Katzung & Trevor's Pharmacology Examination & Board Review PDF

a LANGE medical book Katzung & Trevor’s Pharmacology Examination & Board Review Eleventh Edition Anthony J. Trevor, PhD Professor Emeritus of Pharmacology and Toxicology Department of Cellular & Molecular Pharmacology University of California, San Fran...

a LANGE medical book Katzung & Trevor’s Pharmacology Examination & Board Review Eleventh Edition Anthony J. Trevor, PhD Professor Emeritus of Pharmacology and Toxicology Department of Cellular & Molecular Pharmacology University of California, San Francisco Bertram G. Katzung, MD, PhD Professor Emeritus of Pharmacology Department of Cellular & Molecular Pharmacology University of California, San Francisco Marieke Kruidering-Hall, PhD Associate Professor & Academy Chair of Pharmacology Education 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 Copyright © 2015, 2013, 2010, 2008, 2005, 2002 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 WARRANTIES 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 operation 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 143 1. Introduction 1 16. Histamine, Serotonin, & the Ergot Alkaloids 143 2. Pharmacodynamics 16 17. Vasoactive Peptides 152 3. Pharmacokinetics 26 18. Prostaglandins & Other Eicosanoids 158 4. Drug Metabolism 35 19. Nitric Oxide, Donors, & Inhibitors 165 5. Pharmacogenomics 41 20. Drugs Used in Asthma & Chronic part II Obstructive Pulmonary Disease 169 AUTONOMIC DRUGS 47 part V 6.  Introduction to Autonomic Pharmacology 47 DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEM 179 7. C  holinoceptor-Activating & Cholinesterase-Inhibiting Drugs 60 21. Introduction to CNS Pharmacology 179 8.  Cholinoceptor Blockers & Cholinesterase Regenerators 69 22. Sedative-Hypnotic Drugs 186 9. Sympathomimetics 76 23. Alcohols 194 10. Adrenoceptor Blockers 85 24. Antiseizure Drugs 201 25. General Anesthetics 208 part III 26. Local Anesthetics 216 CARDIOVASCULAR DRUGS 93 27. Skeletal Muscle Relaxants 221 11. Drugs Used in Hypertension 93 28. Drugs Used in Parkinsonism & Other 12. Drugs Used in the Treatment of Angina Movement Disorders 229 Pectoris 103 29. Antipsychotic Agents & Lithium 236 13. Drugs Used in Heart Failure 112 30. Antidepressants 244 14. Antiarrhythmic Drugs 121 31. Opioid Analgesics & Antagonists 252 15. Diuretics & Other Drugs That Act on the Kidney 132 32. Drugs of Abuse 260 iii iv    CONTENTS    47. Antimycobacterial Drugs 389 part VI 48. Antifungal Agents 395 DRUGS WITH IMPORTANT ACTIONS ON BLOOD, INFLAMMATION, 49. Antiviral Chemotherapy & Prophylaxis 402 & GOUT 267 50. Miscellaneous Antimicrobial Agents & Urinary Antiseptics 414 33. Agents Used in Cytopenias; Hematopoietic Growth Factors 267 51. Clinical Use of Antimicrobials 420 34. Drugs Used in Coagulation Disorders 276 52. Antiprotozoal Drugs 426 35. Agents Used in Dyslipidemia 288 53. Antihelminthic Drugs 434 36. NSAIDs, Acetaminophen, & Drugs Used in 54. Cancer Chemotherapy 440 Rheumatoid Arthritis & Gout 296 55. Immunopharmacology 452 part VII part IX ENDOCRINE DRUGS 307 TOXICOLOGY 463 37. Hypothalamic & Pituitary Hormones 307 56. Environmental & Occupational 38. Thyroid & Antithyroid Drugs 316 Toxicology 463 39. Corticosteroids & Antagonists 322 57. Heavy Metals 469 58. Management of the Poisoned Patient 475 40. Gonadal Hormones & Inhibitors 329 41. Pancreatic Hormones, Antidiabetic Agents, part X & Glucagon 340 SPECIAL TOPICS 483 42. Drugs That Affect Bone Mineral Homeostasis 349 59. Drugs Used in Gastrointestinal Disorders 483 part VIII 60. Dietary Supplements & Herbal CHEMOTHERAPEUTIC DRUGS 359 Medications 492 61. Drug Interactions 497 43. Beta-Lactam Antibiotics & Other Cell Wall Synthesis Inhibitors 360 Appendix I. Strategies for Improving Test Performance 503 44. Chloramphenicol, Tetracyclines, Macrolides, Clindamycin, Streptogramins, Appendix II. Key Words for Key Drugs 506 & Linezolid 369 Appendix III. Examination 1 518 45. Aminoglycosides 377 Appendix IV. Examination 2 534 46. Sulfonamides, Trimethoprim, & Fluoroquinolones 382 Index  549 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 eleventh edition has been revised to make Sixth, each chapter includes a Checklist of focused tasks that such preparation as active and efficient as possible. As with you should be able to do once you have finished the chapter. earlier editions, rigorous standards of accuracy and currency Seventh, most chapters end with a Summary Table that lists have been maintained in keeping with the book’s status as the the most important drugs and includes key information concern- companion to the Basic & Clinical Pharmacology textbook. This ing their mechanisms of action, effects, clinical uses, pharmacoki- review book divides pharmacology into the topics used in most netics, drug interactions, and toxicities. courses and textbooks. Major introductory chapters (eg, auto- Eighth, when preparing for a comprehensive examination, you nomic pharmacology and CNS pharmacology) are included should review the strategies described in Appendix I if you have for integration with relevant physiology and biochemistry. The not already done so. Then review the list of drugs in Appendix II: chapter-based approach facilitates use of this book in conjunc- Key Words for Key Drugs. Students are also advised to check tion with course notes or a larger text. We recommend several this appendix as they work through the chapters so they can begin strategies to make reviewing more effective (Appendix I con- to identify drugs out of the context of a chapter that reviews a tains a summary of learning and test-taking strategies that most restricted set of drugs. students find useful). Ninth, after you have worked your way through most or First, each chapter has a short discussion of the major con- all of the chapters and have a good grasp of the Key Drugs, cepts that underlie its basic principles or the specific drug group, you should take the comprehensive examinations, each of 100 accompanied by explanatory figures and tables. The figures questions, presented in Appendices III and IV. These exami- are in full color and some are new to this edition. Students nations are followed by a list of answers, each with a short are advised to read the text thoroughly before they attempt explanation or rationale underlying the correct choice and to answer the study questions at the end of each chapter. If the numbers of the chapters in which more information can a concept is found to be difficult or confusing, the student is be found if needed. We recommend that you take an entire advised to consult a regular textbook such as Basic & Clinical examination or a block of questions as if it were a real exami- Pharmacology, 13th edition. nation: commit to answers for the whole set before you check Second, each drug-oriented chapter opens with an “Overview” the answers. As you work through the answers, make sure that that organizes the group of drugs visually in diagrammatic form. you understand why each answer is