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a LANGE medical book Katzung & Trevor’s Pharmacology Examination & Board Review Twelfth Edition...
a LANGE medical book Katzung & Trevor’s Pharmacology Examination & Board Review Twelfth Edition Bertram G. Katzung, MD, PhD Professor Emeritus of Pharmacology Department of Cellular & Molecular Pharmacology University of California, San Francisco Marieke Kruidering-Hall, PhD Professor & Academy Chair of Pharmacology Education Department of Cellular & Molecular Pharmacology University of California, San Francisco Anthony J. Trevor, PhD Professor Emeritus of Pharmacology and Toxicology Department of Cellular & Molecular Pharmacology University of California, San Francisco New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto Trevor_FM_p0i-vi.indd 1 7/19/18 2:42 PM Copyright © 2019 by McGraw-Hill Education. All rights reserved. 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THE WORK IS PROVIDED “AS IS.” McGRAW-HILL EDUCATION AND ITS LICENSORS MAKE NO GUARANTEES OR WAR- RANTIES AS TO THE ACCURACY, ADEQUACY OR COMPLETENESS OF OR RESULTS TO BE OBTAINED FROM USING THE WORK, INCLUDING ANY INFORMATION THAT CAN BE ACCESSED THROUGH THE WORK VIA HYPERLINK OR OTHERWISE, AND EXPRESSLY DISCLAIM ANY WARRANTY, EXPRESS OR IMPLIED, INCLUDING BUT NOT LIMITED TO IMPLIED WARRANTIES OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. McGraw-Hill Education and its licensors do not warrant or guarantee that the functions contained in the work will meet your requirements or that its opera- tion will be uninterrupted or error free. Neither McGraw-Hill Education nor its licensors shall be liable to you or anyone else for any inaccuracy, error or omission, regardless of cause, in the work or for any damages resulting therefrom. McGraw-Hill Education has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill Education and/ or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, even if any of them has been advised of the possibility of such damages. This limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwise. Contents Preface v part IV part I DRUGS WITH IMPORTANT ACTIONS BASIC PRINCIPLES 1 ON SMOOTH MUSCLE 145 1. Introduction 1 16. H istamine, Serotonin, Drugs Used in Obesity, & the Ergot Alkaloids 145 2. Pharmacodynamics 16 17. Vasoactive Peptides 155 3. Pharmacokinetics 26 18. Prostaglandins & Other Eicosanoids 161 4. Drug Metabolism 35 19. Nitric Oxide, Donors, & Inhibitors 168 5. Pharmacogenomics 41 20. D rugs Used in Asthma & Chronic part II Obstructive Pulmonary Disease 172 AUTONOMIC DRUGS 47 part V 6. Introduction to Autonomic Pharmacology 47 DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEM 181 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 60 21. Introduction to CNS Pharmacology 181 8. Cholinoceptor Blockers & Cholinesterase Regenerators 69 22. Sedative-Hypnotic Drugs 188 9. Sympathomimetics 76 23. Alcohols 196 10. Adrenoceptor Blockers 85 24. Antiseizure Drugs 203 25. General Anesthetics 212 part III CARDIOVASCULAR DRUGS 93 26. Local Anesthetics 220 27. Skeletal Muscle Relaxants 225 11. Drugs Used in Hypertension 93 28. D rugs Used in Parkinsonism & 12. D rugs Used in the Treatment of Angina Other Movement Disorders 233 Pectoris 103 29. Antipsychotic Agents & Lithium 241 13. Drugs Used in Heart Failure 112 30. Antidepressants 249 14. Antiarrhythmic Drugs 122 31. Opioid Analgesics & Antagonists 257 15. D iuretics & Other Drugs That Act on the Kidney 134 32. Drugs of Abuse 266 iii iii Trevor_FM_p0i-vi.indd 3 7/19/18 2:42 PM iv CONTENTS 47. Antimycobacterial Drugs 397 part VI 48. Antifungal Agents 404 DRUGS WITH IMPORTANT ACTIONS ON BLOOD, INFLAMMATION, 49. Antiviral Agents 411 & GOUT 275 50. M iscellaneous Antimicrobial Agents & Disinfectants, Antiseptics, & Sterilants 423 33. A gents Used in Cytopenias; Hematopoietic Growth Factors 275 51. Clinical Use of Antimicrobial Agents 429 34. Drugs Used in Coagulation Disorders 284 52. Antiprotozoal Drugs 435 35. Agents Used in Dyslipidemia 296 53. C linical Pharmacology of the Antihelminthic Drugs 444 36. N SAIDs, Acetaminophen, & Drugs Used in Rheumatoid Arthritis & Gout 304 54. Cancer Chemotherapy 450 55. Immunopharmacology 463 part VII ENDOCRINE DRUGS 315 part IX TOXICOLOGY 477 37. Hypothalamic & Pituitary Hormones 315 38. Thyroid & Antithyroid Drugs 324 56. Environmental & Occupational Toxicology 477 39. A drenocorticosteroids & Adrenocortical 57. Heavy Metals 483 Antagonists 330 58. Management of the Poisoned Patient 489 40. Gonadal Hormones & Inhibitors 337 part X 41. P ancreatic Hormones, Antidiabetic Drugs, SPECIAL TOPICS 497 & Glucagon 348 42. A gents That Affect Bone Mineral 59. D rugs Used in Gastrointestinal Homeostasis 357 Disorders 497 60. D ietary Supplements & Herbal part VIII Medications 507 CHEMOTHERAPEUTIC DRUGS 367 61. I mportant Drug Interactions & Their Mechanisms 512 43. B eta-Lactam Antibiotics & Other Cell Wall- & Membrane-Active Antibiotics 368 Appendix I. S trategies for Improving Test Performance 519 44. T etracyclines, Macrolides, Clindamycin, Chloramphenicol, Streptogramins, & Appendix II. Key Words for Key Drugs 522 Oxazolidinones 377 Appendix III. Examination 1 535 45. Aminoglycosides & Spectinomycin 385 Appendix IV. Examination 2 551 46. Sulfonamides, Trimethoprim, & Fluoroquinolones 390 Index 567 Trevor_FM_p0i-vi.indd 4 7/19/18 2:42 PM Preface This book is designed to help students review pharmacology are analyzing the answers, make sure that you understand why and to prepare for both regular course examinations and board each choice is either correct or incorrect. examinations. The twelfth edition has been revised to make Sixth, each chapter includes a Checklist of focused tasks such preparation as active and efficient as possible. As with that you should be able to do once you have finished the earlier editions, rigorous standards of accuracy and currency chapter. have been maintained in keeping with the book’s status as the Seventh, most chapters end with a Summary Table that companion to the Basic & Clinical Pharmacology textbook. This lists the most important drugs and includes key information review book divides pharmacology into the topics used in most concerning their mechanisms of action, effects, clinical uses, courses and textbooks. Major introductory chapters (eg, auto- pharmacokinetics, drug interactions, and toxicities. nomic pharmacology and CNS pharmacology) are included Eighth, when preparing for a comprehensive examination, for integration with relevant physiology and biochemistry. The you should review the strategies described in Appendix I if chapter-based approach facilitates use of this book in conjunc- you have not already done so. Then review the list of drugs in tion with course notes or a larger text. We recommend several Appendix II: Key Words for Key Drugs. Students are also strategies to make reviewing more effective (Appendix I con- advised to check this appendix as they work