathways of eicosanoid synthesis, perhaps by stimulating the synthesis of several inhibitory proteins collectively called annexins or lipocortins. They inhibit phospholipase A2 activity, probably by interfering with phospholipid binding and thus preventing the release of arachidonic acid. The NSAIDs (eg, aspirin, indomethacin, ibuprofen) block both prostaglandin and thromboxane formation by inhibiting COX activity. For example, aspirin is a long-lasting inhibitor of platelet COX and of TXA2 biosynthesis because it irreversibly acetylates the enzyme. Once acetylated, platelet COX cannot be restored via protein biosynthesis because platelets lack a nucleus. The development of selective thromboxane synthase inhibitors and TXA2 receptor antagonists has required considerable effort. The resulting compounds, eg, sulotroban, have been useful for characterizing TXA2-related effects in vitro and in vivo. They are being tested in the treatment of thromboembolism, pulmonary hypertension, and preeclampsia-eclampsia. Selective inhibitors of the lipoxygenase pathway are also mainly investigational. With a few exceptions, NSAIDs do not inhibit lipoxygenase activity at concentrations that markedly inhibit COX activity. In fact, by preventing arachidonic acid conversion via the COX pathway, NSAIDs may cause more substrate to be metabolized through the lipoxygenase pathways, leading to an increased formation of the inflammatory leukotrienes. Even among the COX-dependent pathways, inhibiting the synthesis of one derivative may increase the synthesis of an enzymatically related product. Therefore, researchers are attempting to develop drugs that inhibit both COX and lipoxygenase. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds > Clinical Pharmacology of Eicosanoids Several approaches have been used in the clinical application of eicosanoids. First, stable oral or parenteral long-acting analogs of the naturally occurring prostaglandins have been developed.
Several such compounds have been approved for clinical use overseas and are being introduced in the USA (Figure 18–4). Second, enzyme inhibitors and receptor antagonists have been developed to interfere with the synthesis or effects of the "pathologic" eicosanoids (ie, thromboxanes and leukotrienes). For example, knowledge of eicosanoid synthesis and metabolism has led to the development of new NSAIDs that inhibit COX (especially COX-2), with improved pharmacokinetic and pharmacodynamic characteristics. One objective, described earlier, is to develop dual inhibitors that block both the COX (especially COX-2) and lipoxygenase pathways. Another goal is to decrease gastrointestinal and renal toxicity. Third, dietary manipulation—to change the polyunsaturated fatty acid precursors in the cell membrane phospholipids and so change eicosanoid synthesis—is used extensively in over-the-counter products and in diets emphasizing increased consumption of cold water fish. Figure 18–4.
Chemical structures of some prostaglandins and prostaglandin analogs currently in clinical use. Female Reproductive System The physiologic role of prostaglandins in reproduction has been intensively studied since the discovery of prostaglandins in the seminal plasma of primates and sheep. It has been suggested that
the prostaglandins in seminal plasma facilitate blastocyst implantation or egg transport and that uterine secretion of prostaglandins causes luteolysis. The latter is not true in humans but appears to be true in cattle and pigs. This finding has led to the marketing of veterinary preparations of PGF2 and its analogs for synchronizing ovulation in animals. Abortion PGE2 and PGF2 have potent oxytocic actions. The ability of the E and F prostaglandins and their analogs to terminate pregnancy at any stage by promoting uterine contractions has been adapted to routine clinical use. Many studies worldwide have established that prostaglandin administration efficiently terminates pregnancy. The drugs are used for first- and second-trimester abortion and for priming or ripening the cervix before abortion. These prostaglandins appear to soften the cervix by increasing proteoglycan content and changing the biophysical properties of collagen. Early studies found that intravenous PGE2 and PGF2 produced abortion in about 80% of cases. The success rate is dependent on the dose, the duration of the infusion, and parity of the woman. Dose-limiting adverse effects include vomiting, diarrhea, fever, and bronchoconstriction. Hypotension, hypertension, syncope, dizziness, and flushing can occur and may be related to the vasomotor and vasovagal effects of PGE2. In current practice, dinoprostone, a synthetic preparation of PGE2, is administered vaginally for oxytocic use. In the USA, it is approved for inducing abortion in the second trimester of pregnancy, for missed abortion, for benign hydatidiform mole, and for ripening of the cervix for induction of labor in patients at or near term. Dinoprostone stimulates the contraction of the uterus throughout pregnancy. As the pregnancy progresses, the uterus increases its contractile response, and the contractile effect of oxytocin is potentiated as well. Dinoprostone also directly affects the collagenase of the cervix, resulting in softening. The vaginal dose enters the maternal circulation, and a small amount is absorbed directly by the uterus via the cervix and the lymphatic system. Dinoprostone is metabolized in local tissues and on the first pass through the lungs (about 95%). The metabolites are mainly excreted in the urine. The plasma half-life is 2.5–5 minutes. For the induction of labor, dinoprostone is available either as a gel (0.5 mg PGE2) or as a controlled-release formulation (10 mg PGE2) that releases PGE2 in vivo at a rate of about 0.3 mg/h over 12 hours. An advantage of the controlled-release formulation is a lower incidence of gastrointestinal side effects (< 1%). A further advantage of this delivery system is that the medication is contained within a vaginal insert that can be retrieved at any time. For abortifacient purposes, the recommended dosage is a 20 mg dinoprostone vaginal suppository repeated at 3- to 5-hour intervals depending on the response of the uterus. The mean time to abortion is 17 hours, but in more than 25% of cases the abortion is incomplete and requires additional intervention. For softening of the cervix at term, the preparations used are either a single vaginal insert containing 10 mg PGE2 or a vaginal gel containing 0.5 mg PGE2 administered every 6 hours. The softening of the cervix for induction of labor substantially shortens the time to onset of labor and the delivery time. The use of PGE analogs for "menstrual regulation" or very early abortions—within 1–2 weeks after the last menstrual period—has been explored extensively. There are two problems: prolonged
vaginal bleeding and severe menstrual cramps. Antiprogestins (eg, mifepristone) have been combined with an oral oxytocic prostaglandin (eg, misoprostol) to produce early abortion. This regimen is now available in the USA (see Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists). The ease of use and the effectiveness of the combination have aroused considerable opposition in some quarters. The major toxicities are cramping pain and diarrhea. PGF2 is available for clinical gynecologic use. This drug, carboprost tromethamine (15-methylPGF2 ; the 15-methyl group prolongs the duration of action) was withdrawn from the United States market. Carboprost is used to induce second-trimester abortions and is usually administered as a single 2.5 mg intra-amniotic injection. The abortion is normally completed in less than 20 hours. The most serious adverse effects of this route of administration involve cardiovascular collapse. Most of the reported cases have been diagnosed as anaphylactic shock, but others may have been due to the drug escaping into the circulation and causing severe pulmonary hypertension. In pregnant anesthetized women, PGF2 , 300 g/min intravenously, doubles pulmonary resistance and increases the work of the right side of the heart three-fold. Thus, only minimal amounts of the 40 mg intra-amniotic dose need to reach the circulation to cause cardiovascular effects. This problem may be avoided by instilling the drug under ultrasonic guidance. Intramuscular injection of carboprost tromethamine can also be used to induce abortion. Unlike the one-time intrauterine instillation of dinoprost, carboprost is given repeatedly up to the total dose of 2.6 mg normally required to cause abortion. Intra-amniotic administration has close to a 100% success rate, with fewer and less severe adverse effects than intravenous administration. Facilitation of Labor Numerous studies have shown that PGE2, PGF2 , and their analogs effectively initiate and stimulate labor. However, this is an unlabeled use. There appears to be no difference in the efficacy of the two drugs when they are administered intravenously, but PGF2 is one tenth as potent as PGE2. These agents and oxytocin have similar success rates and comparable induction-to-delivery intervals. The adverse effects of the prostaglandins are moderate, with a slightly higher incidence of nausea, vomiting, and diarrhea than that produced by oxytocin. PGF2 has more gastrointestinal toxicity than PGE2. Neither drug has significant maternal cardiovascular toxicity in the recommended doses. In fact, PGE2 must be infused at a rate about 20 times faster than that used for induction of labor to decrease blood pressure and increase heart rate. PGF2 is a bronchoconstrictor and should be used with caution in persons with asthma; however, neither asthma attacks nor bronchoconstriction have been observed during the induction of labor. Although both PGE2 and PGF2 pass the fetoplacental barrier, fetal toxicity is uncommon. The effects of oral PGE2 administration (0.5–1.5 mg/h) have been compared with those of intravenous oxytocin and oral demoxytocin, an oxytocin derivative, in the induction of labor. Oral PGE2 is superior to the oral oxytocin derivative and in most studies is as efficient as intravenous oxytocin. However, the only available form of PGE2 in the USA at present is dinoprostone for vaginal administration, and by this route of administration the drug is slightly less effective than oxytocin. Vaginal PGE2 is also used to soften the cervix before inducing labor. Oral PGF2 causes too much gastrointestinal toxicity to be useful by this route. Theoretically, PGE2 and PGF2 should be superior to oxytocin for inducing labor in women with preeclampsia-eclampsia or cardiac and renal diseases because, unlike oxytocin, they have no antidiuretic effect. In addition, PGE2 has natriuretic effects. However, the clinical benefits of these
effects have not been documented. In cases of intrauterine fetal death, the prostaglandins alone or with oxytocin seem to cause delivery effectively. In some cases of postpartum bleeding, 15-methylPGF2 will successfully control hemorrhage when oxytocin and methylergonovine fail to do so. Dysmenorrhea Primary dysmenorrhea is attributable to increased endometrial synthesis of PGE2 and PGF2 during menstruation, with contractions of the uterus that lead to ischemic pain. NSAIDs successfully inhibit the formation of these prostaglandins (see Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout) and so relieve dysmenorrhea in 75–85% of cases. Some of these drugs are available over the counter. Aspirin is also effective in dysmenorrhea, but because it has low potency and is quickly hydrolyzed, large doses and frequent administration are necessary. In addition, the acetylation of platelet COX, causing irreversible inhibition of platelet TXA2 synthesis, may have an adverse effect on the amount of menstrual bleeding. Male Reproductive System Intracavernosal injection or urethral suppository therapy with alprostadil (PGE1) is useful in the treatment of erectile dysfunction, especially in spinal cord injury. Doses of 2.5–25 g are used. Penile pain is a frequent side effect that may be related to the algesic effects of PGE derivatives; however, only a few patients discontinue the use due to pain. Prolonged erection and priapism are less frequent side effects that occur in fewer than 4% of patients and are minimized by careful titration to the minimal effective dose. When given by injection, alprostadil may be used as monotherapy or in combination with either papaverine or phentolamine. Cardiovascular System The vasodilator effects of PGE compounds have been studied extensively in hypertensive patients. These compounds also promote sodium diuresis. Practical application will require derivatives with oral activity, longer half-lives, and fewer adverse effects. Pulmonary Hypertension Prostacyclin lowers peripheral, pulmonary, and coronary resistance. It has been used to treat both primary pulmonary hypertension and secondary pulmonary hypertension, which sometimes occurs after mitral valve surgery. A commercial preparation of prostacyclin (epoprostenol) is approved for treatment of primary pulmonary hypertension, in which it appears to improve symptoms and prolong survival. However, because of its extremely short plasma half-life, the drug must be administered as a continuous intravenous infusion through a central line. Several prostacyclin analogs with longer half-lives have been developed and treprostinil was recently approved for use in pulmonary hypertension (Horn, 2002). This drug is administered by continuous subcutaneous infusion. Peripheral Vascular Disease A number of studies have investigated the use of PGE and PGI2 compounds in Raynaud's phenomenon and peripheral atherosclerosis. In the latter case, prolonged infusions have been used to permit remodeling of the vessel wall and to enhance regression of ischemic ulcers. Patent Ductus Arteriosus
Patency of the fetal ductus arteriosus is now generally believed to depend on local PGE2 and PGI2 synthesis. In certain types of congenital heart disease (eg, transposition of the great arteries, pulmonary atresia, pulmonary artery stenosis), it is important to maintain the patency of the neonate's ductus arteriosus before surgery. This is done with alprostadil, PGE1. Like PGE2, PGE1 is a vasodilator and an inhibitor of platelet aggregation, and it contracts uterine and intestinal smooth muscle. Adverse effects include apnea, bradycardia, hypotension, and hyperpyrexia. Because of rapid pulmonary clearance, the drug must be continuously infused at an initial rate of 0.05–0.1 g/kg/min, which may be increased to 0.4 g/kg/min. Prolonged treatment has been associated with ductal fragility and rupture. In delayed closure of the ductus arteriosus, COX inhibitors are often used to inhibit synthesis of PGE2 and PGI2 and so close the ductus. Premature infants in whom respiratory distress develops due to failure of ductus closure can be treated with a high degree of success with indomethacin. This treatment often precludes the need for surgical closure of the ductus. Blood As noted above, eicosanoids are involved in thrombosis because TXA2 promotes platelet aggregation and PGI2 inhibits it. Aspirin inhibits platelet COX to produce a mild clotting defect. The mildness of this defect is supported by the fact that very modest hemostatic defects are noted in patients with diseases involving deficiencies of platelet COX and thromboxane synthase—eg, these patients have no history of increased or decreased bleeding. Blockade of either of these two enzymes inhibits secondary aggregation of platelets induced by ADP, by low concentrations of thrombin and collagen, or by epinephrine. Thus, these platelet enzymes are not necessary for platelet function but may amplify an aggregating stimulus. Epidemiologic studies in the USA and United Kingdom indicate that low doses of aspirin reduce the risk of death due to infarction but may increase overall mortality rates due to hemorrhagic stroke (see Chapter 34: Drugs Used in Disorders of Coagulation). It is now difficult to find patients at risk for thromboembolism—as in orthopedic surgery or angioplasty for coronary artery stenosis—who do not take aspirin. The beneficial effects of aspirin are discussed in greater detail in Chapter 34: Drugs Used in Disorders of Coagulation. Respiratory System PGE2 is a powerful bronchodilator when given in aerosol form. Unfortunately, it also promotes coughing, and an analog that possesses only the bronchodilator properties has been difficult to obtain. PGF2 and TXA2 are both strong bronchoconstrictors and were once thought to be primary mediators in asthma. However, the identification of the peptidoleukotrienes—LTC4, LTD4, and LTE4—expanded the role of eicosanoids as important mediators in asthma and other immune responses. As described in Chapter 20: Drugs Used in Asthma, leukotriene receptor inhibitors (eg, zafirlukast, montelukast) are effective in asthma. A lipoxygenase inhibitor (zileuton) has also been used in asthma but is not as popular as the receptor inhibitors. It remains unclear whether leukotrienes are partially responsible for the acute respiratory distress syndrome. Corticosteroids and cromolyn are also useful in asthma. Corticosteroids inhibit eicosanoid synthesis and thus limit the amounts of eicosanoid mediator available for release. Cromolyn appears to inhibit the release of eicosanoids and other mediators such as histamine and platelet-activating factor from mast cells.
Gastrointestinal System The word "cytoprotection" was coined to signify the remarkable protective effect of the E prostaglandins against peptic ulcers in animals at doses that do not reduce acid secretion. These prostaglandins were independently discovered also to inhibit gastric acid secretion (at higher doses). Since then, numerous experimental and clinical investigations have shown that the PGE compounds and their analogs protect against peptic ulcers produced by either steroids or NSAIDs. Misoprostol is an orally active synthetic analog of PGE1 available in Europe and the USA for ulcer treatment. The FDA-approved indication is for prevention of NSAID-induced peptic ulcers. The drug is administered at a dosage of 200 g four times daily. This and other PGE analogs (eg, enprostil) are cytoprotective at low doses and inhibit gastric acid secretion at higher doses. The adverse effects are abdominal discomfort and occasional diarrhea; both effects are dose-related. More recently, dosedependent bone pain and hyperostosis have been described in patients with liver disease who were given long-term PGE treatment. This adverse effect can be explained by a PGE-induced, EP4mediated acceleration of osteoclast and osteoblast activity. Recurrent calcium oxalate kidney stones were described in the same group of patients. This may be related to PGE-induced hypercalciuria. Gastrointestinal side effects seen in many patients using NSAIDs may be reduced by the recent introduction of selective inhibitors of COX-2 that spare gastric COX-1 so that the natural cytoprotection by locally synthesized PGE2 is undisturbed (see Chapter 36: Nonsteroidal AntiInflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout). Immune System Monocyte-macrophages are the only principal cells of the immune system that can synthesize all the eicosanoids. T and B lymphocytes are interesting exceptions to the general rule that all nucleated cells produce eicosanoids. However, in a B lymphoma cell line, there is non-receptor-mediated uptake of LTB4 and 5-HETE. Interaction between lymphocytes and monocyte-macrophages may cause the lymphocytes to release arachidonic acid from their cell membranes. The arachidonic acid is then used by the monocyte-macrophages for eicosanoid synthesis. In addition to these cells, there is evidence for eicosanoid-mediated cell-cell interaction by platelets, erythrocytes, PMNs, and endothelial cells. The eicosanoids modulate the effects of the immune system, as illustrated by the cell-mediated immune response. As shown in Figure 18–5, PGE2 and PGI2 affect T cell proliferation in vitro as corticosteroids do. T cell clonal expansion is attenuated through inhibition of interleukin-1 and interleukin-2 and class II antigen expression by macrophages or other antigen-presenting cells. The leukotrienes, TXA2, and platelet-activating factor stimulate T cell clonal expansion. These compounds stimulate the formation of interleukin-1 and interleukin-2 as well as the expression of interleukin-2 receptors. The leukotrienes also promote interferon- release and can replace interleukin-2 as a stimulator of interferon- . These in vitro effects of the eicosanoids agree with in vivo findings in animals with acute organ transplant rejection, as described below. Figure 18–5.
