Basic and Clinical Pharmacology 12th Ed. PDF

 S C H E D U L E O F C O N T R O L L E D D R U G S1 SCHEDULE I Anabolic Steroids:...

 S C H E D U L E O F C O N T R O L L E D D R U G S1 SCHEDULE I Anabolic Steroids: Fluoxymesterone (Androxy) (All nonresearch use illegal under federal law.) Methyltestosterone (Android, Testred, Methitest) Flunitrazepam (Rohypnol) Nandrolone decanoate (Deca-Durabolin) Non US Narcotics: Heroin and many nonmarketed synthetic narcotics Nandrolone phenpropionate (Durabolin) Non US Hallucinogens: Oxandrolone (Oxandrin), Oxymetholone (Androl-50) LSD Stanozolol (Winstrol), MDA, STP, DMT, DET, mescaline, peyote, bufotenine, ibogaine, Testolactone (Teslac), psilocybin, phencyclidine (PCP; veterinary drug only) Testosterone and its esters Marijuana Methaqualone SCHEDULE IV (Prescription must be rewritten after 6 months or five refills; differs from SCHEDULE II Schedule III in penalties for illegal possession.) (No telephone prescriptions, no refills.)2 Opioids: Opioids: Butorphanol (Stadol) Opium Difenoxin 1 mg + atropine 25 mcg (Motofen) Opium alkaloids and derived phenanthrene alkaloids: codeine, Pentazocine (Talwin) morphine, (Avinza, Kadian, MSContin, Roxanol), hydromorphone Stimulants: (Dilaudid ), oxymorphone (, Exalgo), oxycodone (dihydroxycodei- Armodafinil (Nuvigil) none, a component of Oxycontin, Percodan, Percocet, Roxicodone, Diethylpropion (Tenuate) not in US Tylox) Modafinil (Provigil) Designated synthetic drugs: meperidine (Demerol), methadone, levorphanol (Levo-Dromoran), fentanyl (Duragesic, Actiq, Phentermine (Ionamin, Adipex-P) Fentora), alfentanil (Alfenta), sufentanil (Sufenta), remifentanil Depressants: (Ultiva), tapentadol (Nycynta) Benzodiazepines Stimulants: Alprazolam (Xanax) Coca leaves and cocaine Chlordiazepoxide (Librium) Amphetamine Clonazepam (Klonopin) Amphetamine complex (Biphetamine) Clorazepate (Tranxene) Amphetamine salts (Adderall) Diazepam (Valium) Dextroamphetamine (Dexedrine, Procentra) Estazolam (ProSom) Lisdexamfetamine (Vyvanse) Flurazepam (Dalmane) Methamphetamine (Desoxyn) Halazepam (Paxipam) Methylphenidate (Ritalin, Concerta, Methylin, Daytrana, Medadate) Lorazepam (Ativan) Above in mixtures with other controlled or uncontrolled drugs Midazolam (Versed) Cannabinoids: Oxazepam (Serax) Nabilone (Cesamet) Prazepam (Centrax) Depressants: Quazepam (Doral) Amobarbital (Amytal) Temazepam (Restoril) Pentobarbital (Nembutal) Triazolam (Halcion) Secobarbital (Seconal) Chloral hydrate (Somnote) Eszopiclone (Lunesta) SCHEDULE III Meprobamate (Equanil, Miltown, etc) (Prescription must be rewritten after 6 months or five refills.) Methobarbital (Mebaral) Opioids: Methohexital (Brevital) Buprenorphine (Buprenex, Subutex ) Paraldehyde Mixture of above Buprenorphine and Naloxone (Suboxone) Phenobarbital The following opioids in combination with one or more active non- Zaleplon (Sonata) opioid ingredients, provided the amount does not exceed that shown: Zolpidem (Ambien) Codeine and dihydrocodeine: not to exceed 1800 mg/dL or 90 mg/ tablet or other dosage unit SCHEDULE V Dihydrocodeinone (hydrocodone in Hycodan, Vicodin, and Lortab): not to exceed 300 mg/dL or 15 mg/tablet (As any other nonopioid prescription drug) Opium: 500 mg/dL or 25 mg/5 mL or other dosage unit (paregoric) Codeine: 200 mg/100 mL Stimulants: Difenoxin preparations: 0.5 mg + 25 mcg atropine Benzphetamine (Didrex) Dihydrocodeine preparations: 10 mg/100 mL Phendimetrazine (Bontril) Diphenoxylate (not more than 2.5 mg and not less than 0.025 mg of Depressants: atropine per dosage unit, as in Lomotil) Schedule II barbiturates in mixtures with noncontrolled drugs or in Ethylmorphine preparations: 100 mg/100 mL suppository dosage form Opium preparations: 100 mg/100 mL Butabarbital (Butisol) Pregabalin (Lyrica) Ketamine (Ketalar) Pyrovalerone (Centroton, Thymergix) Cannabinoids: Dronabinol (Marinol) 1 See http://www.usdoj.gov/dea/pubs/scheduling.html for additional details. 2 Emergency prescriptions may be telephoned if followed within 7 days by a valid written prescription annotated to indicate that it was previously placed by telephone. a LANGE medical book Basic & Clinical Pharmacology Twelfth Edition Edited by Bertram G. Katzung, MD, PhD Professor Emeritus Department of Cellular & Molecular Pharmacology University of California, San Francisco Associate Editors Susan B. Masters, PhD Professor of Pharmacology & Academy Chair of Pharmacology Education Department of Cellular & Molecular Pharmacology University of California, San Francisco Anthony J. Trevor, PhD Professor Emeritus Department of Cellular & Molecular Pharmacology University of California, San Francisco New York Chicago San Francisco Lisbon London Madrid Mexico City Milan Mil Mi n New lan New Delhi lhii San Delh n Juan San n Seoul Juan SSeoull Singapore SSin porre Sydney ingap Sydn Toronto dney Torront nto Copyright © 2012 by The McGraw-Hill Companies, Inc. All rights reserved. Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without the prior written permission of the publisher. ISBN: 978-0-07-176402-5 MHID: 0-07-176402-X The material in this eBook also appears in the print version of this title: ISBN: 978-0-07-176401-8, MHID: 0-07-176401-1. All trademarks are trademarks of their respective owners. Rather than put a trademark 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 trademark. Where such designations appear in this book, they have been printed with initial caps. McGraw-Hill eBooks are available at special quantity discounts to use as premiums and sales promotions, or for use in corporate training programs. To contact a representative please e-mail us at [email protected]. Previous editions copyright © 2010, 2009, 2007, 2004, 2001 by McGraw-Hill Companies, Inc.; copyright © 1998, 1995, 1992, 1989, 1987 by Appleton & Lange; copyright © 1984, 1982 by Lange Medical Publications 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. 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Neither McGraw-Hill 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 has no responsibility for the content of any information accessed through the work. Under no circumstances shall McGraw-Hill 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 Schedule of Controlled Drugs Inside Front Cover Preface vii Authors ix Key Features xii S E C T I O N I S E C T I O N III BASIC PRINCIPLES 1 CARDIOVASCULAR-RENAL DRUGS 169 1. Introduction Bertram G. Katzung, MD, PhD 1 11. Antihypertensive Agents Neal L. Benowitz, MD 169 2. Drug Receptors & Pharmacodynamics Mark von Zastrow, MD, PhD 15 12. Vasodilators & the Treatment of Angina Pectoris 3. Pharmacokinetics & Pharmacodynamics: Bertram G. Katzung, MD, PhD 193 Rational Dosing & the Time Course of Drug Action 13. Drugs Used in Heart Failure Nicholas H. G. Holford, MB, ChB, FRACP 37 Bertram G. Katzung, MD, PhD 211 4. Drug Biotransformation 14. Agents Used in Cardiac Arrhythmias Maria Almira Correia, PhD 53 Joseph R. Hume, PhD, & Augustus O. Grant, MD, PhD 227 5. Development & Regulation of Drugs Bertram G. Katzung, MD, PhD 69 15. Diuretic Agents Harlan E. Ives, MD, PhD 251 S E C T I O N II S E C T I O N IV AUTONOMIC DRUGS 79 DRUGS WITH IMPORTANT ACTIONS 6. Introduction to Autonomic Pharmacology ON SMOOTH MUSCLE 273 Bertram G. Katzung, MD, PhD 79 16. Histamine, Serotonin, & the Ergot Alkaloids 7. Cholinoceptor-Activating & Bertram G. Katzung, MD, PhD 273 Cholinesterase-Inhibiting Drugs Achilles J. Pappano, PhD 97 17. Vasoactive Peptides Ian A. Reid, PhD 295 8. Cholinoceptor-Blocking Drugs Achilles J. Pappano, PhD 115 18. The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & 9. Adrenoceptor Agonists & Related Compounds Sympathomimetic Drugs Emer M. Smyth, PhD, & Garret A. Italo Biaggioni, MD, & David Robertson, MD 129 FitzGerald, MD 313 10. Adrenoceptor Antagonist Drugs 19. Nitric Oxide David Robertson, MD, & Italo Biaggioni, MD 151 Samie R. Jaffrey, MD, PhD 331 iii iv CONTENTS 20. Drugs Used in Asthma Homer A. Boushey, MD 339 S E C T I O N VI DRUGS USED TO TREAT DISEASES OF S E C T I O N V THE BLOOD, INFLAMMATION, DRUGS THAT ACT IN THE & GOUT 581 CENTRAL NERVOUS SYSTEM 359 33. Agents Used in Anemias; Hematopoietic 21. Introduction to the Pharmacology Growth Factors Susan B. Masters, PhD 581 of CNS Drugs Roger A. Nicoll, MD 359 34. Drugs Used in Disorders of Coagulation James L. Zehnder, MD 601 22. Sedative-Hypnotic Drugs Anthony J. Trevor, PhD, & Walter L. Way, MD 373 35. Agents Used in Dyslipidemia Mary J. Malloy, MD, & John P. Kane, MD, PhD 619 23. The Alcohols Susan B. Masters, PhD 389 36. Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, 24. Antiseizure Drugs Nonopioid Analgesics, & Drugs Used Roger J. Porter, MD, & in Gout Brian S. Meldrum, MB, PhD 403 Daniel E. Furst, MD, Robert W. Ulrich, PharmD, & Shraddha Prakash, MD 635 25. General Anesthetics Helge Eilers, MD, & Spencer Yost, MD 429 S E C T I O N VII 26. Local Anesthetics ENDOCRINE DRUGS 659 Kenneth Drasner, MD 449 37. Hypothalamic & Pituitary Hormones 27. Skeletal Muscle Relaxants Susan B. Masters, PhD, & Stephen M. Marieke Kruidering-Hall, PhD, & Rosenthal, MD 659 Lundy Campbell, MD 465 38. Thyroid & Antithyroid Drugs 28. Pharmacologic Management of Parkinsonism Betty J. Dong, PharmD, FASHP, FCCP, & Francis S. & Other Movement Disorders Greenspan, MD, FACP 681 Michael J. Aminoff, MD, DSc, FRCP 483 39. Adrenocorticosteroids & Adrenocortical 29. Antipsychotic Agents & Lithium Antagonists Herbert Meltzer, MD, PhD 501 George P. Chrousos, MD 697 30. Antidepressant Agents 40. The Gonadal Hormones & Inhibitors Charles DeBattista, MD 521 George P. Chrousos, MD 715 31. Opioid Analgesics & Antagonists 41. Pancreatic Hormones & Antidiabetic Drugs Mark A. Schumacher, PhD, MD, Allan I. Martha S. Nolte Kennedy, MD 743 Basbaum, PhD, & Walter L. Way, MD 543 42. Agents That Affect Bone Mineral 32. Drugs of Abuse Homeostasis Christian Lüscher, MD 565 Daniel D. Bikle, MD, PhD 769  CONTENTS v 54. Cancer Chemotherapy S E C T I O N VIII Edward Chu, MD, & Alan C. Sartorelli, PhD 949 CHEMOTHERAPEUTIC DRUGS 789 55. Immunopharmacology 43. Beta-Lactam & Other Cell Wall- & Douglas F. Lake, PhD, Adrienne D. Briggs, MD, & Membrane-Active Antibiotics Emmanuel T. Akporiaye, PhD 977 Daniel H. Deck, PharmD, & Lisa G. Winston, MD 790 S E C T I O N IX 44. Tetracyclines, Macrolides, Clindamycin, TOXICOLOGY 1001 Chloramphenicol, Streptogramins, & Oxazolidinones 56. Introduction to Toxicology: Occupational Daniel H. Deck, PharmD, & & Environmental Lisa G. Winston, MD 809 Daniel T. Teitelbaum, MD 1001 45. Aminoglycosides & Spectinomycin 57. Heavy Metal Intoxication & Chelators Daniel H. Deck, PharmD, & Michael J. Kosnett, MD, MPH 1013 Lisa G. Winston, MD 821 58. Management of the Poisoned Patient 46. Sulfonamides, Trimethoprim, Kent R. Olson, MD 1027 & Quinolones Daniel H. Deck, PharmD, & Lisa G. Winston, MD 831 S E C T I O N X SPECIAL TOPICS 1039 47. Antimycobacterial Drugs Daniel H. Deck, PharmD, & 59. Special Aspects of Perinatal & Lisa G. Winston, MD 839 Pediatric Pharmacology Gideon Koren, MD 1039 48. Antifungal Agents Don Sheppard, MD, & 60. Special Aspects of Geriatric Pharmacology Harry W. Lampiris, MD 849 Bertram G. Katzung, MD, PhD 1051 49. Antiviral Agents 61. Dermatologic Pharmacology Sharon Safrin, MD 861 Dirk B. Robertson, MD, & Howard I. Maibach, MD 1061 50. Miscellaneous Antimicrobial Agents; Disinfectants, Antiseptics, & Sterilants 62. Drugs Used in the Treatment of Daniel H. Deck, PharmD, & Gastrointestinal Diseases Lisa G. Winston, MD 891 Kenneth R. McQuaid, MD 1081 51. Clinical Use of Antimicrobial Agents 63. Therapeutic & Toxic Potential of Harry W. Lampiris, MD, & Daniel S. Maddix, Over-the-Counter Agents PharmD 901 Robin L. Corelli, PharmD 1115 52. Antiprotozoal Drugs 64. Dietary Supplements & Herbal Medications Philip J. Rosenthal, MD 915 Cathi E. Dennehy, PharmD, & Candy Tsourounis, PharmD 1125 53. Clinical Pharmacology of the Antihelminthic Drugs Philip J. Rosenthal, MD 937 vi CONTENTS 65. Rational Prescribing & Prescription Writing Appendix: Vaccines, Immune Globulins, Paul W. Lofholm, PharmD, & & Other Complex Biologic Products Bertram G. Katzung, MD, PhD 1139 Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD 1163 66. Important Drug Interactions & Their Mechanisms John R. Horn, PharmD, FCCP 1149 Index 1171 Preface The twelfth edition of Basic & Clinical Pharmacology continues trade and generic names and dosage formulations, are provided at the important changes inaugurated in the eleventh edition, with the end of each chapter for easy reference by the house officer or extensive use of full-color illustrations and expanded coverage of practitioner writing a chart order or prescription. transporters, pharmacogenomics, and new drugs. Case studies have been added to several chapters and answers to questions Significant revisions in this edition posed in the case studies now appear at the end of each chapter. include: As in prior editions, the book is designed to provide a compre- hensive, authoritative, and readable pharmacology textbook for In addition to the Case Studies used to open many chapters, students in the health sciences. Frequent revision is necessary to Case Study Answers at the end of these chapters provide an keep pace with the rapid changes in pharmacology and therapeu- introduction to the clinical applications of the drugs discussed. tics; the 2–3 year revision cycle of the printed text is among the A Drug Summary Table is placed at the conclusion of most shortest in the field and the availability of an online version pro- chapters; these provide a concise recapitulation of the most important drugs. vides even greater currency. In addition to the full-color illustra- tions, other new features have been introduced. The Case Study Many new illustrations in full color provide significantly more information about drug mechanisms and effects and help to Answer section at the end of chapters will make the learning pro- clarify important concepts. cess even more interesting and efficient. The book also offers Major revisions of the chapters on sympathomimetic, sym- special features that make it a useful reference for house officers pathoplegic, antipsychotic, antidepressant, antidiabetic, anti- and practicing clinicians. inflammatory, and antiviral drugs, prostaglandins, nitric Information is organized according to the sequence used in oxide, hypothalamic and pituitary hormones, and immuno- many pharmacology courses and in integrated curricula: basic pharmacology. principles; autonomic drugs; cardiovascular-renal drugs; drugs with Continued expansion of the coverage of general concepts relat- important actions on smooth muscle; central nervous system ing to newly discovered receptors, receptor mechanisms, and drugs; drugs used to treat inflammation, gout, and diseases of the drug transporters. blood; endocrine drugs; chemotherapeutic drugs; toxicology; and Descriptions of important new drugs released through August special topics. This sequence builds new information on a founda- 2011. tion of information already assimilated. For example, early presen- An important related educational resource is Katzung & tation of autonomic nervous system pharmacology allows students Trevor’s Pharmacology: Examination & Board Review, ninth edition to integrate the physiology and neuroscience they have learned (Trevor AJ, Katzung BG, & Masters SB: McGraw-Hill, 2010). elsewhere with the pharmacology they are learning and prepares This book provides a succinct review of pharmacology with over them to understand the autonomic effects of other drugs. This is one thousand sample examination questions and answers. It is especially important for the cardiovascular and central nervous especially helpful to students preparing for board-type examina- system drug groups. However, chapters can be used equally well in tions. A more highly condensed source of information suitable courses and curricula that present these topics in a different for review purposes is USMLE Road Map: Pharmacology, second sequence. edition (Katzung BG, Trevor AJ: McGraw-Hill, 2006). Within each chapter, emphasis is placed on discussion of drug This edition marks the 30th year of publication of Basic & groups and prototypes rather than offering repetitive detail about Clinical Pharmacology. The widespread adoption of the first eleven individual drugs. Selection of the subject matter and the order of editions indicates that this book fills an important need. We its presentation are based on the accumulated experience of teach- believe that the twelfth edition will satisfy this need even more ing this material to thousands of medical, pharmacy, dental, successfully. Spanish, Portuguese, Italian, French, Indonesian, podiatry, nursing, and other health science