either correct or incorrect. We recommend that students practice reproducing the overview If you need to, return to the relevant chapters(s) to review the diagram from memory. text that covers key concepts and facts that form the basis for Third, a list of High Yield Terms to Learn and their defini- the question. tions is near the front of most chapters. Make sure that you are We recommend that this book be used with a regular text. able to define those terms. Basic & Clinical Pharmacology, 13th edition (McGraw-Hill, Fourth, many chapters include a “Skill Keeper” question 2015), follows the chapter sequence used here. However, this that prompts the student to review previous material and to see review book is designed to complement any standard medical links between related topics. We suggest that students try to pharmacology text. The student who completes and under- answer Skill Keeper questions on their own before checking the stands Pharmacology: Examination & Board Review will greatly answers that are provided at the end of the chapter. improve his or her performance and will have an excellent com- Fifth, each of the sixty-one chapters contains up to ten mand of pharmacology. sample questions followed by a set of answers with explana- Because it was developed in parallel with the textbook tions. For most effective learning, you should take each set of Basic & Clinical Pharmacology, this review book represents the sample questions as if it were a real examination. After you have authors’ interpretations of chapters written by contributors to answered every question, work through the answers. When you that text. We are grateful to those contributors, to our other v vi    PREFACE faculty colleagues, and to our students, who have taught us most Katharine Katzung for her excellent proofreading contribu- of what we know about teaching. tions to this edition. We very much appreciate the invaluable contributions to this text afforded by the editorial team of Karen Edmonson, Anthony J. Trevor, PhD Rachel D’Annucci Henriquez, Shruti Awasthi, Harriet Bertram G. Katzung, MD, PhD Lebowitz, and Michael Weitz. The authors also thank Marieke Kruidering-Hall, PhD  PART I BASIC PRINCIPLES 1 C H A P T E R Introduction Pharmacology is the body of knowledge concerned with the on drugs, eg, absorption, excretion, etc. Pharmacodynamics action of chemicals on biologic systems. Medical pharmacol- denotes the actions of the drug on the body, such as mechanism ogy is the area of pharmacology concerned with the use of of action and therapeutic and toxic effects. The first part of this chemicals in the prevention, diagnosis, and treatment of disease, chapter reviews the basic principles of pharmacokinetics and especially in humans. Toxicology is the area of pharmacology pharmacodynamics that will be applied in subsequent chapters. concerned with the undesirable effects of chemicals on biologic The second part of the chapter reviews the development and systems. Pharmacokinetics describes the effects of the body 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 2    PART I Basic Principles I. THE NATURE OF DRUGS PHARMACODYNAMIC PRINCIPLES Drugs in common use include inorganic ions, nonpeptide organic A. Receptors molecules, small peptides and proteins, nucleic acids, lipids, and Drug actions are mediated through the effects of drug ligand carbohydrates. Some are found in plants or animals, and others are molecules on drug receptors in the body. Most receptors are partially or completely synthetic. Many drugs found in nature are large regulatory molecules that influence important biochemi- alkaloids, which are molecules that have a basic pH in solution, usu- cal processes (eg, enzymes involved in glucose metabolism) or ally as a result of amine groups in their structure. Many biologically physiologic processes (eg, ion channel receptors, neurotransmitter important endogenous molecules and exogenous drugs are optically reuptake transporters, and ion transporters). active; that is, they contain one or more asymmetric centers and can If drug-receptor binding results in activation of the receptor, exist as enantiomers. The enantiomers of optically active drugs usually the drug is termed an agonist; if inhibition results, the drug is differ, sometimes more than 1000-fold, in their affinity for biologic considered an antagonist. Some drugs mimic agonist molecules by receptor sites. Furthermore, such enantiomers may be metabolized inhibiting metabolic enzymes, eg, acetylcholinesterase inhibitors. at different rates in the body, with important clinical consequences. As suggested in Figure 1–1, a receptor molecule may have several binding sites. Quantitation of the effects of drug-receptor binding A. Size and Molecular Weight as a function of dose yields dose-response curves that provide Drugs vary in size from molecular weight (MW) 7 (lithium) to information about the nature of the drug-receptor interaction. over MW 50,000 (thrombolytic enzymes, antibodies, other pro- Dose-response phenomena are discussed in more detail in Chapter teins). Most drugs, however, have MWs between 100 and 1000. 2. A few drugs are enzymes themselves (eg, thrombolytic enzymes, Drugs smaller than MW 100 are rarely sufficiently selective in pancreatic enzymes). These drugs do not act on endogenous their actions, whereas drugs much larger than MW 1000 are often receptors but on substrate molecules. poorly absorbed and poorly distributed in the body. Most protein drugs (“biologicals”) are commercially produced in cell, bacteria, B. Receptor and Inert Binding Sites or yeast cultures using recombinant DNA technology. Because most ligand molecules are much smaller than their recep- B. Drug-Receptor Bonds tor molecules (discussed in the text that follows), specific regions Drugs bind to receptors with a variety of chemical bonds. These of receptor molecules provide the local areas responsible for drug include very strong covalent bonds (which usually result in binding. Such areas are termed receptor sites or recognition irreversible action), somewhat weaker electrostatic bonds (eg, sites. In addition, drugs bind to some nonregulatory molecules between a cation and an anion), and much weaker interactions in the body without producing a discernible effect. Such binding (eg, hydrogen, van der Waals, and hydrophobic bonds). sites are termed inert binding sites. In some compartments of the High-Yield Terms to Learn 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 material and pulling it into the cell, where it can be processed or released. Exocytosis: Expulsion of material 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  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 Positive control A known standard therapy, to be used along with placebo, to evaluate the superiority or inferiority 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 produced 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.) 