Pharmacology PreTest Self-Assessment and Review Twelfth Edition

Pharmacology PreTestTM Self-Assessment and Review Notice Medicine is an ever-changing science. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy are required. The authors and the publisher of this work have checked with sources believed to be reliable in their efforts to provide information that is complete and generally in accord with the standards accepted at the time of publication. However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omissions or for the results obtained from use of the information contained in this work. Readers are encouraged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the prod- uct information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Pharmacology PreTestTM Self-Assessment and Review Twelfth Edition Marshal Shlafer, PhD Professor, Department of Pharmacology Director of Undergraduate Medical Pharmacology Education University of Michigan Medical School Ann Arbor, Michigan symbol after every occurrence of a trademarked name, we use names in an editorial fashion only, and to the benefit of the trademark owner, with no intention of infringement of the trade- mark. Where such designations appear in this book, they have been printed with initial caps. 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DOI: 10.1036/2 Student Reviewers Tyler James Harris University of Washington—School of Medicine Class of 2007 Mona Karimullah University of Texas—Houston School of Medicine Class of 2006 David Scoville Kansas University—School of Medicine Class of 2008 This page intentionally left blank For more information about this title, click here Contents Preface. ix Introduction xi Cross-References to Selected Pharmacology Texts xxi List of Abbreviations and Acronyms xxiii General Principles Questions 1 Answers 17 The Peripheral Nervous Systems: Autonomic and Somatic Questions 39 Answers 66 The Central Nervous System Questions 103 Answers 131 The Cardiovascular System Questions 165 Answers 200 The Renal System and Diuretics Questions 249 Answers 259 The Respiratory System:Asthma and COPD Questions 275 Answers 281 vii viii Contents Local Control Substances:Autacoids and Drugs for Inflammatory Processes Questions 291 Answers 304 The Gastrointestinal System and Nutrition Questions 321 Answers 330 The Endocrine System, Uterine Stimulants and Relaxants Questions 343 Answers 360 Anti-Infectives Questions 381 Answers 399 Cancer Chemotherapy and Immunosuppressants Questions 419 Answers 426 Toxicology Questions 437 Answers 443 Index 451 Preface Welcome to this, the 12th edition, of Pharmacology: PreTestTM Self-Assessment and Review. I’m pleased to have been invited back to do this edition after doing the 11th. Whether you’re studying for Step 1 of the USMLE or for a course exam that includes pharmacology content, I think you’ll find this helpful. Among the changes here you’ll find are: • Over 200 new or extensively revised questions, most based on clinical vignettes or scenarios, and nearly all pretested on hundreds of first- and second-year medical students • Many more questions in the format you’ll likely see on Step 1 of the USMLE • A better blend of questions that integrate your basic pharmacology knowledge with clinical applications, and with information from other basic preclinical disciplines • More integration of question content between the various areas of phar- macology and therapeutics. This is a general “build upon the base” approach in which questions in later chapters encourage you to integrate new material with content presented earlier • Clearer explanations for why correct answers are correct and the others aren’t • Updates of cross-references to major pharmacology text cross-references in the answers so you can easily find additional information or explana- tions if you wish This page intentionally left blank Introduction Each PreTestTM Self-Assessment and Review helps you evaluate and review your intensive and extensive knowledge of pharmacology and therapeutics, your expected knowledge of basic facts, and your ability to apply facts and con- cepts to some common (yet perhaps new, to you) clinical situations. The 502 questions you’ll find here parallel the format and degree of difficulty of ques- tions likely to be found in the United States Medical Licensing Examination (USMLE) Step 1. They should also help if you want to hone your knowledge base before USMLE Step 2 or 3, or similar licensure exams. At the start of each chapter I provide a short list of key terms (mainly drug classes or basic concepts) to help orient you to the general scope of the ques- tion topics that follow. Each question is accompanied by several answers, only one of which is the “best choice”; explanations of a length, depth, and scope that I deem appropriate to understanding the answer; and cross-references to pages in one or more of three commonly used textbooks so you can get more information if you wish. Study Tips, and How to Use This Book Each of you has a study and review method that has worked best for you over the years. “Go with a winner,” as they say. It has gotten you into medical school, and kept you there. But do prepare yourself to answer the questions in each chapter by reviewing first the corresponding material from your lecture notes and favorite (or, at least, assigned) text. This volume that you hold in your hands is, after all, a review and self-assessment tool, not an original source of learning information. Each multiple-choice question in this book contains four or more possi- ble answer options. In each case, select the ONE BEST ANSWER to the ques- tion. Mark your answer by each question, allowing yourself about a minute or so for each question, but don’t be rushed. There are no negative consequences from going through this review and answering incorrectly, and no rewards for haste. The point is that you learn, or merely refresh your knowledge. Be brave: don’t skip the questions that initially stump you—and there will be a few of them—or those that test beyond the “rat facts,” as there are some of those too. I’m going to implore you not to do one rather tempting thing: read, or even peek, at the answers to individual questions in a chapter before you’ve xi Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. answered all the questions in that chapter. I know this may be painful in a variety of ways (“no pain, no gain” as they say). Nonetheless, explanations for the answers to one question may give you a tip-off (if not the outright correct answer) to another question. That would be fine, ultimately, but in this review process—assessing your own knowledge, understanding, and recall— such tip-offs may lull you into arriving at the correct answer by a short-circuited approach, having just read a similar or applicable answer when you checked your responses of a previous question. There is “planned redundancy” in some of the questions and the answers. After you finish going through all the questions in a chapter, spend as much time as you need verifying your answers and carefully reading the explanations provided. This is particularly important if you’re stumped for a right answer, or even didn’t have a clue about what the right answer might be. However, the explanations I provide as answers to questions should serve as a beneficial review for all of you to reinforce concepts and facts you seem to know already. And if you got a question right, was that because you knew the answer, and understood what was