Basic & Clinical Pharmacology (2017) PDF

a LANGE medical book Basic & Clinical Pharmacology Fourteenth Edition Edited by Bertram G. Katzung, MD, PhD Professor Emeritus Department of Cellular & Molecular Pharmacology University of California, San Francisco New York Chicago San...

a LANGE medical book Basic & Clinical Pharmacology Fourteenth Edition Edited by Bertram G. Katzung, MD, PhD Professor Emeritus Department of Cellular & Molecular Pharmacology University of California, San Francisco New York Chicago San Francisco Athens London Madrid Mexico City Milan New Delhi Singapore Sydney Toronto Basic & Clinical Pharmacology, Fourteenth Edition Copyright © 2018 by McGraw-Hill Education. All rights reserved. Printed in the United States of America. 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 data base or retrieval system, without the prior written permission of the publisher. Previous editions copyright © 2015, 2012, 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. 1 2 3 4 5 6 7 8 9 LWI 22 21 20 19 18 17 ISBN 978-1-259-64115-2 MHID 1-259-64115-5 ISSN 0891-2033 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 informa- tion 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 prepara- tion 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 encour- aged to confirm the information contained herein with other sources. For example and in particular, readers are advised to check the product 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. This book was set in Adobe Garamond by Cenveo® Publisher Services. The editors were Michael Weitz and Peter Boyle. The copyeditors were Caroline Define and Greg Feldman. The production supervisor was Richard Ruzycka. Project management provided by Neha Bhargava, Cenveo Publisher Services. Cover photo: Tumor necrosis factor alpha (TNF-α) cytokine protein molecule, 3D rendering. Clinically used inhibitors include infliximab, adalimumab, certolizumab and etanercept. Photo credit: Shutterstock. This book is printed on acid-free paper. McGraw-Hill Education books 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 visit the Contact Us pages at www.mhprofessional.com. International Edition ISBN 978-1-260-28817-9; MHID 1-260-28817-X. Copyright © 2018. Exclusive rights by McGraw-Hill Education for manufacture and export. This book cannot be re-exported from the country to which it is consigned by McGraw-Hill Education. The International Edition is not available in North America. Contents Preface vii Authors ix S E C T I O N I 10. Adrenoceptor Antagonist Drugs David Robertson, MD, & Italo Biaggioni, MD 156 BASIC PRINCIPLES 1 S E C T I O N III 1. Introduction: The Nature of Drugs & CARDIOVASCULAR-RENAL Drug Development & Regulation Bertram G. Katzung, MD, PhD 1 DRUGS 173 2. Drug Receptors & Pharmacodynamics 11. Antihypertensive Agents Mark von Zastrow, MD, PhD 20 Neal L. Benowitz, MD 173 3. Pharmacokinetics & Pharmacodynamics: 12. Vasodilators & the Treatment of Rational Dosing & the Time Course Angina Pectoris of Drug Action Bertram G. Katzung, MD, PhD 194 Nicholas H. G. Holford, MB, ChB, FRACP 41 13. Drugs Used in Heart Failure 4. Drug Biotransformation Bertram G. Katzung, MD, PhD 212 Maria Almira Correia, PhD 56 14. Agents Used in Cardiac Arrhythmias 5. Pharmacogenomics Robert D. Harvey, PhD, & Augustus O. Grant, MD, PhD 228 Jennifer E. Hibma, PharmD, & Kathleen M. Giacomini, PhD 74 15. Diuretic Agents Ramin Sam, MD, Harlan E. Ives, MD, PhD, S E C T I O N II & David Pearce, MD 254 AUTONOMIC DRUGS 89 S E C T I O N IV 6. Introduction to Autonomic Pharmacology Bertram G. Katzung, MD, PhD 89 DRUGS WITH IMPORTANT ACTIONS ON SMOOTH MUSCLE 277 7. Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs 16. Histamine, Serotonin, & the Ergot Alkaloids Achilles J. Pappano, PhD 107 Bertram G. Katzung, MD, PhD 277 8. Cholinoceptor-Blocking Drugs 17. Vasoactive Peptides Achilles J. Pappano, PhD 124 Ian A. Reid, PhD 300 9. Adrenoceptor Agonists & 18. The Eicosanoids: Prostaglandins, Sympathomimetic Drugs Thromboxanes, Leukotrienes, & Related Italo Biaggioni, MD, & David Robertson, MD 137 Compounds John Hwa, MD, PhD, & Kathleen Martin, PhD 321 iii iv CONTENTS 19. Nitric Oxide 32. Drugs of Abuse Samie R. Jaffrey, MD, PhD 339 Christian Lüscher, MD 575 20. Drugs Used in Asthma S E C T I O N VI Joshua M. Galanter, MD, & Homer A. Boushey, MD 346 DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, S E C T I O N V & GOUT 591 DRUGS THAT ACT IN THE CENTRAL 33. Agents Used in Cytopenias; Hematopoietic NERVOUS SYSTEM 367 Growth Factors James L. Zehnder, MD 591 21. Introduction to the Pharmacology of CNS Drugs 34. Drugs Used in Disorders of Coagulation John A. Gray, MD, PhD 367 James L. Zehnder, MD 608 22. Sedative-Hypnotic Drugs 35. Agents Used in Dyslipidemia Anthony J. Trevor, PhD 381 Mary J. Malloy, MD, & John P. Kane, MD, PhD 626 23. The Alcohols Anthony J. Trevor, PhD 396 36. Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, 24. Antiseizure Drugs Nonopioid Analgesics, & Roger J. Porter, MD, & Drugs Used in Gout Michael A. Rogawski, MD, PhD 409 Ahmed A. Negm, MD, & Daniel E. Furst, MD 642 25. General Anesthetics Helge Eilers, MD, & Spencer Yost, MD 440 S E C T I O N VII 26. Local Anesthetics Kenneth Drasner, MD 459 ENDOCRINE DRUGS 667 37. Hypothalamic & Pituitary Hormones 27. Skeletal Muscle Relaxants Roger K. Long, MD, & Marieke Kruidering-Hall, PhD, & Hakan Cakmak, MD 667 Lundy Campbell, MD 474 38. Thyroid & Antithyroid Drugs 28. Pharmacologic Management of Betty J. Dong, PharmD, FASHP, FCCP, FAPHA 687 Parkinsonism & Other Movement Disorders 39. Adrenocorticosteroids & Adrenocortical Michael J. Aminoff, MD, DSc, FRCP 492 Antagonists George P. Chrousos, MD 703 29. Antipsychotic Agents & Lithium Charles DeBattista, MD 511 40. The Gonadal Hormones & Inhibitors George P. Chrousos, MD 720 30. Antidepressant Agents Charles DeBattista, MD 532 41. Pancreatic Hormones & Antidiabetic 31. Opioid Agonists & Antagonists Drugs Martha S. Nolte Kennedy, MD, & Mark A. Schumacher, PhD, MD, Umesh Masharani, MBBS, MRCP (UK) 747 Allan I. Basbaum, PhD, & Ramana K. Naidu, MD 553  CONTENTS v 42. Agents That Affect Bone Mineral 53. Clinical Pharmacology of the Homeostasis Antihelminthic Drugs Daniel D. Bikle, MD, PhD 772 Philip J. Rosenthal, MD 938 S E C T I O N VIII 54. Cancer Chemotherapy Edward Chu, MD 948 CHEMOTHERAPEUTIC DRUGS 793 55. Immunopharmacology 43. Beta-Lactam & Other Cell Wall- & Douglas F. Lake, PhD, & Membrane-Active Antibiotics Adrienne D. Briggs, MD 977 Camille E. Beauduy, PharmD, & Lisa G. Winston, MD 795 S E C T I O N IX 44. Tetracyclines, Macrolides, Clindamycin, TOXICOLOGY 1003 Chloramphenicol, Streptogramins, & Oxazolidinones 56. Introduction to Toxicology: Occupational & Camille E. Beauduy, PharmD, & Environmental Lisa G. Winston, MD 815 Daniel T. Teitelbaum, MD 1003 45. Aminoglycosides & Spectinomycin 57. Heavy Metal Intoxication & Chelators Camille E. Beauduy, PharmD, & Michael J. Kosnett, MD, MPH 1020 Lisa G. Winston, MD 826 58. Management of the Poisoned Patient 46. Sulfonamides, Trimethoprim, Kent R. Olson, MD 1035 & Quinolones Camille E. Beauduy, PharmD, & Lisa G. Winston, MD 834 S E C T I O N X 47. Antimycobacterial Drugs SPECIAL TOPICS 1047 Camille E. Beauduy, PharmD, & Lisa G. Winston, MD 842 59. Special Aspects of Perinatal & Pediatric Pharmacology 48. Antifungal Agents Gideon Koren, MD, FRCPC, FACMT 1047 Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD 853 60. Special Aspects of Geriatric Pharmacology Bertram G. Katzung, MD, PhD 1058 49. Antiviral Agents Sharon Safrin, MD 863 61. Dermatologic Pharmacology Dirk B. Robertson, MD, & 50. Miscellaneous Antimicrobial Agents; Howard I. Maibach, MD 1068 Disinfectants, Antiseptics, & Sterilants Camille E. Beauduy, PharmD, & 62. Drugs Used in the Treatment of Lisa G. Winston, MD 895 Gastrointestinal Diseases Kenneth R. McQuaid, MD 1087 51. Clinical Use of Antimicrobial Agents Harry W. Lampiris, MD, & 63. Therapeutic & Toxic Potential of Daniel S. Maddix, PharmD 904 Over-the-Counter Agents Valerie B. Clinard, PharmD, & 52. Antiprotozoal Drugs Robin L. Corelli, PharmD 1120 Philip J. Rosenthal, MD 917 vi CONTENTS 64. Dietary Supplements & Herbal Appendix: Vaccines, Immune Globulins, & Medications Other Complex Biologic Products Cathi E. Dennehy, PharmD, & Harry W. Lampiris, MD, & Candy Tsourounis, PharmD 1131 Daniel S. Maddix, PharmD 1175 65. Rational Prescribing & Index 1183 Prescription Writing Paul W. Lofholm, PharmD, & Bertram G. Katzung, MD, PhD 1146 66. Important Drug Interactions & Their Mechanisms John R. Horn, PharmD, FCCP 1156 Preface The fourteenth edition of Basic & Clinical Pharmacology continues Significant revisions in this edition include: the extensive use of full-color illustrations and expanded coverage of transporters, pharmacogenomics, and new