4    PART I Basic Principles body (eg, the plasma), inert binding sites play an important role in 4. Endocytosis—Endocytosis occurs through binding of the buffering the concentration of a drug because bound drug does not transported molecule to specialized components (receptors) on cell contribute directly to the concentration gradient that drives diffu- membranes, with subsequent internalization by infolding of that sion. Albumin and orosomucoid (α1-acid glycoprotein) are two area of the membrane. The contents of the resulting intracellular important plasma proteins with significant drug-binding capacity. vesicle are subsequently released into the cytoplasm of the cell. Endocytosis permits very large or very lipid-insoluble chemicals to enter cells. For example, large molecules such as proteins may cross PHARMACOKINETIC PRINCIPLES cell membranes by endocytosis. Smaller, polar substances such as vitamin B12 and iron combine with special proteins (B12 with intrin- To produce useful therapeutic effects, most drugs must be sic factor and iron with transferrin), and the complexes enter cells absorbed, distributed, and eliminated. Pharmacokinetic principles by this mechanism. Because the substance to be transported must make rational dosing possible by quantifying these processes. combine with a membrane receptor, endocytotic transport can be quite selective. Exocytosis is the reverse process, that is, the expul- The Movement of Drugs in the Body sion of material that is membrane-encapsulated inside the cell from the cell. Most neurotransmitters are released by exocytosis. To reach its receptors and bring about a biologic effect, a drug molecule (eg, a benzodiazepine sedative) must travel from the B. Fick’s Law of Diffusion site of administration (eg, the gastrointestinal tract) to the site of action (eg, the brain). Fick’s law predicts the rate of movement of molecules across a barrier. The concentration gradient (C1 − C2) and permeability coefficient for the drug and the area and thickness of the barrier A. Permeation membrane are used to compute the rate as follows: Permeation is the movement of drug molecules into and within the biologic environment. It involves several processes, the most Permeability coefficient Rate = C1 − C2 × × Area (1) important of which are discussed next. Thickness 1. Aqueous diffusion—Aqueous diffusion is the movement of Thus, drug absorption is faster from organs with large surface molecules through the watery extracellular and intracellular spaces. areas, such as the small intestine, than from organs with smaller The membranes of most capillaries have small water-filled pores absorbing areas (the stomach). Furthermore, drug absorption is that permit the aqueous diffusion of molecules up to the size of faster from organs with thin membrane barriers (eg, the lung) small proteins between the blood and the extravascular space. This than from those with thick barriers (eg, the skin). is a passive process governed by Fick’s law (see later discussion). The capillaries in the brain, testes, and some other organs lack aqueous C. Water and Lipid Solubility of Drugs pores, and these tissues are less exposed to some drugs. 1. Solubility—The aqueous solubility of a drug is often a func- tion of the electrostatic charge (degree of ionization, polarity) of 2. Lipid diffusion—Lipid diffusion is the passive movement of the molecule, because water molecules behave as dipoles and are molecules through membranes and other lipid barriers. Like aque- attracted to charged drug molecules, forming an aqueous shell ous diffusion, this process is governed by Fick’s law. around them. Conversely, the lipid solubility of a molecule is inversely proportional to its charge. 3. Transport by special carriers—Drugs that do not readily Many drugs are weak bases or weak acids. For such molecules, diffuse through membranes may be transported across barriers the pH of the medium determines the fraction of molecules by mechanisms that carry similar endogenous substances. A very charged (ionized) versus uncharged (nonionized). If the pKa of large number of such transporter molecules have been identified, the drug and the pH of the medium are known, the fraction of and many of these are important in the movement of drugs or molecules in the ionized state can be predicted by means of the as targets of drug action. Unlike aqueous and lipid diffusion, Henderson-Hasselbalch equation: carrier transport is not governed by Fick’s law and is capacity- limited. Important examples are transporters for ions (eg, Na+/  Protonated form  K+ ATPase), for neurotransmitters (eg, transporters for serotonin, log  = pK a − pH (2)  Unprotonated form norepinephrine), for metabolites (eg, glucose, amino acids), and for foreign molecules (xenobiotics) such as anticancer drugs. “Protonated” means associated with a proton (a hydrogen ion); After release, amine neurotransmitters (dopamine, norepineph- this form of the equation applies to both acids and bases. rine, and serotonin) and some other transmitters are recycled into nerve endings by transport molecules. Selective inhibitors for these 2. Ionization of weak acids and bases—Weak bases are ion- transporters often have clinical value; for example, several antide- ized—and therefore more polar and more water-soluble—when pressants act by inhibiting the transport of amine neurotransmitters they are protonated. Weak acids are not ionized—and so are less back into the nerve endings from which they have been released. water-soluble—when they are protonated.  CHAPTER 1 Introduction    5 The following equations summarize these points: Absorption of Drugs + H+ A. Routes of Administration RNH3+  RNH2 protonated weak Unprotonated weak proton Drugs usually enter the body at sites remote from the target tissue or base (charged, base (uncharged, (3) organ and thus require transport by the circulation to the intended more water-soluble) more lipid-soluble) site of action. To enter the bloodstream, a drug must be absorbed from its site of administration (unless the drug has been injected RCOOH  RCOO – + H+ directly into the vascular compartment). The rate and efficiency of protonated weak Unprotonated weak proton absorption differ depending on a drug’s route of administration. acid (uncharged, acid (charged, (4) In fact, for some drugs, the amount absorbed may be only a small more lipid-soluble) more water-soluble) fraction of the dose administered when given by certain routes. The amount absorbed into the systemic circulation divided by the amount of drug administered constitutes its bioavailability by that The Henderson-Hasselbalch relationship is clinically impor- route. Common routes of administration and some of their features tant when it is necessary to estimate or alter the partition of drugs are listed in Table 1–1. 