going on, or just made a lucky guess? Regardless, pay special attention to the explanations for the questions you answered incorrectly —but read every explanation. I have designed the explanations to reinforce and supplement the information sought by the questions, and sometimes to gently encourage you to look at (usually earlier) parts of this review book (as well as your class notes and your favorite or required pharmacology text) to see important connections—for example, those essential connections between basic autonomic pharmacology and car- diovascular, respiratory, or CNS topics. Before you work on the questions and your studying overall, try orga- nizing things in these ways, and aim to accomplish the following: Be able to identify main drug classes, recognizing that sometimes we use more than one classification scheme, e.g., chemical; by main mechanism(s) of action; by clinical use; and be able to cite a prototype drug for each. Conversely, given a named prototype or otherwise representative drug, be able to work backward and know the rest of the most relevant information. For example, you can identify a group of drugs that are nonselective cyclooxygenase (COX) inhibitors, a main chemical class of which includes acetylsalicylic acid (salicylates); the prototype drug is aspirin, and the main uses are for management of fever, inflammation, and mild pain. But also know the “special” properties of representative or unique agents in a group: for example, the use of aspirin for prophylaxis of arterial thrombosis, and something important about, say, indomethacin. You could (if not should) take a reverse approach by identifying propra- nolol as the prototype nonselective -adrenergic blocker; identifying the main actions (due to blockade of -adrenergic receptors, which implicitly means your knowing what activating the 1 and 2 receptors does); and recognizing that propranolol has such uses as management of hypertension, certain types of angina pectoris, heart failure, tachycardia, and so on. You should be able to recognize the term catecholamine as applicable to a drug or drug group with structures and actions similar to epinephrine or norepinephrine. Be able to recognize the most common and/or most important (e.g., serious or life-threatening) side effects or adverse responses for the main drugs or drug classes. In my first lectures on pharmacology to every group of new students I teach, I say that if drugs did only the good and predictable things they’re sup- posed to do, life—and learning—would be a heck of a lot simpler for you. For better or worse, however, side effects and other adverse responses hap- pen. Then, too, there are the sometimes unavoidable and potentially disas- trous consequences of polypharmacy drug-drug interactions. These are just as important, if not more important, than knowing merely what the drug does, what it’s used for, or how it works. Often you know intuitively what the side effects or adverse responses to a particular drug or drug group may be. The more common and perhaps important ones are often “extensions” of expected effects of the drug or class. For example, most antihypertensive drugs can cause hypotension (when blood levels are excessive), and many drugs cause nephrotoxicity and/or hepatotoxicity because the kidneys or liver are the main sites of elimination of the drugs, or their metabolites. However, some drugs cause effects that are, for lack of a better phrase, unique or unexpected: ototoxicity from aminogly- coside antibiotics or loop diuretics; a lupus-like syndrome from hydralazine or isoniazid; thyroid hormone and pulmonary problems from amiodarone; cyanide poisoning from nitroprusside. Learn these “unique” responses; I’ll ask you about them, and I won’t be the only one to do that. Learn to recognize that intended effects or side effects that you simply should know give you a good idea of what the relevant precautions or contraindications are, even if you haven’t been taught about the latter, even if your learning focus hasn’t been too clinical. For example, you no doubt learned that -adrenergic blockers can reduce cardiac rate, contractility, and electrical impulse conduction velocity (especially through the AV node), and sometimes these drugs are used specifically to cause one or more of those effects. You should then realize that excessive doses may cause unwanted degrees of suppression of those cardiac parameters. And, although you may not have been taught explicitly, you should realize that the effects of these drugs warrant extra caution (or contraindicate altogether) the use of a -blocker in patients who already have bradycardia, significantly reduced ventricular contractility, or some degree of heart block. Making these associations or extrapolations is not rocket science that you must have been taught about explicitly. You should be able to use your basic knowledge of pharmacology and drug action, and of physiology and pathophysiology, to piece things together and get the correct (or most logical or likely) answer. Breadth and Depth of Questions and Answers Most students who have reviewed previous editions of Pharmacology: PreTestTM found the book to be extremely useful. However, some questions were cited by a few reviewers as being “low-yield,” “too basic,” “too clinical,” and the like. Let me opine that, at this point in your medical education, you’re not in the best position to make valid judgment calls on such matters. What stu- dents often cite as a low-yield question is actually basic but “must know” information, even though the correct answer may be blatantly obvious. Just because you automatically know or recognize the answer doesn’t mean that the information isn’t important, or isn’t high yield, or that your ability to rec- ognize it shouldn’t be evaluated. It could well mean that you’ve learned the essential basics, and that’s a good thing. Conversely, some students have called certain questions “low yield” simply because they haven’t learned about the facts and concepts addressed in the question. It’s very easy to attribute little importance to things one doesn’t know or understand, and shrug-off the question as being trivial. This is a critical, yet odd, place you find yourselves in your medical edu- cation. You are expected to be at your “peak” in terms of basic science knowl- edge, with enough of a foundation that you’ll not only get through “the boards,” but also be able to remember and carry it over to your clinical years when you hit the wards in a very short time. You should be able to do the for- mer more easily than the latter, since knowledge fades with time, especially if you don’t use that knowledge often. Borrowing from literature, you are expected to be like the cheerful Major General in Gilbert and Sullivan’s Pirates of Penzance. You need to know “all the facts” and be able to spit them back almost reflexively. Yet you cannot be like him, whether for the Boards or upcoming years, when you are actually caring for patients and devising or interpreting treatment plans, because you need to be able to make sense of, and apply, all those facts into some more integrated and grander plan that has the greatest likelihood of success and the lowest risk of failure or harm. The truth of the matter is that neither you—nor anyone else—will be able to answer all these questions correctly, or even correctly as far as I cite the answers. There is simply too much information presented to you in the pre- clinical years, and no matter how well you think