Modulation of macrophage and lymphocyte interactions by eicosanoids, platelet-activating factor, and corticosteroids. Corticosteroids, PGE2, and possibly PGI2 inhibit the expression of interleukin1 (IL-1) and its effect on T lymphocytes. Platelet-activating factor (PAF), LTB4, and LTD4 increase IL-1 expression. Similar inhibitory and stimulant effects are exerted on the action of interferon- on the macrophage and on the action of interleukin-2 (IL-2). Agents marked with an asterisk are suspected, but not yet proved, to have the effects indicated. (DR, class II MHC [major histocompatibility complex] receptor; T, T lymphocytes.) (Modified and reproduced, with permission, from Foegh ML, Ramwell PW: PAF and transplant immunology. In: Braquet P [editor]: The Role of Platelet Activating Factor in Immune Disorders. Karger, 1988.) Cell-Mediated Organ Transplant Rejection Acute organ transplant rejection is a cell-mediated immune response. Administration of PGI2 to renal transplant patients has reversed the rejection process in some cases. Experimental in vitro and in vivo data show that PGE2 and PGI2 can attenuate T cell proliferation and rejection, which can also be seen with drugs that inhibit TXA2 and leukotriene formation. In organ transplant patients, urinary excretion of TXB2, a metabolite of TXA2, increases during acute rejection. Corticosteroids, the primary drugs used for treatment of acute rejection due to their effects on lymphocytes, inhibit both phospholipase and COX-2 activity. Inflammation Aspirin has been used to treat arthritis for nearly a century, but its mechanism of action—inhibition of COX activity—was not discovered until 1971. Aspirin and other anti-inflammatory agents that inhibit COX are discussed in Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, DiseaseModifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout. COX-2 appears to be the form of the enzyme associated with cells involved in the inflammatory process. The prostaglandins are not chemoattractants, but the leukotrienes and some of the HETEs (eg, 12HETE) are strong chemoattractants. PGE2 inhibits both antigen-driven and mitogen-induced B
lymphocyte proliferation and differentiation to plasma cells, resulting in inhibition of IgM synthesis. The concomitant elevation of serum IgE and monocyte PGE2 synthesis, seen in patients with severe trauma and patients with Hodgkin's disease, is explained by PGE2 ability to enhance immunoglobulin class switching to IgE. Rheumatoid Arthritis In rheumatoid arthritis, immune complexes are deposited in the affected joints, causing an inflammatory response that is amplified by eicosanoids. Lymphocytes and macrophages accumulate in the synovium, while PMNs localize mainly in the synovial fluid. The major eicosanoids produced by PMNs are leukotrienes, which facilitate T cell proliferation and act as chemoattractants. Human macrophages synthesize the COX products PGE2 and TXA2 and large amounts of leukotrienes. Infection The relationship of eicosanoids to infection is not well defined. The association between the use of the anti-inflammatory steroids and increased risk of infection is well established. However, the NSAIDs do not seem to alter patient responses to infection. Glaucoma Latanoprost, a stable long-acting PGF2 derivative, was the first prostanoid used for glaucoma. The success of latanoprost has stimulated development of similar prostanoids with ocular hypotensive effects, and bimatoprost, travaprost, and unoprostone are now available. These drugs act at the FP receptor and are administered as drops into the conjunctival sac once or twice daily. Adverse effects include irreversible brown pigmentation of the iris and eyelashes, drying of the eyes, and conjunctivitis. Dietary Manipulation of Arachidonic Acid Metabolism Because arachidonic acid is derived from dietary linoleic and -linolenic acids, which are essential fatty acids, the effects of dietary manipulation on arachidonic acid metabolism have been extensively studied. Two approaches have been used. The first adds corn, safflower, and sunflower oils, which contain linoleic acid (C18:2), to the diet. The second approach adds oils containing eicosapentaenoic (C20:5) and docosahexaenoic acids (C22:6), so-called omega-3 fatty acids, from cold water fish. Both types of diet change the phospholipid composition of cell membranes by replacing arachidonic acid with the dietary fatty acids. It has been claimed that the synthesis of both TXA2 and PGI2 is reduced and that changes in platelet aggregation, vasomotor spasm, and cholesterol metabolism follow. As indicated above, there are many possible oxidation products of the different polyenoic acids. It is probably naive to ascribe the effects of dietary intervention reported thus far to such metabolites. Carefully controlled clinical studies will be needed before these questions can be satisfactorily answered. However, subjects on diets containing highly saturated fatty acids clearly show increased platelet aggregation when compared with other study groups. Such diets (eg, in Finland and the USA) are associated with higher rates of myocardial infarction than are more polyunsaturated diets (eg, in Italy).
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds > Preparations Available Nonsteroidal Anti-Inflammatory Drugs Are Listed in Chapter 36: Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout. Alprostadil Penile injection (Caverject, Edex): 5, 10, 20, 40 g sterile powder for reconstitution Penile pellet (Muse): 125, 250, 500, 1000 g Parenteral (Prostin VR Pediatric): 500 g/mL ampules Bimatoprost (Lumigan) Ophthalmic drops: 0.03% solution Carboprost tromethamine (Hemabate) Parenteral: 250 g carboprost and 83 g tromethamine per mL ampules Dinoprostone [prostaglandin E2] (Prostin E2, Prepidil, Cervidil) Vaginal: 20 mg suppositories, 0.5 mg gel, 10 mg controlled release system Epoprostenol [prostacyclin] (Flolan) Intravenous: powder to make 3, 5, 10, 15 g/mL Latanoprost (Xalatan) Topical: 50 g/mL ophthalmic solution Misoprostol (Cytotec) Oral: 100 and 200 g tablets Monteleukast (Singulair) Oral: 5 mg chewable, 10 mg tablets Travaprost (Travatan) Ophthalmic solution: 0.0004% Treprostinil (Remodulin)
Parenteral: 1, 2.5, 5, 10 mg/mL for continuous subcutaneous infusion Unoprostone (Rescula) Ophthalmic solution 0.15% Zafirleukast (Accolate) Oral: 10, 20 mg tablets Zileuton (Zyflo)) Oral: 600 mg tablets
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds >
Chapter 19. Nitric Oxide, Donors, & Inhibitors Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 19. Nitric Oxide, Donors, & Inhibitors > Nitric Oxide, Donors, & Inhibitors: Introduction Nitric oxide (NO) is a gaseous signaling molecule that readily diffuses across cell membranes and regulates a wide range of physiologic and pathophysiologic processes including cardiovascular, inflammation, immune and neuronal functions. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 19. Nitric Oxide, Donors, & Inhibitors > Discovery of Endogenous Nitric Oxide Early observations of the biologic role of endogenously generated NO were made in rodent macrophages and neutrophils: In vitro exposure of these cells to endotoxin lipopolysaccharide released significant amounts of nitrite and nitrate into the cell culture medium. Furthermore, injection of endotoxin in vivo elevated urinary nitrite and nitrate, the two oxidation products of nitric oxide. This nitric oxide was found to originate from oxidation of the guanidino group of Larginine. The second observation was made by Furchgott and Zawadzki in 1980 using isolated vascular smooth muscle preparations. They discovered that following stimulation with acetylcholine or carbachol, the endothelium released a short-lived vasodilator, which—unlike endothelium-derived prostacyclin—was not blocked by cyclooxygenase inhibitors. They named this vasodilator endothelium-derived relaxing factor (EDRF) since it promoted relaxation of precontracted smooth muscle preparations. Other workers confirmed and extended these findings. In 1987, by comparing the pharmacologic and biochemical properties of the suspect molecule, three independent groups reported that EDRF and nitric oxide are the same molecule. It was later reported that other vasodilator molecules may be a part of EDRF, but it appears clear that nitric
oxide provides the major part of its activity. Subsequent studies revealed that nitric oxide was generated by many cells and was, like the eicosanoids (see Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds), found in almost all tissues. The major exogenous donors of nitric oxide (nitrates, nitrites, nitroprusside) have been discussed (see Chapter 11: Antihypertensive Agents and Chapter 12: Vasodilators & the Treatment of Angina Pectoris). Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 19. Nitric Oxide, Donors, & Inhibitors > Biologic Synthesis & Inactivation of Nitric Oxide Synthesis Nitric oxide, written as NO. or simply NO, is a highly diffusible stable gas composed of one atom each of nitrogen and oxygen. It is synthesized by a family of enzymes that are collectively called nitric oxide synthase, NOS (EC 1.14.13.49). Three isoforms of NOS have been identified (Table 19–1). These isoforms are heme-containing flavoproteins employing L-arginine as a substrate and requiring NADPH, flavin adenine dinucleotide, and tetrahydrobiopterin as cofactors. Phosphorylation also has differential regulatory effects on the activity of NOS. For example, phosphorylation significantly reduces the activity of NOS-1, whereas phosphorylation of NOS-3 by a serine-threonine protein kinase activates the enzyme. Furthermore, NOS-2 expression is tightly controlled by several transcription factors. Table 19–1. Properties of the Three Isoforms of Nitric Oxide Synthase (NOS).
Isoform Names Property
NOS-1
NOS-2
NOS-3
Other names
nNOS (neuronal NOS)
iNOS (inducible NOS)
eNOS (endothelial NOS)
Tissue
Neuronal, epithelial cells
Macrophages, smooth muscle Endothelial cells cells
Expression
Constitutive
Transcriptional induction
Constitutive
Calcium requirement
Yes
No
Yes
Chromosome
12
17
7
125–135 kDa
133 kDa
Approximate mass 150–160 kDa
Formation of nitric oxide from L-arginine and several nitric oxide donors is shown in Figure 19–1. Activation of NOS by the influx of extracellular calcium and binding of calmodulin, as in the case of the constitutive enzyme, or following the activation of the inducible NOS (NOS-2) by cytokines, results in the metabolism of L-arginine to L-citrulline and nitric oxide. The conversion of L-arginine to nitric oxide and L-citrulline is inhibited by several arginine competitors such as NG-monomethylL-arginine (below). Some nitric oxide donors, eg, oxygenated nitroprusside, spontaneously generate
such as nitroglycerin, require the presence of a thiol compound such as cysteine. Once generated, nitric oxide interacts with the heme moiety of soluble guanylyl cyclase in the cytoplasm of cells (Figure 19–1, right). This results in allosteric transformation and activation of the enzyme and leads to the formation of 3',5'-cyclic-guanosine monophosphate (cGMP) from GTP. Activation of the soluble guanylyl cyclase by nitric oxide can be inhibited by methylene blue. The affinity of nitric oxide for iron is also responsible for its inhibitory effect on several enzymes by interacting with the iron-sulfur centers of these enzymes. Inhibition of enzymes such as cytochrome P450 by nitric oxide is a major problem in inflammatory liver disease and can be reversed by NO synthase inhibitors. Carbon monoxide, another gaseous compound produced endogenously from the catabolism of heme, shares many of the properties of nitric oxide such as activation of soluble guanylyl cyclase. However, unlike nitric oxide, which has an extra electron, carbon monoxide is a stable molecule in the presence of oxygen. The affinity of nitric oxide for hemoglobin is several orders of magnitude greater than that of carbon monoxide. Nitric oxide undergoes both oxidative and reductive reactions, resulting in the formation of a variety of oxides of nitrogen (Table 19–2). Figure 19–1.
Nitric oxide generation from L-arginine and nitric oxide donors and the formation of cGMP. LNMMA inhibits nitric oxide synthase. Some of the nitric oxide donors such as furoxans and organic nitrates and nitrites require a thiol cofactor such as cysteine or glutathione to form nitric oxide.
Table 19–2. Oxides of Nitrogen.
Name
Symbol Known Function
Nitric oxide
NO
Vasodilator, platelet inhibitor, immune regulator, neurotransmitter
Nitroxyl anion
NO-
Smooth muscle relaxant
Nitrogen dioxide
NO2
Free radical, nitrosating agent, lung irritant
Nitrous oxide
N2O
Anesthetic
Dinitrogen trioxide
N2O3
Nitrosating agent
Dinitrogen tetraoxide N2O4
Nitrosating agent
Nitrite
NO2-
Produce NO at acidic pH
Nitrate
NO3-
Stable oxidation product of NO
Inactivation Nitric oxide is inactivated by heme and by the free radical, superoxide. Thus, scavengers of superoxide anion such as superoxide dismutase may protect nitric oxide, enhancing its potency and prolonging its duration of action. Conversely, interaction of nitric oxide with superoxide may generate the potent tissue-damaging moiety, peroxynitrite (ONOO-), which has a high affinity for sulfhydryl groups and thus inactivates several key sulfhydryl-bearing enzymes. This effect of peroxynitrite is regulated by the cellular content of glutathione. Since glutathione is the major intracellular soluble sulfhydryl-containing compound, factors that regulate the biosynthesis and decomposition of glutathione may have important consequences. Glutathione also interacts with nitric oxide under physiologic conditions to generate Snitrosoglutathione, a more stable form of nitric oxide. Nitrosoglutathione may serve as an endogenous long-lived adduct or carrier of nitric oxide. Vascular glutathione is decreased in diabetes mellitus and atherosclerosis, and this may account for the increased incidence of cardiovascular complications in these conditions. Ischemia followed by reperfusion is another situation in which endothelial function is compromised owing to increased production of free radicals, resulting in reduced nitric oxide formation. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 19. Nitric Oxide, Donors, & Inhibitors > Inhibitors of Nitric Oxide In theory, several methods are available for reducing nitric oxide levels in tissues and thus
inhibiting its actions. Drugs may inhibit the uptake of L-arginine into cells, thus depriving the NOS isoforms of substrate. Other methods include deprivation of the cofactors and calmodulin antagonists; inhibitors of NOS synthesis; inhibitors of binding of arginine to NOS, and scavengers of nitric oxide. The most important thus far have been inhibitors of NOS. Unfortunately, the selectivity of these inhibitors for the individual isoforms is incomplete. Most of these inhibitors are substrate analogs (Table 19–3). Table 19–3. Some Inhibitors of Nitric Oxide Synthesis or Action.
Inhibitor
Mechanism
g
Comment
N –Monomethyl–L–arginine (L–NMMA) NOS inhibition
May act as substrate in some tissues
Ng–Nitro–L–arginine methyl ester (L– NAME)
NOS inhibition
Less selective NOS inhibitor
7–Nitroindazole
NOS inhibition
Markedly selective for NOS–1 in vivo
S–Methylthiocitrulline
NOS inhibition
Partially selective for NOS–1
Heme
Nitric oxide scavenger
Protein inhibitor of NOS
Unknown mechanism
Endogenous inhibitor found in brain
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 19. Nitric Oxide, Donors, & Inhibitors > Effects of Nitric Oxide Nitric oxide has major effects that are mediated by activation of cytoplasmic soluble guanylyl cyclase and stimulated production of cGMP, an important second messenger. In addition, nitric oxide can produce several reactive nitrogen derivatives by interaction with molecular oxygen and superoxide radicals (Table 19–2). These highly unstable molecules react with a variety of proteins, lipids, nucleic acids, and metals (especially iron) in cells (Davis, 2001). The remainder of this chapter discusses some of the second messenger-mediated effects of nitric oxide and the effects of inhibition of its production. Vascular Effects Nitric oxide has a significant effect on vascular smooth muscle tone and blood pressure. As stated previously, it is released by acetylcholine and other endothelium-dependent vasodilators. It may play a role in the normal regulation of vascular tone as suggested by the fact that a reduction of nitric oxide synthesis (caused by knockout mutations, infusion of NOS inhibitors such as L-NMMA, or by injury to the vascular endothelium) increases vascular tone and elevates mean arterial pressure. The effects of vasopressor drugs are increased by inhibition of NOS. As described in Chapter 12: Vasodilators & the Treatment of Angina Pectoris and shown in Figure 12–2, increased cGMP synthesis by guanylyl cyclase results in smooth muscle relaxation.