students. Japanese, Korean, and Turkish translations are available. Major features that make this book particularly useful in inte- Translations into other languages are under way; the publisher grated curricula include sections that specifically address the clini- may be contacted for further information. cal choice and use of drugs in patients and the monitoring of their I wish to acknowledge the prior and continuing efforts of my effects—in other words, clinical pharmacology is an integral part of contributing authors and the major contributions of the staff at this text. Lists of the commercial preparations available, including Lange Medical Publications, Appleton & Lange, and McGraw-Hill, vii viii CONTENTS PREFACE and of our editors for this edition, Donna Frassetto and Rachel Suggestions and comments about Basic & Clinical Pharmacology D’Annucci Henriquez. I also wish to thank my wife, Alice Camp, are always welcome. They may be sent to me in care of the for her expert proofreading contributions since the first edition. publisher. This edition is dedicated to the memory of James Ransom, PhD, the long-time Senior Editor at Lange Medical Publications, Bertram G. Katzung, MD, PhD who provided major inspiration and invaluable guidance through San Francisco the first eight editions of the book. Without him, this book would December, 2011 not exist. Authors Emmanuel T. Akporiaye, PhD Edward Chu, MD Adjunct Professor, Oregon Health Sciences University, Professor of Medicine and Pharmacology & Chemical Laboratory Chief, Earle A. Chiles Research Institute, Biology; Chief, Division of Hematology-Oncology, Deputy Providence Cancer Center, Portland Director, University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh Michael J. Aminoff, MD, DSc, FRCP Professor, Department of Neurology, University of Robin L. Corelli, PharmD California, San Francisco Clinical Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California, San Allan I. Basbaum, PhD Francisco Professor and Chair, Department of Anatomy and W.M. Keck Foundation Center for Integrative Maria Almira Correia, PhD Neuroscience, University of California, San Francisco Professor of Pharmacology, Pharmaceutical Chemistry and Biopharmaceutical Sciences, Department of Cellular Neal L. Benowitz, MD & Molecular Pharmacology, University of California, Professor of Medicine and Bioengineering & Therapeutic San Francisco Science, University of California, San Francisco, San Francisco Charles DeBattista, MD Professor of Psychiatry and Behavioral Sciences, Stanford Italo Biaggioni, MD University School of Medicine, Stanford Professor of Pharmacology, Vanderbilt University School of Medicine, Nashville Daniel H. Deck, PharmD Assistant Clinical Professor, School of Pharmacy, Daniel D. Bikle, MD, PhD University of California, San Francisco; Infectious Professor of Medicine, Department of Medicine, and Diseases Clinical Pharmacist, San Francisco General Co-Director, Special Diagnostic and Treatment Unit, Hospital University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco Cathi E. Dennehy, PharmD Professor, Department of Clinical Pharmacy, University of Homer A. Boushey, MD California, San Francisco School of Pharmacy Chief, Asthma Clinical Research Center and Division of Allergy & Immunology; Professor of Medicine, Betty J. Dong, PharmD, FASHP, FCCP Department of Medicine, University of California, Professor of Clinical Pharmacy and Clinical Professor of San Francisco Family and Community Medicine, Department of Clinical Pharmacy and Department of Family and Community Adrienne D. Briggs, MD Medicine, Schools of Pharmacy and Medicine, University Clinical Director, Bone Marrow Transplant Program, of California, San Francisco Banner Good Samaritan Hospital, Phoenix Kenneth Drasner, MD Lundy Campbell, MD Profesor of Anesthesia and Perioperative Care, University Professor, Department of Anesthesiology and of California, San Francisco Perioperative Medicine, University of California San Francisco, School of Medicine, San Francisco Helge Eilers, MD Professor of Anesthesia and Perioperative Care, University George P. Chrousos, MD of California, San Francisco Professor & Chair, First Department of Pediatrics, Athens University Medical School, Athens ix x AUTHORS Garret A. FitzGerald, MD Michael J. Kosnett, MD, MPH Chair, Department of Pharmacology; Director, Institute Associate Clinical Professor of Medicine, Division of for Translational Medicine and Therapeutics, Perelman Clinical Pharmacology and Toxicology, University of School of Medicine at the University of Pennsylvania, Colorado Health Sciences Center, Denver Philadelphia Marieke Kruidering-Hall, PhD Daniel E. Furst, MD Associate Professor, Department of Cellular and Carl M. Pearson Professor of Rheumatology, Director, Molecular Pharmacology, University of California, San Rheumatology Clinical Research Center, Department of Francisco Rheumatology, University of California, Los Angeles Douglas F. Lake, PhD Augustus O. Grant, MD, PhD Associate Professor, The Biodesign Institute, Arizona State Professor of Medicine, Cardiovascular Division, Duke University, Tempe University Medical Center, Durham Harry W. Lampiris, MD Francis S. Greenspan, MD, FACP Associate Professor of Medicine, University of California, Clinical Professor of Medicine and Radiology and Chief, San Francisco Thyroid Clinic, Division of Endocrinology, Department of Paul W. Lofholm, PharmD Medicine, University of California, San Francisco Clinical Professor of Pharmacy, School of Pharmacy, Nicholas H. G. Holford, MB, ChB, FRACP University of California, San Francisco Professor, Department of Pharmacology and Clinical Christian Lüscher, MD Pharmacology, University of Auckland Medical School, Departments of Basic and Clincial Neurosciences, Medical Auckland Faculty, University Hospital of Geneva, John R. Horn, PharmD, FCCP Geneva, Switzerland Professor of Pharmacy, School of Pharmacy, University of Daniel S. Maddix, PharmD Washington; Associate Director of Pharmacy Services, Associate Clinical Professor of Pharmacy, University of Department of Medicine, University of Washington California, San Francisco Medicine, Seattle Howard I. Maibach, MD Joseph R. Hume, PhD Professor of Dermatology, Department of Dermatology, Professor and Chairman, Department of Pharmacology; University of California, San Francisco Adjunct Professor, Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno Mary J. Malloy, MD Clinical Professor of Pediatrics and Medicine, Harlan E. Ives, MD, PhD Departments of Pediatrics and Medicine, Cardiovascular Professor of Medicine, Department of Medicine, Research Institute, University of California, San Francisco University of California, San Francisco Susan B. Masters, PhD Samie R. Jaffrey, MD, PhD Professor of Pharmacology & Academy Chair of Associate Professor of Pharmacology, Department of Pharmacology Education, Department of Cellular & Pharmacology, Cornell University Weill Medical College, Molecular Pharmacology, University of California, New York City San Francisco John P. Kane, MD, PhD Kenneth R. McQuaid, MD Professor of Medicine, Department of Medicine; Professor Professor of Clinical Medicine, University of California, of Biochemistry and Biophysics; Associate Director, San Francisco; Chief of Gastroenterology, San Francisco Cardiovascular Research Institute, University of Veterans Affairs Medical Center California, San Francisco Brian S. Meldrum, MB, PhD Bertram G. Katzung, MD, PhD Professor Emeritus, GKT School of Medicine, Professor Emeritus, Department of Cellular & Molecular Guy’s Campus, London Pharmacology, University of California, San Francisco Herbert Meltzer, MD, PhD Gideon Koren, MD Professor of Psychiatry and Pharmacology, Vanderbilt Professor of Pediatrics, Pharmacology, Pharmacy, University, Nashville Medicine and Medical Genetics; Director, Motherisk Program, University of Toronto Roger A. Nicoll, MD Professor of Pharmacology and Physiology, Departments of Cellular & Molecular Pharmacology and Physiology, University of California, San Francisco  AUTHORS xi Martha S. Nolte Kennedy, MD Mark A. Schumacher, PhD, MD Clinical Professor, Department of Medicine, University of Associate Professor, Department of Anesthesia and California, San Francisco Perioperative Care, University of California, San Francisco Kent R. Olson, MD Don Sheppard, MD Clinical