you know your information (pharmacology or otherwise), it tends to become jumbled and incomprehensi- ble when you’re faced with the task of knowing it all at once. Much of your knowledge is important now; much more will be important later on (whether for an exam or for a patient); and some of what you’ve been taught is ultimately trivial and useless. But you just don’t know at this time, and so I’ll ask questions as fairly and forthrightly as possible and do my best to explain things in the answers in such a way that the information sticks, and you see the connections between ostensibly diverse areas of pharmacology and therapeutics. My goal is not to show you how much or how little you know. It’s to help you acknowl- edge what you do know, and learn and understand what you don’t. It is in some ways rewarding to answer an ostensibly complicated or detailed question correctly (you possess the main positive attributes of Gilbert and Sullivan’s happy Major General), but you don’t want to find your- self so bogged down in knowing the details that you miss seeing the more important big picture, or how the facts apply or relate to one another (the Major General’s main flaw). The simplest or most basic concepts can be over- looked with teaching or learning that is too detailed in terms of fact and focus. You have had an abundant (or excessive) amount of information about pharmacology presented to you, but that’s only the foundation of a broad knowledge and experience base on which you’ll build over the coming years. Sometimes things aren’t as obvious or as rational as they may seem, and knowing “too much” may not be at all sufficient once we get into a clinical sit- uation. One example of this, which sticks out in my mind, based on years of teaching and some personal experience, has to do with a not-that-common clinical problem, hyperuricemia, gout, and their drug therapy. I’ve had stu- dents (and one new doc) cite every metabolic intermediate, and the responsi- ble enzymes, in the biosynthesis of uric acid by the so-called purine degradation pathway. This is, of course, the metabolic crux of the problems in hyperuricemia and gout. They have correctly stated that allopurinol inhibits the “last two steps” in uric acid synthesis (the conversion of hypoxanthine to xanthine, and xanthine to the final product) by inhibiting xanthine oxidase. That’s great. Unfortunately, the majority of those students (and that one new MD caring for me) then stated what seemed so mechanistically rational but quite wrong: Given the role of uric acid in the pathophysiology of gout, and the efficacy of inhibiting urate synthesis with allopurinol, their first choice therapy for an acute gout attack would be (obviously, they’ve said) allopurinol. Oops. Wrong choice. It’s good to know many important facts, and even to be tested on them, but I don’t necessarily agree that fact-based knowledge alone is sufficient. My philosophy on that point has caused initial consternation for the medical (and Pharm D, nursing, and dental) students I’ve taught for over 25 years. Students often expect such questions as “which of the following is a -adrenergic blocker?” and get pumped when they correctly select propranolol out of a short list of drugs that may or may not do anything to -adrenergic or other adrenergic receptors. I consider that knowledge as being important and essen- tial (what you might call a high-yield fact), but rudimentary, not very chal- lenging, and generally insufficient. That is why I may pepper my exams with a few fact-based fundamental questions, but then go on to require the student to take that fundamental and expected basic knowledge and extrapolate and apply it to new or different situations, or to state the “whys” more than the “whats.” Some questions will go beyond the bounds of what most might con- sider to be traditionally in the domain of pharmacology and pose it in ways that require the student to recall what I’m sure they learned in some other pre- clinical “course” (I use quotation marks because we’ve long abandoned most discipline-based courses in our curriculum), such as physiology. Practicing good medicine requires a better understanding, and rational application of basic knowledge, beyond possessing the rote memory of drugs and their mechanisms. It is, in that way, a creative and thought-provoking (and not necessarily precise) art. You have to go beyond the “use this drug for that purpose” level of knowledge. Your experiences from the courses you’ve taken may be quite different from those of students in other medical schools, or the medical students I’ve taught. After all, there is (for better or worse) no one “standard” pharmacol- ogy curriculum for all medical schools, and points emphasized by a particu- lar instructor that you’ve had can differ (sometimes markedly) in scope and orientation from those made by faculty elsewhere. You may have had a stand-alone pharmacology course or two (at our medical school we no longer have any), perhaps with a focus on basic char- acteristics of drugs. That focus may have been on mechanisms of action (simple and straightforward, or quite detailed and complex), perhaps replete with such things as specific pathways of drug metabolism, structure-activity relationships, mathematical approaches to pharmacokinetics, or detailed cel- lular biochemical mechanisms of action. Little or no clinical relevance or application may have been presented, unfortunately. Or, you may have had your preclinical pharmacology content integrated in some systems-based curriculum (that’s what we do here), which some- times teaches and tests on drug-related material in a very clinically oriented yet pharmacologically simplistic way. For example: “Your 50-year-old male patient has recently been diagnosed with Type 2 diabetes mellitus. He loves to eat. His liver is good. Prescribe metformin.” As Homer Simpson might say, “duh-oh, ok.” But why? “You have a patient on long-term warfarin therapy. You know they shouldn’t take aspirin (really?). Recommend acetaminophen.” Why? Do you have a clue about the rationale, the reason why they shouldn’t take aspirin (or can they?), or why they might be given acetaminophen? What problems might acetaminophen cause? Or do you simply memorize an admonition that doesn’t always apply, and not understand it? What’s the magic of these drugs? How do they work? Are there any prob- lems? What are they? How do you recognize, predict, avoid, or manage them? For some of you it’s tempting to view some of my questions as “too clin- ical”; others may find things “too basic or mechanistic.” However, answering all the questions in this book is relatively simple if you think about the basic drug information you should have acquired; if you integrate it with what you should have learned in other courses (e.g., in a physiology or cell and mole- cular biology course); and if you start doing what you will have to do soon— make reasoned judgments based on applying your knowledge to a possibly new clinical picture: which is “most likely,” for example. What may be “too clinical” for some of you may be old hat for others. What may be a low-yield, no-brainer, or mere rat fact question to you might be assessing essential information overlooked or not presented to someone else who is studying just as diligently, trying to achieve the same goal on the very same exams as you. There’s another point you may be overlooking. You may know very well what you need to know when studying intensively, for example, CNS