through the chap- tains a summary of learning and test-taking strategies that most ters so they can begin to identify drugs out of the context of a students find useful). chapter that reviews a restricted set of drugs. First, each chapter has a short discussion of the major con- Ninth, after you have worked your way through most or cepts that underlie its basic principles or the specific drug group, all of the chapters and have a good grasp of the Key Drugs, accompanied by explanatory figures and tables. The figures you should take the comprehensive examinations, each of 100 are in full color and some are new to this edition. Students questions, presented in Appendices III and IV. These exami- are advised to read the text thoroughly before they attempt to nations are followed by a list of answers, each with a short answer the study questions at the end of each chapter. If a con- explanation or rationale underlying the correct choice and cept is found to be difficult or confusing, the student is advised the numbers of the chapters in which more information can to consult a regular textbook such as Basic & Clinical Pharma- be found if needed. We recommend that you take an entire cology, 14th edition. examination or a block of questions as if it were a real exami- Second, each drug-oriented chapter opens with an Overview nation: commit to answers for the whole set before you check that organizes the group of drugs visually in diagrammatic form. the answers. As you work through the answers, make sure that We recommend that students practice reproducing the overview you understand why each answer is either correct or incorrect. diagram from memory. If you need to, return to the relevant chapters(s) to review the Third, a list of High-Yield Terms to Learn and their defini- text that covers key concepts and facts that form the basis for tions is near the front of most chapters. Make sure that you are the question. able to define those terms. We recommend that this book be used with a regular text. Fourth, many chapters include a Skill Keeper question that Basic & Clinical Pharmacology, 14th edition (McGraw-Hill, prompts the student to review previous material and to see links 2018), follows the chapter sequence used here. However, this between related topics. We suggest that students try to answer review book is designed to complement any standard medical Skill Keeper questions on their own before checking the answers pharmacology text. The student who completes and under- that are provided at the end of the chapter. stands Pharmacology: Examination & Board Review will greatly Fifth, each of the sixty-one chapters contains up to ten improve his or her performance and will have an excellent com- sample questions followed by a set of answers with explana- mand of pharmacology. tions. For most effective learning, you should take each set of Because it was developed in parallel with the textbook sample questions as if it were a real examination. After you have Basic & Clinical Pharmacology, this review book represents the answered every question, work through the answers. When you authors’ interpretations of chapters written by contributors to v Trevor_FM_p0i-vi.indd 5 7/19/18 2:42 PM vi PREFACE that text. We are grateful to those contributors, to our other her excellent copyediting and proofreading contributions to faculty colleagues, and to our students, who have taught us most this edition. of what we know about teaching. We very much appreciate the invaluable contributions to Bertram G. KKatzung, MD, PhD this text afforded by the editorial team of Peter Boyle and Marieke Kruidering-Hall, PhD Michael Weitz. The authors also thank Katharine Katzung for Anthony J. Trevor, PhD Trevor_FM_p0i-vi.indd 6 7/19/18 2:42 PM PART I BASIC PRINCIPLES 1 C H A P T E R Introduction Pharmacology is the body of knowledge concerned with the drugs, eg, absorption, metabolism, excretion, etc. Pharmaco- action of chemicals on biologic systems. Medical pharmacol- dynamics denotes the actions of the drug on the body, such as ogy is the area of pharmacology concerned with the use of mechanism of action and therapeutic and toxic effects. The first chemicals in the prevention, diagnosis, and treatment of disease, part of this chapter reviews the basic principles of pharmacoki- especially in humans. Toxicology is the area of pharmacology netics and pharmacodynamics that will be applied in subsequent concerned with the undesirable effects of chemicals on biologic chapters. The second part of the chapter reviews the discovery systems. Pharmacokinetics describes the effects of the body on and development of new drugs and the regulation of drugs. Nature of drugs Pharmacodynamics Pharmacokinetics Receptor, Inert Movement receptor binding of drugs in Absorption Distribution Metabolism Elimination sites sites body Drug development & regulation Safety & Animal Clinical Patents & efficacy testing trials generic drugs 1 Trevor_Ch01_p001-p015.indd 1 7/13/18 6:00 PM 2 PART I Basic Principles I. THE NATURE OF DRUGS (eg, between a cation and an anion), and much weaker interac- tions (eg, hydrogen, van der Waals, and hydrophobic bonds). Drugs in common use include inorganic ions, nonpeptide organic molecules, small peptides and proteins, nucleic acids, lipids, and carbo- hydrates. Some are found in plants or animals, and others are partially PHARMACODYNAMIC PRINCIPLES or completely synthetic. Many drugs found in nature are alkaloids, A. Receptors which are molecules that have a basic (alkaline) pH in solution, usually as a result of amine groups in their structure. Many biologically impor- Drug actions are mediated through the effects of drug ligand tant endogenous molecules and exogenous drugs are optically active; molecules on drug receptors in the body. Most receptors are large that is, they contain one or more asymmetric centers and can exist as regulatory molecules that influence important biochemical pro- enantiomers. The enantiomers of optically active drugs usually differ, cesses (eg, enzymes involved in glucose metabolism) or physiologic sometimes more than 1000-fold, in their affinity for biologic receptor processes (eg, ion channel receptors, neurotransmitter reuptake sites. Furthermore, such enantiomers may be metabolized at different transporters, and ion transporters). rates in the body, with important clinical consequences. If drug-receptor binding results in activation of the receptor molecule, the drug is termed an agonist; if inhibition results, A. Size and Molecular Weight the drug is considered an antagonist. Some drugs mimic agonist Drugs vary in size from molecular weight (MW) 7 (lithium) molecules by inhibiting metabolic enzymes, eg, acetylcholinesterase to over MW 50,000 (thrombolytic enzymes, antibodies, other inhibitors. As suggested in Figure 1–1, a receptor molecule may proteins). Most drugs, however, have MWs between 100 and have several binding sites. Quantitation