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 over- dose of a weak acid drug, for example, aspirin, the excretion of this TABLE 1–1 Common routes of drug administration. drug is faster in alkaline urine. This is because a drug that is a weak acid dissociates to its charged, polar form in alkaline solution, and Oral (swallowed) Offers maximal convenience; absorption this form cannot readily diffuse from the renal tubule back into the is often slower. Subject to the first-pass blood; that is, the drug is trapped in the tubule. Conversely, excre- effect, in which a significant amount of the agent is metabolized in the gut tion of a weak base (eg, pyrimethamine, amphetamine) is faster in wall, portal circulation, and liver before it acidic urine (Figure 1–2). reaches the systemic circulation Buccal and sublingual Direct absorption into the systemic Membranes of (not swallowed) venous circulation, bypassing the hepatic the nephron Urine portal circuit and first-pass metabolism Blood pH 7.4 pH 6.0 Intravenous Instantaneous and complete absorption 1.0 µM Lipid 1.0 µM (by definition, bioavailability is 100%). H diffusion H Potentially more dangerous R N H R N H Intramuscular Often faster and more complete (higher bioavailability) than with oral adminis- H+ H+ tration. Large volumes may be given if the drug is not too irritating. First-pass metabolism is avoided Subcutaneous Slower absorption than the intramus- H H cular route. First-pass metabolism is R N+ H R N+ H avoided. H H Rectal (suppository) The rectal route offers partial avoidance 0.4 µM 10.0 µM of the first-pass effect. Larger amounts of 1.4 µM total 11.0 µM total drug and drugs with unpleasant tastes are better administered rectally than by the buccal or sublingual routes FIGURE 1–2 The Henderson-Hasselbalch principle applied to Inhalation Route offers delivery closest to respira- drug excretion in the urine. Because the nonionized form diffuses tory tissues (eg, for asthma). Usually readily across the lipid barriers of the nephron, this form may reach very rapid absorption (eg, for anesthetic equal concentrations in the blood and urine; in contrast, the ionized gases) form does not diffuse as readily. Protonation occurs within the blood and the urine according to the Henderson-Hasselbalch equation. Pyri- Topical The topical route includes application to the skin or to the mucous membrane methamine, a weak base of pKa 7.0, is used in this example. At blood of the eye, ear, nose, throat, airway, or pH, only 0.4 μmol of the protonated species will be present for each vagina for local effect 1.0 μmol of the unprotonated form. The total concentration in the blood will thus be 1.4 μmol/L if the concentration of the unprotonated Transdermal The transdermal route involves appli- form is 1.0 μmol/L. In the urine at pH 6.0, 10 μmol of the nondiffusible cation to the skin for systemic effect. ionized form will be present for each 1.0 μmol of the unprotonated, Absorption usually occurs very slowly (because of the thickness of the skin), diffusible form. Therefore, the total urine concentration (11 μmol/L) but the first-pass effect is avoided may be almost 8 times higher than the blood concentration. 6    PART I Basic Principles B. Blood Flow TABLE 1–2 Average values for some physical Blood flow influences absorption from intramuscular and subcu- volumes within the adult human body. taneous sites and, in shock, from the gastrointestinal tract as well. Compartment Volume (L/kg body weight) High blood flow maintains a high drug depot-to-blood concentra- tion gradient and thus facilitates absorption. Plasma 0.04 Blood 0.08 C. Concentration The concentration of drug at the site of administration is Extracellular water 0.2 important in determining the concentration gradient relative Total body water 0.6 to the blood as noted previously. As indicated by Fick’s law (Equation 1), the concentration gradient is a major determinant Fat 0.2–0.35 of the rate of absorption. Drug concentration in the vehicle is par- ticularly important in the absorption of drugs applied topically. distribution of a drug in the body. Vd relates the amount of drug in the body to the concentration in the plasma (Chapter 3). In Distribution of Drugs contrast, the physical volumes of various body compartments are A. Determinants of Distribution less important in pharmacokinetics (Table 1–2). However, obe- 1. Size of the organ—The size of the organ determines the con- sity alters the ratios of total body water to body weight and fat to centration gradient between blood and the organ. For example, total body weight, and this may be important when using highly skeletal muscle can take up a large amount of drug because the lipid-soluble drugs. A simple approximate rule for the aqueous concentration in the muscle tissue remains low (and the blood- compartments of the normal body is as follows: 40% of total body tissue gradient high) even after relatively large amounts of drug weight is intracellular water and 20% is extracellular water; thus, have been transferred; this occurs because skeletal muscle is a very water constitutes approximately 60% of body weight. large organ. In contrast, because the brain is smaller, distribution of a smaller amount of drug into it will raise the tissue concentra- Metabolism of Drugs tion and reduce to zero the blood-tissue concentration gradient, preventing further uptake of drug unless it is actively transported. Drug disposition is a term sometimes used to refer to metabo- lism and elimination of drugs. Some authorities use disposition to denote distribution as well as metabolism and elimination. 2. Blood flow—Blood flow to the tissue is an important deter- Metabolism of a drug sometimes terminates its action, but other minant of the rate of uptake of drug, although blood flow may not effects of drug metabolism are also important. Some drugs when affect the amount of drug in the tissue at equilibrium. As a result, given orally are metabolized before they enter the systemic circula- well-perfused tissues (eg, brain, heart, kidneys, and splanchnic 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 the Termination of Drug Action blood vessels. If the drug is very soluble in the cells, the concentration in the perivascular extracellular space will be lower and diffusion from The action of many drugs (eg, sympathomimetics, phenothi- the vessel into the extravascular tissue space will be facilitated. For azines) is terminated before they are excreted because they are example, some organs (such as the brain) have a high lipid content metabolized to biologically inactive derivatives. Conversion to an and thus dissolve a high concentration of lipid-soluble agents rapidly. inactive metabolite is a form of elimination. In contrast, prodrugs (eg, levodopa, minoxidil) are inactive as administered and must be metabolized in the body to become 4. Binding—Binding of a drug to macromolecules in the blood active. Many drugs are active as administered and have active or a tissue compartment tends to increase the drug’s concentra- metabolites as well (eg, morphine, some benzodiazepines). tion in that compartment. For example, warfarin is strongly bound to plasma albumin, which restricts warfarin’s diffusion B. Drug