drugs. But are you able to extrapolate and integrate that information to a cardiovas- cular or autonomic nervous system problem? That’s precisely what you’ll have to do when you hit your clinical rotations, and what you may be asked to do on Step 1. I’ll challenge you on that cross-disciplinary knowledge here, and so suddenly a question that seems “low yield” when considered in a dis- crete area becomes more challenging (and may shake your confidence) when posed in a broader perspective. How pharmacology is presented, and what “defines” the basics or core of the discipline, vary tremendously from not only one text to another, but also from one medical school, or course, or instructor, to another. What you have learned from your lectures, or from your assigned text, inevitably reflects a bias (that is not meant in a pejorative sense), preference, or didactic style of the lecturers or the text book authors. And, just as your learning and testing experiences may vary, depending on where you are, so may the way you’ve prepared for a standardized exam that includes pharmacology (or any other preclinical content. There is no standardized pharmacology curricu- lum, nor a standardized way to present it in lecture or by way of a text. Nor are you all likely to have had questions written in a format that’s common for other students. Some faculty (whether they are pharmacologists or from some other discipline) write scenario-based questions (in the so-called “board-style”) and many still write questions in other formats (true-false, multiple correct answers, and so on). Once you begin looking at my questions, and my answers to them, you may find that there is no explicit reference to one of the three cross-referenced texts I’ve cited. I’m sure, too, that many of you may find that the questions I ask, the way I ask them, or the answers I give, are different from what you have learned or how you learned it. They may be too clinical, or not mecha- nistic enough (or too mechanistic). They may address drugs you have not studied explicitly. Indeed, some questions may focus on drugs you haven’t heard about at all (some drugs too new to make it into some of the older texts cited above are found below). That is, I have biases or preferences or areas I think are important to emphasize too. Don’t worry. Review, study, read, and learn as much as you can from the questions and the explanations. Keep in mind that content in an ostensibly circumscribed area (or book chapter, or lecture) can have significant ramifi- cations on other areas. Appreciate the fact that in order to understand some concepts you have to integrate material from several disciplines or areas of pharmacology—and, of necessity, you may have to integrate material you have learned from such other basic biomedical disciplines as physiology, pathophysiology, biochemistry, molecular and cell biology, and many more. Realize that whatever text or lecture material you have learned from, you may have to take whatever knowledge you have and apply it in new ways or in different situations. This book is no guarantee for success on Step 1, or in your course exams. However, I humbly believe it is a great start for your study review and your ultimate success in learning the basics and being able to think about drugs in a holistic way. Good luck. Marshal Shlafer, PhD Professor, Department of Pharmacology Director of Undergraduate Medical Pharmacology Education University of Michigan Medical School Ann Arbor, Michigan This page intentionally left blank Cross-References to Selected Pharmacology Texts “Brunton”—Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 11th Edition, L. Brunton, J. Lazo, and K. Parker, eds., McGraw-Hill, 2006. “Craig”—Modern Pharmacology with Clinical Applications, 6th Edition, C. R. Craig and R. E. Stitzel, eds., Lippincott Williams & Wilkins, 2004. “Katzung”—Basic and Clinical Pharmacology, 9th Edition, B. G. Katzung, ed., McGraw-Hill, 2004. Explanations for the answers to the questions provided in this edition of Pharmacology: PreTest are cross-referenced to one or more of these phar- macology texts. Each of these texts excels in certain respects, yet they do differ in terms of actual content and how it is presented. Look at the text cross-references in each of the Pre-Test questions and you’ll see the differential focus. One text may be more mechanistic or more detailed; another may be more clin- ical; one may paint a discussion about certain drugs or drug groups, or a particular medical condition, with broader brush strokes than another. Some texts address a particular point on several pages, another on one or two, and another might have no specific coverage at all. This is not sur- prising, and it parallels the way you were probably taught pharmacology: there is no one standard preclinical pharmacology curriculum for all the medical schools, and how the content may be presented at one school is likely to differ significantly from what one can find elsewhere. xxi Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. This page intentionally left blank List of Abbreviations and Acronyms Here are some of the more common abbreviations you are likely to encounter either in this book or in your texts or lectures. I have omitted common symbols for chemical elements or their cationic or anionic forms (e.g., Ca, Cl), chemical formulae (e.g., NaCl), abbreviations of common biochemicals (ATP, ADP, DNA, etc.), units of measure (volume, weight, time), and Greek letters. 5-FU—5-fluorouracil 5- HT—5-hydroxytryptamine; Serotonin ACE—angiotensin converting enzyme (also known as bradykininase, kininase II) ACh—acetylcholine AChE—acetylcholinesterase AChEI—acetylcholinesterase inhibitor ACS—acute coronary syndrome ACTH—adrenocorticotropic hormone; corticotropin—adrenocorticotropic hormone ADD/ADHD—attention-deficit (hyperactivity) disorder ADH—antidiuretic hormone [vasopressin (VP)] ADHD—attention deficit hyperactivity disorder AF (AFIB)—atrial fibrillation AFL—atrial flutter AIDS—acquired immunodeficiency syndrome ALG—antilymphocyte globulin ANS—autonomic nervous system ATPase—adenosine triphosphatase AUC—area under the (blood concentration vs. time) curve AV—atrioventricular A-V—arteriovenous B. fragilis—Bacteroides fragilis BAL—British anti-Lewisite (dimercaprol) BPH—benign prostatic hypertrophy BPM—beats per minute BUN—blood urea nitrogen Cav—average (mean) plasma concentration Cmax—maximum plasma concentration Cmin—minimum plasma concentration Css—steady-state plasma concentration C. albicans—Candida albicans C. botulinum—Clostridium botulinum C. difficile—Clostridium difficile C. neoformans—Cryptococcus neoformans CAD—coronary artery disease CCB—calcium channel blocker xxiii Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. CHD—coronary heart disease CHF—congestive heart failure CK—creatine kinase Cl—clearance (of drug) Cl—chloride Cltotal — total body clearance CNS—central nervous system COMT—catechol-O-methyltransferase COPD—chronic obstructive pulmonary disease COX—cyclooxygenase(s); may be modified as COX-1 or COX-2 CRF—corticotropin-releasing factor CSF—cerebrospinal fluid CYP—cytochrome P450 (system or member of it) D1 or D2—dopamine D1 or D2 receptor DA—dopamine DHT—dihydrotestosterone DOPA—dihydroxyphenylalanine DVT—deep venous thrombosis ECG—electrocardiogram; EKG E. coli—Escherichia coli EDRF—endothelium-derived relaxing factor (nitric oxide) EEG—electroencephalogram EKG—electrocardiogram EPI—epinephrine ER—endoplasmic reticulum EtOH—ethanol FH2—7,8-dihydrofolic acid FH4—5,6,7,8-tetrahydrofolic acid FSH—follicle-stimulating hormone FU—fluorouracil G. lamblia—Giardia lamblia G protein—guanine nucleotide-binding protein GABA—-aminobutyric acid G-CSF—granulocyte colony–stimulating factor GERD—gastroesophageal reflux disease GI—gastrointestinal GM-CSF—granulocyte macrophage colony–stimulating factor GnRH—gonadotropin-releasing hormone GSH, GSSG—glutathione, reduced or oxidized GU—genitourinary H1—histamine H1 receptor H2—histamine H2 receptor H. influenzae—Haemophilus influenzae H. pylori—Helicobacter pylori Hb—hemoglobin hCG—human chorionic gonadotropin HF—heart failure HDL—high-density lipoprotein HIT—heparin-induced thrombocytopenia HIV—human immunodeficiency virus H+, K+, ATPase—hydrogen–potassium–adenosine triphosphatase; proton pump hMG—human menopausal gonadotropin HMG—CoA--hydroxy--methylglutaryl-coenzyme A HRT—hormone replacement therapy HTN—hypertension IDDM—insulin-dependent diabetes mellitus, often called (not always appropriately) Type I diabetes mellitus IgE, G (etc.)