drugs of all types Major revisions of the chapters on immunopharmacology, emphasized in prior editions. In addition, it reflects the major antiseizure, antipsychotic, antidepressant, antidiabetic, anti- expansion of large-molecule drugs in the pharmacopeia, with inflammatory, and antiviral drugs, prostaglandins, and central nervous system neurotransmitters. numerous new monoclonal antibodies and other biologic agents. Continued expansion of the coverage of general concepts relat- Case studies accompany most chapters, and answers to ques- ing to newly discovered receptors, receptor mechanisms, and tions posed in the case studies appear at the end of each chapter. drug transporters. The book is designed to provide a comprehensive, authoritative, Descriptions of important new drugs released through May 2017. and readable pharmacology textbook for students in the health Many revised illustrations in full color that provide significantly sciences. Frequent revision is necessary to keep pace with the rapid more information about drug mechanisms and effects and help changes in pharmacology and therapeutics; the 2–3 year revision to clarify important concepts. cycle of this text is among the shortest in the field, and the avail- An important related educational resource is Katzung & ability of an online version provides even greater currency. The Trevor’s Pharmacology: Examination & Board Review, (Trevor AJ, book also offers special features that make it a useful reference for Katzung BG, & Kruidering-Hall, M: McGraw-Hill). This book house officers and practicing clinicians. provides a succinct review of pharmacology with approximately This edition continues the sequence used in many pharmacol- one thousand sample examination questions and answers. It is ogy courses and in integrated curricula: basic principles of drug especially helpful to students preparing for board-type examina- discovery, pharmacodynamics, pharmacokinetics, and pharma- tions. A more highly condensed source of information suitable for cogenomics; autonomic drugs; cardiovascular-renal drugs; drugs review purposes is USMLE Road Map: Pharmacology, second edi- with important actions on smooth muscle; central nervous system tion (Katzung BG, Trevor AJ: McGraw-Hill, 2006). An extremely drugs; drugs used to treat inflammation, gout, and diseases of useful manual of toxicity due to drugs and other products the blood; endocrine drugs; chemotherapeutic drugs; toxicology; is Poisoning & Drug Overdose, by Olson KR, ed; 7th edition, and special topics. This sequence builds new information on a McGraw-Hill, 2017. foundation of information already assimilated. For example, early This edition marks the 35th year of publication of Basic & presentation of autonomic nervous system pharmacology allows Clinical Pharmacology. The widespread adoption of the first students to integrate the physiology and neuroscience they have thirteen editions indicates that this book fills an important need. learned elsewhere with the pharmacology they are learning and We believe that the fourteenth edition will satisfy this need even prepares them to understand the autonomic effects of other drugs. more successfully. Chinese, Croatian, Czech, French, Georgian, This is especially important for the cardiovascular and central ner- Indonesian, Italian, Japanese, Korean, Lithuanian, Portuguese, vous system drug groups. However, chapters can be used equally Spanish, Turkish, and Ukrainian translations of various editions well in courses and curricula that present these topics in a different are available. The publisher may be contacted for further sequence. information. Within each chapter, emphasis is placed on discussion of drug I wish to acknowledge the prior and continuing efforts of groups and prototypes rather than offering repetitive detail about my contributing authors and the major contributions of the individual drugs. Selection of the subject matter and the order staff at Lange Medical Publications, Appleton & Lange, and of its presentation are based on the accumulated experience of McGraw-Hill, and of our editors for this edition, Caroline teaching this material to thousands of medical, pharmacy, dental, Define and Greg Feldman. I also wish to thank Alice Camp and podiatry, nursing, and other health science students. Katharine Katzung for their expert proofreading contributions. Major features that make