Elimination Without Metabolism out of the vascular compartment. Conversely, chloroquine is strongly bound to extravascular tissue proteins, which results in Some drugs (eg, lithium, many others) are not modified by the a marked reduction in the plasma concentration of chloroquine. body; they continue to act until they are excreted. B. Apparent Volume of Distribution and Physical Elimination of Drugs Volumes Along with the dosage, the rate of elimination following the last The apparent volume of distribution (Vd) is an important phar- dose (disappearance of the active molecules from the site of action, macokinetic parameter that reflects the above determinants of the the bloodstream, and the body) determines the duration of action  CHAPTER 1 Introduction    7 for many drugs. Therefore, knowledge of the time course of con- Such drugs do not have a constant half-life. This is typical of etha- centration in plasma is important in predicting the intensity and nol (over most of its plasma concentration range) and of phenytoin duration of effect for most drugs. Note: Drug elimination is not the and aspirin at high therapeutic or toxic concentrations. same as drug excretion: A drug may be eliminated by metabolism long before the modified molecules are excreted from the body. Pharmacokinetic Models For most drugs and their metabolites, excretion is primarily by A. Multicompartment Distribution way of the kidney. Volatile anesthetic gases, a major exception, are excreted primarily by the lungs. For drugs with active metabolites After absorption into the circulation, many drugs undergo an (eg, diazepam), elimination of the parent molecule by metabolism is early distribution phase followed by a slower elimination phase. not synonymous with termination of action. For drugs that are not Mathematically, this behavior can be simulated by means of a metabolized, excretion is the mode of elimination. A small number “two-compartment model” as shown in Figure 1–4. The two of drugs combine irreversibly with their receptors, so that disappear- compartments consist of the blood and the extravascular tissues. ance from the bloodstream is not equivalent to cessation of drug (Note that each phase is associated with a characteristic half-life: action: These drugs may have a very prolonged action. For example, t1/2α for the first phase, t1/2β for the second phase. Note also that phenoxybenzamine, an irreversible inhibitor of α adrenoceptors, is when concentration is plotted on a logarithmic axis, the elimina- eliminated from the bloodstream in less than 1 h after administra- tion phase for a first-order drug is a straight line.) tion. The drug’s action, however, lasts for 48 h, the time required for turnover of the receptors. B. Other Distribution Models A few drugs behave as if they were distributed to only 1 compart- A. First-Order Elimination ment (eg, if they are restricted to the vascular compartment). The term first-order elimination indicates that the rate of elimination Others have more complex distributions that require more than is proportional to the concentration (ie, the higher the concentra- 2 compartments for construction of accurate mathematical tion, the greater the amount of drug eliminated per unit time). The models. result is that the drug’s concentration in plasma decreases exponen- tially with time (Figure 1–3, left). Drugs with first-order elimina- tion have a characteristic half-life of elimination that is constant II. DRUG DEVELOPMENT regardless of the amount of drug in the body. The concentration of such a drug in the blood will decrease by 50% for every half-life. & REGULATION Most drugs in clinical use demonstrate first-order kinetics. The sale and use of drugs are regulated in almost all countries by governmental agencies. In the United States, regulation is by the B. Zero-Order Elimination Food and Drug Administration (FDA). New drugs are developed The term zero-order elimination implies that the rate of elimination in industrial or academic laboratories. Before a new drug can be is constant regardless of concentration (Figure 1–3, right). This approved for regular therapeutic use in humans, a series of animal occurs with drugs that saturate their elimination mechanisms at and experimental human studies (clinical trials) must be carried out. concentrations of clinical interest. As a result, the concentrations New drugs may emerge from a variety of sources. Some of these drugs in plasma decrease in a linear fashion over time. are the result of identification of a new target for a disease. 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. 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 two 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 two plasma concentration points on the elimination phase that differ by twofold. (See Chapter 3 for additional details.) Rational molecular design or screening is then used to find a ANIMAL TESTING molecule that selectively alters the function of the target. New drugs may result from the screening of hundreds of compounds The animal testing of a specific drug that is required before human against model diseases in animals. In contrast, many (so-called studies can begin is a function of its proposed use and the urgency “me-too” drugs) are the result of simple chemical alteration of of the application. Thus, a drug proposed for occasional topical use the pharmacokinetic properties of the original prototype agent. requires less extensive testing than one destined for chronic systemic administration. Because of the urgent need, anticancer drugs and anti-HIV drugs SAFETY & EFFICACY require less evidence of safety than do drugs used in treatment of less threatening diseases. Urgently needed drugs are often investigated Because society expects prescription drugs to be safe and effec- and approved on an accelerated schedule. tive, governments regulate the development and marketing of new drugs. Current regulations in the USA require evidence of A. Acute Toxicity relative safety (derived from acute and subacute toxicity testing Acute toxicity studies are required for all new drugs. These in animals) and probable therapeutic action (from the pharmaco- studies involve administration of incrementing doses of the logic profile in animals) before human testing is permitted. Some agent up to the lethal level in at least 2 species (eg, 1 rodent and information about the pharmacokinetics of a compound is also 1 nonrodent). required before clinical evaluation is begun. Chronic toxicity test 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. Tests are usually con- new drug, including false starts and discarded molecules, is often ducted for 2–4 weeks (subacute) and 6–24 months (chronic), in greater than 500 million dollars. at least 2 species.  