of the effects of drug- 1000. Drugs smaller than MW 100 are rarely sufficiently selective receptor interaction as a function of dose (or concentration) yields in their actions, whereas drugs much larger than MW 1000 are dose-response curves that provide information about the nature of often poorly absorbed and poorly distributed in the body. Most the drug-receptor interaction. Dose-response phenomena are dis- protein drugs (“biologicals”) are commercially produced in cell, cussed in more detail in Chapter 2. A few drugs are enzymes them- bacteria, or yeast cultures using recombinant DNA technology. selves (eg, thrombolytic enzymes, pancreatic enzymes). These drugs do not act on endogenous receptors but on substrate molecules. B. Drug-Receptor Bonds Drugs bind to receptors with a variety of chemical bonds. These B. Receptor and Inert Binding Sites include very strong covalent bonds (which usually result in irre- Because most ligand molecules are much smaller than their recep- versible action), somewhat weaker reversible electrostatic bonds tor molecules (discussed in the text that follows), specific regions High-Yield Terms to Learn (continued) Drugs Substances that act on biologic systems at the chemical (molecular) level and alter their functions Drug receptors The molecular components of the body with which drugs interact to bring about their effects Distribution phase The phase of drug movement from the site of administration into the tissues Elimination phase The phase of drug inactivation or removal from the body by metabolism or excretion Endocytosis, exocytosis Endocytosis: Absorption of material across a cell membrane by enclosing it in cell membrane mate- rial and pulling it into the cell, where it can be processed or released. Exocytosis: Expulsion of mate- rial from vesicles in the cell into the extracellular space Permeation Movement of a molecule (eg, drug) through the biologic medium Pharmacodynamics The actions of a drug on the body, including receptor interactions, dose-response phenomena, and mechanisms of therapeutic and toxic actions Pharmacokinetics The actions of the body on the drug, including absorption, distribution, metabolism, and elimina- tion. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is a term sometimes used to describe the processes of metabolism and excretion Transporter A specialized molecule, usually a protein, that carries a drug, transmitter, or other molecule across a membrane in which it is not permeable, eg, Na+/K+ ATPase, serotonin reuptake transporter, etc Mutagenic An effect on the inheritable characteristics of a cell or organism—a mutation in the DNA; usually tested in microorganisms with the Ames test Carcinogenic An effect of inducing malignant characteristics Teratogenic An effect on the in utero development of an organism resulting in abnormal structure or function; not generally heritable Trevor_Ch01_p001-p015.indd 2 7/13/18 6:00 PM CHAPTER 1 Introduction 3 High-Yield Terms to Learn (continued) Placebo An inactive “dummy” medication made up to resemble the active investigational formulation as much as possible but lacking therapeutic effect Single-blind study A clinical trial in which the investigators—but not the subjects—know which subjects are receiving active drug and which are receiving placebos Double-blind study A clinical trial in which neither the subjects nor the investigators know which subjects are receiving placebos; the code is held by a third party IND Investigational New Drug Exemption; an application for FDA approval to carry out new drug trials in humans; requires animal data NDA New Drug Application; seeks FDA approval to market a new drug for ordinary clinical use; requires data from clinical trials as well as preclinical (animal) data Phases 1, 2, and 3 of Three parts of a clinical trial that are usually carried out before submitting an NDA to the FDA; clinical trials adaptive trials, combined two or more phases Positive control A known standard therapy, to be used in addition to placebo, to evaluate the superiority or inferior- ity of a new drug in relation to the other drugs available Orphan drugs Drugs developed for diseases in which the expected number of patients is small. Some countries bestow certain commercial advantages on companies that develop drugs for uncommon diseases Drug Receptor Effects A Agonist + A+C A alone Response – A+B B A+D Log Dose Competitive inhibitor C Allosteric activator D Allosteric inhibitor FIGURE 1–1 Potential mechanisms of drug interaction with a receptor. Possible effects resulting from these interactions are diagrammed in the dose-response curves at the right. The traditional agonist (drug A)-receptor binding process results in the dose-response curve denoted “A alone.” B is a pharmacologic antagonist drug that competes with the agonist for binding to the receptor site. The dose-response curve pro- duced by increasing doses of A in the presence of a fixed concentration of B is indicated by the curve “A + B.” Drugs C and D act at different sites on the receptor molecule; they are allosteric activators or inhibitors. Note that allosteric inhibitors do not compete with the agonist drug for binding to the receptor, and they may bind reversibly or irreversibly. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 1–3.) Trevor_Ch01_p001-p015.indd 3 7/13/18 6:00 PM 4 PART I Basic Principles of receptor molecules provide the local areas responsible for drug into nerve endings by selective transport molecules. Selective binding. Such areas are termed receptor sites or recognition sites. inhibitors for these transporters often have clinical value; for In addition, drugs bind to some nonregulatory molecules in the example, several antidepressants act by inhibiting the transport of body without producing a discernible effect. Such binding sites amine neurotransmitters back into the nerve endings from which are termed inert binding sites. In some compartments of the they have been released or into nearby cells. body (eg, the plasma), inert binding sites play an important role in buffering the concentration of a drug because bound drug does 4. Endocytosis—Endocytosis occurs through binding of the not contribute directly to the concentration gradient that drives molecule to specialized components (receptors) on cell mem- diffusion. Albumin and orosomucoid (α1-acid glycoprotein) are 2 branes, with subsequent internalization by infolding of that area of important plasma proteins with significant drug-binding capacity. the membrane. The contents of the resulting intracellular vesicle are subsequently released into the cytoplasm of the cell. Endocy- tosis permits very large or very lipid-insoluble chemicals to enter PHARMACOKINETIC PRINCIPLES cells. For example, large molecules such as proteins may cross cell membranes by endocytosis. Smaller, polar substances such To produce useful therapeutic effects, most drugs must be as vitamin B12 and iron