SECTION I-BASIC PRINCIPLES 1.Introduction-Bertram G.Katzung,MD,PhD INTRODUCTION 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. THE HISTORY OF PHARMACOLOGY Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials.Early written records from China and from Egypt list remedies of many types,including a few still recognized as useful drugs today.Most,however,were worthless or actually harmful.In the 1500 years or so preceding the present,there were sporadic attempts to introduce rational methods into medicine,but none was 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 real 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,Francois 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
SECTION I - BASIC PRINCIPLES 1. Introduction Bertram G. Katzung, MD, PhD INTRODUCTION 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. THE HISTORY OF PHARMACOLOGY Prehistoric people undoubtedly recognized the beneficial or toxic effects of many plant and animal materials. Early written records from China and from Egypt list remedies of many types, including a few still recognized as useful drugs today. Most, however, were worthless or actually harmful. In the 1500 years or so preceding the present, there were sporadic attempts to introduce rational methods into medicine, but none was 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 medicathe science of drug preparation and the medical use of drugsbegan to develop as the precursor to pharmacology. However, any real 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 andeven moreby the lack of methods for testing hypotheses about the nature of drug actions. In the late 18th and early 19th centuries, Francois 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."Not until the concepts of rational therapeutics,especially that of the controlled clinical trial,were reintroduced into medicine-only about 50 years ago-did it become possible to accurately evaluate therapeutic claims. Around the same time,a major expansion of research efforts in all areas of biology began.As new concepts and new techniques were introduced,information accumulated about drug action and the biologic substrate of that action,the drug receptor.During the last half-century,many fundamentally new drug groups and new members of old groups were introduced.The last three 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)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 and the ways that receptor proteins have evolved.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 Box:Pharmacology Genetics).Much of that progress is summarized in this book. The extension of scientific principles into everyday therapeutics is still going on,although 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 have led to rejection of medical science by a segment of the public and to 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 dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety,ie,there should be no artificial separation between scientific medicine and "alternative"or "complementary"medicine. PHARMACOLOGY GENETICS 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.During the last 10 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
medicines." Not until the concepts of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicineonly about 50 years agodid it become possible to accurately evaluate therapeutic claims. Around the same time, a major expansion of research efforts in all areas of biology began. As new concepts and new techniques were introduced, information accumulated about drug action and the biologic substrate of that action, the drug receptor. During the last half-century, many fundamentally new drug groups and new members of old groups were introduced. The last three 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) has led to the discovery of many orphan receptorsreceptors 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 speciesfrom bacteria to humanshas led to the recognition of unsuspected relationships between receptor families and the ways that receptor proteins have evolved. Pharmacogenomicsthe relation of the individual's genetic makeup to his or her response to specific drugsis close to becoming a practical area of therapy (see Box: Pharmacology & Genetics). Much of that progress is summarized in this book. The extension of scientific principles into everyday therapeutics is still going on, although 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 have led to rejection of medical science by a segment of the public and to 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 dietary supplements and all therapies promoted as health-enhancing should meet the same standards of efficacy and safety, ie, there should be no artificial separation between scientific medicine and "alternative" or "complementary" medicine. PHARMACOLOGY GENETICS 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. During the last 10 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 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 usually have complete suppression of that function, whereas heterozygous animals usually have partial suppression.Observation of the behavior, biochemistry,and physiology of the knockout mice often defines 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,which overexpress certain proteins of interest. Some patients respond to certain drugs with greater than usual sensitivity to standard doses.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.(Such variations are discussed in Chapter 4.)Pharmacogenomics(or pharmacogenetics)is the study of the genetic variations that cause differences in drug response among individuals or populations. Future clinicians may screen every patient for a variety of such differences before prescribing a drug. PHARMACOLOGY THE PHARMACEUTICAL INDUSTRY Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to "big pharma,"the multibillion-dollar corporations that specialize in drug discovery and development.These entities deserve great credit for making possible many of the therapeutic advances that we enjoy today.As described in Chapter 5,these companies are uniquely skilled in exploiting discoveries from academic and governmental laboratories and translating these basic findings into commercially successful therapeutic breakthroughs. Such breakthroughs come at a price,however,and the escalating cost of drugs has become a significant contributor to the inflationary increase in the cost of health care.Development of new drugs is enormously expensive and to survive and prosper,big pharma must pay the costs of drug development and marketing and return a profit to its shareholders.At present,considerable controversy surrounds drug pricing.Critics claim that the costs of development and marketing are
treatment. 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 usually have complete suppression of that function, whereas heterozygous animals usually have partial suppression. Observation of the behavior, biochemistry, and physiology of the knockout mice often defines 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, which overexpress certain proteins of interest. Some patients respond to certain drugs with greater than usual sensitivity to standard doses. 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. (Such variations are discussed in Chapter 4.) Pharmacogenomics (or pharmacogenetics) is the study of the genetic variations that cause differences in drug response among individuals or populations. Future clinicians may screen every patient for a variety of such differences before prescribing a drug. PHARMACOLOGY THE PHARMACEUTICAL INDUSTRY Much of the recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry and specifically to "big pharma," the multibillion-dollar corporations that specialize in drug discovery and development. These entities deserve great credit for making possible many of the therapeutic advances that we enjoy today. As described in Chapter 5, these companies are uniquely skilled in exploiting discoveries from academic and governmental laboratories and translating these basic findings into commercially successful therapeutic breakthroughs. Such breakthroughs come at a price, however, and the escalating cost of drugs has become a significant contributor to the inflationary increase in the cost of health care. Development of new drugs is enormously expensive and to survive and prosper, big pharma must pay the costs of drug development and marketing and return a profit to its shareholders. At present, considerable controversy surrounds drug pricing. Critics claim that the costs of development and marketing are