this book particularly useful in Suggestions and comments about Basic & Clinical Pharmacology integrated curricula include sections that specifically address the are always welcome. They may be sent to me in care of the clinical choice and use of drugs in patients and the monitoring of publisher. their effects—in other words, clinical pharmacology is an integral part of this text. Lists of the trade and generic names of commer- Bertram G. Katzung, MD, PhD cial preparations available are provided at the end of each chapter San Francisco for easy reference by the house officer or practitioner evaluating a June 2017 patient’s drug list or writing a prescription. vii Authors Michael J. Aminoff, MD, DSc, FRCP Edward Chu, MD Professor, Department of Neurology, University of Professor of Medicine and Pharmacology & Chemical California, San Francisco Biology; Chief, Division of Hematology-Oncology, Director, University of Pittsburgh Cancer Institute, Allan I. Basbaum, PhD University of Pittsburgh School of Medicine, Pittsburgh Professor and Chair, Department of Anatomy and W.M. Keck Foundation Center for Integrative Neuroscience, Valerie B. Clinard, PharmD University of California, San Francisco Associate Professor, Department of Clinical Pharmacy, School of Pharmacy, University of California, Camille E. Beauduy, PharmD San Francisco Assistant Clinical Professor, School of Pharmacy, University of California, San Francisco Robin L. Corelli, PharmD Clinical Professor, Department of Clinical Pharmacy, Neal L. Benowitz, MD School of Pharmacy, University of California, Professor of Medicine and Bioengineering & San Francisco Therapeutic Science, University of California, San Francisco Maria Almira Correia, PhD Professor of Pharmacology, Pharmaceutical Chemistry Italo Biaggioni, MD and Biopharmaceutical Sciences, Department of Cellular Professor of Pharmacology, Vanderbilt University School & Molecular Pharmacology, University of California, of Medicine, Nashville San Francisco Daniel D. Bikle, MD, PhD Charles DeBattista, MD Professor of Medicine, Department of Medicine, and Professor of Psychiatry and Behavioral Sciences, Stanford Co-Director, Special Diagnostic and Treatment Unit, University School of Medicine, Stanford University of California, San Francisco, and Veterans Affairs Medical Center, San Francisco Cathi E. Dennehy, PharmD Professor, Department of Clinical Pharmacy, University Homer A. Boushey, MD of California, San Francisco School of Pharmacy, Chief, Asthma Clinical Research Center and Division San Francisco of Allergy & Immunology; Professor of Medicine, Department of Medicine, University of California, Betty J. Dong, PharmD, FASHP, FCCP, FAPHA San Francisco Professor of Clinical Pharmacy and Clinical Professor of Family and Community Medicine, Department of Adrienne D. Briggs, MD Clinical Pharmacy and Department of Family and Clinical Director, Bone Marrow Transplant Program, Community Medicine, Schools of Pharmacy and Banner Good Samaritan Hospital, Phoenix Medicine, University of California, San Francisco Hakan Cakmak, MD Kenneth Drasner, MD Department of Medicine, University of California, Professor of Anesthesia and Perioperative Care, San Francisco University of California, San Francisco Lundy Campbell, MD Helge Eilers, MD Professor, Department of Anesthesiology and Professor of Anesthesia and Perioperative Care, Perioperative Medicine, University of California University of California, San Francisco San Francisco, School of Medicine, San Francisco Daniel E. Furst, MD George P. Chrousos, MD Carl M. Pearson Professor of Rheumatology, Director, Professor & Chair, First Department of Pediatrics, Rheumatology Clinical Research Center, Department of Athens University Medical School, Athens, Greece Rheumatology, University of California, Los Angeles ix x AUTHORS Joshua M. Galanter, MD Michael J. Kosnett, MD, MPH Department of Medicine, University of California, Associate Clinical Professor of Medicine, Division of San Francisco Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Denver Kathleen M. Giacomini, PhD Professor of Bioengineering and Therapeutic Sciences, Marieke Kruidering-Hall, PhD Schools of Pharmacy and Medicine, University of Academy Chair in Pharmacology Education; Professor, California, San Francisco Department of Cellular and Molecular Pharmacology, University of California, San Francisco Augustus O. Grant, MD, PhD