combine with special proteins (B12 with absorbed, distributed, and eliminated. Pharmacokinetic principles intrinsic factor and iron with transferrin), and the complexes enter make rational dosing possible by quantifying these processes. cells by this mechanism. Because the substance to be transported must combine with a membrane receptor, endocytotic transport The Movement of Drugs in the Body can be quite selective. Exocytosis is the reverse process, that is, the expulsion of material that is membrane-encapsulated inside the cell To reach its receptors and bring about a biologic effect, a drug out of the cell. Most neurotransmitters are released by exocytosis. molecule (eg, a benzodiazepine sedative) must travel from the site of administration (eg, the gastrointestinal tract) to the site of action (eg, the brain). B. Fick’s Law of Diffusion Fick’s law predicts the rate of movement of molecules across a A. Permeation barrier. The concentration gradient (C1 – C2) and permeability Permeation is the movement of drug molecules into and within coefficient for the drug and the area and thickness of the barrier the biologic environment. It involves several processes, the most membrane are used to compute the rate as follows: important of which include the following: Permeability coefficient Rate = C1 − C2 × × Area (1) 1. Aqueous diffusion—Aqueous diffusion is the movement of Thickness molecules through the watery extracellular and intracellular spaces. The membranes of most capillaries have small water-filled pores Thus, drug absorption into the blood is faster within organs that permit the aqueous diffusion of molecules up to the size of with large surface areas, such as the small intestine, than from small proteins between the blood and the extravascular space. This organs with smaller absorbing areas (the stomach). Furthermore, is a passive process governed by Fick’s law (see later discussion). drug absorption is faster from organs with thin membrane barriers The capillaries in the brain, testes, and some other organs lack (eg, the lung) than from those with thick barriers (eg, the skin). aqueous pores, and these tissues are less exposed to some drugs. C. Water and Lipid Solubility of Drugs 2. Lipid diffusion—Lipid diffusion is the passive movement of 1. Solubility—The aqueous solubility of a drug is often a func- molecules through lipid bilayer cell membranes and other lipid bar- tion of the electrostatic charge (degree of ionization, polarity) of riers. Like aqueous diffusion, this process is governed by Fick’s law. the molecule, because water molecules behave as dipoles and are attracted to charged drug molecules, forming an aqueous shell 3. Transport by special carriers—Drugs that do not readily around them. Conversely, the lipid solubility of a molecule is diffuse through membranes may be transported across barriers inversely proportional to its charge. by mechanisms that carry similar endogenous substances. A very Many drugs are weak bases or weak acids. For such molecules, large number of such transporter molecules have been identified, the pH of the medium determines the fraction of molecules and many of these are important in the movement of drugs or as charged (ionized) versus uncharged (nonionized). If the pKa of targets of drug action. Unlike aqueous and lipid diffusion, car- the drug and the pH of the medium are known, the fraction of rier transport is not governed by Fick’s law and has a maximum molecules in the ionized state can be predicted by means of the capacity, ie, is saturable. Important examples are transporters for Henderson-Hasselbalch equation: ions (eg, Na+/K+ ATPase), for neurotransmitters (eg, transport- ers for serotonin, norepinephrine), for metabolites (eg, glucose, Protonated form log = pK a − pH (2) amino acids), and for foreign molecules (xenobiotics) such as Unprotonated form anticancer drugs. After release, amine neurotransmitters (dopamine, norepi- “Protonated” means associated with a proton (a hydrogen ion); nephrine, and serotonin) and some other transmitters are recycled this form of the equation applies to both acids and bases. Trevor_Ch01_p001-p015.indd 4 7/13/18 6:00 PM CHAPTER 1 Introduction 5 2. Ionization of weak acids and bases—Weak bases are Membranes of ionized—and therefore more polar and more water-soluble—when the nephron Blood Urine they are protonated. Weak acids are not ionized—and so are less pH 7.4 pH 6.0 water-soluble—when they are protonated. 1.0 µM Lipid 1.0 µM The following equations summarize these points: diffusion H H RNH3+ RNH2 + H+ R N H R N H protonated weak Unprotonated weak proton base (charged, base (uncharged, (3) H+ H+ more water-soluble) more lipid-soluble) RCOOH RCOO – + H+ protonated weak Unprotonated weak proton H H acid (uncharged, acid (charged, (4) R N+ H R N+ H more lipid-soluble) more water-soluble) H H 0.4 µM 10.0 µM The Henderson-Hasselbalch relationship is clinically impor- tant when it is necessary to estimate or alter the partition of drugs 1.4 µM total 11.0 µM total between compartments of differing pH. For example, most drugs are freely filtered at the glomerulus, but lipid-soluble drugs can be rapidly reabsorbed from the tubular urine. If a patient takes an FIGURE 1–2 The Henderson-Hasselbalch principle applied to overdose of a weak acid drug, for example, aspirin, the excretion drug excretion in the urine. Because the nonionized, uncharged form diffuses readily across the lipid barriers of the nephron, this form may of this drug is faster in alkaline urine. This is because a drug that is reach equal concentrations in the blood and urine; in contrast, the a weak acid dissociates to its charged, polar form in alkaline solu- ionized form does not diffuse as readily. Protonation occurs within tion, and this form cannot readily diffuse from the renal tubule the blood and the urine according to the Henderson-Hasselbalch back into the blood; that is, the drug is trapped in the tubule. equation. Pyrimethamine, a weak base of pKa 7.0, is used in this Conversely, excretion of a weak base (eg, pyrimethamine, amphet- example. At blood pH, only 0.4 μmol of the protonated species will amine) is faster in acidic urine (Figure 1–2). be present for each 1.0 μmol of the unprotonated form. The total concentration in the blood will thus be 1.4 μmol/L if the concentra- tion of the unprotonated form is 1.0 μmol/L. In the urine at pH 6.0, Absorption of Drugs 10 μmol of the nondiffusible ionized form will be present for each A. Routes of Administration 1.0 μmol of the unprotonated, diffusible form. Therefore, the total Drugs usually enter the body at sites remote from the target tis- urine concentration (11 μmol/L) may be almost 8 times higher than sue or organ and thus require transport by the circulation to the the blood concentration. intended site of action. To enter the bloodstream, a drug must be absorbed from its site of administration (unless the drug has concentration gradient