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.) TYPES OF ANIMAL TESTS TABLE 1–3 FDA ratings of drug safety in pregnancy. Category Description A. Pharmacologic Profile The pharmacologic profile is a description of all the pharma- A Controlled studies in women fail to demonstrate cologic effects of a drug (eg, effects on cardiovascular function, a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimesters), and gastrointestinal activity, respiration, hepatic and renal function, the possibility of fetal harm appears remote endocrine function, CNS). Both graded and quantal dose- response data are gathered. B Either animal reproduction studies have not demonstrated a fetal risk but there are no con- trolled studies in pregnant women, or animal reproduction studies have shown an adverse B. Reproductive Toxicity effect (other than a decrease in fertility) that was Reproductive toxicity testing involves the study of the fertility not confirmed in controlled studies in women in effects of the candidate drug and its teratogenic and mutagenic the first trimester (and there is no evidence of a risk in later trimesters) toxicity. The FDA has used a 5-level descriptive scale to sum- marize information regarding the safety of drugs in pregnancy C Either studies in animals have revealed adverse (Table 1–3). Teratogenesis can be defined as the induction of effects on the fetus (teratogenic or embryocidal developmental defects in the somatic tissues of the fetus (eg, or other) and there are no controlled studies in women, or studies in women and animals are by exposure of the fetus to a chemical, infection, or radiation). not available. Drugs should be given only when Teratogenesis is studied by treating pregnant female animals the potential benefit justifies the potential risk of at least 2 species at selected times during early pregnancy to the fetus when organogenesis is known to take place and by later exam- D There is positive evidence of human fetal risk, ining the fetuses or neonates for abnormalities. Examples of but the benefits from use in pregnant women drugs known to have teratogenic effects include thalidomide, may be acceptable despite the risk (eg, if the isotretinoin, valproic acid, ethanol, glucocorticoids, warfarin, drug is needed in a life-threatening situation or for a serious disease for which safer drugs can- lithium, and androgens. Mutagenesis denotes induction of not be used or are ineffective) changes in the genetic material of animals of any age and therefore induction of heritable abnormalities. The Ames test, X Studies in animals or human beings have dem- onstrated fetal abnormalities or there is evidence the standard in vitro test for mutagenicity, uses a special strain of fetal risk based on human experience or both, of salmonella bacteria that depends on specific nutrients in the and the risk of the use of the drug in pregnant culture medium. Loss of this dependence as a result of exposure women clearly outweighs any possible benefit. to the test drug signals a mutation. Many carcinogens (eg, afla- The drug is contraindicated in women who are or may become pregnant toxin, cancer chemotherapeutic drugs, and other agents that 10    PART I Basic Principles bind to DNA) have mutagenic effects and test positive in the conditions, and patients are closely monitored, often in a hospital Ames test. The dominant lethal test is an in vivo mutagenicity research ward. The goal is to determine whether the agent has the test carried out in mice. Male animals are exposed to the test desired efficacy (ie, produces adequate therapeutic response) at substance before mating. Abnormalities in the results of subse- doses that are tolerated by sick patients. Detailed data are collected quent mating (eg, loss of embryos, deformed fetuses) signal a regarding the pharmacokinetics and pharmacodynamics of the drug mutation in the male’s germ cells. in this patient population. C. Carcinogenesis C. Phase 3 Carcinogenesis is the induction of malignant characteristics in cells. A phase 3 trial usually involves many patients (eg, 1000–6000 or Carcinogenicity is difficult and expensive to study, and the Ames more, in many centers) and many clinicians who are using the drug test is often used to screen chemicals because there is a moderately in the manner proposed for its ultimate general use (eg, in outpa- high degree of correlation between mutagenicity in the Ames test tients). Such studies usually include placebo and positive controls in a and carcinogenicity in some animal tests, as previously noted. double-blind crossover design. The goals are to explore further, under Agents with known carcinogenic effects include coal tar, aflatoxin, the conditions of the proposed clinical use, the spectrum of beneficial dimethylnitrosamine and other nitrosamines, urethane, vinyl chlo- actions of the new drug, to compare it with placebo (negative control) ride, and the polycyclic aromatic hydrocarbons in tobacco smoke and older therapy (positive control), and to discover toxicities, if any, (eg, benzo[a]pyrene) and other tobacco products. that occur so infrequently as to be undetectable in phase 2 studies. Very large amounts of data are collected and these studies are usually very expensive. Unfortunately, relatively few phase 3 trials include the CLINICAL TRIALS current standard of care as a positive control. Human testing of new drugs in the United States requires If the drug successfully completes phase 3, an NDA is submit- approval by institutional committees that monitor the ethical ted to the FDA. If the NDA is approved, the drug can be mar- (informed consent, patient safety) and scientific aspects (study keted and phase 4 begins. design, statistical power) of the proposed tests. Such testing also requires the prior approval by the FDA of an Investigational D. Phase 4 New Drug Exemption application (IND), which is submitted Phase 4 represents the postmarketing surveillance phase of by the manufacturer to the FDA (Figure 1–5). The IND includes evaluation, in which it is hoped that toxicities that occur very all the preclinical data collected up to the time of submission and infrequently will be detected and reported early enough to pre- the detailed proposal for clinical trials. The major clinical testing vent major therapeutic disasters. Manufacturers are required to process is usually divided into 3 phases that are carried out to inform the FDA at regular intervals of all reported untoward provide information for a New Drug Application (NDA). The drug reactions. Unlike the first 3 phases, phase 4 has not been NDA includes all the results of preclinical and clinical testing and rigidly regulated by the FDA in the past. Because so many drugs constitutes the request for FDA approval of general marketing of have been found to be unacceptably toxic only after they have the new agent for prescription use. A fourth phase of study (the been marketed, there is considerable current interest in making surveillance phase) follows NDA approval. In particularly lethal phase 4 surveillance more consistent, effective, and informative. conditions, the FDA may permit carefully monitored treatment of patients before phases 2 and 3 are completed. DRUG PATENTS & GENERIC