—immunoglobulin E, G, etc. IL (-1, -2, etc.)—interleukin(s)-1, -2, etc. IM—intramuscular(ly) INH—isoniazid IP3—inositol-1,4,5-trisphosphate IV—intravenous(ly) ke—elimination rate constant K. pneumoniae—Klebsiella pneumoniae L. pneumophilia—Legionella pneumophilia L-dopa—levodopa L-thyroxine (T4)—levothyroxine LDL—low-density lipoprotein LHRH—luteinizing hormone–releasing hormone (hypothalamic) LSD—lysergic acid diethylamide LT—leukotriene MAO—monoamine oxidase MAO-A, -B—MAO type A, type B MAOI—monoamine oxidase inhibitor MI—myocardial infarction mRNA—messenger ribonucleic acid MTX—methotrexate NE—norepinephrine NM receptors—nicotinic-skeletal muscle receptors (found at the skeletal-somatic neuromuscular junction) NN receptors—nicotinic-neural receptors (found in sympathetic ganglia and on cells of the adrenal (suprarenal) medulla) N. gonorrhoeae—Neisseria gonorrhoeae NADH—nicotinamide adenine dinucleotide NADPH—nicotinamide adenine dinucleotide phosphate Na, K, ATPase—sodium–potassium–adenosine triphosphatase NAPA—N-acetylprocainamide NE—norepinephrine NIDDM—non-insulin-dependent diabetes mellitus; usually associated with Type II diabetes mellitus NMDA—N-methyl-D-aspartate (glutamate channel) NMS—neuroleptic malignant syndrome NNRTI—nonnucleoside reverse transcriptase inhibitor NPH—isophane (Neutral protamine Hagedorn) insulin NRTI—nucleotide reverse transcriptase inhibitor NSAID—nonsteroidal anti-inflammatory drug (nonopioid analgesic/antipyretic) NTG—nitroglycerin P450—the cytochrome P450 mixed-function oxidase system P. aeruginosa—Pseudomonas aeruginosa P. carinii—Pneumocystis carinii P. falciparum—Plasmodium falciparum P. mirabilis—Proteus mirabilis P. vivax—Plasmodium vivax PABA—p-aminobenzoic acid PAC—premature atrial contraction PAM (2-PAM)—pralidoxime PAS—para-aminosalicylic acid PDGF—platelet-derived growth factor PG —prostaglandin PGE1—prostaglandin E1 (alprostadil) PGE2—prostaglandin E2 (dinoprostone) PGI2—prostaglandin I2 (prostacyclin) PNS—parasympathetic nervous system PO—(administration route) by mouth (per os) PO2—partial pressure (tension) of oxygen, arterial PPD—purified protein derivative of tuberculin protein G—guanine nucleotide–binding protein PTH—parathyroid hormone PVC—premature ventricular contraction RDA—recommended daily allowance REM—rapid eye movement 6- MP— mercaptopurine S. aureus—Staphylococcus aureus S. haematobiu—Schistosoma haematobium SA—sinoatrial SAR—structure-activity relationship SC—subcutaneous [administration route] SH—sulfhydryl SK—streptokinase SR—sarcoplasmic reticulum SRS-A—slow-reacting substance of anaphylaxis SSRI—selective serotonin reuptake inhibitor SVT—supraventricular tachycardia T1/2—half-life (e.g., biologic or plasma half-life) of a drug T3—triiodothyronine T4—thyroxine TB—tuberculosis TG—triglyceride(s) TIA—transient ischemic attack TNF—tumor necrosis factor tPA— tissue plasminogen activator TRH—thyrotropin-releasing hormone tRNA—transfer ribonucleic acid TSH—thyroid stimulating hormone TXA2—thromboxane A2 UTI—urinary tract infection Vd—volume of distribution VIP—vasoactive intestinal peptide vitamin B1—thiamine vitamin B2—riboflavin vitamin B6—pyridoxine vitamin C—ascorbic acid vitamin D—calcitriol (metabolite [active form-1,25-(OH)2D3]) VLDL—very-low-density lipoprotein VP—vasopressin (antidiuretic hormone [ADH]) VT (VTACH)—ventricular tachycardia This page intentionally left blank General Principles Biotransformation Factors affecting drug dosage Development of new drugs Molecular models of receptors and Dosage regimens and pharmaco- signal transduction mechanisms kinetic profiles Pharmacodynamics Dose-response relationships Pharmacokinetics Drug names and nomenclature Regulation by the Food and Drug Drug receptor interactions Administration Questions DIRECTIONS: Each item contains a question or incomplete statement that is followed by several responses. Select the one best response to each question. 1. Azithromycin, an antibiotic, has an apparent volume of distribution (Vd) of approximately 30 L/kg. The best interpretation of this information is that azithromycin is which of the following? a. Effective only when given intravenously b. Eliminated mainly by renal excretion, without prior metabolism c. Extensively distributed to sites outside the vascular and interstitial spaces d. Not extensively bound to plasma proteins e. Unable to cross the blood-brain or placental barriers 2. Experimental evaluation of the pharmacokinetics of a drug under development leads to the finding that it “undergoes significant first-pass hepatic metabolism.” Which of the following administration routes was most likely used to reach this conclusion? a. Intramuscular b. Intravenous c. Oral d. Rectal e. Sublingual (SL) 1 Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. 3. Two drugs act on the same tissue or organ via activation of different receptors, resulting in effects that are qualitatively the opposite of one another. An example would be the direct effects of norepinephrine and acetylcholine on heart rate. This represents which of the following types of antagonism? a. Chemical b. Competitive c. Dispositional d. Pharmacologic e. Physiologic 4. We are repeatedly administering a drug orally. Every dose is 50 mg; the interval between doses is 8 h, which is identical to the drug’s plasma half- life. The bioavailability is 0.5. For as long as we conduct the experiment no interacting drugs are added or stopped, and there are no patient-related factors (affecting such things as absorption or elimination) that might change the drug’s pharmacokinetics. Which of the following formulas gives the best estimate of how long it will take for the drug to reach steady-state serum concentrations (CSS)? Abbreviations: AUC: area under the concentration-time curve Cl: clearance (mL/min) D: dose (mg) F: bioavailability (<1.0 for this drug given orally) ke: elimination rate constant t1/2: half-life (h) Vd: volume of distribution a. (0.693 ¥ Vd)/Cl b. 1/ke c. 4.5 ¥ t1/2 d. (t1/2) ¥ (ke) e. D/(F ¥ t1/2) 5. We want to estimate, following drug administration, some measure that most reliably reflects the total amount of drug reaching the target tissue(s), over time. We’re giving the drug orally. Which of the following would pro- vide that measure best? a. Area under the blood concentration-time curve (AUC) b. Peak (maximum) blood concentration c. Product of the Vd and the first-order rate constant d. Time-to-peak blood concentration e. Vd 6. Experiments show that 95% of an