grossly inflated by marketing procedures,which may consume as much as 25%or more of a company's budget in advertising and other promotional efforts.Furthermore,profit margins for big pharma have historically exceeded all other industries by a significant factor.Finally,pricing schedules for many drugs vary dramatically from country to country and even within countries, where large organizations can negotiate favorable prices and small ones cannot.Some countries have already addressed these problems,and it seems likely that all countries will have to do so during the next few decades. GENERAL PRINCIPLES OF PHARMACOLOGY 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.In a very small number of cases,drugs known as chemical antagonists may interact directly with other drugs,whereas a few drugs (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 the Greek xenos,meaning "stranger").Poisons are drugs that have almost exclusively harmful effects.However,Paracelsus (1493-1541)famously stated that "the dose makes the poison,"meaning that almost all substances can be harmful if taken in the wrong dosage.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. 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. A.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.The most common routes of administration are described in Chapter 3.The various classes of organic compounds-carbohydrates,proteins,lipids,and their constituents-are all represented in pharmacology A number of useful or dangerous drugs are inorganic elements,eg,lithium,iron,and heavy metals. Many organic 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)
grossly inflated by marketing procedures, which may consume as much as 25% or more of a company's budget in advertising and other promotional efforts. Furthermore, profit margins for big pharma have historically exceeded all other industries by a significant factor. Finally, pricing schedules for many drugs vary dramatically from country to country and even within countries, where large organizations can negotiate favorable prices and small ones cannot. Some countries have already addressed these problems, and it seems likely that all countries will have to do so during the next few decades. GENERAL PRINCIPLES OF PHARMACOLOGY 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. In a very small number of cases, drugs known as chemical antagonists may interact directly with other drugs, whereas a few drugs (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 the Greek xenos, meaning "stranger"). Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus (1493-1541) famously stated that "the dose makes the poison," meaning that almost all substances can be harmful if taken in the wrong dosage. 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. 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. A. 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. The most common routes of administration are described in Chapter 3. The various classes of organic compoundscarbohydrates, proteins, lipids, and their constituentsare all represented in pharmacology. A number of useful or dangerous drugs are inorganic elements, eg, lithium, iron, and heavy metals. Many organic 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)
B.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,most 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.To have a good "fit"to only one type of receptor,a drug molecule must be sufficiently unique in shape,charge,and other properties,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 do not diffuse readily between compartments of the body (see Permeation,below).Therefore,very large drugs (usually proteins)must often 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 or intra-arterial infusion. C.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 acetyl group of aspirin and its enzyme target in platelets,cyclooxygenase,is not readily broken.The platelet aggregation-blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes)and is reversed only by the synthesis of new enzyme in new platelets,a process that takes about 7 days.Other examples of highly reactive, covalent bond-forming drugs are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor. 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 that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of 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 short-acting 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
B. 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, most 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. To have a good "fit" to only one type of receptor, a drug molecule must be sufficiently unique in shape, charge, and other properties, 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 do not diffuse readily between compartments of the body (see Permeation, below). Therefore, very large drugs (usually proteins) must often 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 or intra-arterial infusion. C. 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 acetyl group of aspirin and its enzyme target in platelets, cyclooxygenase, is not readily broken. The platelet aggregation-blocking effect of aspirin lasts long after free acetylsalicylic acid has disappeared from the bloodstream (about 15 minutes) and is reversed only by the synthesis of new enzyme in new platelets, a process that takes about 7 days. Other examples of highly reactive, covalent bond-forming drugs are the DNA-alkylating agents used in cancer chemotherapy to disrupt cell division in the tumor. 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 that bind through weak bonds to their receptors are generally more selective than drugs that bind by means of 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 short-acting 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 D.DRUG SHAPE The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds just described.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;that is,they exist as enantiomeric pairs.Drugs with two asymmetric centers have four diastereomers,eg,ephedrine,a sympathomimetic drug.In most cases,one of these enantiomers is 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 is more effective in binding to a left-hand receptor than 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 other 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 B-receptor blocker.The (R)(+)isomer is 100-fold weaker at the B receptor.However,the isomers are approximately equipotent as a-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 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 less active,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. E.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). However,during the past three 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