Professor of Medicine, Cardiovascular Division, Duke Douglas F. Lake, PhD University Medical Center, Durham Associate Professor, The Biodesign Institute, Arizona State University, Tempe John A. Gray, MD, PhD Associate Professor, Department of Neurology, Center for Harry W. Lampiris, MD Neuroscience, University of California, Davis Professor of Clinical Medicine, UCSF, Interim Chief, Robert D. Harvey, PhD ID Section, Medical Service, San Francisco VA Medical Professor of Pharmacology and Physiology, University of Center, San Francisco Nevada School of Medicine, Reno Paul W. Lofholm, PharmD Jennifer E. Hibma, PharmD Clinical Professor of Pharmacy, School of Pharmacy, Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco Schools of Pharmacy and Medicine, University of Roger K. Long, MD California, San Francisco Professor of Pediatrics, Department of Pediatrics, 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 Clinical Neurosciences, Auckland Medical Faculty, University Hospital of Geneva, Geneva, John R. Horn, PharmD, FCCP Switzerland Professor of Pharmacy, School of Pharmacy, University Daniel S. Maddix, PharmD of 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 John Hwa, MD, PhD Professor of Dermatology, Department of Dermatology, Professor of Medicine and Pharmacology, Yale University University of California, San Francisco School of Medicine, New Haven Mary J. Malloy, MD Harlan E. Ives, MD, PhD Clinical Professor of Pediatrics and Medicine, Professor Emeritus of Medicine, Department of Departments of Pediatrics and Medicine, Cardiovascular Medicine, University of California, San Francisco Research Institute, University of California, Samie R. Jaffrey, MD, PhD San Francisco Greenberg-Starr Professor of Pharmacology, Kathleen Martin, PhD Department of Pharmacology, Cornell University Weill Associate Professor, Yale Cardiovascular Center, Yale Medical College, New York City University, New Haven John P. Kane, MD, PhD Umesh Masharani, MBBS, MRCP (UK) Professor of Medicine, Department of Medicine; Professor of Medicine, Department of Medicine, Professor of Biochemistry and Biophysics; Associate University of California, San Francisco Director, Cardiovascular Research Institute, University of California, San Francisco Kenneth R. McQuaid, MD Professor of Clinical Medicine, University of California, Bertram G. Katzung, MD, PhD San Francisco; Chief of Gastroenterology, San Francisco Professor Emeritus, Department of Cellular & Molecular Veterans Affairs Medical Center, San Francisco Pharmacology, University of California, San Francisco Ramana K. Naidu, MD Gideon Koren, MD, FRCPC, FACMT Department of Anesthesia and Perioperative Care, Consultant, Kiryat Ono, Israel University of California, San Francisco  AUTHORS xi Ahmed A. Negm, MD Sharon Safrin, MD Department of Medicine, University of California, Associate Clinical Professor, Department of Medicine, Los Angeles University of California, San Francisco; President, Safrin Clinical Research, Hillsborough Martha S. Nolte Kennedy, MD Clinical Professor, Department of Medicine, University Ramin Sam, MD of California, San Francisco Associate Professor, Department of Medicine, University of California, San Francisco Kent R. Olson, MD Clinical Professor, Department of Medicine, Schools of Mark A. Schumacher, PhD, MD Medicine and Pharmacy, University of California, San Professor, Department of Anesthesia and Perioperative Francisco; Medical Director, San Francisco Division, Care, University of California, San Francisco California Poison Control System, San Francisco Daniel T. Teitelbaum, MD Achilles J. Pappano, PhD Adjunct Professor of Occupational and Environmental Professor Emeritus, Department of Cell Biology and Health, Colorado School of Public Health, Denver; Calhoun Cardiology Center, University of Connecticut and Adjunct Professor, Civil and Environmental Health Center, Farmington Engineering, Colorado School of Mines, Golden David Pearce, MD Anthony J. Trevor, PhD Professor of Medicine, University of California, Professor Emeritus, Department of Cellular & Molecular San Francisco Pharmacology, University of California, San Francisco Roger J. Porter, MD Candy Tsourounis, PharmD Adjunct Professor of Neurology, University of Professor of Clinical Pharmacy, Medication Outcomes Pennsylvania, Philadelphia; Adjunct Professor of Center, University of California, San Francisco