DRUGS A. Phase 1 A patent application is usually submitted around the time that a A phase 1 trial consists of careful evaluation of the dose-response new drug enters animal testing (Figure 1–5). In the United States, relationship and the pharmacokinetics of the new drug in a small approval of the patent and completion of the NDA approval number of normal human volunteers (eg, 20–100). An exception process give the originator the right to market the drug without is the phase 1 trials of cancer chemotherapeutic agents and other competition from other firms for a period of 10–14 years from the highly toxic drugs; these are carried out by administering the NDA approval date. After expiration of the patent, any company agents to volunteer patients with the target disease. In phase 1 may apply to the FDA for permission to market a generic version studies, the acute effects of the agent are studied over a broad of the same drug if they demonstrate that their generic drug mol- range of dosages, starting with one that produces no detectable ecule is bioequivalent (ie, meets certain requirements for content, effect and progressing to one that produces either a significant purity, and bioavailability) to the original product. physiologic response or a very minor toxic effect. B. Phase 2 DRUG LEGISLATION A phase 2 trial involves evaluation of a drug in a moderate number of sick patients (eg, 100–200) with the target disease. A placebo or Many laws regulating drugs in the United States were passed dur- positive control drug is included in a single-blind or double-blind ing the 20th century. Refer to Table 1–4 for a partial list of this design. The study is carried out under very carefully controlled legislation.  CHAPTER 1 Introduction    11 TABLE 1–4 Selected legislation pertaining to drugs 2. Botulinum toxin is a large protein molecule. Its action on in the United States. cholinergic transmission depends on an intracellular action within nerve endings. Which one of the following processes Law Purpose and Effect is best suited for permeation of very large protein molecules into cells? Pure Food and Drug Prohibited mislabeling and adulteration of (A) Aqueous diffusion Act of 1906 foods and drugs (but no requirement for (B) Endocytosis efficacy or safety) (C) First-pass effect Harrison Narcotics Act Established regulations for the use of opium, (D) Lipid diffusion of 1914 opioids, and cocaine (marijuana added in (E) Special carrier transport 1937) 3. A 12-year-old child has bacterial pharyngitis and is to receive Food, Drug, and Cos- Required that new drugs be tested for safety an oral antibiotic. She complains of a sore throat and pain on metics Act of 1938 as well as purity swallowing. The tympanic membranes are slightly reddened bilaterally, but she does not complain of earache. Blood pres- Kefauver-Harris Required proof of efficacy as well as safety sure is 105/70 mm Hg, heart rate 100/mm, temperature Amendment (1962) for new drugs 37.8 °C (100.1 °F). Ampicillin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in the Dietary Supplement Amended the Food, Drug, and Cosmetics and Health Education act of 1938 to establish standards for dietary lipid-soluble form in the duodenum at a pH of 4.5? Act (1994) supplements but prohibited the FDA from (A) About 1% applying drug efficacy and safety standards (B) About 10% to supplements (C) About 50% (D) About 90% (E) About 99% ORPHAN DRUGS 4. Ampicillin is eliminated by first-order kinetics. Which of the following statements best describes the process by which the An orphan drug is a drug for a rare disease (one affecting fewer plasma concentration of this drug declines? (A) There is only 1 metabolic path for drug elimination than 200,000 people in the United States). The study of such (B) The half-life is the same regardless of the plasma agents has often been neglected because profits from the sales of concentration an effective agent for an uncommon ailment might not pay the (C) The drug is largely metabolized in the liver after oral costs of development. In the United States, current legislation administration and has low bioavailability provides for tax relief and other incentives designed to encourage (D) The rate of elimination is proportional to the rate of the development of orphan drugs. administration at all times (E) The drug is distributed to only 1 compartment outside the vascular system 5. The pharmacokinetics of a new drug are under study in a QUESTIONS phase 1 clinical trial. Which statement about the distribution of drugs to specific tissues is most correct? 1. A 3-year-old is brought to the emergency department hav- (A) Distribution to an organ is independent of blood flow ing just ingested a large overdose of tolbutamide, an oral (B) Distribution is independent of the solubility of the drug antidiabetic drug. Tolbutamide is a weak acid with a pKa in that tissue of 5.3. It is capable of entering most tissues, including the (C) Distribution into a tissue depends on the unbound drug brain. On physical examination, the heart rate is 100/min, concentration gradient between blood and the tissue blood pressure 90/50 mm Hg, and respiratory rate 20/min. (D) Distribution is increased for drugs that are strongly Which of the following statements about this case of tolbu- bound to plasma proteins tamide overdose is most correct? (E) Distribution has no effect on the half-life of the drug (A) Urinary excretion would be accelerated by administra- tion of NH4Cl, an acidifying agent 6. The pharmacokinetic process or property that distinguishes (B) Urinary excretion would be accelerated by giving the elimination of ethanol and high doses of phenytoin and NaHCO3, an alkalinizing agent aspirin from the elimination of most other drugs is called (C) Less of the drug would be ionized at blood pH than at (A) Distribution stomach pH (B) Excretion (D) Absorption of the drug would be slower from the stom- (C) First-pass effect ach than from the small intestine (D) First-order elimination (E) Hemodialysis is the only effective therapy (E) Zero-order elimination 12    PART I Basic Principles 7. A new drug was administered intravenously, and its plasma 10. The “dominant lethal” test involves the treatment of a male levels were measured for several hours. A graph was prepared adult animal with a chemical before mating; the pregnant as shown below, with the plasma levels plotted on a logarith- female is later examined for fetal death and abnormalities. mic ordinate and time on a linear abscissa. It was concluded The dominant lethal test therefore is a test of that the drug has first-order kinetics. From this graph, what (A) Teratogenicity is the best estimate of the half-life? (B) Mutagenicity (C) Carcinogenicity (D) Sperm viability 11. Which of the following would probably not be included in an 32 optimal phase 3 clinical trial of a new analgesic drug for mild pain? Plasma concentration 16 (A) A negative control (placebo) (B) A positive control (current standard analgesic therapy) 