significant pharmacologic effects. For example, xenon, an "inert" gas, has anesthetic effects at elevated pressures. D. DRUG SHAPE The shape of a drug molecule must be such as to permit binding to its receptor site via the bonds just described. 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; that is, they exist as enantiomeric pairs. Drugs with two asymmetric centers have four diastereomers, eg, ephedrine, a sympathomimetic drug. In most cases, one of these enantiomers is 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 is more effective in binding to a left-hand receptor than 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 other 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. 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 isomerthe rest are available only as racemic mixtures. As a result, many patients are receiving drug doses of which 50% or more is less active, 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. E. 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). However, during the past three 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 common. F.RECEPTOR NOMENCLATURE The spectacular success of newer,more efficient ways to identify and characterize receptors(see Chapter 2)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 Alexander SPH,Mathie A,Peters JA:Guide to receptors and channels.Br J Pharmacol 2006;147(Suppl 3):S1-S180.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.These properties determine the group in which the drug is classified and 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,a patient with impaired renal function.The following paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics. Pharmacodynamic Principles 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. A.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 five major types of drug-receptor-effector coupling systems are discussed in Chapter 2.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 molecules in the body
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 common. F. RECEPTOR NOMENCLATURE The spectacular success of newer, more efficient ways to identify and characterize receptors (see Chapter 2) 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 Alexander SPH, Mathie A, Peters JA: Guide to receptors and channels. Br J Pharmacol 2006;147(Suppl 3):S1-S180. 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. These properties determine the group in which the drug is classified and 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, a patient with impaired renal function. The following paragraphs provide a brief introduction to pharmacodynamics and pharmacokinetics. Pharmacodynamic Principles 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. A. 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 five major types of drug-receptor-effector coupling systems are discussed in Chapter 2. 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 molecules in the body
B.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 bind or only incidentally 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 so-called full agonists.Thus,pindolol,a B 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 epinephrine is present).(See Chapter 2.) C.DURATION OF DRUGACTION 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 site,the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized,as described previously for aspirin.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 for additional details. D.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,because it affects the distribution of drug within the body and determines the amount of free drug in the circulation.Both of these factors are of pharmacokinetic importance(see below and Chapter 3). 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
B. 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 bind or only incidentally 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 so-called 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 epinephrine is present). (See Chapter 2.) C. 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 site, the effect may persist until the drug-receptor complex is destroyed and new receptors or enzymes are synthesized, as described previously for aspirin. 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 for additional details. D. 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, because it affects the distribution of drug within the body and determines the amount of free drug in the circulation. Both of these factors are of pharmacokinetic importance (see below and Chapter 3). 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 processesinside 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 make up 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. A.PERMEATION Drug permeation proceeds by several 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. 1.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.* 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)do not permeate most vascular 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). 2.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). 3.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
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 make up 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. A. PERMEATION Drug permeation proceeds by several 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. 1. 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 thatin some tissuespermit the passage of molecules as large as MW 20,000-30,000.* 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) do not permeate most vascular aqueous pores. If the drug is charged, its flux is also influenced by electrical fields (eg, the membrane potential andin parts of the nephronthe transtubular potential). 2. 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). 3. 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.One large family of such transporters bind adenosine triphosphate(ATP)and is called the ABC (ATP-binding cassette)family.This family includes the P-glycoprotein or multidrug-resistance type 1(MDRI)transporter found in the brain,testes,and other tissues, and in some drug-resistant neoplastic cells.Similar transport molecules from the ABC family,the multidrug resistance-associated protein (MRP1 through MRP5)transporters,play important roles in excretion of some drugs or their metabolites into urine and bile and in resistance of some tumors to chemotherapeutic drugs.Several other transporter families have been identified that do not bind ATP but use ion gradients for transport energy.Some of these are particularly important in the uptake of neurotransmitters across nerve ending membranes. 4.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). "The capillaries of the brain,the testes,and some other tissues are characterized by the absence of pores that permit aqueous diffusion.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. B.FICK'S LAW OF DIFFUSION The passive flux of molecules down a concentration gradient is given by Fick's law: where Ci 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 because it determines how readily the drug enters the lipid membrane from the aqueous medium
Many cells also contain less selective membrane carriers that are specialized for expelling foreign molecules. One large family of such transporters bind adenosine triphosphate (ATP) and is called the ABC (ATP-binding cassette) family. This family includes 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. Similar transport molecules from the ABC family, the multidrug resistance-associated protein (MRP1 through MRP5) transporters, play important roles in excretion of some drugs or their metabolites into urine and bile and in resistance of some tumors to chemotherapeutic drugs. Several other transporter families have been identified that do not bind ATP but use ion gradients for transport energy. Some of these are particularly important in the uptake of neurotransmitters across nerve ending membranes. 4. 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). *The capillaries of the brain, the testes, and some other tissues are characterized by the absence of pores that permit aqueous diffusion. 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. B. 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, because it determines how readily the drug enters the lipid membrane from the aqueous medium