oral 80-mg dose of Drug X is absorbed in a 70-kg test subject. However, because of extensive biotrans- formation during its first pass through the hepatic portal circulation, the bioavailability was only 0.25 (25%). Assuming a liver blood flow of 1500 mL/min, which of the following is the hepatic clearance of Drug X in this situation? a. 60 mL/min b. 375 mL/min c. 740 mL/min d. 1110 mL/min e. 1425 mL/min 7. A speaker at Grand Rounds is summarizing the literature on a very small subset of patients who develop acute hemolytic disease in response to drug therapy. The causative agents included common antimalarial drugs (chloroquine, quinine, and especially primaquine); cardiovascular drugs (hydralazine, procainamide, quinidine); and various antimicrobials (chlo- ramphenicol, nitrofurantoin, sulfonamide antibiotics). Which of the fol- lowing patient-related factors most likely accounts for their susceptibility to hemolysis? a. Concurrently taking aspirin b. Genetically based glucose 6-phosphate dehydrogenase (G6PD) deficiency c. Primary renal disease d. Recently received chemotherapy with vincristine e. Serum cholinesterase deficiency 8. We are conducting pharmacokinetic studies on a new drug that we hope will be approved for clinical use. We insert a venous catheter to sam- ple blood at various times after drug administration, and also take a sam- ple for the immediate predrug blood level of the drug (which should be zero). After assaying the blood samples for the drug we make a graph that plots serum drug concentrations over time, continuing until tests reveal blood levels as undetectable. Which of the following is calculated as the ratio of the area under the curve (AUC) obtained by oral administration vs. the AUC for intravenous administration of the same drug? a. Absorption b. Bioavailability c. Clearance d. Elimination rate constant e. Extraction ratio f. Volume of distribution 9. We administer an acidic drug (A) with a pKa of 3.4 orally. But pH is 1.4, and plasma pH is 7.4. Assume the drug crosses membranes by simple pas- sive diffusion (e.g., no transporters are involved). Which of the following observations would be true? a. Only ionized forms of the drug, A, will be absorbed from the gut into the plasma b. The concentration ratio of total drug (A  HA) would be 10,000:1 (gut > plasma) c. The drug will be hydrolyzed by a reaction with HCl, and so cannot be absorbed d. The drug will not be absorbed unless we raise gastric pH to equal pKa, as might be done with an antacid e. The drug would be absorbed, and at equilibrium the plasma concentration of the nonionized moiety (HA) would be 104 times higher than the plasma con- centration of A. 10. Identical doses of a drug are given orally (■) and intravenously (•), we sample blood at various times, measure blood concentrations of the drug, and plot the data (shown in the figure). Further analysis of these data will allow us to determine which of the following? a. Elimination route(s) b. Extent of plasma protein binding c. Oral bioavailability d. Potency e. Therapeutic effectiveness 11. The elimination of a drug is described as being heavily dependent on Phase II metabolic reactions. Which of the following is a Phase II reaction as far as drug elimination goes? a. Glucuronidation b. Deamination c. Ester hydrolysis d. Nitro reduction e. Sulfoxide formation 12. We start intravenous infusion of a drug using a pump that ensures that the rate of drug delivery is constant over time. Which of the following fac- tors determines how long it will take for the drug to reach a steady-state concentration (CSS) in the blood? a. Apparent volume of distribution b. Bioavailability c. Clearance d. Half-life e. Infusion rate (mg of drug/min) 13. Yee et al. (Effect of grapefruit juice on blood cyclosporine concentra- tion; Lancet 345:955–956, 1995) examined several pharmacokinetic vari- ables related to oral cyclosporine administration with water, grapefruit juice, and orange juice: Grapefruit Juice Orange Juice Water p* AUC (ng•h/mL) 7057 ± 2172 4871 ± 2045 4932 ± 1451 <0.0001 Cmax (ng/mL) 1269 ± 381 972 ± 379 1080 ± 269 0.01 Tmax (hr) 2.86 ± 0.77 2.57 ± 0.85 2.36 ± 0.63 0.14 The numbers listed are arithmetic means ± one standard deviation of the mean. Cmax is the peak blood concentration, and Tmax is the time after administration at which peak serum concentrations of the drug are reached. p values are based on analysis of variance (ANOVA) corrected for repeated measures. These data, and what you should have learned from your basic pharma- cology studies, are most consistent with the hypothesis that grapefruit juice does which of the following? a. Acidifies the urine, favoring cyclosporine’s tubular reabsorption via a pH- dependent effect b. Activates an intestinal wall transporter for cyclosporine c. Alters the route(s) of elimination for cyclosporine d. Inhibits the first-pass metabolism of cyclosporine e. Reduces binding of cyclosporine to plasma proteins, thereby raising free (active) drug levels in the circulation 14. A 60-year-old man with rheumatoid arthritis will be started on a non- steroidal anti-inflammatory drug to suppress the joint inflammation. Pub- lished pharmacokinetic data for this drug include: Bioavailability (F): 1.0 (100%) Plasma half-life (t1/2): 0.5 h Volume of distribution (Vd): 45 L For this drug it is important to maintain an average steady-state concentration 2.0 mcg/mL in order to ensure adequate and continued anti-inflammatory activity. The drug will be given (taken) every 4 h. What dose will be needed to obtain an average steady-state drug con- centration of 2.0 mcg/mL? a. 5 mg b. 100 mg c. 325 mg d. 500 mg e. 625 mg 15. We take a blood sample from a patient (baseline measurement) and then administer Drug A intravenously. We take additional blood samples periodically thereafter and measure drug concentration in each sample. We repeat the experiment, this time giving the same drug orally. Then we plot the logarithm of drug concentration vs. time with data from both adminis- tration routes, and find to comparable elimination “curves” indicative of first-order elimination. What do the slopes of the resulting concentration vs. time curves tell us best about the pharmacokinetics of Drug A? a. Area under the curve (AUC) b. Bioavailability c. Elimination rate constant d. Extraction ratio e. Volume of distribution 16. We want to determine some important pharmacokinetic properties of a new aminoglycoside antibiotic that we’re putting through preclinical test- ing. We give an IV dose (5 mg/kg) of the drug to a 70-kg volunteer, 19- years-old, who is healthy and taking no other drugs. After allowing time for redistribution and equilibration of the drug in various body compartments, we measure plasma concentrations at various times. The data are shown in the table and figure; assume that the drug is being eliminated at a rate that reflects typical first-order kinetics. Time After Dosing Stopped (h) Plasma Aminoglycoside Concentration (mcg/mL) 1.0 5.8 2.0 4.6 3.0 3.7 4.0 3.0 5.0 2.4 6.0 1.9 8.0 1.3 Which of the following values comes closest to the elimination rate con- stant (ke) for this drug in this patient? a. 0.15 h1 b. 0.22 h1 c. 0.33 h1 d. 0.60 h1 e. 1.13 h1 17. When we evaluate new drugs in preclinical testing, one of many things we’d like to know is whether it’s largely confined to the vascular compart- ment (before it is eliminated) or distributes more widely. This is, of course, ultimately important to you, the clinician who may prescribe or adminis- ter