Apart from being a vasodilator, nitric oxide is also a potent inhibitor of neutrophil adhesion to the vascular endothelium. This is due to the inhibitory effect of nitric oxide on the expression of adhesion molecules on the endothelial surface. The role of nitric oxide in protecting the endothelium has been demonstrated by studies that showed that treatment with nitric oxide donors protects against ischemia- and reperfusion-mediated endothelial dysfunction. Respiratory Disorders Nitric oxide has been shown to improve cardiopulmonary function in adult patients with pulmonary artery hypertension and is approved for this indication (see Preparations Available). It is administered by inhalation. It has also been administered by inhalation to newborns with pulmonary hypertension and acute respiratory distress syndrome. The current treatment for severely defective gas exchange in the newborn is with extracorporeal membrane oxygenation (ECMO), which does not directly affect pulmonary vascular pressures. Nitric oxide inhalation decreases pulmonary arterial pressure and improves blood oxygenation. Thus, when pulmonary resistance is elevated, it is possible to exploit the vasodilator properties of nitric oxide by administering it via inhalation of a few parts per million. Adults with respiratory distress syndrome also appear—in open trials—to benefit from nitric oxide inhalation. Nitric oxide may have an additional role in relaxing airway smooth muscle and thus acting as a bronchodilator. For these reasons, nitric oxide inhalation therapy is being widely tested in both infants and adults with acute respiratory distress syndrome. The adverse effects of this use of nitric oxide are being assessed. Septic Shock As mentioned previously, increased urinary excretion of nitrate, the oxidative product of nitric oxide, is reported in gram-negative bacterial infection. Lipopolysaccharide components from the bacterial wall activate the inducible NOS (NOS-2), resulting in exaggerated hypotension, shock, and possible death. This hypotension is reversed by NOS inhibitors such as L-NMMA (Table 19–3) in humans as well as animal models and by compounds such as methylene blue, which prevent the action of nitric oxide, as well as by scavengers of nitric oxide such as hemoglobin. Furthermore, knockout mice lacking a functional NOS-2 gene are more resistant to endotoxin than wild-type mice. However, there has been no correlation between the hemodynamic effects of the nitric oxide inhibitors and survival rate in gram-negative sepsis thus far. Atherosclerosis Vascular plaque formation in hypercholesterolemia leads to reduced nitric oxide formation and endothelium-dependent vasodilator responses. In vitro, nitric oxide carriers and donors and cGMP analogs inhibit smooth muscle cell proliferation. In animal models, myointimal proliferation following angioplasty can be blocked by feeding arginine, by using nitric oxide donors, by NOS gene transfer, and by nitric oxide inhalation. In addition, nitric oxide may act as an antioxidant, blocking the oxidation of low-density lipoproteins (LDL) and thus preventing the formation of foam cells in the vascular wall. Platelets Abnormal activation of platelets is associated with increased platelet adhesion and aggregation and therefore a higher incidence of thrombotic events. Platelet activation also leads to release of smooth muscle mitogens such as growth factors and thromboxane. Nitric oxide is a potent inhibitor of platelet adhesion and aggregation. Thus, endothelial dysfunction and the associated decrease in nitric oxide generation may result in abnormal platelet function. Platelets also contain both
constitutive and inducible NOS, although to a much lesser extent than endothelial cells. As in vascular smooth muscle, cGMP mediates the protective effect of nitric oxide in platelets. Nitric oxide may have an additional beneficial effect on blood coagulation by enhancing fibrinolysis via an effect on plasminogen. Organ Transplantation Accelerated graft atherosclerosis following organ transplantation is a chronic condition and is a major cause of transplant failure, leading to retransplantation or death. Continuous vascular smooth muscle proliferation occurs within the vasculature of most grafts and is a central event in luminal narrowing. Ischemic and reperfusion injuries at the time of organ harvesting, preservation, and revascularization initiate myointimal proliferation, which is also promoted by the continuous immune response to the allogeneic organ graft. By reducing free radical toxicity under these conditions, nitric oxide may act as a cytoprotective agent, inhibiting platelet and neutrophil aggregation and adhesion to the vascular wall. Dietary L-arginine supplementation increases plasma nitrite and nitrate formation and has been shown to attenuate accelerated graft atherosclerosis. However, excessively high concentrations of nitric oxide may be detrimental during acute organ rejection due to up-regulation of inducible NOS by cytokines; under these circumstances, inhibition of nitric oxide synthesis has been shown to prolong graft survival in experimental animals. The Central Nervous System Nitric oxide has been proposed to have a major role in the central nervous system—as a neurotransmitter, as a modulator of ligand-gated receptors, or both. In addition, nitric oxide probably plays a role in neuronal degeneration in some conditions. The likely cellular targets of nitric oxide in the central nervous system include presynaptic and postsynaptic nerve terminals. Nitric oxide modifies neurotransmitter release in different areas of the brain. Postsynaptic release of nitric oxide following activation of the NMDA receptor may initiate presynaptic transmitter release of glutamate, ie, nitric oxide may function as a retrograde messenger that is synthesized in postsynaptic sites following opening of the Ca2+ channels and activation of NOS. It is proposed that the nitric oxide thus produced rapidly diffuses to the presynaptic nerve terminal where guanylyl cyclase is activated to yield cGMP and thus facilitate transmitter release. In the cerebellum and in neuroblastoma cells, this effect is blocked by NOS inhibitors such as L-NMMA and is enhanced by L-arginine. It has been suggested that nitric oxide (like many other substances) may have a role in short- and long-term potentiating effects on excitatory amino acids in brain development and learning. 7-Nitroindazole, an inhibitor of NOS-1, and L-NAME, a less selective inhibitor of neuronal NOS, have significant antinociceptive effects in humans and animals and 7-nitroindazol reduces the signs of opioid withdrawal and cocaine action in animal models. This inhibitor also reduces cerebral blood flow. Nevertheless, 7-nitroindazole can reduce the size of cerebral infarcts in animal models. In contrast, NOS-3-deficient mice are more susceptible to ischemic cerebral damage. NOS-1 inhibition by 7-nitroindazole also reduces the neurotoxicity of MPTP and MPP+ (see Chapter 28: Pharmacologic Management of Parkinsonism & Other Movement Disorders) in several animal models. It is well known that prolonged NMDA glutamate receptor activation results in degeneration of neurons (excitotoxicity). This has been attributed to a large increase in calcium influx, which activates the calmodulin-dependent NOS-1 and leads to sustained elevation of nitric oxide concentrations. The increase in neurodegeneration caused by excitatory amino acids may be due to enhanced oxygen radical formation since superoxide dismutase has a beneficial effect in
experimental models. The damage may also be mediated by the generation of secondary radicals such as peroxynitrite, which has a high affinity for sulfhydryl-containing enzymes such as calcium ATPase. Inhibition of calcium ATPases by peroxynitrite may in turn lead to enhanced Ca2+ accumulation and associated neurodegeneration. NOS-2 has been implicated in several other degenerative neurologic conditions, eg, Alzheimer's disease, multiple sclerosis, and Huntington's disease. High levels of nitric oxide have also been shown to cause destruction of photoreceptor cells in the retina. This is believed to be due to a prolonged increase in cGMP formation. Finally, nitric oxide and cGMP have been reported to have a role in epileptic seizures. The Peripheral Nervous System Nonadrenergic, noncholinergic (NANC) neurons are widely distributed in peripheral tissues, especially the gastrointestinal and reproductive tracts (see Chapter 6: Introduction to Autonomic Pharmacology). Considerable evidence implicates nitric oxide as a mediator of certain NANC actions, and some NANC neurons appear to release nitric oxide. Penile erection is thought to be caused by the release of nitric oxide from NANC neurons; it is well documented that nitric oxide promotes relaxation of the smooth muscle in the corpora cavernosa—the initiating factor in penile erection—and inhibitors of NOS have been shown to prevent erection caused by pelvic nerve stimulation in the rat. Thus, impotence is a possible clinical indication for the use of a nitric oxide donor, and trials have been carried out with nitroglycerin ointment and the nitroglycerin patch. Another approach is to inhibit the breakdown of cGMP by the phosphodiesterase (PDE isoform 5) present in the smooth muscle of the corpora cavernosa with drugs such as sildenafil (see Chapter 12: Vasodilators & the Treatment of Angina Pectoris). Inflammation Nitric oxide has a role in both acute and chronic inflammation. NOS-3 is involved in the vasodilation associated with acute inflammation. In experimental models of acute inflammation, inhibitors of NOS-3 have a dose-dependent protective effect, suggesting that nitric oxide promotes edema and vascular permeability. Nitric oxide has a detrimental effect in chronic models of arthritis; dietary L-arginine supplementation exacerbates arthritis whereas protection is seen with NOS-2 inhibitors. Psoriasis lesions, airway epithelium in asthma, and inflammatory bowel lesions in humans all demonstrate elevated levels of nitric oxide and NOS-2. Synovial fluid from patients with arthritis contains increased oxidation products of nitric oxide, particularly peroxynitrite. Recent studies have shown that nitric oxide stimulates the synthesis of inflammatory prostaglandins by activating cyclooxygenase isoenzyme II (COX-2). Thus, inhibition of the nitric oxide pathway may have a beneficial effect on inflammatory diseases, including joint diseases. Studies using inhibitors of NOS-2 have shown that nitric oxide is required for maintaining COX-2 gene expression. Nitric oxide also appears to play an important protective role in the body via immune cell function. When challenged with foreign antigens, TH1 cells (see Chapter 56: Immunopharmacology) respond by synthesizing nitric oxide. Inhibition of NOS and knockout of the NOS-2 gene can markedly impair the protective response to injected parasites in animal models.
Preparations Available
Nitric Oxide (INOmax) Inhalation: 100, 800 ppm gas Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 19. Nitric Oxide, Donors, & Inhibitors >
Chapter 20. Drugs Used in Asthma Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 20. Drugs Used in Asthma > Drugs Used in Asthma: Introduction The clinical hallmarks of asthma are recurrent, episodic bouts of coughing, shortness of breath, chest tightness, and wheezing. In mild asthma, symptoms occur only occasionally, eg, on exposure to allergens or certain pollutants, on exercise, or after a viral upper respiratory infection. More severe forms of asthma are associated with frequent attacks of wheezing dyspnea, especially at night, and even chronic limitation of activity. Asthma is the most common chronic disabling disease of childhood, but it affects all age groups. Asthma is physiologically characterized by increased responsiveness of the trachea and bronchi to various stimuli and by widespread narrowing of the airways that changes in severity either spontaneously or as a result of therapy. Its pathologic features are contraction of airway smooth muscle, mucosal thickening from edema and cellular infiltration, and inspissation in the airway lumen of abnormally thick, viscid plugs of mucus. Of these causes of airway obstruction, contraction of smooth muscle is most easily reversed by current therapy; reversal of the edema and cellular infiltration requires sustained treatment with anti-inflammatory agents. Asthma therapies are thus sometimes divided into two categories: "short-term relievers" and "long-term controllers." Short-term relief is most effectively achieved with bronchodilators, agents that increase airway caliber by relaxing airway smooth muscle, and of these the -adrenoceptor stimulants (see Chapter 9: Adrenoceptor-Activating & Other Sympathomimetic Drugs) are the most widely used. Theophylline, a methylxanthine drug, and antimuscarinic agents (see Chapter 8: CholinoceptorBlocking Drugs) are also used for reversal of airway constriction. Long-term control is most often achieved with an anti-inflammatory agent such as an inhaled corticosteroid, with a leukotriene antagonist, or with an inhibitor of mast cell degranulation, eg, cromolyn or nedocromil. The distinction between "short-term relievers" and "long-term controllers" has become blurred by the finding that theophylline inhibits some lymphocyte functions and modestly reduces airway mucosal inflammation and that budesonide, an inhaled corticosteroid, produces modest immediate bronchodilation. Similarly, two recently released long-acting -adrenoceptor stimulants, salmeterol and formoterol, appear to be effective in improving asthma control when taken regularly. Finally, clinical trials are demonstrating the efficacy of specifically targeting a mechanism thought to be fundamental to asthma's pathogenesis by repeated treatment with a humanized monoclonal anti-IgE antibody. This chapter presents the basic pharmacology of the methylxanthines, cromolyn, leukotriene pathway inhibitors, and monoclonal anti-IgE antibody—agents whose medical use is almost exclusively for pulmonary disease. The other classes of drugs listed above are discussed in relation
to the therapy of asthma. Pathogenesis of Asthma A rational approach to the pharmacotherapy of asthma depends on an understanding of the disease's pathogenesis. In the classic immunologic model, asthma is a disease mediated by reaginic (IgE) antibodies bound to mast cells in the airway mucosa (Figure 20–1). On reexposure to an antigen, antigen-antibody interaction on the surface of the mast cells triggers both the release of mediators stored in the cells' granules and the synthesis and release of other mediators. The agents responsible for the early reaction—immediate bronchoconstriction—include histamine, tryptase and other neutral proteases, leukotrienes C4 and D4, and prostaglandins. These agents diffuse throughout the airway wall and cause muscle contraction and vascular leakage. Other mediators are responsible for the more sustained bronchoconstriction, cellular infiltration of the airway mucosa, and mucus hypersecretion of the late asthmatic reaction that occurs 2–8 hours later. These mediators are thought to be cytokines characteristically produced by TH2 lymphocytes, especially GM-CSF and interleukins 4, 5, 9, and 13, which attract and activate eosinophils and stimulate IgE production by B lymphocytes. It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the cytokines and other mediators responsible for the late inflammatory response, but it is now thought that the benefits of corticosteroid therapy may result from their inhibition of cytokine production in the airways. Figure 20–1.
Conceptual model for the immunopathogenesis of asthma. Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On reexposure to allergen, antigenantibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene C4, and platelet-activating factor (PAF). These agents provoke contraction of airway smooth muscle, causing the immediate fall in FEV1. Reexposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins 4 and 5, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late asthmatic response, indicated by a fall in FEV1 2–8 hours after the exposure.
with asthma have no evidence of immediate hypersensitivity to antigens, most severe exacerbations of asthma appear to be provoked by viral respiratory infection, the severity of symptoms correlates poorly with the quantity of antigen in the atmosphere, and in many patients bronchospasm can be provoked by nonantigenic stimuli such as distilled water, exercise, cold air, sulfur dioxide, and rapid respiratory maneuvers. This tendency to develop bronchospasm upon encountering stimuli that do not affect healthy nonasthmatic airways is characteristic of asthma and is sometimes called "nonspecific bronchial hyperreactivity" to distinguish it from bronchial responsiveness to specific antigens. Bronchial hyperreactivity is quantitated by measuring the fall in forced expiratory volume in 1 second (FEV1) provoked by inhaling serially increasing concentrations of aerosolized histamine or methacholine. This exaggerated sensitivity of the airways appears to be fundamental to asthma's pathogenesis, for it is nearly ubiquitous in patients with asthma and its degree correlates with the symptomatic severity of the disease. The mechanisms underlying bronchial hyperreactivity are somehow related to inflammation of the airway mucosa. The agents that increase bronchial reactivity, such as ozone exposure, allergen inhalation, and infection with respiratory viruses, also cause airway inflammation. In both dogs and humans, the increase in bronchial reactivity induced by ozone is associated with an increase in the number of polymorphonuclear leukocytes found in fluid obtained by bronchial lavage or from bronchial mucosal biopsies. The increase in reactivity due to allergen inhalation is associated with an increase in both eosinophils and polymorphonuclear leukocytes in bronchial lavage fluid. The increase in reactivity that is associated with the late asthmatic response to allergen inhalation (Figure 20–1) is sustained and, because it is prevented by treatment with inhaled corticosteroids immediately before antigen challenge, is thought to be caused by airway inflammation. How the increase in airway reactivity is linked to inflammation is uncertain. Much evidence points to the eosinophil. The most consistent difference in bronchial mucosal biopsies obtained from asthmatic and healthy subjects is an increase in the number of eosinophils found beneath the airway epithelium. Immunohistochemical staining shows increased levels of eosinophil cationic protein, indicating activation of the cells. The number of eosinophils in expectorated sputum or in fluid lavaged from the lungs correlates roughly with the degree of bronchial hyperreactivity. Eosinophil products have in turn been shown to cause epithelial sloughing and an increase in contractile responsiveness of airway smooth muscle. The importance of the eosinophil has been challenged, however, by a study showing that treatment with an anti-IL-5 monoclonal antibody effectively blocks airway eosinophilia caused by allergen challenge but does not prevent bronchoconstriction or any further increase in bronchial hyperactivity (Leckie, 2000). The products of other cells in the airways, such as lymphocytes, macrophages, mast cells, sensory nerves, and epithelial cells, have also been shown to alter airway smooth muscle function, so a specific antagonist to a single mediator or class of mediators might not prove wholly effective as asthma therapy. Other evidence suggests a role for sensitization of sensory nerves in the airways as a mechanism for hyperreactivity (see Pharmacologic Significance of Lung Innervation). Whatever the mechanisms responsible for bronchial hyperreactivity, bronchoconstriction itself seems to result not simply from the direct effect of the released mediators but also from their activation of neural or humoral pathways. Evidence for the importance of neural pathways stems largely from studies of laboratory animals. Thus, the bronchospasm provoked in dogs by histamine can be greatly reduced by pretreatment with an inhaled topical anesthetic agent, by transection of the vagus nerves, and by pretreatment with atropine. Studies of asthmatic humans, however, have shown that treatment with atropine causes only a reduction in—not abolition of—the
bronchospastic responses to antigens and to nonantigenic stimuli. While it is possible that activity in some other neural pathway (eg, the nonadrenergic, noncholinergic system; see Pharmacologic Significance of Lung Innervation) contributes to bronchomotor responses to nonspecific nonantigenic stimuli, their inhibition by cromolyn, a drug that appears to inhibit mast cell degranulation, suggests that both antigenic and nonantigenic stimuli may provoke the release from mast cells of mediators that stimulate smooth muscle contraction by direct and indirect mechanisms (Figure 20–2). Figure 20–2.
Mechanisms of response to inhaled irritants. The airway is represented microscopically by a crosssection of the wall with branching vagal sensory endings lying adjacent to the lumen. Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release acetylcholine
(ACh), which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction. The hypothesis suggested by these studies—that asthmatic bronchospasm results from a combination of release of mediators and an exaggeration of responsiveness to their effects— predicts that asthma may be effectively treated by drugs with different modes of action. Asthmatic bronchospasm might be reversed or prevented, for example, by drugs that reduce the amount of IgE bound to mast cells (anti-IgE antibody), prevent mast cell degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel blockers), block the action of the products released (antihistamines and leukotriene receptor antagonists), inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonists), or directly relax airway smooth muscle (sympathomimetic agents, theophylline). The second approach to the treatment of asthma is aimed not just at preventing or reversing acute bronchospasm but at reducing the level of bronchial responsiveness. Because increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented both by reducing exposure to the allergens that provoke inflammation and by prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 20. Drugs Used in Asthma > Pharmacologic Significance of Lung Innervation As noted previously, the airways are richly supplied with afferent and efferent vagal nerves. The cholinergic motor fibers are clearly responsible in some patients for a portion of the bronchoconstriction characteristic of acute asthma. Such fibers innervate M3 receptors on the smooth muscle and contain modulatory M2 receptors on the nerve terminals. Selective inhibition of M2 receptors can increase bronchoconstrictor responses to a variety of stimuli, while M3 inhibitors can produce dilation of constricted airways. In contrast, noradrenergic sympathetic innervation of the airways is sparse, and these fibers do not appear to play a major role in controlling airway diameter. Bronchodilation may be brought about by nonadrenergic, noncholinergic nerves releasing nitric oxide since nitric oxide synthase inhibitors have been shown to reduce bronchodilation produced by electrical field stimulation in vitro. The role of peptidergic neurons is not so clear. Capsaicin, the hot chile pepper chemical that evokes release of peptide transmitters from several types of sensory nerves, has been shown to reproduce some of the signs of bronchial hyperreactivity in animal and human experiments. These findings led to the proposal that sensitization of afferent nerve endings played a major role in chronic airway hyperreactivity. However, peptide transmitter antagonists have not been able to prevent bronchoconstriction in several models. Clearly, much remains to be learned about airway pharmacology.
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 20. Drugs Used in Asthma > Basic Pharmacology of Agents Used in the Treatment of Asthma The drugs most used for management of asthma are adrenoceptor agonists (used as "relievers" or bronchodilators) and inhaled corticosteroids (used as "controllers" or anti-inflammatory agents). Their basic pharmacology is presented elsewhere (see Chapter 9: Adrenoceptor-Activating & Other Sympathomimetic Drugs and Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists). In this chapter, we review their pharmacology relevant to asthma. Sympathomimetic Agents The adrenoceptor agonists have several pharmacologic actions important in the treatment of asthma. They relax airway smooth muscle and inhibit release of some bronchoconstricting substances from mast cells. They may also inhibit microvascular leakage and increase mucociliary transport by increasing ciliary activity or by affecting the composition of mucous secretions. As in other tissues, the agonists stimulate adenylyl cyclase and increase the formation of cAMP in the airway tissues (Figure 20–3). Figure 20–3.
Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists.
The best-characterized action of the adrenoceptor agonists on airways is relaxation of airway smooth muscle that results in bronchodilation. Although there is no evidence for significant sympathetic innervation of human airway smooth muscle, there is ample evidence for the presence
smooth muscle, inhibits mediator release, and causes tachycardia and skeletal muscle tremor as toxic effects. The sympathomimetic agents that have been widely used in the treatment of asthma include epinephrine, ephedrine, isoproterenol, and a number of 2-selective agents (Figure 20–4). Because epinephrine and isoproterenol cause more cardiac stimulation (mediated mainly by 1 receptors), they should probably be reserved for special situations (see below). Figure 20–4.
Structures of isoproterenol and several
2-selective
analogs.
Epinephrine is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 g per puff). Maximal bronchodilation is achieved 15 minutes after inhalation and lasts 60–90 minutes. Because epinephrine stimulates 1 as well as 2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are troublesome adverse effects. Epinephrine is the active agent in many nonprescription inhalants (eg, Primatene Mist) but is now rarely prescribed.