Professor, Departments of Medicine and Associate Professor, Departments of Microbiology and Pharmacy, University of California, San Francisco; Immunology and Medicine, McGill University; Program Medical Director, San Francisco Division, California Director, McGill Royal College Training Program in Poison Control System Medical Microbiology and Infectious Diseases, Montreal Achilles J. Pappano, PhD Emer M. Smyth, PhD Professor Emeritus, Department of Cell Biology and Assistant Professor, Department of Pharmacology, Calhoun Cardiology Center, University of Connecticut University of Pennsylvania School of Medicine, Philadelphia Health Center, Farmington Daniel T. Teitelbaum, MD Roger J. Porter, MD Professor, University of Colorado School of Medicine, Adjunct Professor of Neurology, University of Aurora, and Colorado School of Mines, Golden Pennsylvania, Philadelphia; Adjunct Professor of Anthony J. Trevor, PhD Pharmacology, Uniformed Services University of the Professor Emeritus, Department of Cellular & Molecular Health Sciences, Bethesda Pharmacology, University of California, San Francisco Shraddha Prakash, MD Candy Tsourounis, PharmD Senior Fellow in Rheumatology, David Geffen School of Professor of Clinical Pharmacy, Medication Outcomes Medicine, University of California, Los Angeles Center, University of California, San Francisco School of Ian A. Reid, PhD Pharmacy Professor Emeritus, Department of Physiology, University Robert W. Ulrich, PharmD of California, San Francisco Senior Clinical Science Manager, Abbott Laboratories Inc., David Robertson, MD Covina, California Elton Yates Professor of Medicine, Pharmacology and Mark von Zastrow, MD, PhD Neurology, Vanderbilt University; Director, Clinical & Professor, Departments of Psychiatry and Cellular & Translational Research Center, Vanderbilt Institute for Molecular Pharmacology, University of California, Clinical and Translational Research, Nashville San Francisco Dirk B. Robertson, MD Walter L. Way, MD* Professor of Clinical Dermatology, Department of Professor Emeritus, Departments of Anesthesia and Dermatology, Emory University School of Medicine, Cellular & Molecular Pharmacology, University of Atlanta California, San Francisco Philip J. Rosenthal, MD Lisa G. Winston, MD Professor of Medicine, University of California, Associate Professor, Department of Medicine, Division of San Francisco, San Francisco General Hospital Infectious Diseases, University of California, San Francisco; Stephen M. Rosenthal, MD Hospital Epidemiologist, San Francisco General Hospital Professor of Pediatrics, Associate Program Director, Spencer Yost, MD Pediatric Endocrinology; Director, Pediatric Endocrine Professor, Department of Anesthesia and Perioperative Outpatient Services, University of California, Care, University of California, San Francisco; Medical San Francisco Director, UCSF-Mt. Zion ICU, Chief of Anesthesia, Sharon Safrin, MD UCSF-Mt. Zion Hospital Associate Clinical Professor, Department of Medicine, James L. Zehnder, MD University of California, San Francisco; President, Professor of Pathology and Medicine, Pathology Department, Safrin Clinical Research Stanford University School of Medicine, Stanford Alan C. Sartorelli, PhD Alfred Gilman Professor of Pharmacology, Department of Pharmacology, Yale University School of Medicine, New Haven ∗Deceased xii KEY FEATURES xiii This page intentionally left blank  SECTION I BASIC PRINCIPLES 1 C H A P T E R Introduction Bertram G. Katzung, MD, PhD CASE STUDY A 26-year-old man is brought by friends to the emergency him from walking out of the emergency department and department of the city hospital because he has been behav- into traffic on the street. His blood pressure is 160/100 mm ing strangely for several days. A known user of metham- Hg, heart rate 100, temperature 39°C, and respirations 30/ phetamine, he has not eaten or slept in 48 hours. He min. His arms show evidence of numerous intravenous threatened to shoot one of his friends because he believes injections. The remainder of his physical examination is this friend is plotting against him. On admission, the man is unremarkable. After evaluation, the man is given a sedative, extremely agitated, appears to be underweight, and is unable fluids, a diuretic, and ammonium chloride parenterally. to give a coherent history. He has to be restrained to prevent What is the purpose of the ammonium chloride? Pharmacology can be defined as the study of substances that THE HISTORY OF PHARMACOLOGY interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting Prehistoric people undoubtedly recognized the beneficial or normal body processes. These substances may be chemicals toxic effects of many plant and animal materials. Early written administered to achieve a beneficial therapeutic effect on some records from China and Egypt and the traditions of India list process within the patient or for their toxic effects on regulatory remedies of many types, including a few that are still recognized processes in parasites infecting the patient. Such deliberate thera- as useful drugs today. Most, however, were worthless or actually peutic applications may be considered the proper role of medical harmful. In the 1500 years or so preceding the present, there pharmacology, which is often defined as the science of substances were sporadic attempts to introduce rational methods into used to prevent, diagnose, and treat disease. Toxicology is the medicine, but none was successful owing to the dominance of branch of pharmacology that deals with the undesirable effects of systems of thought that purported to explain all of biology and chemicals on living systems, from individual cells to humans to disease without the need for experimentation and observation. complex ecosystems (Figure 1–1). These schools promulgated bizarre notions such as the idea that 1 2 SECTION I Basic Principles 19th, and early 20th centuries laid the foundation needed for Chemical understanding how drugs work at the organ and tissue levels. Paradoxically, real advances in basic pharmacology during this time were accompanied by an outburst of unscientific claims by Pharmacokinetics Patient Environment manufacturers and marketers of worthless “patent medicines.” Not until the concepts of rational therapeutics, especially that of the controlled clinical trial, were reintroduced into medicine— only about 60 years ago—did it become possible to accurately Intended Unintended Other evaluate therapeutic claims. target targets organisms Around the same time, a major expansion of research efforts in tissues all areas of biology began. As new concepts and new techniques Pharmacodynamics were introduced, information accumulated about drug action and Food the biologic substrate of that action, the drug receptor. During chain the last half-century, many fundamentally new drug groups and Therapeutic effects new members of old groups were introduced. The last three decades have seen an even more rapid growth of information and understanding of the molecular basis for drug action. The molec- Toxic More ular mechanisms of action of many drugs have now been identi- effects organisms fied, and numerous receptors have been isolated, structurally characterized, and cloned. In fact, the use of receptor identifica- Medical pharmacology Environmental and toxicology toxicology tion methods (described in Chapter 2) has led to the discovery of many orphan receptors—receptors for which no ligand has been FIGURE 1–1 Major areas of study in pharmacology. The actions discovered and whose function can only be surmised. Studies of of chemicals can be divided into two large domains. The first (left the local molecular environment of receptors have shown that side) is that of medical pharmacology and toxicology, which is aimed receptors and effectors do not function in isolation; they are at understanding the actions of drugs as chemicals on individual strongly influenced by other receptors and by companion regula- organisms, especially humans and domestic animals. Both beneficial tory proteins. and toxic effects are included. Pharmacokinetics deals with the Pharmacogenomics—the relation of the individual’s genetic absorption, distribution, and elimination of drugs. Pharmaco- makeup to his or her response to specific drugs—is close to dynamics concerns the actions of the chemical on the