is a major determinant of the rate of absorp- been injected directly into the vascular compartment). The rate tion. Drug concentration in the vehicle is particularly important in and efficiency of absorption differ depending on a drug’s route of the absorption of drugs applied topically. administration as well as the drug’s physicochemical properties. In fact, for some drugs, the amount absorbed may be only a small Distribution of Drugs fraction of the dose administered when given by certain routes. A. Determinants of Distribution The amount absorbed into the systemic circulation divided by the 1. Size of the organ—The size of the organ determines the con- amount of drug administered constitutes its bioavailability by centration gradient between blood and the organ. For example, that route. Common routes of administration and some of their skeletal muscle can take up a large amount of drug because the features are listed in Table 1–1. concentration in the muscle tissue remains low (and the blood- tissue gradient high) even after relatively large amounts of drug B. Blood Flow have been transferred; this occurs because skeletal muscle is a very Blood flow influences absorption from intramuscular and subcu- large organ. In contrast, because the brain is smaller, distribution taneous sites and, in shock, from the gastrointestinal tract as well. of a smaller amount of drug into it will raise the tissue concentra- High blood flow maintains a high concentration gradient between tion and reduce to zero the blood-tissue concentration gradient, the drug depot and the blood and thus facilitates absorption. preventing further uptake of drug unless it is actively transported. C. Concentration 2. Blood flow—Blood flow to the tissue is an important deter- The concentration of drug at the site of administration is important minant of the rate of uptake of drug, although blood flow may not in determining the concentration gradient relative to the blood affect the amount of drug in the tissue at equilibrium. As a result, as noted previously. As indicated by Fick’s law (Equation 1), the well-perfused tissues (eg, brain, heart, kidneys, and splanchnic Trevor_Ch01_p001-p015.indd 5 7/13/18 6:00 PM 6 PART I Basic Principles TABLE 1–1 Common routes of drug administration. TABLE 1–2 Average values for some physical volumes within the adult human body. Oral (swallowed) Offers maximal convenience; absorption is often slower. Subject to the first-pass Compartment Volume (L/kg body weight) effect, in which a significant amount of the agent is metabolized in the gut wall, portal Plasma 0.04 circulation, and liver before it reaches the systemic circulation. Bioavailability may be Blood 0.08 limited by the first pass effect. Extracellular water 0.2 Buccal and sublingual Direct absorption into the systemic venous (not swallowed) circulation, bypassing the hepatic portal Total body water 0.6 circuit and first-pass metabolism. Fat 0.2–0.35 Intravenous Instantaneous and complete absorption (by definition, bioavailability is 100%). Poten- tially more dangerous. to extravascular tissue proteins, which results in a marked reduc- tion in the plasma concentration of chloroquine. Intramuscular Often faster and more complete (higher bio- availability) than with oral administration. Large volumes may be given if the drug is B. Apparent Volume of Distribution and Physical Volumes not too irritating. First-pass metabolism is The apparent volume of distribution (Vd) is an important phar- avoided. macokinetic parameter that reflects the above determinants of the Subcutaneous Slower absorption than the intramuscular distribution of a drug in the body. Vd relates the amount of drug route. First-pass metabolism is avoided. in the body to the concentration in the plasma (Chapter 3). In Rectal (suppository) The rectal route offers partial avoidance of contrast, the physical volumes of various body compartments are the first-pass effect. Larger amounts of drug less important in pharmacokinetics (Table 1–2). However, obe- and drugs with unpleasant taste are better sity alters the ratios of total body water to body weight and fat to administered rectally than by the buccal or total body weight, and this may be important when using highly sublingual routes. lipid-soluble drugs. A simple approximate rule for the aqueous Inhalation Route offers delivery closest to respiratory compartments of the normal body is as follows: 40% of total body tissues (eg, for asthma). Usually very rapid weight is intracellular water and 20% is extracellular water; thus, absorption (eg, for anesthetic gases). water constitutes approximately 60% of body weight. Topical The topical route includes application to the skin or to the mucous membrane of the eye, ear, nose, throat, airway, or vagina for Metabolism of Drugs local effect. Drug disposition is a term sometimes used to refer to metabo- lism and elimination of drugs. Some authorities use disposition Transdermal The transdermal route utilizes application to the skin for systemic effect. Absorption usu- to denote distribution as well as metabolism and elimination. ally occurs very slowly (because of the thick- Metabolism of a drug sometimes terminates its action, but other ness of the skin), but the first-pass effect is effects of drug metabolism are also important. Some drugs when avoided. given orally are metabolized before they enter the systemic circula- tion. This first-pass metabolism was referred to in Table 1–1 as organs) usually achieve high tissue concentrations sooner than one cause of low bioavailability. Drug metabolism occurs primar- poorly perfused tissues (eg, fat, bone). ily in the liver and is discussed in greater detail in Chapter 4. 3. Solubility—The solubility of a drug in tissue influences the A. Drug Metabolism as a Mechanism of Activation or concentration of the drug in the extracellular fluid surrounding Termination of Drug Action the blood vessels. If the drug is very soluble in the cells, the con- The action of many drugs (eg, sympathomimetics, phenothi- centration in the perivascular extracellular space will be lower and azines) is terminated before they are excreted because they are diffusion from the vessel into the extravascular tissue space will be metabolized to biologically inactive derivatives. Conversion to an facilitated. For example, some organs (such as the brain) have a inactive metabolite is a form of elimination. high lipid content and thus dissolve a high concentration of lipid- In contrast, prodrugs (eg, levodopa, minoxidil) are inactive soluble agents rapidly. as administered and must be metabolized in the body to become active. Many drugs are active as administered and have active 4. Binding—Binding of a drug to macromolecules in the blood metabolites as well (eg, morphine, some benzodiazepines). or a tissue compartment tends to increase the drug’s concentration in that compartment. For example, warfarin is strongly bound