the drug if it gets FDA approval. One way to get a handle on that is to calculate the apparent volume of distribution (Vd). Using the data for the hypothetical aminoglycoside, shown in Question 16, which of the following values comes closest to the apparent Vd for this drug? a. 0.62 L b. 19 L c. 50 L d. 110 L e. 350 L 18. When evaluating the effects of certain adrenergic agonists in a variety of in vitro and in vivo models, we find that the responses exhibit the phe- nomenon of tachyphylaxis. Which of the following best describes what the term tachyphylaxis means? a. An increase in the rate of the response, for example, an increase of the rate of muscle contraction b. Immediate hypersensitivity reactions (i.e., anaphylaxis) c. Prompt conformational changes of the receptor such that agonists, but not antagonists, are able to bind and cause a response d. Quick and progressive rises in the intensity of drug response, with repeated administration, even when the doses are unchanged e. Rapid development of tolerance to the drug’s effects 19. A postoperative patient will require prolonged analgesia. We choose a drug that has the following pharmacokinetic properties: Half-life: 12 h Clearance: 0.08 L/min Volume of distribution: 60 L The patient has an indwelling venous catheter with a slow drip of 0.9% NaCl, and we will use this to administer intermittent injections of the drug every 4 h. The target blood level of the drug, following each injection, is 8 mcg/mL. With this plan in mind, which of the following comes closest to the dose that should be administered every 4 h? a. 0.960 mg (or 1 mg) b. 6.4 mg (or 6 mg) c. 25.6 mg (or 25 mg) d. 150 mg e. 550 mg 20. A patient is experiencing severe postoperative pain, and we need to give a loading dose of an analgesic drug for prompt relief of discomfort. The drug we choose has the same pharmacokinetic properties as the one described in Question 19: Half-life: 12 h Clearance: 0.08 L/min Volume of distribution: 60 L Our target serum concentration for the drug is 8 mcg/mL. Which of the following comes closest to the correct loading dose? a. 0.48 mg (rounded to 0.5 mg) b. 150 mg c. 320 mg d. 480 mg e. 640 mg 21. We administer a highly lipid-soluble drug and monitor its elimination in vivo and in vitro. All the data indicate that it is transformed to a variety of more polar metabolites by a group of heme proteins that activate molecu- lar oxygen to a form that is capable of interacting with organic substrates such as our test drug. Which of the following is the most likely enzyme or enzyme system involved in the initial metabolism of our test drug? a. Cyclooxygenase b. Cytochrome P450s c. Monoamine oxidase (MAO) d. Nicotinamide adenine dinucleotide phosphate (NADPH) e. UDP–glucuronosyltransferase 22. We measure the heart rate of a healthy subject under the folowing con- ditions, allowing ample time for return to baseline conditions and full elim- ination of drugs between each . . . 1. at rest 2. during treadmill exercise sufficient to activate the sympathetic nervous system at a time when maximum heart rate is reached 3. after administration of acebutolol, a drug with affinity for -adrenergic receptors 4. after giving acebutolol, followed by exercise at the same level used in condition 2 Acebutolol given at rest causes a slight but consistent increase of heart rate. Give a bigger dose at rest and heart rate rises a bit more. When the patient exercises after receiving a low dose acebutolol, heart rate rises significantly less than it did in the absence of acebutolol. With exercise after the higher dose of acebutolol, the tachycardia is blunted even more. The figure summarizes the main findings. Which of the following statements best summarizes the actions of acebutolol? a. Has higher affinity for adrenergic receptors than the endogenous agonists, epi- nephrine, and norepinephrine b. Is a partial agonist for -adrenergic receptors c. Is activating spare receptors on myocardial cells d. Is an irreversible or noncompetitive  blocker e. Is changing conformation of the adrenergic receptors 23. We are planning to infuse a drug intravenously at a constant amount per unit time (rate). It has a first-order elimination rate constant (kel) of 0.35 h1. No loading dose will be given. Approximately how long will it take for blood levels to reach steady state after the infusion begins? a. 0.7 h b. 1.2 h c. 3.5 h d. 9 h e. 24 h 24. A patient who is supposed to be taking a drug once a day gets con- fused and for a couple of days takes excessive daily doses, leading to toxic- ity. The drug has a mean plasma half-life of 40 h. Right now the patient’s plasma concentration of the drug is 6 mcg/mL. Although what to do next will depend on actual blood tests for drug levels, the usual plan in this case is to have the patient skip one or several daily doses of the drug until blood levels first enter the therapeutic and nontoxic range, which in this case is 0.8 mcg/mL. How many daily doses should be withheld? a. 1 b. 2 c. 3 d. 4 e. 5 25. We want to calculate the apparent volume of distribution (Vd) for a hypothetical drug (Drug A) that has a half-life of 4 h. All (100%) of an absorbed dose of this drug undergoes Phase I oxidation, followed by con- jugation (Phase II reaction). We rapidly inject a known dose, and 30 min later begin taking serial blood samples (30 min apart) and quantifying drug concentration in each sample. Which of the following information must we measure or other- wise determine to calculate Vd in the easiest possible way? a. Area under the drug concentration-time curve (AUC) b. Bioavailability c. Clearance d. Elimination rate constant (kel) e. Maximum blood concentration immediately after the bolus injection (C0) 26. A patient with a bacterial infection requires intravenous antibiotic therapy. The chosen drug has a clearance (Cl) of 70 mL/min. The apparent volume of distribution (Vd) is 50 L. The plan is to administer the drug intravenously every 6 h and achieve a 4-mg/L steady-state blood level of the drug. No loading dose strategy is to be used. Which of the following maintenance doses is needed to achieve this? a. 14 mg b. 24 mg c. 100 mg d. 300 mg e. 1200 mg 27. We are working with a pharmacologically inert but easily measured substance, X. Its elimination shows linear kinetics (first-order plot of log drug concentration vs. time during elimination is a straight line). The plasma half-life is 30 min. Bolus IV doses well in excess of 100 mg must be given in order to saturate the enzymes responsible for metabolizing the drug, which will then lead to zero-order elimination kinetics. We infuse a solution of X intravenously. The concentration of the solu- tion is 2 mg/mL; the infusion rate is 1 mL/min and is kept constant at that. We continue the infusion for 24 h. After allowing ample time for the drug to be eliminated completely, we repeat the administration. This time the concentration of the solution of X is 4 mg/mL, and we infuse it at a rate of 2 mL/min. Which of the following other variables will also be changed as a result of the stated changes to the infusion protocol? a. Elimination rate constant b. Half-life c. Plasma concentration when CSS is reached d. Time to reach steady-state concentration (CSS) e. Total body clearance f. Volume of distribution 28. A new drug, Drug A, undergoes a series of Phase I metabolic reactions before its metabolites ultimately are eliminated. Which of the following statements best describes the characteristics of Drug A, or the role of Phase I reactions