organism. The becoming a practical area of therapy (see Box: Pharmacology & second domain (right side) is that of environmental toxicology, which Genetics). Decoding of the genomes of many species—from is concerned with the effects of chemicals on all organisms and their bacteria to humans—has led to the recognition of unsuspected survival in groups and as species. relationships between receptor families and the ways that recep- tor proteins have evolved. Discovery that small segments of RNA can interfere with protein synthesis with extreme selectivity has disease was caused by excesses of bile or blood in the body, that led to investigation of small interfering RNAs (siRNAs) and wounds could be healed by applying a salve to the weapon that microRNAs (miRNAs) as therapeutic agents. Similarly, short caused the wound, and so on. nucleotide chains called antisense oligonucleotides (ANOs) Around the end of the 17th century, and following the example synthesized to be complementary to natural RNA or DNA can of the physical sciences, reliance on observation and experimentation interfere with the readout of genes and the transcription of RNA. began to replace theorizing in medicine. As the value of these These intracellular targets may provide the next major wave of methods in the study of disease became clear, physicians in Great advances in therapeutics. Britain and on the Continent began to apply them to the effects The extension of scientific principles into everyday therapeutics is of traditional drugs used in their own practices. Thus, materia still going on, although the medication-consuming public is still medica—the science of drug preparation and the medical use of exposed to vast amounts of inaccurate, incomplete, or unscientific drugs—began to develop as the precursor to pharmacology. information regarding the pharmacologic effects of chemicals. This has However, any real understanding of the mechanisms of action of resulted in the irrational use of innumerable expensive, ineffective, drugs was prevented by the absence of methods for purifying and sometimes harmful remedies and the growth of a huge “alterna- active agents from the crude materials that were available and— tive health care” industry. Unfortunately, manipulation of the legisla- even more—by the lack of methods for testing hypotheses about tive process in the United States has allowed many substances the nature of drug actions. promoted for health—but not promoted specifically as “drugs”—to In the late 18th and early 19th centuries, François Magendie, avoid meeting the Food and Drug Administration (FDA) standards and later his student Claude Bernard, began to develop the meth- described in Chapter 5. Conversely, lack of understanding of basic ods of experimental physiology and pharmacology. Advances in scientific principles in biology and statistics and the absence of critical chemistry and the further development of physiology in the 18th, thinking about public health issues have led to rejection of medical  CHAPTER 1 Introduction 3 Pharmacology & Genetics It has been known for centuries that certain diseases are inherited, absent or nonfunctional. Homozygous knockout mice usually and we now understand that individuals with such diseases have have complete suppression of that function, whereas heterozy- a heritable abnormality in their DNA. During the last 10 years, the gous animals usually have partial suppression. Observation of genomes of humans, mice, and many other organisms have been the behavior, biochemistry, and physiology of the knockout mice decoded in considerable detail. This has opened the door to a often defines the role of the missing gene product very clearly. remarkable range of new approaches to research and treatment. It When the products of a particular gene are so essential that even is now possible in the case of some inherited diseases to define heterozygotes do not survive to birth, it is sometimes possible to exactly which DNA base pairs are anomalous and in which chro- breed “knockdown” versions with only limited suppression of mosome they appear. In a small number of animal models of such function. Conversely, “knockin” mice, which overexpress certain diseases, it has been possible to correct the abnormality by gene proteins of interest, have been bred. therapy, ie, insertion of an appropriate “healthy” gene into somatic Some patients respond to certain drugs with greater than usual cells. Human somatic cell gene therapy has been attempted, but sensitivity to standard doses. It is now clear that such increased the technical difficulties are great. sensitivity is often due to a very small genetic modification that Studies of a newly discovered receptor or endogenous ligand results in decreased activity of a particular enzyme responsible for are often confounded by incomplete knowledge of the exact role eliminating that drug. (Such variations are discussed in Chapter 4.) of that receptor or ligand. One of the most powerful of the new Pharmacogenomics (or pharmacogenetics) is the study of the genetic techniques is the ability to breed animals (usually mice) in genetic variations that cause differences in drug response among which the gene for the receptor or its endogenous ligand has individuals or populations. Future clinicians may screen every been “knocked out,” ie, mutated so that the gene product is patient for a variety of such differences before prescribing a drug. science by a segment of the public and to a common tendency to are uniquely skilled in exploiting discoveries from academic and assume that all adverse drug effects are the result of malpractice. governmental laboratories and translating these basic findings into Two general principles that the student should remember are (1) commercially successful therapeutic breakthroughs. that all substances can under certain circumstances be toxic, and the Such breakthroughs come at a price, however, and the escalat- chemicals in botanicals (herbs and plant extracts) are no different ing cost of drugs has become a significant contributor to the from chemicals in manufactured drugs except for the proportion of inflationary increase in the cost of health care. Development of impurities (greater in botanicals); and, (2) that all dietary supplements new drugs is enormously expensive, and to survive and prosper, and all therapies promoted as health-enhancing should meet the same big pharma must pay the costs of drug development and market- standards of efficacy and safety as conventional drugs and medical ing and return a profit to its shareholders. Today, considerable therapies. That is, there should be no artificial separation between controversy surrounds drug pricing. Critics claim that the costs of scientific medicine and “alternative” or “complementary” medicine. development and marketing are grossly inflated by marketing activities, which may consume as much as 25% or more of a com- pany’s budget in advertising and other promotional efforts. PHARMACOLOGY & THE Furthermore, profit margins for big pharma have historically PHARMACEUTICAL INDUSTRY exceeded all other industries by a significant factor. Finally, pricing schedules for many drugs vary dramatically from country to coun- A truly new drug (one that does not simply mimic the structure try and even within countries, where large organizations can and action of previously available drugs) requires the discovery of negotiate favorable prices and small ones cannot. Some countries a new drug target, ie, the pathophysiologic process or substrate of have already addressed these inequities, and it seems likely that all a disease. Such discoveries are usually made in public sector insti- countries will have to do so during the next few decades. tutions (universities and research institutes), and the molecules that have beneficial effects on such targets are often discovered in the same laboratories. However, the development of new drugs usu- GENERAL PRINCIPLES OF ally takes place in industrial laboratories because optimization of a class of new drugs requires painstaking and expensive chemical, PHARMACOLOGY pharmacologic, and toxicologic research. In fact, much of the THE NATURE OF DRUGS recent progress in the application of drugs to disease problems can be ascribed to the pharmaceutical industry including “big pharma,” In the most general sense, a drug