to B. Drug Elimination Without Metabolism plasma albumin, which restricts warfarin’s diffusion out of the Some drugs (eg, lithium, many others) are not modified by the vascular compartment. Conversely, chloroquine is strongly bound body; they continue to act until they are excreted. Trevor_Ch01_p001-p015.indd 6 7/13/18 6:00 PM CHAPTER 1 Introduction 7 First-order elimination Zero-order elimination 5 units/h 2.5 units/h elimination elimination rate Plasma concentration Plasma concentration rate 2.5 units/h 2.5 units/h 2.5 units/h 1.25 units/h Time (h) Time (h) FIGURE 1–3 Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left), rate of elimination (units per hour) is proportional to concentration; this is the more common process. In the case of zero-order elimination (right), the rate is constant and independent of concentration. Elimination of Drugs This occurs with drugs that saturate their elimination mechanisms at concentrations of clinical interest. As a result, the concentra- Along with the dosage, the rate of elimination following the last tions of these drugs in plasma decrease in a linear fashion over dose (disappearance of the active molecules from the site of action, time. Such drugs do not have a constant half-life. This is typical the bloodstream, and the body) determines the duration of action of ethanol (over most of its plasma concentration range) and of for many drugs. Therefore, knowledge of the time course of con- phenytoin and aspirin at high therapeutic or toxic concentrations. centration in plasma is one factor used in predicting the intensity and duration of effect for most drugs. Note: Drug elimination is not the same as drug excretion: A drug may be eliminated by Pharmacokinetic Models metabolism long before the modified molecules are excreted A. Multicompartment Distribution from the body. For most drugs and their metabolites, excretion After absorption into the circulation, many drugs undergo an is primarily by way of the kidney. Volatile anesthetic gases, a early distribution phase followed by a slower elimination phase. major exception, are excreted primarily by the lungs. For drugs Mathematically, this behavior can be simulated by means of a with active metabolites (eg, diazepam), elimination of the parent “two-compartment model” as shown in Figure 1–4. The two molecule by metabolism is not synonymous with termination of compartments consist of the blood and the extravascular tissues. action. For drugs that are not metabolized, excretion is the mode (Note that each phase is associated with a characteristic half-life: of elimination. A small number of drugs combine irreversibly with t1/2α for the first phase, t1/2β for the second phase. Note also that their receptors, so that disappearance from the bloodstream is not when concentration is plotted on a logarithmic axis, the elimina- equivalent to cessation of drug action: These drugs may have a very tion phase for a first-order drug is a straight line.) prolonged action. For example, phenoxybenzamine, an irreversible inhibitor of α adrenoceptors, is eliminated from the bloodstream B. Other Distribution Models in less than 1 h after administration. The drug’s action, however, A few drugs behave as if they were distributed to only 1 compart- lasts for 48 h, the time required for turnover of the receptors. ment (eg, if they are restricted to the vascular compartment). A. First-Order Elimination Others have more complex distributions that require more than 2 compartments for construction of accurate mathematical models. The term first-order elimination indicates that the rate of elimina- tion is proportional to the concentration (ie, the higher the concen- tration, the greater the amount of drug eliminated per unit time). The result is that the drug’s concentration in plasma decreases II. DRUG DEVELOPMENT exponentially with time (Figure 1–3, left). Drugs with first-order & REGULATION elimination have a characteristic half-life of elimination that is constant regardless of the amount of drug in the body. The concen- The sale and use of drugs are regulated in most countries by tration of such a drug in the blood will decrease by 50% for every governmental agencies. In the United States, regulation is by the half-life. Most drugs in clinical use demonstrate first-order kinetics. Food and Drug Administration (FDA). New drugs are devel- oped in industrial or academic laboratories. Before a new drug B. Zero-Order Elimination can be approved for regular therapeutic use in humans, a series The term zero-order elimination implies that the rate of elimina- of animal and experimental human studies (clinical trials) must tion is constant regardless of concentration (Figure 1–3, right). be carried out. Trevor_Ch01_p001-p015.indd 7 7/13/18 6:00 PM 8 PART I Basic Principles 64.0 Dose Serum concentration (C) (µg/mL) (logarithmic scale) Distribution Distribution 32.0 Blood Tissues phase t1/2α Elimination t1/2β 16.0 8.0 Elimination phase 4.0 t1/2β 2.0 1.0 0 2 4 6 12 18 24 Time (h) (linear scale) FIGURE 1–4 Serum concentration-time curve after administration of a drug as an intravenous bolus. This drug follows first-order kinetics and appears to occupy 2 compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (t1/2β) can be extracted graphically as shown by measuring the time between any 2 plasma concentration points on the elimination phase that differ by twofold. (See Chapter 3 for additional details.) New drugs may emerge from a variety of sources. Some are greater than $500 million although the true cost is often hidden the result of identification of a new target for a disease. Rational by the manufacturer. molecular design or screening is then used to find a molecule that selectively alters the function of the target. New drugs may result from the screening of hundreds of compounds against model dis- ANIMAL TESTING eases in animals. In contrast, many so-called “me-too” drugs are the result of simple chemical alteration of the pharmacokinetic The animal testing of a specific drug that is required before human properties of an original prototype agent. studies can begin is a function of its proposed use and the urgency of the application. Thus, a drug proposed for occasional topical use requires less extensive testing than one destined for chronic systemic SAFETY & EFFICACY administration. Because of the urgent need, anticancer drugs and some anti- Because society expects prescription drugs to be safe and effec- viral drugs require less evidence of safety than do drugs used in tive, governments regulate the development and marketing of treatment of less threatening diseases. Urgently needed drugs are new drugs. Current regulations in the USA require evidence of often investigated and approved on an accelerated schedule. relative safety (derived from acute and subacute toxicity testing in animals) and probable therapeutic action (from the pharmaco- A. Acute Toxicity logic profile in