Ephedrine was used in China for more than 2000 years before its introduction into Western medicine in 1924. Compared with epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and 2-selective agonists, ephedrine is now used infrequently in treating asthma. Isoproterenol is a potent bronchodilator; when inhaled as a microaerosol from a pressurized canister, 80–120 g causes maximal bronchodilation within 5 minutes. Isoproterenol has a 60- to 90-minute duration of action. An increase in the asthma mortality rate that occurred in the United Kingdom in the mid 1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol, though this attribution remains a subject of controversy. Beta2 Selective Drugs The 2-selective adrenoceptor agonist drugs are the most widely used sympathomimetics for the treatment of asthma at the present time (Figure 20–4). These agents differ structurally from epinephrine in having a larger substitution on the amino group and in the position of the hydroxyl groups on the aromatic ring. They are effective after inhaled or oral administration and have a long duration of action and significant 2 selectivity. Albuterol, terbutaline, metaproterenol, and pirbuterol are available as metered-dose inhalers. Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol. Bronchodilation is maximal by 30 minutes and persists for 3–4 hours. Albuterol, levalbuterol, bitolterol, and metaproterenol can be diluted in saline for administration from a handheld nebulizer. Because the particles generated by a nebulizer are much larger than those from a metered-dose inhaler, much higher doses must be given (15 mg vs 2.5–5 mg) but are no more effective. Nebulized therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler. Albuterol and terbutaline are also prepared in tablet form. One tablet two or three times daily is the usual regimen; the principal adverse effects of skeletal muscle tremor, nervousness, and occasional weakness may be reduced by starting the patient on half-strength tablets for the first 2 weeks of therapy. Of these agents, only terbutaline is available for subcutaneous injection (0.25 mg). The indications for this route are similar to those for subcutaneous epinephrine—severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective—but it should be remembered that terbutaline's longer duration of action means that cumulative effects may be seen after repeated injections. A new generation of long-acting 2-selective agonists includes salmeterol and formoterol. Both drugs are potent selective 2 agonists that appear to achieve their long duration of action (12 hours or more) as a result of high lipid solubility, which permits them to dissolve in the smooth muscle cell membrane in high concentration or, possibly, attach to "mooring" molecules in the vicinity of the adrenoceptor. It is postulated that this local drug functions as a slow-release depot that provides drug to adjacent receptors over a long period. These drugs appear to interact with inhaled corticosteroids to improve asthma control. They are not recommended as the sole therapy for asthma. Although adrenoceptor agonists may be administered by inhalation or by the oral or parenteral routes, delivery by inhalation results in the greatest local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on the particle size, the pattern of breathing
(tidal volume and rate of airflow), and the geometry of the airways. Even with particles in the optimal size range of 2–5 m, 80–90% of the total dose of aerosol is deposited in the mouth or pharynx. Particles under 1–2 m in size remain suspended and may be exhaled. Deposition can be increased by holding the breath in inspiration. Toxicities The use of sympathomimetic agents by inhalation at first raised fears about possible tachyphylaxis or tolerance to agonists, cardiac arrhythmias, and hypoxemia. The concept that -agonist drugs cause worsening of clinical asthma by inducing tachyphylaxis to their own action remains unestablished. Most studies have shown only a small change in the bronchodilator response to stimulation after prolonged treatment with -agonist drugs, but other studies have shown a loss in the ability of -agonist treatment to inhibit the response to subsequent challenge with exercise, methacholine, or antigen challenge (referred to as a loss of bronchoprotective action). Other experiments have demonstrated that arterial oxygen tension (PaO2) may decrease after administration of agonists if ventilation/perfusion ratios in the lung worsen. This effect is usually small, however, and may occur with any bronchodilator drug; the significance of such an effect will depend on the initial PaO2 of the patient. Supplemental oxygen may be necessary if the initial PaO2 is decreased markedly or if there is a large decrease in PaO2 during treatment with bronchodilators. Finally, there is concern over myocardial toxicity from Freon propellants contained in all of the commercially available metered-dose canisters. While fluorocarbons may sensitize the heart to toxic effects of catecholamines, such an effect occurs only at very high myocardial concentrations, which are not achieved if inhalers are used as recommended. Under the terms of an international agreement, fluorocarbon-free inhalers will soon replace existing preparations. Fears that heavy use of -agonist inhalers could actually increase morbidity and mortality have not been borne out by careful epidemiologic investigations. Heavy use most often indicates that the patient should be receiving more effective prophylactic therapy with corticosteroids. In general, 2adrenoceptor agonists are safe and effective bronchodilators when given in doses that avoid systemic adverse effects. Methylxanthine Drugs The three important methylxanthines are theophylline,theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee, respectively). The importance of theophylline as a therapeutic agent in the treatment of asthma has waned as the greater effectiveness of inhaled adrenoceptor agents for acute asthma and of inhaled anti-inflammatory agents for chronic asthma has been established, but theophylline's very low cost is an important advantage for economically disadvantaged patients in societies where health care resources are limited. Chemistry As shown below, theophylline is 1,3-dimethylxanthine; theobromine is 3,7-dimethylxanthine; and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophylline-ethylenediamine complex. A synthetic analog of theophylline (dyphylline) is both less potent and shorter-acting than theophylline. The pharmacokinetics of theophylline are discussed below (see Clinical Use of Methylxanthines). The metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine.
Mechanism of Action Theophylline produces direct bronchodilation and has some anti-inflammatory actions in the airway as well. Several mechanisms have been proposed for these actions, but none have been firmly established. At high concentrations, the methylxanthines can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family (Figure 20–3). Since the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cAMP and, in some tissues, cGMP. This effect could explain the cardiac stimulation and smooth muscle relaxation produced by these drugs as well as decreased release of inflammatory mediators from mast cells. PDE4 appears to be the isoform most directly involved in the airway actions of methylxanthines. More selective inhibitors of PDE4 have been developed in an effort to reduce toxicity while maintaining therapeutic efficacy. Thus far, such selective PDE4 inhibitors have proved more effective in chronic obstructive pulmonary disease (COPD) than in asthma. A major adverse effect of the PDE4-selective drugs is nausea and vomiting. Another proposed mechanism is the inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to cause contraction of isolated airway smooth muscle and to provoke histamine release from airway mast cells. These effects are antagonized by theophylline, which blocks cell surface adenosine receptors. It has also been shown, however, that xanthine derivatives devoid of adenosine-antagonistic properties (eg, enprofylline) may be more potent than theophylline in inhibiting bronchoconstriction in asthmatic subjects. Pharmacodynamics of Methylxanthines The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, while caffeine has the most marked central nervous system effects. Central Nervous System Effects
In low and moderate doses, the methylxanthines—especially caffeine—cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages—eg, 100 mg in a cup of coffee—is sufficient to cause nervousness and insomnia in unusually sensitive individuals and slight bronchodilation in patients with asthma. At very high doses, medullary stimulation and convulsions may occur and can lead to death; theophylline has been used successfully in suicide attempts. Nervousness and tremor are primary side effects in patients taking large doses of aminophylline for asthma. Cardiovascular Effects The methylxanthines have direct positive chronotropic and inotropic effects on the heart. At low concentrations, these effects appear to result from increased catecholamine release that is caused by inhibition of presynaptic adenosine receptors. At higher concentrations (> 10 mol/L), calcium influx may be increased directly through the increase in cAMP that results from inhibition of phosphodiesterase. At very high concentrations (> 100 mol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired. In unusually sensitive individuals, consumption of a few cups of coffee may result in arrhythmias, but in most people even parenteral administration of higher doses of the methylxanthines produces only sinus tachycardia and increased cardiac output. In large doses, these agents also relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction. Ordinary consumption of coffee and other methylxanthine-containing beverages, however, usually raises the peripheral vascular resistance and blood pressure slightly, probably through the release of catecholamines. Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent. However, no evidence suggests that this therapy is superior to other approaches. Effects on Gastrointestinal Tract The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine. Effects on Kidney The methylxanthines—especially theophylline—are weak diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically useful. Effects on Smooth Muscle The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, may limit the dose (see below). In addition to this direct effect on the airway smooth muscle, these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown. Effects on Skeletal Muscle The therapeutic actions of the methylxanthines may not be confined to the airways, for they also
strengthen the contractions of isolated skeletal muscle in vitro and have potent effects in improving contractility and in reversing fatigue of the diaphragm in patients with chronic obstructive lung diseases. This effect on diaphragmatic performance—rather than an effect on the respiratory center—may account for theophylline's ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction. Clinical Use of Methylxanthines Of the xanthines, theophylline is the most effective bronchodilator, and it has been shown repeatedly both to relieve airflow obstruction in acute asthma and to reduce the severity of symptoms and time lost from work or school in patients with chronic asthma. Theophylline base is only slightly soluble in water, so it has been administered as several salts containing varying amounts of theophylline base. Most preparations are well absorbed from the gastrointestinal tract, but absorption of rectal suppositories is unreliable. Improvements in theophylline preparations have come from alterations in the physical state of the drugs rather than from new chemical formulations. For example, several companies now provide anhydrous theophylline in a microcrystalline form in which the increased surface area facilitates solubilization for complete and rapid absorption after oral administration. In addition, several sustained-release preparations (eg, Slo-Phyllin, Theo-Dur) are available and can produce therapeutic blood levels of theophylline for 12 hours or more. These preparations offer the advantages of less frequent drug administration, less fluctuation of theophylline blood levels, and, in many cases, more effective treatment of nocturnal bronchospasm. Theophylline should only be used where methods to measure theophylline blood levels are available because it has a narrow therapeutic window and its therapeutic and toxic effects are related to its plasma concentrations. Improvement in pulmonary function is correlated with plasma concentration in the range of 5–20 mg/L. Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety occur at concentrations of 15 mg/L in some patients and become common at concentrations greater than 20 mg/L. Higher levels (> 40 mg/L) may cause seizures or arrhythmias; these may not be preceded by gastrointestinal or neurologic warning symptoms. The plasma clearance of theophylline varies widely. Theophylline is metabolized by the liver, so usual doses may lead to toxic concentrations of the drug in patients with liver disease. Conversely, clearance may be increased through the induction of hepatic enzymes by cigarette smoking or by changes in diet. In normal adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear theophylline faster than adults (1–1.5 mL/kg/min). Neonates and young infants have the slowest clearance (see Chapter 60: Special Aspects of Perinatal & Pediatric Pharmacology). Even when maintenance doses are altered to correct for the above factors, plasma concentrations vary widely. Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. It is inexpensive, and it can be taken orally. Its use, however, also requires occasional measurement of plasma levels; it often causes unpleasant minor side effects (especially insomnia); and accidental or intentional overdose can result in severe toxicity or death. For oral therapy with the prompt-release formulation, the usual dose is 3–4 mg/kg of theophylline every 6 hours. Changes in dosage will result in a new steady state concentration of theophylline in 1–2 days, so the dose may be increased at intervals of 2–3 days until therapeutic plasma concentrations are achieved (10–20 mg/L) or until adverse effects develop. Antimuscarinic Agents
Leaves from Datura stramonium have been used in treating asthma for hundreds of years. Interest in the potential value of antimuscarinic agents increased with demonstration of the importance of the vagus in bronchospastic responses of laboratory animals and by the development of a potent antimuscarinic agent that is poorly absorbed after aerosol administration to the airways and is therefore not associated with systemic atropine effects. Mechanism of Action Muscarinic antagonists competitively inhibit the effect of acetylcholine at muscarinic receptors (see Chapter 8: Cholinoceptor-Blocking Drugs). In the airways, acetylcholine is released from efferent endings of the vagus nerves, and muscarinic antagonists can effectively block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity (Figure 20–2). Very high concentrations—well above those achieved even with maximal therapy—are required to inhibit the response of airway smooth muscle to nonmuscarinic stimulation. This selectivity of muscarinic antagonists accounts for their usefulness as investigative tools in examining the role of parasympathetic pathways in bronchomotor responses but limits their usefulness in preventing bronchospasm. In the doses given, antimuscarinic agents inhibit only that portion of the response mediated by muscarinic receptors, and the involvement of parasympathetic pathways in bronchospastic responses appears to vary among individuals. Clinical Use of Muscarinic Antagonists Antimuscarinic agents are effective bronchodilators. When given intravenously, atropine, the prototypical muscarinic antagonist, causes bronchodilation at a lower dose than that needed to cause an increase in heart rate. The selectivity of atropine's effect can be increased further by administering the drug by inhalation or by use of a more selective quaternary ammonium derivative of atropine, ipratropium bromide. Ipratropium can be delivered in high doses to muscarinic receptors in the airways because this compound is poorly absorbed and does not readily enter the central nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. In some, bronchoconstriction is inhibited effectively; in others, only modestly. The failure of higher doses of the muscarinic antagonist to further inhibit the response in these individuals indicates that mechanisms other than parasympathetic reflex pathways must be involved. Even in the subjects least protected by this antimuscarinic agent, however, the bronchodilation and partial inhibition of provoked bronchoconstriction are of potential clinical value, and antimuscarinic agents are valuable for patients intolerant of inhaled -agonist agents. While antimuscarinic drugs appear to be slightly less effective than -agonist agents in reversing asthmatic bronchospasm, the addition of ipratropium enhances the bronchodilation produced by nebulized albuterol in acute severe asthma. Ipratropium appears to be at least as effective in patients with chronic obstructive pulmonary disease that includes a partially reversible component. A longer-acting, selective antimuscarinic agent, tiotropium, is in clinical trials as treatment for COPD. This drug's 24-hour duration of action is a potentially important advantage. Corticosteroids Mechanism of Action Corticosteroids have been used to treat asthma since 1950 and are presumed to act by their broad
anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines (see Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists). They do not relax airway smooth muscle directly but reduce bronchial reactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction may be due in part to their potentiation of the effects of -receptor agonists, but their most important action is their inhibition of the lymphocytic, eosinophilic airway mucosal inflammation of asthmatic airways. Clinical Use of Corticosteroids Clinical studies of corticosteroids consistently show them to be effective in improving all indices of asthma control—severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life. Because of severe adverse effects when given chronically, oral and parenteral corticosteroids are reserved for patients who require urgent treatment, ie, those who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy. Regular or "controller" therapy is maintained with aerosol corticosteroids. Urgent treatment is often begun with an oral dose of 30–60 mg of prednisone per day or an intravenous dose of 1 mg/kg of methylprednisolone every 6 hours; the daily dose is decreased gradually after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in a week or 10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels. Because adrenal suppression by corticosteroids is related to dose and because secretion of corticosteroids has a diurnal variation, it has become customary to administer corticosteroids early in the morning, after endogenous ACTH secretion has peaked. For prevention of nocturnal asthma, however, oral or inhaled corticosteroids are most effective when given in the late afternoon. Aerosol treatment is the most effective way to decrease the systemic adverse effects of corticosteroid therapy. The introduction of lipid-soluble corticosteroids such as beclomethasone, budesonide, flunisolide, fluticasone, and triamcinolone makes it possible to deliver corticosteroids to the airways with minimal systemic absorption. An average daily dose of four puffs twice daily of beclomethasone (400 g/d) is equivalent to about 10–15 mg/d of oral prednisone for the control of asthma, with far fewer systemic effects. Indeed, one of the cautions in switching patients from oral to inhaled corticosteroid therapy is to taper oral therapy slowly to avoid precipitation of adrenal insufficiency. In patients requiring continued prednisone treatment despite inhalation of standard doses of an aerosol corticosteroid, higher doses appear to be more effective; inhaled dosages up to 2000 g/d of fluticasone are effective in weaning patients from chronic prednisone therapy. While these high doses of inhaled steroids may cause adrenal suppression, the risks of systemic toxicity from chronic use appear negligible compared with those of the oral corticosteroid therapy they replace. A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis. The risk of this complication can be reduced by having patients gargle water and spit after each inhaled treatment. Hoarseness can also result from a direct local effect of inhaled corticosteroids on the vocal cords. These agents are remarkably free of other short-term complications in adults but may increase the risks of osteoporosis and cataracts over the long term. In children, inhaled corticosterone therapy has been shown to slow the rate of growth, but asthma itself delays puberty, and there is no evidence that inhaled corticosteroid therapy influences adult height. Chronic use of inhaled corticosteroids effectively reduces symptoms and improves pulmonary function in patients with mild asthma. Such use also reduces or eliminates the need for oral corticosteroids in patients with more severe disease. In contrast to -stimulant agents and theophylline, chronic use of inhaled corticosteroids reduces bronchial reactivity. Because of the
efficacy and safety of inhaled corticosteroids, they are now routinely prescribed for patients who require more than occasional inhalations of a agonist for relief of symptoms. This therapy is continued for 10–12 weeks and then withdrawn to determine if more prolonged therapy is needed. Inhaled corticosteroids are not curative. In most patients, the manifestations of asthma return within a few weeks after stopping therapy even if they have been taken in high doses for 2 years or longer. Cromolyn & Nedocromil Cromolyn sodium (disodium cromoglycate) and nedocromil sodium are stable but extremely insoluble salts (see structures below). When used as aerosols (metered-dose inhalers), they effectively inhibit both antigen- and exercise-induced asthma, and chronic use (four times daily) slightly reduces the overall level of bronchial reactivity. However, these drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm; they are only of value when taken prophylactically.
Cromolyn is poorly absorbed from the gastrointestinal tract and must be inhaled as a microfine powder or aerosolized solution. Nedocromil also has a very low bioavailability and is available only in metered-dose aerosol form. Mechanism of Action Cromolyn and nedocromil differ structurally but are thought to share a common mechanism of action, an alteration in the function of delayed chloride channels in the cell membrane, inhibiting cellular activation. This action on airway nerves is thought to be responsible for nedocromil's inhibition of cough; on mast cells, for inhibition of the early response to antigen challenge; and on eosinophils, for inhibition of the inflammatory response to inhalation of allergens. The inhibitory effect on mast cells appears to be specific for cell type, since cromolyn has little inhibitory effect on mediator release from human basophils. It may also be specific for different organs, since cromolyn inhibits mast cell degranulation in human and primate lung but not in skin. This in turn may reflect known differences in mast cells found in different sites, as in their neutral protease content.
Until recently, the idea that cromolyn inhibits mast cell degranulation was so well accepted that the inhibition of a response by cromolyn was thought to indicate the involvement of mast cells in the response. This simplistic idea has been overturned in part by the finding that cromolyn and nedocromil inhibit the function of cells other than mast cells and in part by the finding that nedocromil inhibits appearance of the late response even when given after the early response to antigen challenge, ie, after mast cell degranulation has occurred. Clinical Use of Cromolyn & Nedocromil In short-term clinical trials, pretreatment with cromolyn or nedocromil blocks the bronchoconstriction caused by antigen inhalation, by exercise, by aspirin, and by a variety of causes of occupational asthma. This acute protective effect of a single treatment makes cromolyn useful for administration shortly before exercise or before unavoidable exposure to an allergen. When taken regularly (two to four puffs two to four times daily) by patients with perennial asthma, both agents reduce symptomatic severity and the need for bronchodilator medications. These drugs are neither as potent nor as predictably effective as inhaled corticosteroids. In general, young patients with extrinsic asthma are most likely to respond favorably. At present, the only way of determining whether a patient will respond is by a therapeutic trial for 4 weeks. The addition of nedocromil to a standard dose of an inhaled corticosteroid appears to improve asthma control. Cromolyn solution is also useful in reducing symptoms of allergic rhinoconjunctivitis. Applying the solution by nasal spray or eye drops several times a day is effective in about 75% of patients, even during the peak pollen season. Because the drugs are so poorly absorbed, adverse effects of cromolyn and nedocromil are minor and are localized to the sites of deposition. These include such symptoms as throat irritation, cough, mouth dryness, chest tightness, and wheezing. Some of these symptoms can be prevented by inhaling a 2-adrenoceptor agonist before cromolyn or nedocromil treatment. Serious adverse effects are rare. Reversible dermatitis, myositis, or gastroenteritis occurs in fewer than 2% of patients, and a very few cases of pulmonary infiltration with eosinophilia and anaphylaxis have been reported. This lack of toxicity accounts for cromolyn's widespread use in children, especially those at ages of rapid growth. For children who have difficulty coordinating the use of the inhaler device, cromolyn may be given by aerosol of a 1% solution. Leukotriene Pathway Inhibitors Because of the evidence of leukotriene involvement in many inflammatory diseases (see Chapter 18: The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds) and in anaphylaxis, considerable effort has been expended on the development of drugs that block the synthesis of these arachidonic acid derivatives or their receptors. Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and are synthesized by a variety of inflammatory cells in the airways, including eosinophils, mast cells, macrophages, and basophils. Leukotriene B4 is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion. Early studies established that antigen challenge of sensitized human lung tissue results in the generation of leukotrienes, while other studies of human subjects have shown that inhalation of leukotrienes causes not only bronchoconstriction but also an increase in bronchial reactivity to histamine that persists for several days. Two approaches to interrupting the leukotriene pathway have been pursued: inhibition of 5-
lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of leukotriene D4 to its receptor on target tissues, thereby preventing its action. Efficacy in blocking airway responses to exercise and to antigen challenge has been shown for drugs in both categories: zileuton, a 5-lipoxygenase inhibitor, and zafirlukast and montelukast, LTD4-receptor antagonists. All have been shown to be effective when taken regularly in outpatient clinical trials. Their effects on symptoms, airway caliber, bronchial reactivity, and airway inflammation are less marked than the effects of inhaled corticosteroids, but they are almost equally effective in reducing the frequency of exacerbations. Their principal advantage is that they are taken orally; some patients—especially children—comply poorly with inhaled therapies. Montelukast is approved for children as young as 6 years of age.