School of Pharmacology, Uniformed Services University of the Pharmacy, San Francisco Health Sciences, Bethesda Mark von Zastrow, MD, PhD Ian A. Reid, PhD Professor, Departments of Psychiatry and Cellular & Professor Emeritus, Department of Physiology, Molecular Pharmacology, University of California, University of California, San Francisco San Francisco David Robertson, MD Lisa G. Winston, MD Elton Yates Professor of Medicine, Pharmacology and Clinical Professor, Department of Medicine, Division Neurology, Vanderbilt University; Director, Clinical & of Infectious Diseases, University of California, Translational Research Center, Vanderbilt Institute for San Francisco; Hospital Epidemiologist, San Francisco Clinical and Translational Research, Nashville General Hospital, San Francisco Dirk B. Robertson, MD Spencer Yost, MD Professor of Clinical Dermatology, Department of Professor, Department of Anesthesia and Perioperative Dermatology, Emory University School of Medicine, Care, University of California, San Francisco; Medical Atlanta Director, UCSF-Mt. Zion ICU, Chief of Anesthesia, UCSF-Mt. Zion Hospital, San Francisco Michael A. Rogawski, MD, PhD Professor of Neurology, Department of Neurology, James L. Zehnder, MD University of California, Davis Professor of Pathology and Medicine, Pathology Department, Stanford University School of Medicine, Philip J. Rosenthal, MD Stanford Professor of Medicine, San Francisco General Hospital, University of California, San Francisco  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 Depressants: Schedule II barbiturates in mixtures with noncontrolled drugs or in (All nonresearch use illegal under federal law.) suppository dosage form Flunitrazepam (Rohypnol) Barbiturates (butabarbital [Butisol], butalbital [Fiorinal]) Narcotics: Ketamine (Ketalar) Heroin and many nonmarketed synthetic narcotics Cannabinoids: Hallucinogens: Dronabinol (Marinol) LSD Anabolic Steroids: MDA, STP, DMT, DET, mescaline, peyote, bufotenine, ibogaine, Fluoxymesterone (Androxy), Methyltestosterone (Android, Testred), psilocybin, phencyclidine (PCP; veterinary drug only) Oxandrolone (Oxandrin), Oxymetholone (Androl-50), Marijuana Testosterone and its esters (Androgel) Methaqualone SCHEDULE II SCHEDULE IV (Prescription must be rewritten after 6 months or five refills; differs from (No telephone prescriptions, no refills.)2 Schedule III in penalties for illegal possession.) Opioids: Opioids: Opium: Opium alkaloids and derived phenanthrene alkaloids: Butorphanol (Stadol) codeine, morphine (Avinza, Kadian, MSContin, Roxanol), hydrocodone and hydrocodone combinations (Zohydro ER, Difenoxin 1 mg + atropine 25 mcg (Motofen) Hycodan, Vicodin, Lortab), hydromorphone (Dilaudid), Pentazocine (Talwin) oxymorphone (Exalgo), oxycodone (dihydroxycodeinone, a Stimulants: component of Oxycontin, Percodan, Percocet, Roxicodone, Tylox) Armodafinil (Nuvigil) Designated synthetic drugs: meperidine (Demerol), methadone, Diethylpropion (Tenuate) not in USA levorphanol (Levo-Dromoran), fentanyl (Duragesic, Actiq, Modafinil (Provigil) Fentora), alfentanil (Alfenta), sufentanil (Sufenta), remifentanil Phentermine (Adipex-P) (Ultiva), tapentadol (Nycynta) Depressants: Stimulants: Benzodiazepines: Alprazolam (Xanax), Chlordiazepoxide (Librium), Coca leaves and cocaine Clobazam (Onfi), Clonazepam (Klonopin), Clorazepate (Tranxene), Amphetamines: Amphetamine complex (Biphetamine), Diazepam (Valium), Estazolam, Flurazepam (Dalmane), Lorazepam Amphetamine salts (Adderall), Dextroamphetamine (Dexedrine, (Ativan), Midazolam (Versed), Oxazepam, Quazepam (Doral), Procentra), Lisdexamfetamine (Vyvanse), Methamphetamine Temazepam (Restoril), Triazolam (Halcion) (Desoxyn), Methylphenidate (Ritalin, Concerta, Methylin, Carisoprodol (Soma) Daytrana, Medadate), Above in mixtures with other controlled or Chloral hydrate uncontrolled drugs Eszopiclone (Lunesta) Cannabinoids: Nabilone (Cesamet) Lacosamide (Vimpat) Depressants: Meprobamate Amobarbital (Amytal) Methohexital (Brevital) Pentobarbital (Nembutal) Paraldehyde not in USA Secobarbital (Seconal) Phenobarbital Tramadol (Ultram) Zaleplon (Sonata) SCHEDULE III Zolpidem (Ambien) (Prescription must be rewritten after 6 months or five refills.) Opioids: Buprenorphine (Buprenex, Subutex) SCHEDULE V Mixture of above Buprenorphine and Naloxone (Suboxone) (As any other nonopioid prescription drug) The following opioids in combination with one or more active Codeine: 200 mg/100 mL nonopioid ingredients, provided the amount does not exceed that Difenoxin preparations: 0.5 mg + 25 mcg atropine shown: Dihydrocodeine preparations: 10 mg/100 mL Codeine and dihydrocodeine: not to exceed 1800 mg/dL or 90 mg/ Diphenoxylate (not more than 2.5 mg and not less than 0.025 mg of tablet or other dosage unit atropine per dosage unit, as in Lomotil) Opium: 500 mg/dL or 25 mg/5 mL or other dosage unit (paregoric) Opium preparations: 100 mg/100 mL Stimulants: Pregabalin (Lyrica) Benzphetamine (Regimex) Phendimetrazine 1 See https://www.deadiversion.usdoj.gov/schedules. 