animals) before human testing is permitted. Some Acute toxicity studies are required for all new drugs. These studies information about the pharmacokinetics of a compound is also involve administration of incrementing doses of the agent up to required before clinical evaluation is begun. Chronic toxicity test the lethal level in at least 2 species (eg, 1 rodent and 1 nonrodent). results are generally not required, but testing must be underway before human studies are started. The development of a new B. Subacute and Chronic Toxicity drug and its pathway through various levels of testing and regula- Subacute and chronic toxicity testing is required for most agents, tion are illustrated in Figure 1–5. The cost of development of a especially those intended for chronic use. Doses are selected new drug, including false starts and discarded molecules, may be based on the results of acute tests. Tests are usually conducted Trevor_Ch01_p001-p015.indd 8 7/13/18 6:00 PM CHAPTER 1 Introduction 9 In vitro Animal Clinical testing Marketing studies testing (Is it safe Phase 1 pharmacokinetics?) Generics Biologic become products 20–100 subjects (Does it available Phase 2 work in patients?) 100–200 Efficacy, patients Lead compound selectivity, Phase 3 mechanism (Does it work, double blind?) Phase 4 1000–6000 patients (Postmarketing Chemical surveillance) synthesis Drug metabolism, safety assessment 0 2 4 8–9 20 Years (average) IND NDA (Patent expires (Investigational (New Drug 20 years after filing New Drug) Application) of application) FIGURE 1–5 The development and testing process required to bring a new drug to market in the United States. Some requirements may be different for drugs used in life-threatening diseases. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 5–1.) for 2–4 weeks (subacute) and 6–24 months (chronic), in at least TABLE 1–3 FDA ratings of drug safety in pregnancy.* 2 species. Category Description A Controlled studies in women fail to demonstrate a TYPES OF ANIMAL TESTS risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and the pos- A. Pharmacologic Profile sibility of fetal harm appears remote The pharmacologic profile is a description of all the pharmacologic B Either animal reproduction studies have not demon- effects of a drug (eg, effects on cardiovascular function, gastroin- strated a fetal risk but there are no controlled studies testinal activity, respiration, hepatic and renal function, endocrine in pregnant women, or animal reproduction studies have shown an adverse effect (other than a decrease function, CNS). Both graded and quantal dose-response data are in fertility) that was not confirmed in controlled gathered. studies in women in the first trimester (and there is no evidence of a risk in later trimesters) B. Reproductive Toxicity C Either studies in animals have revealed adverse effects Reproductive toxicity testing involves the study of the fertility on the fetus (teratogenic or embryocidal or other) and effects of the candidate drug and its teratogenic and mutagenic there are no controlled studies in women, or studies toxicity. Until 2015, the FDA had used a 5-level (A, B, C, D, X) in women and animals are not available. Drugs should be given only when the potential benefit justifies the minimally descriptive scale to summarize information regarding the potential risk to the fetus safety of drugs in pregnancy (Table 1–3). For drugs submitted after June 2015, the letter scale has been abolished in favor of a narra- D There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be tive description of the safety or hazards of each drug, and separate acceptable despite the risk (eg, if the drug is needed categories are established for pregnancy, lactation, and for males in a life-threatening situation or for a serious dis- and females of reproductive potential. The new system is designated ease for which safer drugs cannot be used or are the Pregnancy and Lactation Labeling Rule (PLLR) and is set ineffective) forth at https://www.fda.gov/Drugs/DevelopmentApprovalProcess/ X Studies in animals or human beings have demon- DevelopmentResources/Labeling/ucm093307.htm. New labeling strated fetal abnormalities or there is evidence of fetal for drugs approved after 2001 will be phased in. Teratogenesis can risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly be defined as the induction of developmental defects in the somatic outweighs any possible benefit. The drug is contrain- tissues of the fetus (eg, by exposure of the fetus to a chemical, infec- dicated in women who are or may become pregnant tion, or radiation). Teratogenesis is studied by treating pregnant * Because of lack of definitive evidence for many drugs, many experts consider the female animals of at least 2 species at selected times during early A through X ranking system to be too simplistic and inaccurate; they prefer more pregnancy when organogenesis is known to take place and by later detailed narrative descriptions of evidence available for each drug in question. See examining the fetuses or neonates for abnormalities. Examples Pregnancy and Lactation Labeling Rule, text. Trevor_Ch01_p001-p015.indd 9 7/13/18 6:00 PM 10 PART I Basic Principles of drugs known to have teratogenic effects include thalidomide, other highly toxic drugs; these are carried out by administering isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, lith- the agents to volunteer patients with the target disease. In phase ium, and androgens. Mutagenesis denotes induction of changes in 1 studies, the acute effects of the agent are studied over a broad the genetic material of animals of any age and therefore induction range of dosages, starting with one that produces no detectable of heritable abnormalities. The Ames test, the standard in vitro test effect and progressing to one that produces either a significant for mutagenicity, uses a special strain of salmonella bacteria whose physiologic response or a very minor toxic effect. growth depends on specific nutrients in the culture medium. Loss of this dependence as a result of exposure to the test drug signals B. Phase 2 a mutation. Many carcinogens (eg, aflatoxin, cancer chemothera- A phase 2 trial involves evaluation of a drug in a moderate number peutic drugs, and other agents that bind to DNA) have mutagenic of sick patients (eg, 100–200) with the target disease. A placebo or effects and test positive in the Ames test. The dominant lethal test positive control drug is included in a single-blind or double-blind is an in vivo mutagenicity test carried out in mice. Male animals are design. The study is carried out under very carefully controlled exposed to the test substance before mating. Abnormalities in the conditions, and patients are closely monitored, often in a hospital results of subsequent mating (eg, loss of embryos, deformed fetuses) research ward. The goal is to determine whether the agent has signal a mutation in