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