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. CMEA (Combat Methamphetamine Epidemic Act of 2005) establishes regulations for ephedrine, pseudoephedrine, and phenylpropanolamine over-the-counter sales and purchases.  SECTION I BASIC PRINCIPLES 1 C H A P T E R Introduction: The Nature of Drugs & Drug Development & Regulation Bertram G. Katzung, MD, PhD* C ASE STUDY A 78-year-old woman is brought to the hospital because of In the emergency department, samples of venous and arterial suspected aspirin overdose. She has taken aspirin for joint pain blood are obtained while the airway, breathing, and circulation for many years without incident, but during the past year, she are evaluated. An intravenous (IV) drip is started, and gastro- has exhibited many signs of cognitive decline. Her caregiver intestinal decontamination is begun. After blood gas results are finds her confused, hyperventilating, and vomiting. The care- reported, sodium bicarbonate is administered via the IV. What giver finds an empty bottle of aspirin tablets and calls 9-1-1. is the purpose of the sodium bicarbonate? Pharmacology can be defined as the study of substances that the patient. Such deliberate therapeutic applications may be con- interact with living systems through chemical processes. These sidered the proper role of medical pharmacology, which is often interactions usually occur by binding of the substance to regula- defined as the science of substances used to prevent, diagnose, and tory molecules and activating or inhibiting normal body processes. treat disease. Toxicology is the branch of pharmacology that deals These substances may be chemicals administered to achieve a with the undesirable effects of chemicals on living systems, from beneficial therapeutic effect on some process within the patient or individual cells to humans to complex ecosystems (Figure 1–1). for their toxic effects on regulatory processes in parasites infecting The nature of drugs—their physical properties and their inter- actions with biological systems—is discussed in part I of this ∗ The author thanks Barry Berkowitz, PhD, for contributions to the chapter. The development of new drugs and their regulation by second part of this chapter. government agencies are discussed in part II. 1 2 SECTION I Basic Principles drug preparation and the medical uses of drugs—began to develop Chemical as the precursor to pharmacology. However, any real understand- ing of the mechanisms of action of drugs was prevented by the absence of methods for purifying active agents from the crude Pharmacokinetics Patient Environment materials that were available and—even more—by the lack of methods for testing hypotheses about the nature of drug actions. In the late 18th and early 19th centuries, François Magendie and his student Claude Bernard began to develop the methods Intended Unintended Other of experimental physiology and pharmacology. Advances in target targets organisms chemistry and the further development of physiology in the tissues 18th, 19th, and early 20th centuries laid the foundation needed Pharmacodynamics for understanding how drugs work at the organ and tissue levels. Food Paradoxically, real advances in basic pharmacology during this chain time were accompanied by an outburst of unscientific claims by Therapeutic effects 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 Toxic More about 60 years ago—did it become possible to adequately evaluate effects organisms therapeutic claims. Around the 1940s and 1950s, a major expansion of research Medical pharmacology Environmental and toxicology toxicology efforts in all areas of biology began. As new concepts and new techniques were introduced, information accumulated about drug FIGURE 1–1 Major