8 (C) Double-blind protocol (in which neither the patient nor immediate observers of the patient know which agent is active) 4 (D) A group of 1000–5000 subjects with a clinical condition requiring analgesia 2 (E) Prior submission of an NDA (new drug application) to the FDA 1 0 1 2 3 4 5 6 7 12. Which of the following statements about the testing of new compounds for potential therapeutic use in the treatment of Time (h) hypertension is most correct? (A) Animal tests cannot be used to predict the types of clini- cal toxicities that may occur because there is no correla- (A) 0.5 h tion with human toxicity (B) 1h (B) Human studies in normal individuals will be done (C) 3h before the drug is used in individuals with hypertension (D) 4h (C) The degree of risk must be assessed in at least 3 species (E) 7h of animals, including 1 primate species 8. A large pharmaceutical company has conducted extensive (D) The animal therapeutic index must be known before animal testing of a new drug for the treatment of advanced trial of the agents in humans prostate cancer. The chief of research and development rec- 13. The Ames test is frequently carried out before clinical trials ommends that the company now submit an IND application are begun. The Ames test is a method that detects in order to start clinical trials. Which of the following state- (A) Carcinogenesis in primates ments is most correct regarding clinical trials of new drugs? (B) Carcinogenesis in rodents (A) Phase 1 involves the study of a small number of normal (C) Mutagenesis in bacteria volunteers by highly trained clinical pharmacologists (D) Teratogenesis in any mammalian species (B) Phase 2 involves the use of the new drug in a large (E) Teratogenesis in primates number of patients (1000–5000) who have the disease to be treated under conditions of proposed use (eg, 14. Which of the following statements about new drug develop- outpatients) ment is most correct? (C) Chronic animal toxicity studies must be complete and (A) Drugs that test positive for teratogenicity, mutagenicity, reported in the IND or carcinogenicity can be tested in humans (D) Phase 4 involves the detailed study of toxic effects that (B) Food supplements and herbal (botanical) remedies are have been discovered in phase 3 subject to the same FDA regulation as ordinary drugs (E) Phase 2 requires the use of a positive control (a known (C) All new drugs must be studied in at least 1 primate spe- effective drug) and a placebo cies before NDA submission (D) Orphan drugs are drugs that are no longer produced by 9. Which of the following statements about animal testing of the original manufacturer potential new therapeutic agents is most correct? (E) Phase 4 (surveillance) is the most rigidly regulated phase (A) Extends at least 3 years to discover late toxicities of clinical drug trials (B) Requires at least 1 primate species (eg, rhesus monkey) (C) Requires the submission of histopathologic slides and specimens to the FDA for evaluation by government scientists (D) Has good predictability for drug allergy-type reactions (E) May be abbreviated in the case of some very toxic agents used in cancer  CHAPTER 1 Introduction    13 ANSWERS is plotted versus time, a straight line results. The half-life is defined as the time required for the concentration to decrease 1. Questions that deal with acid-base (Henderson-Hasselbalch) by 50%. As shown in the graph, the concentration decreased manipulations are common on examinations. Since absorption from 16 units at 1 h to 8 units at 4 h and 4 units at 7 h; there- involves permeation across lipid membranes, we can in theory fore, the half-life is 7 h minus 4 h or 3 h. The answer is C. treat an overdose by decreasing absorption from the gut and 8. Except for known toxic drugs (eg, cancer chemotherapy reabsorption from the tubular urine by making the drug less drugs), phase 1 is carried out in 25–50 normal volunteers. lipid-soluble. Ionization attracts water molecules and decreases Phase 2 is carried out in several hundred closely monitored lipid solubility. Tolbutamide is a weak acid, which means that patients with the disease. Results of chronic toxicity studies it is less ionized when protonated, ie, at acid pH. Choice C in animals are required in the NDA and are usually underway suggests that the drug would be less ionized at pH 7.4 than at at the time of IND submission. However, they do not have pH 2.0, which is clearly wrong for weak acids. Choice D says to be completed and reported in the IND. Phase 4 is the (in effect) that the more ionized form is absorbed faster, which general surveillance phase that follows marketing of the new is incorrect. A and B are opposites because NH4Cl is an acidi- drug. It is not targeted at specific effects. Positive controls and fying salt and sodium bicarbonate an alkalinizing one. (From placebos are not a rigid requirement of any phase of clinical the point of view of test strategy, opposites in a list of answers trials, although placebos are often used in phase 2 and phase always deserve careful attention.) E is a distracter. Because 3 studies. The answer is A. an alkaline environment favors ionization of a weak acid, we should give bicarbonate. The answer is B. Note that clinical 9. Drugs proposed for short-term use may not require long- management of overdose involves many other considerations term chronic testing. For some drugs, no primates are used; in addition to trapping the drug in urine; manipulation of for other agents, only 1 species is used. The data from the urine pH may be contraindicated for other reasons. tests, not the evidence itself, must be submitted to the FDA. Prediction of human drug allergy from animal testing is use- 2. Endocytosis is an important mechanism for transport of ful but not definitive (see answer 12). The answer is E. very large molecules across membranes. Aqueous diffusion is not involved in transport across the lipid barrier of cell 10. The description of the test indicates that a chromosomal membranes. Lipid diffusion and special carrier transport change (passed from father to fetus) is the toxicity detected. are common for smaller molecules. The first-pass effect has This is a mutation. The answer is B. nothing to do with the mechanisms of permeation; rather, it 11. The first 4 items (A–D) are correct; they would be included. denotes drug metabolism or excretion before absorption into An NDA cannot be acted upon until the first 3 phases the systemic circulation. The answer is B. of clinical trials have been completed. (The IND must 3. U.S. Medical Licensing Examination (USMLE)-type questions be approved before clinical trials can be conducted.) The often contain a lengthy clinical description in the stem. One can answer is E. often determine the relevance of the clinical data by scanning the 12. Animal tests in a single species do not always predict human last sentence in the stem and the list of answers, see Appendix IV. toxicities. However, when these tests are carried out in s