Some patients appear to have particularly favorable responses, but no clinical features allow identification of "responders" before a trial of therapy. In the USA, zileuton is approved for use in an oral dosage of 600 mg given four times daily; zafirlukast, 20 mg twice daily; and montelukast, 10 mg once daily. Trials with leukotriene inhibitors have demonstrated an important role for leukotrienes in aspirininduced asthma. It has long been known that 5–10% of asthmatics are exquisitely sensitive to aspirin, so that ingestion of even a very small dose causes profound bronchoconstriction and symptoms of systemic release of histamine, such as flushing and abdominal cramping. Because this reaction to aspirin is not associated with any evidence of allergic sensitization to aspirin or its metabolites, and because it is produced by any of the nonsteroidal anti-inflammatory agents, it is thought to result from inhibition of prostaglandin synthetase, shifting arachidonic acid metabolism from the prostaglandin to the leukotriene pathway. Support for this idea was provided by the
demonstration that leukotriene pathway inhibitors impressively reduce the response to aspirin challenge and improve overall control of asthma on a day-to-day basis. Of these agents, zileuton is the least prescribed because of the requirement of four times daily dosing and because of occasional liver toxicity. The receptor antagonists appear to be safe to use. Reports of Churg-Strauss syndrome (a systemic vasculitis characterized by worsening asthma, pulmonary infiltrates, and eosinophilia) appear to have been coincidental, with the syndrome unmasked by the reduction in prednisone dosage made possible by the addition of zafirlukast or montelukast. Other Drugs in the Treatment of Asthma Anti-IgE Monoclonal Antibodies An entirely new approach to the treatment of asthma exploits advances in molecular biology to target IgE antibody. From a collection of monoclonal antibodies raised in mice against IgE antibody itself, a monoclonal antibody was selected that appeared to be targeted against the portion of IgE that binds to its receptors (FCe-R1 and -R2 receptors) on mast cells and other inflammatory cells. Omalizumab (anti-IgE Mab) inhibits the binding of IgE to mast cells but does not activate IgE already bound to these cells and thus does not provoke mast cell degranulation. In mice, it also appears to inhibit IgE synthesis by B lymphocytes. The murine antibody has been genetically "humanized" by replacing all but a small fraction of its amino acids with those found in human proteins, and it does not appear to cause sensitization when given to human subjects. Studies of omalizumab in asthmatic volunteers showed that its administration over 10 weeks lowered plasma IgE to undetectable levels and significantly reduced the magnitude of both the early and the late bronchospastic responses to antigen challenge. Clinical trials have shown repeated intravenous or subcutaneous injection of anti-IgE MAb to lessen asthma severity and reduce the corticosteroid requirement in patients with moderate to severe disease, especially those with a clear environmental antigen precipitating factor, and to improve nasal and conjunctival symptoms in patients with perennial or seasonal allergic rhinitis. Calcium Channel Blockers Each of the cell functions that may become abnormal in patients with asthma depends to some degree on the movement of calcium into cells. The calcium channel blockers have no effect on baseline airway diameter but do significantly inhibit the airway narrowing that is induced by various stimuli. In patients, both nifedipine and verapamil given by inhalation significantly inhibited the bronchoconstriction induced by a variety of stimuli. However, both drugs were much less effective than inhaled albuterol. Nitric Oxide Donors Preliminary studies in animals suggest that airway smooth muscle, like that in the vasculature, is effectively relaxed by nitric oxide. This very lipophilic drug can be inhaled as a gas in acute asthma and dilates the pulmonary blood vessels as well as the airway smooth muscle. Although nitric oxide itself—or nitric oxide donors—may prove of value in acute severe asthma, it appears likely that they will be more useful in pulmonary hypertension (for which nitric oxide is already approved). Possible Future Therapies
The rapid advance in the scientific description of the immunopathogenesis of asthma has spurred the development of many new therapies targeting different sites in the immune cascade. These include monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-8), antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 phenotype. There is evidence that asthma may be aggravated—or even caused—by chronic airway infection with Chlamydia pneumoniae or Mycoplasma pneumoniae. This may explain the reports of benefit from treatment with macrolide antibiotics and, if confirmed, would stimulate the development of new diagnostic methods and antimicrobial therapies.
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 20. Drugs Used in Asthma > Clinical Pharmacology of Drugs Used in the Treatment of Asthma Bronchodilators Patients with mild asthma and only occasional symptoms require no more than an inhaled receptor agonist (eg, albuterol) on an "as-needed" basis. If symptoms require frequent inhalations (more often than twice a week), or if nocturnal symptoms occur, additional treatment is needed, preferably with an inhaled anti-inflammatory agent such as a corticosteroid or cromolyn, or with oral therapy with a leukotriene receptor antagonist. Theophylline is now largely reserved for patients in whom symptoms remain poorly controlled despite the combination of regular treatment with an inhaled anti-inflammatory agent and as-needed use of a 2 agonist. If the addition of theophylline fails to improve symptoms or if adverse effects become bothersome, it is important to check the plasma level of theophylline to be sure it is in the therapeutic range (10–20 mg/L). Corticosteroids If asthmatic symptoms occur frequently or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV1 < 1.5 L), initial treatment with oral corticosteroid (eg, 30 mg/d of prednisone for 3 weeks) is appropriate. Once clinical improvement is noted, inhaled corticosteroid treatment should be started and the oral dose reduced to the minimum necessary to control symptoms. For patients with milder symptoms but still inadequately controlled by as-needed use of an inhaled bronchodilator, corticosteroids may be initiated by the inhaled route. In patients whose symptoms are inadequately controlled by a standard dose of an inhaled corticosteroid, the addition of a long-acting inhaled -receptor agonist (salmeterol, formoterol) is more effective than is doubling the dose of the inhaled corticosteroid. The improvement in clinical symptoms and peak flow is usually prompt and sustained. In patients on such a combined treatment regimen, it is important to provide explicit instructions that a standard, short-acting inhaled agonist, like albuterol, be used for relief of acute symptoms. It is also important that the patient not stop the inhaled corticosteroid, continuing only the long-acting agonist, because exacerbations are not prevented by this monotherapy. For this reason—and because long-acting agonists appear to enhance the local but not the systemic actions of inhaled corticosteroids—inhalers containing both agents have been developed (see Preparations Available).
Cromolyn & Nedocromil Cromolyn or nedocromil may be considered as an alternative to inhaled corticosteroids in patients with symptoms occurring more than twice a week or who are wakened from sleep by asthma. They may also be useful in patients whose symptoms occur seasonally or after clear-cut inciting stimuli such as exercise or exposure to animal danders or irritants. In patients whose symptoms are continuous or occur without an obvious inciting stimulus, the value of these drugs can only be established with a therapeutic trial of inhaled drug four times a day for 4 weeks. If the patient responds to this therapy, the dose can be reduced. Maintenance therapy with cromolyn appears to be as effective as maintenance therapy with theophylline and, because of concerns over the possible long-term toxicity of systemic absorption of inhaled corticosteroids, has become widely used for treating children in the USA. Muscarinic Antagonists Inhaled muscarinic antagonists have so far earned a limited place in the treatment of asthma. When adequate doses are given, their effect on baseline airway resistance is nearly as great as that of the sympathomimetic drugs. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to have significant additive effects only in patients with severe airflow obstruction who present for emergency care. Antimuscarinic agents appear to be of significant value in chronic obstructive pulmonary disease—perhaps more so than in asthma. They are useful as alternative therapies for patients intolerant of -adrenoceptor agonists. When muscarinic antagonists are used for long-term treatment, they appear to be effective bronchodilators. Although it was predicted that muscarinic antagonists might dry airway secretions, direct measurements of fluid volume secretion from single airway submucosal glands in animals show that atropine decreases secretory rates only slightly; however, the drug does prevent excessive secretion caused by vagal reflex stimulation. No cases of inspissation of mucus have been reported following administration of these drugs. Other Anti-Inflammatory Therapies Some recent reports suggest that agents commonly used to treat rheumatoid arthritis might also be used to treat patients with chronic steroid-dependent asthma. The development of an alternative treatment is important, since chronic treatment with oral corticosteroids may cause osteoporosis, cataracts, glucose intolerance, worsening of hypertension, and cushingoid changes in appearance. Initial studies suggested that oral methotrexate or gold salt injections were beneficial in prednisonedependent asthmatics, but subsequent studies did not confirm this promise. The benefit from treatment with cyclosporine seems real. However, this drug's great toxicity makes this finding only a source of hope that other immunomodulatory therapies will ultimately be developed for the small proportion of patients whose asthma can be managed only with high oral doses of prednisone. Management of Acute Asthma The treatment of acute attacks of asthma in patients reporting to the hospital requires more continuous assessment and repeated objective measurement of lung function. For patients with mild attacks, inhalation of a -receptor agonist is as effective as subcutaneous injection of epinephrine. Both of these treatments are more effective than intravenous administration of aminophylline. Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6 hours). Even this aggressive treatment is not invariably effective, and patients must be watched closely for
signs of deterioration. Intubation and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes. Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 20. Drugs Used in Asthma > Preparations Available Sympathomimetics Used in Asthma Albuterol (generic, Proventil, Ventolin, others) Inhalant: 90 g/puff aerosol; 0.083, 0.5% solution for nebulization Oral: 2, 4 mg tablets; 2 mg/5 mL syrup Oral sustained-release: 4, 8 mg tablets Albuterol/Ipratropium (Combivent, DuoNeb) Inhalant: 103 g albuterol + 18 g ipratropium/ puff; 3 mg albuterol + 0.5 mg ipratropium/3 mL solution for nebulization Bitolterol (Tornalate) Inhalant: 0.2% solution for nebulization Ephedrine (generic) Oral: 25 mg capsules Parenteral: 50 mg/mL for injection Epinephrine (generic, Adrenalin, others) Inhalant: 1, 10 mg/mL for nebulization; 0.22 mg epinephrine base aerosol Parenteral: 1:10,000 (0.1 mg/mL), 1:1000 (1 mg/mL) Formoterol (Foradil) Inhalant: 12 g/puff aerosol; 12 g/unit inhalant powder Isoetharine (generic) Inhalant: 1% solution for nebulization Isoproterenol (generic, Isuprel, others) Inhalant: 0.5, 1% for nebulization; 80, 131 g/puff aerosols
Parenteral: 0.02, 0.2 mg/mL for injection Levalbuterol (Xenopex) Inhalant: 0.31, 0.63, 1.25 mg/3 mL solution Metaproterenol (Alupent, generic) Inhalant: 0.65 mg/puff aerosol in 7, 14 g containers; 0.4, 0.6, 5% for nebulization Pirbuterol (Maxair) Inhalant: 0.2 mg/puff aerosol in 80 and 300 dose containers Salmeterol (Serevent) Inhalant aerosol: 25 g salmeterol base/puff in 60 and 120 dose containers Inhalant powder: 50 g/unit Salmeterol/Fluticasone (Advair Diskus) Inhalant: 100, 250, 500 g fluticasone + 50 g salmeterol/unit Terbutaline (Brethine, Bricanyl) Inhalant: 0.2 mg/puff aerosol Oral: 2.5, 5 mg tablets Parenteral: 1 mg/mL for injection Aerosol Corticosteroids (See Also Chapter 39: Adrenocorticosteroids & Adrenocortical Antagonists.) Beclomethasone (QVAR, Vanceril) Aerosol: 40, 80 g/puff in 200 dose containers Budesonide (Pulmicort) Aerosol powder: 160 g/activation Flunisolide (AeroBid) Aerosol: 250 g/puff in 100 dose container Fluticasone (Flovent) Aerosol: 44, 110, and 220 g/puff in 120 dose container; powder, 50, 100, 250 g/activation
Fluticasone/Salmeterol (Advair Diskus) Inhalant: 100, 250, 500 g fluticasone + 50 g salmeterol/unit Triamcinolone (Azmacort) Aerosol: 100 g/puff in 240 dose container Leukotriene Inhibitors Montelukast (Singulair) Oral: 10 mg tablets; 4, 5 mg chewable tablets; 4 mg/packet granules Zafirlukast (Accolate) Oral: 10, 20 mg tablets Zileuton (Zyflo) Oral: 600 mg tablets Cromolyn Sodium & Nedocromil Sodium Cromolyn sodium Pulmonary aerosol (generic, Intal): 800 g/puff in 200 dose container; 20 mg/2 mL for nebulization (for asthma) Nasal aerosol (Nasalcrom):* 5.2 mg/puff (for hay fever) Oral (Gastrocrom): 100 mg/5 mL concentrate (for gastrointestinal allergy) Nedocromil sodium (Tilade) Pulmonary aerosol: 1.75 mg/puff in 112 metered-dose container *OTC preparation. Methylxanthines: Theophylline & Derivatives Aminophylline (theophylline ethylenediamine, 79% theophylline) (generic, others) Oral: 105 mg/5 mL liquid; 100, 200 mg tablets Oral sustained-release: 225 mg tablets Rectal: 250, 500 mg suppositories Parenteral: 250 mg/10 mL for injection
Theophylline (generic, Elixophyllin, Slo-Phyllin, Uniphyl, Theo-Dur, Theo-24, others) Oral: 100, 125, 200, 250, 300 mg tablets; 100, 200 mg capsules; 26.7, 50 mg/5 mL elixirs, syrups, and solutions Oral sustained-release, 8–12 hours: 50, 60, 75, 100, 125, 130, 200, 250, 260, 300 mg capsules Oral sustained-release, 8–24 hours: 100, 200, 300, 450 mg tablets Oral sustained-release, 12 hours: 100, 125, 130, 200, 250, 260, 300 mg capsules Oral sustained-release, 12–24 hours: 100, 200, 300 tablets Oral sustained-release, 24 hours: 100, 200, 300 mg tablets and capsules; 400, 600 mg tablets Parenteral: 200, 400, 800 mg/container, theophylline and 5% dextrose for injection Other Methylxanthines Dyphylline (generic, other) Oral: 200, 400 mg tablets; 33.3, 53.3 mg/5 mL elixir Parenteral: 250 mg/mL for injection Oxtriphylline (generic, Choledyl) Oral: equivalent to 64, 127, 254, 382 mg theophylline tablets; 32, 64 mg/5 mL syrup Pentoxifylline (generic, Trental) Oral: 400 mg tablets and controlled-release tablets Note: Pentoxifylline is labeled for use in intermittent claudication only. Antimuscarinic Drugs Used in Asthma Ipratropium (generic, Atrovent) Aerosol: 18 g/puff in 200 metered-dose inhaler; 0.02% (500 g/vial) for nebulization Nasal spray: 21, 42 g/spray Antibody Omalizumab (Xolair) Powder for SC injection, 202.5 mg
Katzung PHARMACOLOGY, 9e > Section IV. Drugs with Important Actions on Smooth Muscle > Chapter 20. Drugs Used in Asthma >
Section V. Drugs That Act in the Central Nervous System
Chapter 21. Introduction to the Pharmacology of CNS Drugs Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Introduction to the Pharmacology of CNS Drugs Drugs acting in the central nervous system (CNS) were among the first to be discovered by primitive humans and are still the most widely used group of pharmacologic agents. In addition to their use in therapy, many drugs acting on the CNS are used without prescription to increase one's sense of well-being. The mechanisms by which various drugs act in the CNS have not always been clearly understood. Since the causes of many of the conditions for which these drugs are used (schizophrenia, anxiety, etc) are themselves poorly understood, it is not surprising that in the past much of CNS pharmacology has been purely descriptive. In the last 3 decades, however, dramatic advances have been made in the methodology of CNS pharmacology. It is now possible to study the action of a drug on individual cells and even single ion channels within synapses. The information obtained from such studies is the basis for several major developments in studies of the CNS. First, it is clear that nearly all drugs with CNS effects act on specific receptors that modulate synaptic transmission. A very few agents such as general anesthetics and alcohol may have nonspecific actions on membranes (although these exceptions are not fully accepted), but even these non-receptor-mediated actions result in demonstrable alterations in synaptic transmission. Second, drugs are among the most important tools for studying all aspects of CNS physiology, from the mechanism of convulsions to the laying down of long-term memory. As will be described below, agonists that mimic natural transmitters (and in many cases are more selective than the endogenous substances) and antagonists are extremely useful in such studies. The section on Natural Toxins: Tools for Characterizing Ion Channels describes the uses of some of these substances. Third, unraveling the actions of drugs with known clinical efficacy has led to some of the most fruitful hypotheses regarding the mechanisms of disease. For example, information on the action of antipsychotic drugs on dopamine receptors has provided the basis for important hypotheses regarding the pathophysiology of schizophrenia. Studies of the effects of a variety of agonists and antagonists on -aminobutyric acid (GABA) receptors are resulting in new concepts pertaining to the pathophysiology of several diseases, including anxiety and epilepsy. This chapter provides an introduction to the functional organization of the CNS and its synaptic transmitters as a basis for understanding the actions of the drugs described in the following
chapters. Methods for the Study of CNS Pharmacology Although scientists (and the public) have always been interested in the action of drugs in the CNS, a detailed description of synaptic transmission was not possible until glass microelectrodes, which permit intracellular recording, were developed. Detailed electrophysiologic studies of the action of drugs on both voltage- and transmitter-operated channels were further facilitated by the introduction of the patch clamp technique, which permits the recording of current through single channels. Histochemical, immunologic, and radioisotopic methods are widely used to map the distribution of specific transmitters, their associated enzyme systems, and their receptors. Molecular cloning has had a major impact on our understanding of CNS receptors. These techniques make it possible to determine the precise molecular structure of the receptors and their associated channels. Finally, mice with mutated genes for specific receptors or enzymes (knockout mice) can provide important information regarding the physiologic and pharmacologic roles of these components.
Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Natural Toxins: Tools for Characterizing Ion Channels Evolution is a tireless chemist when it comes to inventing toxins. A vast number of variations are possible with even a small number of amino acids in peptides, and peptides are only one of a broad array of toxic compounds. For example, the predatory marine snail genus Conus is estimated to include at least 500 different species. Each species kills or paralyzes its prey with a venom that contains 50–200 different peptides or proteins. Furthermore, there is little duplication of peptides among Conus species. Other animals with useful toxins include snakes, frogs, spiders, bees, wasps, and scorpions. Plant species with toxic (or therapeutic) substances are too numerous to mention here; they are referred to in many chapters of this book. Since many toxins act on ion channels, they provide a wealth of chemical tools for studying the function of these channels. In fact, much of our current understanding of the properties of ion channels comes from studies utilizing only a small fraction of the highly potent and selective toxins that are now available. The toxins typically target voltage-sensitive ion channels, but a number of very useful toxins block ionotropic neurotransmitter receptors. Table 21–1 lists some of the toxins most commonly used in research, their mode of action, and their source. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Ion Channels & Neurotransmitter Receptors The membranes of nerve cells contain two types of channels defined on the basis of the mechanisms controlling their gating (opening and closing): voltage-gated and ligand-gated channels (Figures 21–1 A and B). Voltage-gated channels respond to changes in the membrane potential of the cell. The voltage-gated sodium channel described in Chapter 14: Agents Used in Cardiac Arrhythmias for the heart is an example of the first type and is very important in the CNS. In nerve cells, these channels are concentrated on the initial segment and the axon and are responsible for the fast action potential, which transmits the signal from cell body to nerve terminal. There are many types of voltage-sensitive calcium and potassium channels on the cell body, dendrites, and initial segment,
which act on a much slower time scale and modulate the rate at which the neuron discharges. For example, some types of potassium channels opened by depolarization of the cell result in slowing of further depolarization and act as a brake to limit further action potential discharge. Figure 21–1.
Types of ion channels and neurotransmitter receptors in the CNS. A shows a voltage-gated channel in which a voltage sensor controls the gating (broken arrow) of the channel. B shows a ligand-gated channel in which the binding of the neurotransmitter to the channel controls the gating (broken arrow) of the channel. C shows a G protein coupled receptor, which when bound, activates a G protein which then interacts directly with an ion channel. D shows a G protein coupled receptor, which when bound, activates a G protein which then activates an enzyme. The activated enzyme generates a diffusible second messenger that interacts with an ion channel.
Ligand-gated channels, also called ionotropic receptors, are opened by the binding of neurotransmitters to the channel. The receptor is formed of subunits, and the channel is an integral part of the receptor complex. These channels are insensitive or only weakly sensitive to membrane potential. Activation of these channels typically results in a brief (a few milliseconds to tens of milliseconds) opening of the channel. Ligand-gated channels are responsible for fast synaptic transmission typical of hierarchical pathways in the CNS (see below). It is now well established that the traditional view of completely separate voltage-gated and ligandgated channels requires substantial modifications. As discussed in Chapter 2: Drug Receptors & Pharmacodynamics, most neurotransmitters, in addition to binding to ionotropic receptors, also bind to G protein-coupled receptors, often referred to as metabotropic receptors. Metabotropic receptors, via G proteins, modulate voltage-gated channels. This interaction can occur entirely within the membrane and is referred to as a membrane delimited pathway (Figure 21–1 C). In this case the G protein interacts directly with the voltage-gated ion channel. In general, two types of voltage-gated ion channel are involved in this type of signaling: calcium channels and potassium channels. When G proteins interact with calcium channels, they inhibit channel function. This mechanism accounts for the presynaptic inhibition that occurs when presynaptic metabotropic receptors are activated. In contrast, when these receptors are postsynaptic, they activate (cause the opening of) potassium channels, resulting in a slow postsynaptic inhibition. Metabotropic receptors can also modulate voltage-gated channels less directly by the generation of diffusible second messengers (Figure 21–1 D). A classic example of this type of action is provided by the adrenoceptor, which generates cAMP via the activation of adenylyl cyclase (see Chapter 2: Drug Receptors & Pharmacodynamics). Whereas membrane-delimited actions occur within microdomains in the membrane, second messenger-mediated effects can occur over considerable distances. Finally, an important consequence of the involvement of G proteins in receptor signaling is that, in contrast to the brief effect of ionotropic receptors, the effects of metabotropic receptor activation can last tens of seconds to minutes. Metabotropic receptors predominate in the diffuse neuronal systems in the CNS (see below). Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > The Synapse & Synaptic Potentials The communication between neurons in the CNS occurs through chemical synapses in the vast majority of cases. (A few instances of electrical coupling between neurons have been documented, and such coupling may play a role in synchronizing neuronal discharge. However, it is unlikely that these electrical synapses are an important site of drug action.) The events involved in the release of transmitter from the presynaptic terminal have been studied most extensively at the vertebrate neuromuscular junction and at the giant synapse of the squid. More recently, the calix of Held synapse, a specialized synapse in the brain stem with a large presynaptic terminal, has served as a model for the study of transmitter release from CNS synapses. An action potential in the presynaptic fiber propagates into the synaptic terminal and activates voltage-sensitive calcium channels in the membrane of the terminal (Figure 6–3). The calcium channels responsible for the release of transmitter are generally resistant to the calcium channelblocking agents discussed in Chapter 12: Vasodilators & the Treatment of Angina Pectoris (verapamil, etc) but are sensitive to blockade by certain marine toxins and metal ions (Tables 12–4 and 21–1). Calcium flows into the terminal, and the increase in intraterminal calcium concentration promotes the fusion of synaptic vesicles with the presynaptic membrane. The transmitter contained in the vesicles is released into the synaptic cleft and diffuses to the receptors on the postsynaptic
membrane. Binding of the transmitter to its receptor causes a brief change in membrane conductance (permeability to ions) of the postsynaptic cell. The time delay from the arrival of the presynaptic action potential to the onset of the postsynaptic response is approximately 0.5 ms. Most of this delay is consumed by the release process, particularly the time required for calcium channels to open. Table 21–1. Some Toxins Used to Characterize Ion Channels.
Channel Types
Mode of Toxin Action
Source
Blocks from outside
Puffer fish
Slows inactivation
Scorpion
Slows inactivation, shifts activation
Colombian frog
Apamin
Blocks "small Ca2+-activated" K+ channel
Honeybee
Charybdotoxin
Blocks "big Ca2+-activated" K+ channel
Scorpion
Dendrotoxin
Blocks delayed rectifier
Snake
Omega conotoxin ( -CTXGVIA)
Blocks N-type channel
Pacific cone snail
Agatoxin ( -AGA-IVA)
Blocks P-type channel
Funnel web spider
Irreversible antagonist
Marine snake
Competitive antagonist
Amazon plant
Picrotoxin
Blocks channel
South Pacific plant
Bicuculline
Competitive antagonist
Plant
Competitive antagonist
Indian plant
Blocks channel
Wasp
Voltage-gated Sodium channels Tetrodotoxin (TTX) -Scorpion toxin Batrachotoxin (BTX) Potassium channels
Calcium channels
Ligand-gated Nicotinic ACh receptor -Bungarotoxin d-Tubocurarine GABAA receptor
Glycine receptor Strychnine AMPA receptor Philanthotoxin
associates, who recorded intracellularly from spinal motoneurons. When a microelectrode enters a cell, there is a sudden change in the potential recorded by the electrode, which is typically about – 70 mV (Figure 21–2). This is the resting membrane potential of the neuron. Two types of pathways, excitatory and inhibitory, impinge on the motoneuron. When an excitatory pathway is stimulated, a small depolarization or excitatory postsynaptic potential (EPSP) is recorded. This potential is due to the excitatory transmitter acting on an ionotropic receptor, causing an increase in sodium and potassium permeability. The duration of these potentials is quite brief, usually less than 20 ms. Changing the stimulus intensity to the pathway and therefore the number of presynaptic fibers activated results in a graded change in the size of the depolarization. This indicates that the contribution a single fiber makes to the EPSP is quite small. When a sufficient number of excitatory fibers are activated, the EPSP depolarizes the postsynaptic cell to threshold, and an all-or-none action potential is generated. Figure 21–2.
Excitatory synaptic potentials and spike generation. The figure shows a resting membrane potential of –70 mV in a postsynaptic cell. Stimulation of an excitatory pathway (E) generates transient depolarization. Increasing the stimulus strength (second E) increases the size of the depolarization, so that the threshold for spike generation is reached.
When an inhibitory pathway is stimulated, the postsynaptic membrane is hyperpolarized, producing an inhibitory postsynaptic potential (IPSP) (Figure 21–3). A number of inhibitory synapses must be activated simultaneously to appreciably alter the membrane potential. This hyperpolarization is due to a selective increase in membrane permeability to chloride ions that flow into the cell during the IPSP. If an EPSP that under resting conditions would evoke an action potential in the postsynaptic cell (Figure 21–3) is elicited during an IPSP, it no longer evokes an action potential, because the IPSP has moved the membrane potential farther away from the threshold for action potential generation. A second type of inhibition is termed presynaptic inhibition. It was first described for sensory fibers entering the spinal cord, where excitatory synaptic terminals receive synapses called axoaxonic synapses (Figure 21–5 B). When activated, axoaxonic synapses reduce the amount of transmitter released from the synapses of sensory fibers. Interestingly, presynaptic inhibitory receptors are present on virtually all presynaptic terminals in the brain even though axoaxonic synapses appear to be restricted to the spinal cord. In this case, transmitter spills over to neighboring synapses to activate those presynaptic receptors.
Figure 21–3.
Interaction of excitatory and inhibitory synapses. On the left, a suprathreshold stimulus is given to an excitatory pathway (E). On the right, this same stimulus is given shortly after stimulating an inhibitory pathway (I), which prevents the excitatory potential from reaching threshold. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Sites of Drug Action Virtually all of the drugs that act in the CNS produce their effects by modifying some step in chemical synaptic transmission. Figure 21–4 illustrates some of the steps that can be altered. These transmitter-dependent actions can be divided into presynaptic and postsynaptic categories. Figure 21–4.
Sites of drug action. Schematic drawing of steps at which drugs can alter synaptic transmission. (1) Action potential in presynaptic fiber; (2) synthesis of transmitter; (3) storage; (4) metabolism; (5) release; (6) reuptake; (7) degradation; (8) receptor for the transmitter; (9) receptor-induced increase or decrease in ionic conductance. Drugs acting on the synthesis, storage, metabolism, and release of neurotransmitters fall into the presynaptic category. Synaptic transmission can be depressed by blockade of transmitter synthesis or storage. For example, p-chlorophenylalanine blocks the synthesis of serotonin, and reserpine depletes the synapses of monoamines by interfering with intracellular storage. Blockade of transmitter catabolism can increase transmitter concentrations and has been reported to increase the amount of transmitter released per impulse. Drugs can also alter the release of transmitter. The stimulant amphetamine induces the release of catecholamines from adrenergic synapses. Capsaicin causes the release of the peptide substance P from sensory neurons, and tetanus toxin blocks the release of transmitters. After a transmitter has been released into the synaptic cleft, its action is terminated either by uptake or degradation. For most neurotransmitters, there are uptake mechanisms into the synaptic terminal and also into surrounding neuroglia. Cocaine, for example, blocks the uptake of catecholamines at adrenergic synapses and thus potentiates the action of these amines. However, acetylcholine is inactivated by enzymatic degradation. Anticholinesterases block the degradation of acetylcholine and thereby prolong its action. In contrast, no uptake mechanism has been found for any of the numerous CNS peptides, and it has yet to be demonstrated whether specific enzymatic degradation terminates the action of peptide transmitters. In the postsynaptic region, the transmitter receptor provides the primary site of drug action. Drugs
can act either as neurotransmitter agonists, such as the opioids, which mimic the action of enkephalin, or they can block receptor function. Receptor antagonism is a common mechanism of action for CNS drugs. An example is strychnine's blockade of the receptor for the inhibitory transmitter glycine. This block, which underlies strychnine's convulsant action, illustrates how the blockade of inhibitory processes results in excitation. Drugs can also act directly on the ion channel of ionotropic receptors. For example, barbiturates can enter and block the channel of many excitatory ionotropic receptors. In the case of metabotropic receptors, drugs can act at any of the steps downstream of the receptor. Perhaps the best example is provided by the methylxanthines, which can modify neurotransmitter responses mediated through the second-messenger cAMP. At high concentrations, the methylxanthines elevate the level of cAMP by blocking its metabolism and thereby prolong its action in the postsynaptic cell. The selectivity of CNS drug action is based almost entirely on the fact that different transmitters are used by different groups of neurons. Furthermore, these transmitters are often segregated into neuronal systems that subserve broadly different CNS functions. Without such segregation, it would be impossible to selectively modify CNS function even if one had a drug that operated on a single neurotransmitter system. It is not entirely clear why the CNS has relied on so many neurotransmitters and segregated them into different neuronal systems, since the primary function of a transmitter is either excitation or inhibition; this could be accomplished with two transmitter substances or perhaps even one. That such segregation does occur has provided neuroscientists with a powerful pharmacologic approach for analyzing CNS function and treating pathologic conditions. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Identification of Central Neurotransmitters Since drug selectivity is based on the fact that different pathways utilize different transmitters, it is a primary goal of neuropharmacologists to identify the transmitters in CNS pathways. Establishing that a chemical substance is a transmitter has been far more difficult for central synapses than for peripheral synapses. In theory, to identify a transmitter it is sufficient to show that stimulation of a pathway releases enough of the substance to produce the postsynaptic response. In practice, this experiment cannot be done satisfactorily for at least two reasons. First, the anatomic complexity of the CNS prevents the selective activation of a single set of synaptic terminals. Second, available techniques for measuring the released transmitter and applying the transmitter are not sufficiently precise to satisfy the quantitative requirements. Therefore, the following criteria have been established for transmitter identification. Localization A number of approaches have been used to prove that a suspected transmitter resides in the presynaptic terminal of the pathway under study. These include biochemical analysis of regional concentrations of suspected transmitters, often combined with interruption of specific pathways, and microcytochemical techniques. Immunocytochemical techniques have proved very useful in localizing peptides and enzymes that synthesize or degrade nonpeptide transmitters. Release To determine whether the substance can be released from a particular region, local collection (in vivo) of the extracellular fluid can sometimes be accomplished. In addition, slices of brain tissue can be electrically or chemically stimulated in vitro and the released substances measured. To determine if the release is relevant to synaptic transmission, it is important to establish that the
release is calcium-dependent. As mentioned above, anatomic complexity often prevents identification of the synaptic terminals responsible for the release, and the amount collected in the perfusate is a small fraction of the amount actually released. Synaptic Mimicry Finally, application of the suspected substance should produce a response that mimics the action of the transmitter released by nerve stimulation. Microiontophoresis, which permits highly localized drug administration, has been a valuable technique in assessing the action of suspected transmitters. In practice, this criterion has two parts: physiologic and pharmacologic identity. To establish physiologic identity of action, the substance must be shown to initiate the same change in ionic conductance in the postsynaptic cell as synaptically released transmitter. This requires intracellular recording and determination of the reversal potential and ionic dependencies of the responses. However, since different transmitters can elicit identical ionic conductance changes, this finding is not sufficient. Thus, selective pharmacologic antagonism is used to further establish that the suspected transmitter is acting in a manner identical to synaptically released transmitter. Because of the complexity of the CNS, specific pharmacologic antagonism of a synaptic response provides a particularly powerful technique for transmitter identification.
Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Cellular Organization of the Brain Most of the neuronal systems in the CNS can be divided into two broad categories: hierarchical systems and nonspecific or diffuse neuronal systems. Hierarchical Systems These systems include all of the pathways directly involved in sensory perception and motor control. The pathways are generally clearly delineated, being composed of large myelinated fibers that can often conduct action potentials at a rate in excess of 50 m/s. The information is typically phasic, and in sensory systems the information is processed sequentially by successive integrations at each relay nucleus on its way to the cortex. A lesion at any link will incapacitate the system. Within each nucleus and in the cortex, there are two types of cells: relay or projection neurons and local circuit neurons (Figure 21–5 A). The projection neurons that form the interconnecting pathways transmit signals over long distances. The cell bodies are relatively large, and their axons emit collaterals that arborize extensively in the vicinity of the neuron. These neurons are excitatory, and their synaptic influences, which involve ionotropic receptors, are very short-lived. The excitatory transmitter released from these cells is, in most instances, glutamate. Local circuit neurons are typically smaller than projection neurons, and their axons arborize in the immediate vicinity of the cell body. The vast majority of these neurons are inhibitory, and they release either GABA or glycine. They synapse primarily on the cell body of the projection neurons but can also synapse on the dendrites of projection neurons as well as with each other. A special class of local circuit neurons in the spinal cord forms axoaxonic synapses on the terminals of sensory axons (Figure 21–5 B). Two common types of pathways for these neurons (Figure 21–5 A) include recurrent feedback pathways and feed-forward pathways. In some sensory pathways such as the retina and olfactory bulb, local circuit neurons may actually lack an axon and release neurotransmitter from dendritic synapses in a graded fashion in the absence of action potentials.
Some pathways involving presynaptic dendrites of local circuit neurons are shown in Figure 21–5 C. Figure 21–5.