may be defined as any substance the multibillion-dollar corporations that specialize in drug discov- that brings about a change in biologic function through its ery and development. As described in Chapter 5, these companies chemical actions. In most cases, the drug molecule interacts as an 4 SECTION I Basic Principles agonist (activator) or antagonist (inhibitor) with a specific mol- body (eg, from the site of administration to the site of action). ecule in the biologic system that plays a regulatory role. This target Drugs much larger than MW 1000 do not diffuse readily between molecule is called a receptor. The nature of receptors is discussed compartments of the body (see Permeation, in following text). more fully in Chapter 2. In a very small number of cases, drugs Therefore, very large drugs (usually proteins) must often be known as chemical antagonists may interact directly with other administered directly into the compartment where they have their drugs, whereas a few drugs (osmotic agents) interact almost exclu- effect. In the case of alteplase, a clot-dissolving enzyme, the drug sively with water molecules. Drugs may be synthesized within the is administered directly into the vascular compartment by intrave- body (eg, hormones) or may be chemicals not synthesized in the nous or intra-arterial infusion. body (ie, xenobiotics, from the Greek xenos, meaning “stranger”). Poisons are drugs that have almost exclusively harmful effects. Drug Reactivity and Drug-Receptor Bonds However, Paracelsus (1493–1541) famously stated that “the dose Drugs interact with receptors by means of chemical forces or makes the poison,” meaning that any substance can be harmful if bonds. These are of three major types: covalent, electrostatic, and taken in the wrong dosage. Toxins are usually defined as poisons hydrophobic. Covalent bonds are very strong and in many cases of biologic origin, ie, synthesized by plants or animals, in contrast not reversible under biologic conditions. Thus, the covalent bond to inorganic poisons such as lead and arsenic. formed between the acetyl group of acetylsalicylic acid (aspirin) To interact chemically with its receptor, a drug molecule must and cyclooxygenase, its enzyme target in platelets, is not readily have the appropriate size, electrical charge, shape, and atomic broken. The platelet aggregation–blocking effect of aspirin lasts composition. Furthermore, a drug is often administered at a loca- long after free acetylsalicylic acid has disappeared from the blood- tion distant from its intended site of action, eg, a pill given orally stream (about 15 minutes) and is reversed only by the synthesis of to relieve a headache. Therefore, a useful drug must have the nec- new enzyme in new platelets, a process that takes several days. essary properties to be transported from its site of administration Other examples of highly reactive, covalent bond-forming drugs to its site of action. Finally, a practical drug should be inactivated are the DNA-alkylating agents used in cancer chemotherapy to or excreted from the body at a reasonable rate so that its actions disrupt cell division in the tumor. will be of appropriate duration. Electrostatic bonding is much more common than covalent bonding in drug-receptor interactions. Electrostatic bonds vary The Physical Nature of Drugs from relatively strong linkages between permanently charged ionic molecules to weaker hydrogen bonds and very weak induced Drugs may be solid at room temperature (eg, aspirin, atropine), dipole interactions such as van der Waals forces and similar phe- liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide). These nomena. Electrostatic bonds are weaker than covalent bonds. factors often determine the best route of administration. The most Hydrophobic bonds are usually quite weak and are probably common routes of administration are described in Table 3–3. The important in the interactions of highly lipid-soluble drugs with various classes of organic compounds—carbohydrates, proteins, the lipids of cell membranes and perhaps in the interaction of lipids, and their constituents—are all represented in pharmacol- drugs with the internal walls of receptor “pockets.” ogy. As noted above, oligonucleotides, in the form of small seg- The specific nature of a particular drug-receptor bond is of less ments of RNA, have entered clinical trials and are on the threshold practical importance than the fact that drugs that bind through of introduction into therapeutics. weak bonds to their receptors are generally more selective than A number of useful or dangerous drugs are inorganic elements, drugs that bind by means of very strong bonds. This is because weak eg, lithium, iron, and heavy metals. Many organic drugs are weak bonds require a very precise fit of the drug to its receptor if an inter- acids or bases. This fact has important implications for the way action is to occur. Only a few receptor types are likely to provide they are handled by the body, because pH differences in the vari- such a precise fit for a particular drug structure. Thus, if we wished ous compartments of the body may alter the degree of ionization to design a highly selective short-acting drug for a particular recep- of such drugs (see text that follows). tor, we would avoid highly reactive molecules that form covalent bonds and instead choose a molecule that forms weaker bonds. Drug Size A few substances that are almost completely inert in the The molecular size of drugs varies from very small (lithium ion, chemical sense nevertheless have significant pharmacologic effects. MW 7) to very large (eg, alteplase [t-PA], a protein of MW For example, xenon, an “inert” gas, has anesthetic effects at ele- 59,050). However, most drugs have molecular weights between vated pressures. 100 and 1000. The lower limit of this narrow range is probably set by the requirements for specificity of action. To have a good “fit” Drug Shape to only one type of receptor, a drug molecule must be sufficiently The shape of a drug molecule must be such as to permit binding to unique in shape, charge, and other properties, to prevent its bind- its receptor site via the bonds just described. Optimally, the drug’s ing to other receptors. To achieve such selective binding, it appears shape is complementary to that of the receptor site in the same way that a molecule should in most cases be at least 100 MW units in that a key is complementary to a lock. Furthermore, the phenome- size. The upper limit in molecular weight is determined primarily non of chirality (stereoisomerism) is so common in biology that by the requirement that drugs must be able to move within the more than half of all useful drugs are chiral molecules; that is, they  CHAPTER 1 Introduction 5 More active isomer Less active isomer * * X Flat, hydrophobic regions Polar region FIGURE 1–2 Cartoon illustrating the nonsuperimposibility of the two stereoisomers of carvedilol on the β receptor. The “receptor surface” has been grossly oversimplified. The chiral center carbon is denoted with an asterisk. One of the two isomers fits the three-dimensional configu- ration of binding site of the β-adrenoceptor molecule very well (left), and three groups, including an important polar moiety (an hydroxyl group, indicated by the central dashed line), bind to key areas of the surface. The less active isomer cannot orient all three binding areas to the recep- tor surface (right). (Molecule generated by means of Jmol, an open-source Java viewer for chemical structures in 3D [http://jmol.sourceforge. net/] with data from DrugBank [http://www.drugbank.ca].) can exist as enantiomeric pairs. Drugs with two asymmetric centers drugs rather than with the separate enantiomers. At present, only a have four diastereomers, eg, ephedrine, a sympathomimetic drug. In small percentage of the chiral drugs used clinically are marketed as most cases, one of these enantiomers is much more potent than its the active isomer—the rest are available only as racemic mixtures. mirror image enantiomer, reflecting a better fit to the receptor mol- As a result, many patients are receiving drug doses of which 50% ecule. If one imagines the receptor site to be like a glove into which is less active, inactive, or actively toxic. Some drugs are currently the drug molecule must fit to bring about its effect, it is