in its metabolism or actions? a. Complete metabolism of Drug A by Phase I reactions will yield products that are less likely to undergo renal tubular reabsorption b. Drug A is a very polar substance c. Drug A will be biologically inactive until it is metabolized d. Phase I metabolism of Drug A involves conjugation, as with glucuronic acid or sulfate e. Phase I metabolism of Drug A will increase its intracellular access and actions 29. Dopamine, epinephrine (or norepinephrine), and histamine are impor- tant neurotransmitter agonists. When these ligands interact with their cellu- lar receptors, how do they mainly elicit their responses? a. Activating adenylyl cyclase, leading to increased intracellular cAMP levels b. Activating phospholipase C c. Inducing or inhibiting synthesis of ligand-specific intracellular proteins d. Opening or closing ligand-gated ion channels e. Regulating intracellular second messengers through G protein–coupled receptors 30. The FDA assigns the letters A, B, C, D, and X to drugs approved for human use. To which of the following does this classification apply? a. Amount of dosage reduction needed as serum creatinine clearances fall b. Amount of dosage reduction needed in presence of liver dysfunction c. Fetal risk when given to pregnant women d. Relative margins of safety/therapeutic index e. The number of unlabeled uses for a drug 31. The Food and Drug Administration has regulatory authority over pre- scription drugs, OTC drugs, and nutritional supplements (herbals and other so-called nutriceuticals). Such authority includes approval, market- ing (advertising), and withdrawal of drugs from the market. Which of the following statements about these regulatory matters is correct? a. Drugs approved for sale OTC first received FDA approval for sale and market- ing “by prescription only” b. If a pharmaceutical manufacturer provides data sufficient to obtain FDA approval for sale by prescription, the manufacturer is then allowed to sell the drug over-the-counter (OTC) c. If the FDA approves a prescription drug for sale (prescribing), the MD can pre- scribe the drug only for the FDA-approved indication (use) d. Nutritional supplements can be marketed without providing proof of efficacy or safety to the FDA e. Phase III testing of prescription drugs that have been approved by the FDA gives complete information about adverse responses and pertinent drug-drug interactions General Principles Answers 1. The answer is c. (Brunton, pp 14–16; Craig, pp 28–29, 51–52; Katzung, pp 34–38.) For a 70-kg individual, total body water is about 40 L (0.6 L/kg); interstitial plus plasma water occupies about 12 L (0.17 L/kg). Azithromycin, with a Vd of 30 L/kg, would be distributed in an appar- ent volume of about 2100 L in a typical 70-kg person. Use simple logic to answer this question, but look at the answer to Question 17, if you wish. Even if you don’t remember what total body water is (about 40 L or 0.6 L/kg), or the approximate value for interstitial plus plasma water (about 12 L or 0.17 L/kg), do the quick math. If you take the stated 30 L/kg and compute the total (and very hypothetical) apparent vol- ume for a 70-kg individual, you would arrive at 2100 L. That number not only reflects distribution into a hypothetical volume far in excess of vascu- lar and interstitial volumes, but is also far beyond what could be physically real. After all, 2100 L of water equals 2100 kg; you won’t find human beings weighing that much! Without more information, you cannot make definitive conclusions about the other properties listed as answer choices. 2. The answer is c. (Brunton, pp 4, 11, 18; Craig, p 25; Katzung, pp 42–43.) The first-pass effect is commonly considered to involve the biotransforma- tion of a drug during its first passage through the portal circulation of the liver. Drugs that are administered orally enter the hepatic portal circulation first and can be biotransformed there, extensively, before reaching the sys- temic circulation. Typically, and sometimes significantly, this can reduce bioavailability and systemic blood concentrations of the drug. The net ther- apeutic consequence of first-pass metabolism depends on the drug. If hepatic metabolism inactivates a drug (as it often does), then serum levels and the magnitude of the effects will be reduced accordingly. However, if the orally administered drug is a prodrug (one that is inactive in the form administered, but is metabolized to one or more active metabolites), then the outcome will be greater activity due to greater bioavailability of the bio- logically active metabolite. 17 Administration by the intravenous, intramuscular, and sublingual routes usually allows the drug to attain effective concentrations in the sys- temic circulation, and to be distributed throughout the body before hepatic metabolism has had much of an impact on the administered dose “going in.” Rectal administration also avoids the problems to a great degree since, for example, the inferior rectal vein flows into the inferior vena cava, bypass- ing the liver initially. Finally, the lungs can subject some inhaled drugs to a significant “first- pass” effect, but such a situation is uncommon in the grander scheme of things. 3. The answer is e. (Brunton, pp 35–38; Craig, pp 16–18; Katzung, pp 14–17.) Physiologic, or functional, antagonism occurs when two drugs produce opposite effects on the same physiologic function by interacting with different types of receptors. A practical example of this, in addition to what is described in the question, is the use of epinephrine as a bron- chodilator to counteract the bronchoconstriction that occurs when the parasympathetic nervous system releases ACh or when we administer bethanechol or an acetylcholinesterase inhibitor to a patient with asthma. ACh constricts airway smooth muscle by acting as an agonist on mus- carinic receptors. Epinephrine relaxes airway smooth-muscle cells and dilates the bronchi, through its agonist activity on 2-adrenergic receptors. Chemical antagonism (a) typically is said to occur when two drugs combine with each other chemically and the activity of one or both is reduced or abolished. For example, dimercaprol chelates lead and reduces the toxicity of this heavy metal; and calcium in certain foods or beverages (e.g., milk) interacts with tetracycline antibiotics and reduces bioavailability. Competitive antagonism (b) is one of the two main types of pharma- cologic antagonism (d). It occurs when two compounds (drugs) compete for the same receptor site—both having affinity for the receptor, only one having efficacy (or one having much more efficacy than another with par- tial agonist activity). With competitive antagonism this is a reversible inter- action (because both the agonist and the antagonist can dissociate from the receptor sites)—and a surmountable (“overcomeable”) one. It is certainly the most common form of drug-drug antagonism when we think of often- used therapeutic agents. Thus, atropine (the prototype muscarinic receptor antagonist) antagonizes the effects of ACh on the S-A node by competing for the same population of receptors. Propranolol does the same with respect to antagonizing the 1-stimulatory effects of epinephrine, norepi- nephrine, and such other  agonists on the heart. Irreversible antagonism, the other main type of pharmacologic antago- nism (d), generally results from the binding of an antagonist to the same receptor site as the agonist by covalent interaction or by a very slowly disso-