the male’s germ cells. the desired efficacy (ie, produces adequate therapeutic response) at doses that are tolerated by sick patients. Detailed data are col- C. Carcinogenesis lected regarding the pharmacokinetics and pharmacodynamics of Carcinogenesis is the induction of malignant characteristics in the drug in this patient population. cells. Carcinogenicity is difficult and expensive to study, and the Ames test is often used to screen chemicals because there is C. Phase 3 a moderately high degree of correlation between mutagenicity in A phase 3 trial usually involves many patients (eg, 1000–6000 the Ames test and carcinogenicity in some animal tests, as previ- or more, in many centers) and many clinicians who are using ously noted. Agents with known carcinogenic effects include the drug in the manner proposed for its ultimate general use (eg, coal tar, aflatoxin, dimethylnitrosamine and other nitrosamines, in outpatients). Such studies usually include placebo and posi- urethane, vinyl chloride, and the polycyclic aromatic hydrocar- tive controls in a double-blind crossover design. The goals are to bons in tobacco smoke (eg, benzo[a]pyrene) and other tobacco explore further, under the conditions of the proposed clinical use, products. the spectrum of beneficial actions of the new drug, to compare it with placebo (negative control) and older therapy (positive con- trol), and to discover toxicities, if any, that occur so infrequently CLINICAL TRIALS as to be undetectable in phase 2 studies. Very large amounts of data are collected and these studies are usually very expensive. Human testing of new drugs in the United States requires Unfortunately, relatively few phase 3 trials include the current approval by institutional committees that monitor the ethical standard of care as a positive control. (informed consent, patient safety) and scientific aspects (study If the drug successfully completes phase 3, an NDA is submit- design, statistical power) of the proposed tests. Such testing also ted to the FDA. If the NDA is approved, the drug can be mar- requires the prior approval by the FDA of an Investigational keted and phase 4 begins. New Drug (IND) Exemption application, which is submitted by the developer to the FDA (Figure 1–5). The IND includes D. Phase 4 all the preclinical data collected up to the time of submission Phase 4 represents the postmarketing surveillance phase of and the detailed proposal for clinical trials. The major clinical evaluation, in which it is hoped that toxicities that occur very testing process is usually divided into 3 phases that are car- infrequently will be detected and reported early enough to pre- ried out to provide information for a New Drug Application vent major therapeutic disasters. Manufacturers are required to (NDA). The NDA includes all the results of preclinical and inform the FDA at regular intervals of all reported untoward drug clinical testing and constitutes the request for FDA approval reactions. Unlike the first 3 phases, phase 4 has not been rigidly of general marketing of the new agent for prescription use. A regulated by the FDA in the past. Because so many drugs have fourth phase of study (the surveillance phase) follows NDA been found to be unacceptably toxic only after they have been approval. In particularly lethal conditions, the FDA may permit marketed, there is considerable current interest in making phase 4 carefully monitored treatment of patients before phases 2 and surveillance more consistent, effective, and informative. 3 are completed. E. Adaptive Clinical Trials A. Phase 1 Because the traditional 3-phase clinical trials are often prolonged A phase 1 trial consists of careful evaluation of the dose-response and expensive, a newer type of clinical trial is currently under relationship and the pharmacokinetics of the new drug in a small development. Adaptive trials are aimed at combining 2 or more of number of normal human volunteers (eg, 20–100). An excep- the traditional phases and altering conditions, dosage, and targets tion is the phase 1 trials of cancer chemotherapeutic agents and as the trial progresses, based on data being collected. Trevor_Ch01_p001-p015.indd 10 7/13/18 6:00 PM CHAPTER 1 Introduction 11 DRUG PATENTS & GENERIC DRUGS QUESTIONS A patent application is usually submitted around the time that a 1. A 3-year-old is brought to the emergency department hav- ing just ingested a large overdose of chlorpropamide, an oral new drug enters animal testing (Figure 1–5). In the United States, antidiabetic drug. Chlorpropamide is a weak acid with approval of the patent and completion of the NDA approval a pKa of 5.0. It is capable of entering most tissues. On process give the originator the right to market the drug without physical examination, the heart rate is 110/min, blood pres- competition from other firms for a period of 10–14 years from the sure 90/50 mm Hg, and respiratory rate 30/min. Which of NDA approval date. After expiration of the patent, any company the following statements about this case of chlorpropamide may apply to the FDA for permission to market a generic version overdose is most correct? of the same drug if they demonstrate that their generic drug mol- (A) Urinary excretion would be accelerated by administra- tion of NH4Cl, an acidifying agent ecule is bioequivalent (ie, meets certain requirements for content, (B) Urinary excretion would be accelerated by giving purity, and bioavailability) to the original product. NaHCO3, an alkalinizing agent (C) Less of the drug would be ionized at blood pH than at stomach pH DRUG LEGISLATION (D) Absorption of the drug would be slower from the stom- ach than from the small intestine Many laws regulating drugs in the United States were passed dur- ing the 20th century. Refer to Table 1–4 for a partial list of this 2. Botulinum toxin is a large protein molecule. Its action on cholinergic transmission depends on an intracellular action legislation. within nerve endings. Which one of the following processes is best suited for permeation of very large protein molecules into cells? ORPHAN DRUGS (A) Aqueous diffusion (B) Endocytosis An orphan drug is a drug for a rare disease (in the United States, (C) First-pass effect defined as one affecting fewer than 200,000 people). The study of (D) Lipid diffusion such agents has often been neglected because profits from the sales (E) Special carrier transport of an effective agent for an uncommon ailment might not pay the 3. A 12-year-old child has bacterial pharyngitis and is to receive costs of development. In the United States, current legislation an oral antibiotic. She complains of a sore throat and pain provides for tax relief and other incentives designed to encourage on swallowing. The tympanic membranes are slightly red- the development of orphan drugs. dened bilaterally, but she does not complain of earache. Blood pressure is 105/70 mm Hg, heart rate 100/min, temperature