clear why a available in both the racemic and the pure, active isomer forms. “left-oriented” drug is more effective in binding to a left-hand Unfortunately, the hope that administration of the pure, active receptor than its “right-oriented” enantiomer. enantiomer would decrease adverse effects relative to those pro- The more active enantiomer at one type of receptor site may duced by racemic formulations has not been firmly established. not be more active at another receptor type, eg, a type that may be However, there is increasing interest at both the scientific and the responsible for some other effect. For example, carvedilol, a drug regulatory levels in making more chiral drugs available as their that interacts with adrenoceptors, has a single chiral center and active enantiomers. thus two enantiomers (Figure 1–2, Table 1–1). One of these enantiomers, the (S)(−) isomer, is a potent β-receptor blocker. The (R)(+) isomer is 100-fold weaker at the β receptor. However, the TABLE 1–1 Dissociation constants (Kd) of the isomers are approximately equipotent as α-receptor blockers. enantiomers and racemate of carvedilol. Ketamine is an intravenous anesthetic. The (+) enantiomer is a α Receptors β Receptors more potent anesthetic and is less toxic than the (−) enantiomer. Form of Carvedilol (Kd, nmol/L1) (Kd, nmol/L) Unfortunately, the drug is still used as the racemic mixture. Finally, because enzymes are usually stereoselective, one drug R(+) enantiomer 14 45 enantiomer is often more susceptible than the other to drug- S(−) enantiomer 16 0.4 metabolizing enzymes. As a result, the duration of action of one R,S(±) enantiomers 11 0.9 enantiomer may be quite different from that of the other. 1 The Kd is the concentration for 50% saturation of the receptors and is inversely pro- Similarly, drug transporters may be stereoselective. portionate to the affinity of the drug for the receptors. Unfortunately, most studies of clinical efficacy and drug elimi- Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Pharmacol nation in humans have been carried out with racemic mixtures of 1990;38:S82. 6 SECTION I Basic Principles Rational Drug Design D + R → drug-receptor complex → effector molecule → effect D + R → D-R complex → activation of coupling molecule → Rational design of drugs implies the ability to predict the appropri- effector molecule → effect ate molecular structure of a drug on the basis of information about Inhibition of metabolism of endogenous activator → increased its biologic receptor. Until recently, no receptor was known in suf- activator action on an effector molecule → increased effect ficient detail to permit such drug design. Instead, drugs were devel- oped through random testing of chemicals or modification of drugs Note that the final change in function is accomplished by an already known to have some effect (see Chapter 5). However, the effector mechanism. The effector may be part of the receptor characterization of many receptors during the past three decades has molecule or may be a separate molecule. A very large number of changed this picture. A few drugs now in use were developed receptors communicate with their effectors through coupling mol- through molecular design based on knowledge of the three-dimen- ecules, as described in Chapter 2. sional structure of the receptor site. Computer programs are now available that can iteratively optimize drug structures to fit known A. Types of Drug-Receptor Interactions receptors. As more becomes known about receptor structure, ratio- Agonist drugs bind to and activate the receptor in some fashion, nal drug design will become more common. which directly or indirectly brings about the effect (Figure 1–3A). Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level. Receptor Nomenclature Some receptors incorporate effector machinery in the same mol- The spectacular success of newer, more efficient ways to identify ecule, so that drug binding brings about the effect directly, eg, and characterize receptors (see Chapter 2) has resulted in a variety opening of an ion channel or activation of enzyme activity. of differing, and sometimes confusing, systems for naming them. Other receptors are linked through one or more intervening This in turn has led to a number of suggestions regarding more coupling molecules to a separate effector molecule. The five rational methods of naming receptors. The interested reader is major types of drug-receptor-effector coupling systems are dis- referred for details to the efforts of the International Union of cussed in Chapter 2. Pharmacologic antagonist drugs, by bind- Pharmacology (IUPHAR) Committee on Receptor Nomenclature and ing to a receptor, compete with and prevent binding by other Drug Classification (reported in various issues of Pharmacological molecules. For example, acetylcholine receptor blockers such as Reviews) and to Alexander SPH, Mathie A, Peters JA: Guide to atropine are antagonists because they prevent access of acetylcho- receptors and channels (GRAC), 4th edition. Br J Pharmacol line and similar agonist drugs to the acetylcholine receptor site 2009;158(Suppl 1):S1–S254. The chapters in this book mainly and they stabilize the receptor in its inactive state (or some state use these sources for naming receptors. other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similar molecules in the body (Figure 1–3B), but their action can be overcome by increasing the DRUG-BODY INTERACTIONS dosage of agonist. Some antagonists bind very tightly to the recep- tor site in an irreversible or pseudoirreversible fashion and cannot The interactions between a drug and the body are conveniently be displaced by increasing the agonist concentration. Drugs that divided into two classes. The actions of the drug on the body are bind to the same receptor molecule but do not prevent binding of termed pharmacodynamic processes (Figure 1–1); the principles the agonist are said to act allosterically and may enhance (Figure of pharmacodynamics are presented in greater detail in Chapter 2. 1–3C) or inhibit (Figure 1–3D) the action of the agonist mole- These properties determine the group in which the drug is classi- cule. Allosteric inhibition is not overcome by increasing the dose fied, and they play the major role in deciding whether that group of agonist. is appropriate therapy for a particular symptom or disease. The actions of the body on the drug are called pharmacokinetic pro- B. Agonists That Inhibit Their Binding Molecules cesses and are described in Chapters 3 and 4. Pharmacokinetic processes govern the absorption, distribution, and elimination of Some drugs mimic agonist drugs by inhibiting the molecules drugs and are of great practical importance in the choice and responsible for terminating the action of an endogenous agonist. administration of a particular drug for a particular patient, eg, a For example, acetylcholinesterase inhibitors, by slowing the patient with impaired renal function. The following paragraphs destruction of endogenous acetylcholine, cause cholinomimetic provide a brief introduction to pharmacodynamics and pharma- effects that closely resemble the actions of cholinoceptor agonist cokinetics. molecules even though cholinesterase inhibitors do not bind or only incidentally bind to cholinoceptors (see Chapter 7). Because they amplify the effects of physiologically released agonist ligands, Pharmacodynamic Principles their effects are sometimes more selective and less toxic than those Most drugs must bind to a receptor to bring about an effect. of exogenous agonists. However, at the cellular level, drug binding is only the first in what is often a complex sequence of steps: C. Agonists, Partial Agonists, and Inverse Agonists Drug (D) + receptor-effector (R) → drug-receptor-effector Figure 1–4 describes a useful model of drug-receptor interaction. complex → effect As indicated, the receptor is postulated to exist in the inactive,  CHAPTER 1 Introduction 7 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 1–3 Drugs may interact with receptors in several ways. The effects resulting from these interactions are diagrammed in the dose- response curves at the right. Drugs that alter the agonist (A) response may activate the agonist binding site, compete with the agonist (compet- itive inhibitors, B), or act at separate (allosteric) sites, increasing (C) or decreasing (D) the response to the agonist. Allosteric activators (C) may increase the efficacy of the agonist or its binding affinity. The curve shown reflects an increase in efficacy; an increase in affinity would result in a leftward shift of the curve. nonfunctional form (Ri) and in the activated form (Ra). in the same way but do not evoke as great a response, no matter Thermodynamic considerations indicate that even in the absence how high the concentration. In the model in Figure 1–4, partial of any agonist, some of the receptor pool must exist in the Ra form agonists do not stabilize the Ra configuration as fully as full ago- some of the time and may produce the same physiologic effect as nists, so that a significant fraction of receptors exists in the Ri–D agonist-induced activity. This effect, occurring in the absence of pool. Such drugs are said to have low intrinsic efficacy. Thus, agonist, is termed constitutive activity. Agonists are those drugs pindolol, a β-adrenoceptor partial agonist, may act either as an that have a much higher affinity for the Ra configuration and agonist (if no full agonist is present) or as an antagonist (if a full stabilize it, so that a large percentage of the total pool resides in agonist such as epinephrine is present). (See Chapter 2.) Intrinsic the Ra–D fraction and a large effect is produced. The recognition efficacy is independent of affinity (as usually measured) for the of constitutive activity may depend on the receptor density, the receptor. concentration of coupling molecules (if a coupled system), and the In the same model, conventional antagonist action can be number of effectors in the system. explained as fixing the fractions of drug-bound Ri and Ra in the Many agonist drugs, when administered at concentrations suf- same relative amounts as in the absence of any drug. In this situa- ficient to saturate the receptor pool, can activate their receptor-ef- tion, no change will be observed, so the drug will appear to be fector systems to the maximum extent of which the system is without effect. However, the presence of the antagonist at the capable; that is, they cause a shift of almost all of the receptor pool receptor site will block access of agonists to the receptor and pre- to the Ra–D pool. Such drugs are termed full agonists. Other drugs, vent the usual agonist effect. Such blocking action can be termed called partial agonists, bind to the same receptors and activate them neutral antagonism. 8 SECTION I Basic Principles agitation, the inverse of sedation (see Chapter 22). Similar inverse Effect agonists have been found for β-adrenoceptors, histamine H1 and Ri Ra H2 receptors, and several other receptor systems. D D D. Duration of Drug Action Termination of drug action is a result of one of several processes. In some cases, the effect lasts only as long as the drug occupies the Ri – D Ra – D receptor, and dissociation of drug from the receptor automatically Effect terminates the effect. In many cases, however, the action may persist after the drug has dissociated because, for example, some coupling molecule is still present in activated form. In the case of Ra + Da drugs that bind covalently to the receptor site, the effect may per- Full agonist sist until the drug-receptor complex is destroyed and new recep- tors or enzymes are synthesized, as described previously for aspirin. In addition, many receptor-effector systems incorporate desensiti- Response zation mechanisms for preventing excessive activation when ago- Ra + Dpa nist molecules continue to be present for long periods. (See Partial agonist Chapter 2 for additional details.) Ra + Ri Ra + Dant + Ri + Dant Constitutive Antagonist E. Receptors and Inert Binding Sites activity Ri + Di To function as a receptor, an endogenous molecule must first be Inverse agonist selective in choosing ligands (drug molecules) to bind; and second, Log Dose it must change its function upon binding in such a way that the function of the biologic system (cell, tissue, etc) is altered. The FIGURE 1–4 A model of drug-receptor interaction. The receptor selectivity characteristic is required to avoid constant activation of is able to assume two conformations. In the Ri conformation, it is the receptor by promiscuous binding of many different ligands. The inactive and produces no effect, even when combined with a drug ability to change function is clearly necessary if the ligand is to cause molecule. In the Ra conformation, the receptor can activate down- a pharmacologic effect. The body contains a vast array of molecules stream mechanisms that produce a small observable effect, even in that are capable of binding drugs, however, and not all of these the absence of drug (constitutive activity). In the absence of drugs, endogenous molecules are regulatory molecules. Binding of a drug the two isoforms are in equilibrium, and the Ri form is favored. Conventional full agonist drugs have a much higher affinity for the Ra to a nonregulatory molecule such as plasma albumin will result in conformation, and mass action thus favors the formation of the Ra–D no detectable change in the function of the biologic system, so this complex with a much larger observed effect. Partial agonists have an endogenous molecule can be called an inert binding site. Such intermediate affinity for both Ri and Ra forms. Conventional antago- binding is not completely without significance, however, because it nists, according to this hypothesis, have equal affinity for both recep- affects the distribution of drug within the body and determines the tor forms and maintain the same level of constitutive activity. Inverse amount of free drug in the circulation. Both of these factors are of agonists, on the other hand, have a much higher affinity for the Ri pharmacokinetic importance (see also Chapter 3). form, reduce constitutive activity, and may produce a contrasting physiologic result. Pharmacokinetic Principles In practical therapeutics, a drug should be able to reach its What will happen if a drug has a much stronger affinity for the intended site of action after administration by some convenient Ri than for the Ra state and stabilizes a large fraction in the Ri–D route. In many cases, the active drug molecule is sufficiently lipid- pool? In this scenario the drug would reduce any constitutive soluble and stable to be given as such. In some cases, however, an activity, thus resulting in effects that are the opposite of the effects inactive precursor chemical that is readily absorbed and distrib- produced by conventional agonists at that receptor. Such drugs uted must be administered and then converted to the active drug have been termed inverse agonists (Figure 1–4). One of the best by biologic processes—inside the body. Such a precursor chemical documented examples of such a system is the γ-aminobutyric acid is called a prodrug. (GABAA) receptor-effector (a chloride channel) in the nervous In only a few situations is it possible to apply a drug directly to system. This receptor is activated by the endogenous transmitter its target tissue, eg, by topical application of an anti-inflammatory GABA and causes inhibition of postsynaptic cells. Conventional agent to inflamed skin or mucous membrane. Most often, a drug exogenous agonists such as benzodiazepines also facilitate the is administered into one body compartment, eg, the gut, and must receptor-effector system and cause GABA-like inhibition with move to its site of action in another compartment, eg, the brain in sedation as the therapeutic result. This inhibition can be blocked the case of an antiseizure medication. This requires that the drug by conventional neutral antagonists such as flumazenil. In addi- be absorbed into the blood from its site of administration and tion, inverse agonists have been found that cause anxiety and distributed to its site of action, permeating through the various  CHAPTER 1 Introduction 9 Lumen Interstitium A B C D FIGURE 1–5 Mechanisms of drug permeation. Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg, tight junctions, A), or through lipid cell membranes (B). Drugs with the appropriate characteristics may be transported by carriers into or out of cells (C). Very impermeant drugs may also bind to cell surface receptors (dark binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the mem