Pathways in the central nervous system. A shows two relay neurons and two types of inhibitory pathways, recurrent and feed-forward. The inhibitory neurons are shown in black. B shows the pathway responsible for presynaptic inhibition in which the axon of an inhibitory neuron synapses on the axon terminal of an excitatory fiber. C: Diagram illustrating that dendrites may be both preand postsynaptic to each other, forming reciprocal synapses, two of which are shown between the same dendrite pair. In triads, an axon synapses on two dendrites, and one of these dendrites synapses on the second. In serial synapses, a dendrite may be postsynaptic to one dendrite and presynaptic to another, thus connecting a series of dendrites. Dendrites also interact through lowresistance electrotonic ("gap") junctions (two of which are shown). Except for one axon, all
structures shown in C are dendrites. (Reproduced, with permission, from Schmitt FO, Dev P, Smith BH: Electrotonic processing of information by brain cells. Science 1976;193:114. Copyright © 1976 by the American Association for the Advancement of Science.) Although there is a great variety of synaptic connections in these hierarchical systems, the fact that a limited number of transmitters are utilized by these neurons indicates that any major pharmacologic manipulation of this system will have a profound effect on the overall excitability of the CNS. For instance, selectively blocking GABA receptors with a drug such as picrotoxin results in generalized convulsions. Thus, while the mechanism of action of picrotoxin is quite specific in blocking the effects of GABA, the overall functional effect appears to be quite nonspecific, since GABA-mediated synaptic inhibition is so widely utilized in the brain. Nonspecific or Diffuse Neuronal Systems Neuronal systems that contain one of the monoamines—norepinephrine, dopamine, or 5hydroxytryptamine (serotonin)—provide examples in this category. Certain other pathways emanating from the reticular formation and possibly some peptide-containing pathways also fall into this category. These systems differ in fundamental ways from the hierarchical systems, and the noradrenergic systems will serve to illustrate the differences. Noradrenergic cell bodies are found primarily in a compact cell group called the locus ceruleus located in the caudal pontine central gray matter. The number of neurons in this cell group is quite small, approximately 1500 on each side of the brain in the rat. The axons of these neurons are very fine and unmyelinated. Indeed, they were entirely missed with classic anatomic techniques. It was not until the mid 1960s, when the formaldehyde fluorescence histochemical technique was applied to the study of CNS tissues, that the anatomy of the monoamine-containing systems was described. Because these axons are fine and unmyelinated, they conduct very slowly, at about 0.5 m/s. The axons branch repeatedly and are extraordinarily divergent. Branches from the same neuron can innervate several functionally different parts of the CNS. In the neocortex, these fibers have a tangential organization and therefore can monosynaptically influence large areas of cortex. The pattern of innervation in the cortex and nuclei of the hierarchical systems is diffuse, and the noradrenergic fibers form a very small percentage of the total number in the area. In addition, the axons are studded with periodic enlargements called varicosities that contain large numbers of vesicles. In some instances, these varicosities do not form synaptic contacts, suggesting that norepinephrine may be released in a rather diffuse manner, as occurs with the noradrenergic innervation of smooth muscle. This indicates that the cellular targets of these systems will be determined largely by the location of the receptors rather than the location of the release sites. Finally, most neurotransmitters utilized by diffuse neuronal systems, including norepinephrine, act—perhaps exclusively—on metabotropic receptors and therefore initiate long-lasting synaptic effects. Based on all of these observations, it is clear that the monoamine systems cannot be conveying specific topographic types of information—rather, vast areas of the CNS must be affected simultaneously and in a rather uniform way. It is not surprising, then, that these systems have been implicated in such global functions as sleeping and waking, attention, appetite, and emotional states. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs > Central Neurotransmitters A vast number of small molecules have been isolated from brain, and studies using a variety of approaches suggest that the agents listed in Table 21–2 are neurotransmitters. A brief summary of
the evidence for some of these compounds follows. Table 21–2. Summary of Neurotransmitter Pharmacology in the Central Nervous System.
Transmitter
Anatomy
Receptor Subtypes and Preferred Agonists
Acetylcholine
Cell bodies at all levels; long and short connections
Muscarinic (M1): Pirenzepine, muscarine, McN- atropine A-343
Excitatory: in K+ conductance; IP3, DAG
Muscarinic (M2): Atropine, muscarine, methoctramine bethanechol
Inhibitory: K+ conductance; cAMP
Nicotinic: nicotine
Dihydro- erythroidine, bungarotoxin
Excitatory: cation conductance
Cell bodies at D1: SKF 38393 all levels; short, medium, and D2: quinpirole, long bromocriptine connections
Phenothiazines, SCH 23390
Inhibitory (?): cAMP
Phenothiazines, butyrophenones
Inhibitory (presynaptic): Ca2+; Inhibitory (postsynaptic): in K+ conductance, cAMP
Supraspinal interneurons involved in preand postsynaptic inhibition
GABAA: muscimol
Bicuculline, picrotoxin
Inhibitory: Clconductance
GABAB: baclofen
2-OH saclofen, CGP 35348, CGP55845
Inhibitory (presynaptic): Ca2+ conductance; Inhibitory (postsynaptic): K+ conductance
Relay neurons at all levels and some interneurons
N-Methyl-Daspartate (NMDA): NMDA
2-Amino-5Excitatory: phosphonovalerate, cation CPP, MK-801 conductance, particularly Ca2+
AMPA: AMPA
CNQX,
MotoneuronRenshaw cell synapse Dopamine
GABA
Glutamate
Receptor Antagonists
Mechanisms
Excitatory:
GYKI52466 Kainate: kainate, CNQX domoic acid Metabotropic: ACPD, quisqualate
Glycine
Spinal Taurine, interneurons alanine and some brain stem interneurons
5Hydroxytryptamine (serotonin)
Cell bodies in midbrain and pons project to all levels
Norepinephrine
Cell bodies in pons and brain stem project to all levels
cation conductance
MCPG
Inhibitory (presynaptic): Ca2+ conductance; cAMP; Excitatory: K+ conductance, IP3, DAG
Strychnine
Inhibitory: Clconductance
5-HT1A: LSD, 8- Metergoline, OH-DPAT spiperone
Inhibitory: K+ conductance, cAMP
5-HT2A: LSD, DOB
Excitatory: K+ conductance, IP3, DAG
Ketanserin
5-HT3: 2-methyl- ICS 205930, 5-HT, ondansetron phenylbiguanide
Excitatory: cation conductance
5-HT4: BIMU8
Excitatory: K+ conductance
GR 1138089
1:
phenylephrine Prazosin
Excitatory: K+ conductance, IP3, DAG
2:
clonidine
Inhibitory (presynaptic): Ca2+ conductance: Inhibitory: K+ conductance, cAMP
1:
Yohimbine
isoproterenol, Atenolol, practolol dobutamine
Excitatory: K+ conductance, cAMP
2:
Histamine
salbutamol
Butoxamine
Inhibitory: may involve in electrogenic sodium pump; cAMP
Cells in ventral H1: 2(mMepyramine posterior fluorophenyl)hypothalamus histamine phenylhistamine
Excitatory: K+ conductance, IP3, DAG
H2: dimaprit
Opioid peptides
Cell bodies at all levels; long and short connections
Mu: bendorphin, Naloxone, CTOP DAMGO
Delta: enkephalin, DPDPE Kappa: dynorphin, U69593 Tachykinins
Endocannabinoids (anandamide, 2arachidonylglyerol
Ranitidine
Excitatory: K+ conductance, cAMP Inhibitory (presynaptic): Ca2+ conductance, cAMP
Naloxone
Inhibitory (postsynaptic): K+ conductance, Naloxone, nor-BNI cAMP
Primary sensory neurons, cell bodies at all levels; long and short connections
NK1: Substance P methylester
CP99994
NK2: -[Ala8] NKA4–10
SR48968
Widely distributed
CB1: WIN55212- SR141716 2 methylester
Excitatory: K+ conductance, IP3, DAG
NK3: GR138676 [Pro7]NKB Inhibitory (presynaptic): Ca2+ conductance, cAMP
8-OH DPAT, 8-hydroxy-2(di-n-propylamino)tetralin; ACPD, trans-1-amino-cyclopentyl-1,3dicarboxylate; AMPA, DL- -amino-3-hydroxy-5-methylisoxazole-4-propionate; BIMU8, [endo-N-8methyl-8-azabicyclo(3.2.1)oct-3-yl]-2,3-dihydro-3-isopropyl-2-oxo-1H-benzimidazol-1carboxamide hydrochloride; CGP 35348, 3-aminopropyl(diethoxymethyl)phosphinic acid; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; CP 99994, (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-
phenylpiperidine; CPP, 3-(2-carboxypiperazin-4-yI)propyl-1-phosphonic acid; CTOP, D-Phe-CysTyr-D-Trp-Orn-Thr-Pen-Thr-NH2; DAG, diacylglycerol; DAMGO, D-ala-2,Me-Phe4,Gly1enkephalin; DOB, 5-bromo-2,5-dimethoxyamphetamine; DPDPE, D-pen2D-pen5(-enkephalin); GR 113808, (1-{2-[(methylsulfonyl)amino]ethyl}-4-piperidinyl)methyl-1-methyl-1H-indole-3carboxylate; GYKI 52466, 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3benzodiazepine; IP3, inositol trisphosphate; MCPG, -methyl-4-carboxyphenylglycine; MK-801, (dizocilpine), 10,11-dihydro-5-methyl-5H-dibenzo(a,d)cyclohepten-5,10-imine; NK1,2,3, neurokinin and derivatives; nor-BNI, nor-binaltorphimine; SR 141716, N-(piperidine-1yl)-5-(4chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; SR 48968, (S)-Nmethyl-N-(4-acetylamino-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylbenzamide; U-69593, (+)-(5 ,7 ,8 )-N-methyl-N-[7-(1-pyrrolidinyl)]-1-oxaspiro(4,5)dec-8-yl-benzenacetamide; WIN 55212-2, (R)-(+)-[2,3-dihydro-5-methyl-3-[(morpholino)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazin6-yl] (1-naphthyl)methanone Amino Acids The amino acids of primary interest to the pharmacologist fall into two categories: the neutral amino acids glycine and GABA and the acidic amino acid glutamate. All of these compounds are present in high concentrations in the CNS and are extremely potent modifiers of neuronal excitability. Neutral Amino Acids The neutral amino acids are inhibitory and increase membrane permeability to chloride ions, thus mimicking the IPSP. Glycine concentrations are particularly high in the gray matter of the spinal cord, and strychnine, which is a potent spinal cord convulsant and has been used in some rat poisons, selectively antagonizes both the action of glycine and the IPSPs recorded in spinal cord neurons. Thus, it is generally agreed that glycine is released from spinal cord inhibitory local circuit neurons involved in postsynaptic inhibition. GABA receptors are divided into two types: GABAA and GABAB. GABAA receptors open chloride channels and are antagonized by picrotoxin and bicuculline, which both cause generalized convulsions. GABAB receptors, which can be selectively activated by the antispastic drug baclofen, are coupled to G proteins that either inhibit calcium channels or activate potassium channels. In most regions of the brain, IPSPs have a fast and slow component mediated by GABAA and GABAB receptors, respectively. Immunohistochemical studies indicate that a large majority of the local circuit neurons synthesize GABA. A special class of local circuit neuron localized in the dorsal horn of the spinal cord also synthesizes GABA. These neurons form axoaxonic synapses with primary sensory nerve terminals and are responsible for presynaptic inhibition (Figure 21–5 B). Acidic Amino Acids Glutamate is present in very high concentrations in the CNS. Virtually all neurons that have been tested are strongly excited by this amino acid. This excitation is caused by the activation of both ionotropic and metabotropic receptors, which have been extensively characterized by molecular cloning. The ionotropic receptors can be further divided into three subtypes based on the action of the selective agonists: kainate (KA), -amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA), and N-methyl-D-aspartate (NMDA). The AMPA- and KA-activated channels are permeable to sodium and potassium ions and, for certain subtypes, calcium as well. They are often grouped together and referred to as non-NMDA channels. The NMDA-activated channel is highly permeable to sodium, potassium, and calcium ions.
The metabotropic glutamate receptors act indirectly on ion channels via G proteins. They are selectively activated by trans-1-amino-cyclopentyl-1,3-dicarboxylate (ACPD). These G proteincoupled receptors are either positively coupled to (ie, stimulate) phospholipase C or negatively coupled to adenylyl cyclase. Depending on the type of synapse, metabotropic glutamate receptors can initiate a slow postsynaptic excitation or a presynaptic inhibition. Although the presence of metabotropic receptors at excitatory synapses varies, most excitatory synapses contain both NMDA receptors and non-NMDA receptors in the postsynaptic membrane. The role of NMDA receptors has received considerable attention. These receptors play a critical role in synaptic plasticity, which is thought to underlie certain forms of learning and memory. They are selectively blocked by the dissociative anesthetic ketamine and the hallucinogenic drug phencyclidine. These drugs exert their effects by entering and blocking the open channel. Some drugs that block this receptor channel have potent antiepileptic activity in animal models, though these drugs have yet to be tested clinically. Considerable evidence exists that the release of glutamate during neuronal injury can, by activating the NMDA receptor, cause further cell injury and death. Thus, a particularly exciting finding is that blocking the NMDA receptor can attenuate the neuronal damage caused by anoxia in experimental animals. The potential therapeutic benefits of this action are considerable, although clinical trials to date have been disappointing. Acetylcholine Acetylcholine was the first compound to be identified pharmacologically as a transmitter in the CNS. Eccles showed in the early 1950s that excitation of Renshaw cells by motor axon collaterals was blocked by nicotinic antagonists. Furthermore, Renshaw cells were extremely sensitive to nicotinic agonists. These experiments were remarkable for two reasons. First, this early success at identifying a transmitter for a central synapse was followed by disappointment, because it remained the sole central synapse for which the transmitter was known until the late 1960s, when comparable data became available for the neutral amino acids. Second, the motor axon collateral synapse remains one of the best-documented examples of a cholinergic nicotinic synapse in the mammalian CNS, despite the rather widespread distribution of nicotinic receptors as defined by in situ hybridization studies. Most CNS responses to acetylcholine are mediated by a large family of G protein-coupled muscarinic receptors. At a few sites, acetylcholine causes slow inhibition of the neuron by activating the M2 subtype of receptor, which opens potassium channels. A far more widespread muscarinic action in response to acetylcholine is a slow excitation that in some cases is mediated by M1 receptors. These muscarinic effects are much slower than either nicotinic effects on Renshaw cells or the effect of amino acids. Furthermore, this muscarinic excitation is unusual in that acetylcholine produces it by decreasing the membrane permeability to potassium, ie, the opposite of conventional transmitter action. A number of pathways contain acetylcholine, including neurons in the neostriatum, the medial septal nucleus, and the reticular formation. Cholinergic pathways appear to play an important role in cognitive functions, especially memory. Presenile dementia of the Alzheimer type is reportedly associated with a profound loss of cholinergic neurons. However, the specificity of this loss has been questioned since the levels of other putative transmitters, eg, somatostatin, are also decreased. Monoamines Monoamines include the catecholamines (dopamine and norepinephrine) and 5-hydroxytryptamine. Although these compounds are present in very small amounts in the CNS, they can be localized using extremely sensitive histochemical methods. These pathways are the site of action of many drugs; for example, the CNS stimulants cocaine and amphetamine are believed to act primarily at
catecholamine synapses. Cocaine blocks the reuptake of dopamine and norepinephrine, while amphetamines cause presynaptic terminals to release these transmitters. Dopamine The major pathways containing dopamine are the projection linking the substantia nigra to the neostriatum and the projection linking the ventral tegmental region to limbic structures, particularly the limbic cortex. The therapeutic action of the antiparkinsonism drug levodopa is associated with the former area, whereas the therapeutic action of the antipsychotic drugs is thought to be associated with the latter area. Dopamine-containing neurons in the tuberobasal ventral hypothalamus play an important role in regulating hypothalamohypophysial function. A number of dopamine receptors have been identified, and they fall into two categories: D1-like and D2-like. All dopamine receptors are metabotropic. Dopamine generally exerts a slow inhibitory action on CNS neurons. This action has been best characterized on dopamine-containing substantia nigra neurons, where D2 receptor activation opens potassium channels. Norepinephrine This system has already been discussed. Most noradrenergic neurons are located in the locus ceruleus or the lateral tegmental area of the reticular formation. Although the density of fibers innervating various sites differs considerably, most regions of the central nervous system receive diffuse noradrenergic input. All noradrenergic receptor subtypes are metabotropic. When applied to neurons, norepinephrine can hyperpolarize them by increasing potassium conductance. This effect is mediated by 2 receptors and has been characterized most thoroughly on locus ceruleus neurons. In many regions of the CNS, norepinephrine actually enhances excitatory inputs by both indirect and direct mechanisms. The indirect mechanism involves disinhibition, ie, inhibitory local circuit neurons are inhibited. The direct mechanism is blockade of potassium conductances that slow neuronal discharge. Depending on the type of neuron, this effect is mediated by either 1 or receptors. Facilitation of excitatory synaptic transmission is in accordance with many of the behavioral processes thought to involve noradrenergic pathways, eg, attention and arousal. 5-Hydroxytryptamine Most 5-hydroxytryptamine (5-HT, serotonin) pathways originate from neurons in the raphe or midline regions of the pons and upper brain stem. 5-HT is contained in unmyelinated fibers that diffusely innervate most regions of the CNS, but the density of the innervation varies. 5-HT acts on more than a dozen receptor subtypes. Except for the 5-HT3 receptor, all of these receptors are metabotropic. The ionotropic 5-HT3 receptor exerts a rapid excitatory action at a very limited number of sites in the CNS. In most areas of the central nervous system, 5-HT has a strong inhibitory action. This action is mediated by 5-HT1A receptors and is associated with membrane hyperpolarization caused by an increase in potassium conductance. It has been found that 5-HT1A receptors and GABAB receptors share the same potassium channels. Some cell types are slowly excited by 5-HT owing to its blockade of potassium channels via 5-HT2 or 5-HT4 receptors. Both excitatory and inhibitory actions can occur on the same neurons. It has often been speculated that 5HT pathways may be involved in the hallucinations induced by LSD, since this compound can antagonize the peripheral actions of 5-HT. However, LSD does not appear to be a 5-HT antagonist in the central nervous system, and typical LSD-induced behavior is still seen in animals after raphe nuclei are destroyed. Other proposed regulatory functions of 5-HT-containing neurons include sleep, temperature, appetite, and neuroendocrine control. Peptides
A great many CNS peptides have been discovered that produce dramatic effects both on animal behavior and on the activity of individual neurons. Many of the peptides have been mapped with immunohistochemical techniques and include opioid peptides (enkephalins, endorphins, etc), neurotensin, substance P, somatostatin, cholecystokinin, vasoactive intestinal polypeptide, neuropeptide Y, and thyrotropin-releasing hormone. As in the peripheral autonomic nervous system, peptides often coexist with a conventional nonpeptide transmitter in the same neuron. A good example of the approaches used to define the role of these peptides in the central nervous system comes from studies on substance P and its association with sensory fibers. Substance P is contained in and released from small unmyelinated primary sensory neurons of the spinal cord and brain stem and causes a slow EPSP in target neurons. These sensory fibers are known to transmit noxious stimuli, and it is therefore surprising that—while substance P receptor antagonists can modify responses to certain types of pain—they do not block the response. Glutamate, which is released with substance P from these synapses, presumably plays an important role in transmitting pain stimuli. Substance P is certainly involved in many other functions, since it is found in many areas of the central nervous system that are unrelated to pain pathways. Many of these peptides are also found in peripheral structures, including peripheral synapses. They are described in Chapter 6: Introduction to Autonomic Pharmacology and Chapter 17: Vasoactive Peptides. Nitric Oxide The CNS contains a substantial amount of nitric oxide synthase (NOS), which is found within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMDA receptors, which increases intracellular calcium, results in the generation of nitric oxide. While a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. Endocannabinoids The primary psychoactive ingredient in cannabis, 9-tetrahydrocannabinol ( 9-THC), affects the brain mainly by activating a specific cannabinoid receptor, CB1. CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids, including anandamide and 2arachidonylglycerol, have been identified as CB1 ligands. These ligands are not stored, as are classic neurotransmitters, but instead are rapidly synthesized by neurons in response to depolarization and consequent calcium influx. In further contradistinction to classic neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: they are released from postsynaptic neurons and travel backward across synapses, activating CB1 receptors on presynaptic neurons and suppressing transmitter release. Cannabinoids may affect memory, cognition, and pain perception by this mechanism. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 21. Introduction to the Pharmacology of CNS Drugs >
Chapter 22. Sedative-Hypnotic Drugs Sedative-Hypnotic Drugs: Introduction Assignment of a drug to the sedative-hypnotic class indicates that its major therapeutic use is to cause sedation (with concomitant relief of anxiety) or to encourage sleep. Because there is considerable chemical variation within this group, this drug classification is based on clinical uses
rather than on similarities in chemical structure. Anxiety states and sleep disorders are common problems, and sedative-hypnotics are among the most widely prescribed drugs worldwide. Katzung PHARMACOLOGY, 9e > Section V. Drugs That Act in the Central Nervous System > Chapter 22. Sedative-Hypnotic Drugs > Basic Pharmacology of Sedative-Hypnotics An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect. The degree of central nervous system depression caused by a sedative should be the minimum consistent with therapeutic efficacy. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep. Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most drugs in this class simply by increasing the dose. Graded dose-dependent depression of central nervous system function is a characteristic of sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of central nervous system depression. Two examples of such dose-response relationships are shown in Figure 22–1. The linear slope for drug A is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose above that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, will require proportionately greater dosage increments in order to achieve central nervous system depression more profound than hypnosis. This appears to be the case for benzodiazepines and certain newer hypnotics; the greater margin of safety this offers is an important reason for their widespread use to treat anxiety states and sleep disorders. Figure 22–1.
Dose-response curves for two hypothetical sedative-hypnotics. Chemical Classification The benzodiazepines (Figure 22–2) are the most widely used sedative-hypnotics. All of the structures shown are 1,4-benzodiazepines, and most contain a carboxamide group in the 7-
membered heterocyclic ring structure. A substituent in the 7 position, such as a halogen or a nitro group, is required for sedative-hypnotic activity. The structures of triazolam and alprazolam include the addition of a triazole ring at the 1,2-position, and such drugs are sometimes referred to as triazolobenzodiazepines. Figure 22–2.
Chemical structures of benzodiazepines.
The chemical structures of some older and less commonly used sedative-hypnotics, including several barbiturates, are shown in Figure 22–3. Glutethimide (a piperidinedione) and meprobamate (a carbamate) are of distinctive chemical structure but are practically equivalent to barbiturates in their pharmacologic effects, and their clinical use is rapidly declining. The sedative-hypnotic class also includes compounds of simple chemical structure, including ethanol (see Chapter 23: The Alcohols), chloral hydrate, trichloroethanol, and paraldehyde (not shown). Figure 22–3.
Chemical structures of barbiturates and other sedative-hypnotics. Several drugs with novel chemical structures have been introduced recently. Buspirone is an anxiolytic agent that has actions different from those of conventional sedative-hypnotic drugs. Zolpidem and zaleplon, while structurally unrelated to benzodiazepines, share a similar mechanism of action.
Other classes of drugs not included in Figure 22–3 that may exert sedative effects include most antipsychotic and many antidepressant drugs and certain antihistaminic agents (eg, hydroxyzine, promethazine). As discussed in other chapters, these agents differ from conventional sedativehypnotics in both their effects and their major therapeutic uses. Since they commonly exert marked effects on the peripheral autonomic nervous system, they are sometimes referred to as "sedativeautonomic" drugs. Certain antihistaminics with sedative effects are available in over-the-counter sleep aids. Their autonomic properties and their long durations of action can result in adverse effects. The Benzodiazepines & Barbiturates Pharmacokinetics Absorption and Distribution The rates of oral absorption of benzodiazepines differ depending on a number of factors, including lipophilicity. Oral absorption of triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines. Clorazepate is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Oxazepam, lorazepam, and temazepam are absorbed from the gut at slower rates than other benzodiazepines. The bioavailability of several benzodiazepines, including chlordiazepoxide and diazepam, may be unreliable after intramuscular injection. Most of the barbiturates and other older sedative-hypnotics are absorbed rapidly into the blood following their oral administration. Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the central nervous system. For example, diazepam and triazolam are more lipid-soluble than chlordiazepoxide and lorazepam; thus, the central nervous system actions of the former drugs are
more rapid in onset. The thiobarbiturates (eg, thiopental), in which the oxygen on C2 is replaced by sulfur, are very lipid-soluble, and a high rate of entry into the central nervous system contributes to the rapid onset of their central effects (see Chapter 25: General Anesthetics). In contrast, phenobarbital and meprobamate have quite low lipid solubility and penetrate the brain slowly. All sedative-hypnotics cross the placental barrier during pregnancy. If sedative-hypnotics are given in the predelivery period, they may contribute to the depression of neonatal vital functions. Sedative-hypnotics are detectable in breast milk and may exert depressant effects in the nursing infant. Although sedative-hypnotic drugs, including benzodiazepines, bind to plasma proteins, few clinically significant interactions involving these drugs appear to be based on such protein binding. One exception is chloral hydrate, which transiently increases the anticoagulant effects of warfarin by displacement of the anticoagulant drug from such binding sites. Biotransformation Metabolic transformation to more water-soluble metabolites is necessary for clearance of sedativehypnotics from the body. The microsomal drug-metabolizing enzyme systems of the liver are most important in this regard. Few sedative-hypnotics are excreted from the body in unchanged form, so elimination half-life depends mainly on the rate of metabolic transformation. Benzodiazepines Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including N-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, with long half-lives. As shown in Figure 22–4, desmethyldiazepam, which has an elimination half-life of more than 40 hours, is an active metabolite of chlordiazepoxide, diazepam, prazepam, and clorazepate. Desmethyldiazepam in turn is biotransformed to the active compound, oxazepam. Other active metabolites of chlordiazepoxide include desmethylchlordiazepoxide and demoxepam. While diazepam is metabolized mainly to desmethyldiazepam, it is also converted to temazepam (not shown in Figure 22–4), which is further metabolized in part to oxazepam. Flurazepam, which is used mainly for hypnosis, is oxidized by hepatic enzymes to three active metabolites, desalkylflurazepam, hydroxyethylflurazepam, and flurazepam aldehyde (not shown), which have elimination half-lives ranging from 30 to 100 hours. Alprazolam and triazolam undergo hydroxylation, and the resulting metabolites appear to exert short-lived pharmacologic effects since they are rapidly conjugated to form inactive glucuronides. Figure 22–4.
Biotransformation of benzodiazepines. (Boldface, drugs available for clinical use; *, active metabolite.) The formation of active metabolites has complicated studies on the pharmacokinetics of the benzodiazepines in humans because the elimination half-life of the parent drug may have little relationship to the time course of pharmacologic effects. Those benzodiazepines for which the parent drug or active metabolites have long half-lives are more likely to cause cumulative effects with multiple doses. Cumulative and residual effects such as excessive drowsiness appear to be less of a problem with such drugs as estazolam, oxazepam, and lorazepam, which have shorter half-lives and are metabolized directly to inactive glucuronides. Some pharmacokinetic properties of selected benzodiazepines are listed in Table 22–1. Table 22–1. Pharmacokinetic Properties of Benzodiazepines in Humans.
Drug
Peak Blood Level (hours)
Elimination HalfLife1 (hours)
Comments
Alprazolam
1–2
12–15
Rapid oral absorption
Chlordiazepoxide 2–4
15–40
Active metabolites; erratic bioavailability from IM injection
Clorazepate
50–100
Prodrug; hydrolyzed to active form in stomach
1–2 (nordiazepam)
Diazepam
1–2
20–80
Active metabolites; erratic bioavailability from IM injection
Estazolam
2
10–24
No active metabolites
Flurazepam
1–2
40–100
Active metabolites with long halflives
Lorazepam
1–6
10–20
No active metabolites
Oxazepam
2–4
10–20
No active metabolites
Prazepam
1–2
50–100
Active metabolites with long halflives
Quazepam
2
30–100
Active metabolites with long halflives
Temazepam
2–3
10–40
Slow oral absorption
Triazolam
1
2–3
Rapid onset; short duration of action
1
Includes half-lives of major metabolites.
Barbiturates With the exception of phenobarbital, only insignificant quantities of the barbiturates are excreted unchanged. The major metabolic pathways involve oxidation by hepatic enzymes of chemical groups attached to C5, which are different for the individual barbiturates. The alcohols, acids, and ketones formed appear in the urine as glucuronide conjugates. With very few exceptions, the metabolites of the barbiturates lack pharmacologic activity. The overall rate of hepatic metabolism in humans depends on the individual drug but (with the exception of the thiobarbiturates) is usually slow. The elimination half-lives of secobarbital and pentobarbital range from 18 to 48 hours in different individuals. The elimination half-life of phenobarbital in humans is 4–5 days. Multiple dosing with these agents can lead to cumulative effects. Excretion The water-soluble metabolites of benzodiazepines and other sedative-hypnotics are excreted mainly via the kidney. In most cases, changes in renal function do not have a marked effect on the elimination of parent drugs. Phenobarbital is excreted unchanged in the urine to a certain extent (20–30% in humans), and its elimination rate can be increased significantly by alkalinization of the urine. This is partly due to increased ionization at alkaline pH, since phenobarbital is a weak acid with a pKa of 7.4. Only trace amounts of the benzodiazepines appear in the urine unchanged. Factors Affecting Biodisposition The biodisposition of sedative-hypnotics can be influenced by several factors, particularly alterations in hepatic function resulting from disease or drug-induced increases or decreases in microsomal enzyme activities (see Chapter 4: Drug Biotransformation). In very old patients and in patients with severe liver disease, the elimination half-lives of these drugs are often increased significantly. In such cases, multiple normal doses of these sedativehypnotics often result in excessive central nervous system effects.
The activity of hepatic microsomal drug-metabolizing enzymes may be increased in patients exposed to certain older sedative-hypnotics on a chronic basis (enzyme induction; see Chapter 4: Drug Biotransformation). Barbiturates (especially phenobarbital) and meprobamate are most likely to cause this effect, which may result in an increase in their hepatic metabolism as well as that of other drugs. Increased biotransformation of other pharmacologic agents as a result of enzyme induction by barbiturates is a potential mechanism underlying drug interactions (Appendix II). In contrast, the benzodiazepines do not change hepatic drug-metabolizing enzyme activity with continuous use. Pharmacodynamics of Benzodiazepines & Barbiturates Molecular Pharmacology of the GABAA Receptor The benzodiazepines, the barbiturates, zolpidem, and many other drugs bind to molecular components of the GABAA receptor present in neuronal membranes in the central nervous system. This receptor, which functions as a chloride ion channel, is activated by the inhibitory neurotransmitter GABA (see Chapter 21: Introduction to the Pharmacology of CNS Drugs). The GABAA receptor has a pentameric structure assembled from five subunits (each with four transmembrane-spanning domains) selected from multiple polypeptide classes ( , , , , , , , etc). Different subunits of several of these classes have been characterized, eg, six different , four , and three . A major isoform of the GABAA receptor found in many regions of the brain consists of two 1 and two 2 subunits and one 2 subunit. In this receptor isoform, the binding site for GABA is located between an 1 and a 2 subunit and the binding pocket for benzodiazepines (a benzodiazepine receptor subtype, BZ1 or 1) is between an 1 and the 2 subunit. However, GABAA receptors in different areas of the central nervous system consist of various combinations of the essential subunits, and the benzodiazepines bind to many of these, including receptor isoforms containing 2, 3, and 5 subunits. Barbiturates also bind to multiple isoforms of the GABAA receptor but at different sites from those with which benzodiazepines interact. In contrast to benzodiazepines, zolpidem and zaleplon bind more selectively since these drugs only interact with GABAA receptor isoforms that contain 1 subunits (BZ1 subtype). The heterogeneity of GABAA receptors may constitute the molecular basis for the varied pharmacologic actions of benzodiazepines and related drugs (see GABA Receptor Heterogeneity & Pharmacologic Selectivity). A model of the hypothetical GABA-BZ receptor-chloride ion channel macromolecular complex is shown in Figure 22–5. Figure 22–5.
A model of the GABAA receptor-chloride ion channel macromolecular complex (many others could be proposed). A heteroligomeric glycoprotein, the complex consists of five or more membrane-spanning subunits. Multiple forms of , , and subunits are arranged in different pentameric combinations so that GABAA receptors exhibit molecular heterogeneity. GABA appears to interact with or subunits triggering chloride channel opening with resultant membrane hyperpolarization. Binding of benzodiazepines to subunits or to an area of the unit influenced by the unit facilitates the process of channel opening but does not directly initiate chloride current. (Modified and reproduced, with permission, from Zorumsky CF, Isenberg KE: Insights into the structure and function of GABA-benzodiazepine receptors: Ion channels and psychiatry. Am J Psychiatry 1991;148:162.) Neuropharmacology Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Electrophysiologic studies have shown that benzodiazepines potentiate GABAergic inhibition at all levels of the neuraxis, including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex, and cerebral cortex. Benzodiazepines appear to increase the efficiency of GABAergic synaptic inhibition. The benzodiazepines do not substitute for GABA but appear to enhance GABA's effects without directly activating GABA receptors or opening the associated chloride channels. The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes the form of an increase in the frequency of channel-opening events Barbiturates also facilitate the actions of GABA at multiple sites in the central nervous system, but—in contrast to benzodiazepines—they appear to increase the duration of the GABA-gated chloride channel openings. At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. These effects involve a binding site or sites distinct from the benzodiazepine binding sites. Barbiturates are less selective in their actions than benzodiazepines, since they also depress the actions of excitatory neurotransmitters (eg, glutamic acid) and exert nonsynaptic membrane effects in parallel with their effects on GABA neurotransmission. This
multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia (see Chapter 25: General Anesthetics) and for their more pronounced central depressant effects (which result in their low margin of safety) compared to benzodiazepines. Benzodiazepine Receptor Ligands The components of the GABAA receptor-chloride ion channel macromolecule that function as benzodiazepine receptors exhibit heterogeneity and include BZ1 ( 1) and BZ2 ( 2) subtypes (see The Versatility of the Chloride Channel GABA Receptor Complex). Three types of ligandbenzodiazepine receptor interactions have been reported: (1) Agonists facilitate GABA actions, and this occurs at multiple BZ receptor sites in the case of the benzodiazepines. The nonbenzodiazepines zolpidem and zaleplon are selective agonists at the BZ1 ( 1) receptor subtype. Endogenous agonist ligands for the BZ receptors have been proposed, since benzodiazepine-like chemicals have been isolated from brain tissue of animals never exposed to these drugs. Nonbenzodiazepine molecules that have affinity for benzodiazepine receptors have also been detected in human brain. Such "endozepines" facilitate GABA-mediated chloride channel gating in cultured neurons. (2) Antagonists are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines and zolpidem but does not antagonize the actions of barbiturates, meprobamate, or ethanol. Certain endogenous compounds, eg, diazepambinding inhibitor (DBI), are also capable of blocking the interaction of benzodiazepines with benzodiazepine receptors. (3) Inverse agonists act as negative allosteric modulators of GABA receptor function. Their interaction with benzodiazepine receptors can produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the -carbolines, eg, n-butyl- -carboline-3-carboxylate ( -CCB). In addition to their direct actions, these molecules can block the effects of benzodiazepines. The physiologic significance of endogenous modulators of the functions of GABA in the central nervous system remains unclear. To date it has not been established that the putative endogenous ligands of BZ receptors play a role in the control of states of anxiety, sleep patterns, or any other characteristic behavioral expression of central nervous system function. Organ Level Effects Sedation Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic actions of sedative-hypnotics are accompanied by some decremental effects on psychomotor and cognitive functions. In experimental animal models, sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the tricyclic antidepressants and antihistamines. However, the disinhibition of previously suppressed behavior may be more related to behavioral disinhibitory effects of sedative-hypnotics, including euphoria, impaired judgment, and loss of self-control, which can occur at dosages in the range of those used for management of anxiety. The benzodiazepines also exert dose-dependent anterograde amnesic effects (inability to remember events occurring during the drug's duration of action). Hypnosis By definition, all of the sedative-hypnotics will induce sleep if high enough doses are given. The effects of sedative-hypnotics on the stages of sleep depend on several factors, including the specific
drug, the dose, and the frequency of its administration. The effects of benzodiazepines and older sedative-hypnotics on patterns of normal sleep are as follows: (1) the latency of sleep onset is decreased (time to fall asleep); (2) the duration of stage 2 NREM sleep is increased; (3) the duration of REM sleep is decreased; and (4) the duration of stage 4 NREM slow-wave sleep is decreased. Zolpidem also decreases REM sleep but has minimal effect on slow-wave sleep. Zaleplon decreases the latency of sleep onset with little effect on total sleep time, NREM, or REM sleep. More rapid onset of sleep and prolongation of stage 2 are presumably clinically useful effects. However, the significance of sedative-hypnotic drug effects on REM and slow-wave sleep is not clear. Deliberate interruption of REM sleep causes anxiety and irritability followed by a rebound increase in REM sleep at the end of the experiment. A similar pattern of "REM rebound" can be detected following abrupt cessation of drug treatment with sedative-hypnotics, especially when drugs with short durations of action are used at high doses. Despite possible reductions in slowwave sleep, there are no reports of disturbances in the secretion of pituitary or adrenal hormones when either barbiturates or benzodiazepines are used as hypnotics. The use of sedative-hypnotics for more than 1–2 weeks leads to some tolerance to their effects on sleep patterns. Anesthesia As shown in Figure 22–1, certain sedative-hypnotics in high doses will depress the central nervous system to the point known as stage III of general anesthesia (see Chapter 25: General Anesthetics). However, the suitability of a particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous administration, a characteristic favoring their use for induction of the anesthetic state. Rapid tissue redistribution accounts for the short duration of action of these drugs, a feature useful in recovery from anesthesia. Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25: General Anesthetics), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. Anticonvulsant Effects Most of the sedative-hypnotics are capable of inhibiting the development and spread of epileptiform activity in the central nervous system. Some selectivity exists in that some members of the group can exert anticonvulsant effects without marked central nervous system depression (although psychomotor function may be impaired). Several benzodiazepines—including clonazepam, nitrazepam, lorazepam, and diazepam—are sufficiently selective to be clinically useful in the management of seizure states (see Chapter 24: Antiseizure Drugs). Of the barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizures. Muscle Relaxation Some sedative-hypnotics, particularly members of the carbamate and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of
usefulness for relaxing contracted voluntary muscle in joint disease or muscle spasm (see Clinical Pharmacology). Effects on Respiration and Cardiovascular Function At hypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are comparable to changes during natural sleep. However, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics. At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. Tolerance; Psychologic & Physiologic Dependence Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in an increase in the dose needed to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (Chapter 23: The Alcohols)—a feature of some clinical importance, as explained below. The mechanisms respo