areas of study in pharmacology. The actions action and the biologic substrate of that action, the drug receptor. of chemicals can be divided into two large domains. The first (left During the last 60 years, many fundamentally new drug groups side) is that of medical pharmacology and toxicology, which is aimed and new members of old groups were introduced. The last four at understanding the actions of drugs as chemicals on individual decades have seen an even more rapid growth of information organisms, especially humans and domestic animals. Both beneficial and understanding of the molecular basis for drug action. The and toxic effects are included. Pharmacokinetics deals with the molecular mechanisms of action of many drugs have now been absorption, distribution, and elimination of drugs. Pharmacodynamics identified, and numerous receptors have been isolated, structurally concerns the actions of the chemical on the organism. The second characterized, and cloned. In fact, the use of receptor identifica- domain (right side) is that of environmental toxicology, which is tion methods (described in Chapter 2) has led to the discovery concerned with the effects of chemicals on all organisms and their of many orphan receptors—receptors for which no ligand has survival in groups and as species. been discovered and whose function can only be guessed. Stud- ies of the local molecular environment of receptors have shown THE HISTORY OF PHARMACOLOGY that receptors and effectors do not function in isolation; they are strongly influenced by other receptors and by companion regula- Prehistoric people undoubtedly recognized the beneficial or toxic tory proteins. effects of many plant and animal materials. Early written records Pharmacogenomics—the relation of the individual’s genetic list remedies of many types, including a few that are still recog- makeup to his or her response to specific drugs—is becoming an nized as useful drugs today. Most, however, were worthless or important part of therapeutics (see Chapter 5). Decoding of the actually harmful. In the last 1500 years, sporadic attempts were genomes of many species—from bacteria to humans—has led made to introduce rational methods into medicine, but none to the recognition of unsuspected relationships between recep- was successful owing to the dominance of systems of thought tor families and the ways that receptor proteins have evolved. (“schools”) that purported to explain all of biology and disease Discovery that small segments of RNA can interfere with protein without the need for experimentation and observation. These synthesis with extreme selectivity has led to investigation of small schools promulgated bizarre notions such as the idea that disease interfering RNAs (siRNAs) and micro-RNAs (miRNAs) as ther- was caused by excesses of bile or blood in the body, that wounds apeutic agents. Similarly, short nucleotide chains called antisense could be healed by applying a salve to the weapon that caused the oligonucleotides (ANOs), synthesized to be complementary to wound, and so on. natural RNA or DNA, can interfere with the readout of genes and Around the end of the 17th century, reliance on observation the transcription of RNA. These intracellular targets may provide and experimentation began to replace theorizing in physiology the next major wave of advances in therapeutics. and clinical medicine. As the value of these methods in the study Unfortunately, the medication-consuming public is still of disease became clear, physicians in Great Britain and on the exposed to vast amounts of inaccurate or unscientific information Continent began to apply them to the effects of traditional drugs regarding the pharmacologic effects of chemicals. This has resulted used in their own practices. Thus, materia medica—the science of in the irrational use of innumerable expensive, ineffective, and  CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation 3 sometimes harmful remedies and the growth of a huge “alternative location distant from its intended site of action, eg, a pill given health care” industry. Furthermore, manipulation of the legislative orally to relieve a headache. Therefore, a useful drug must have process in the United States has allowed many substances pro- the necessary properties to be transported from its site of admin- moted for health—but not promoted specifically as “drugs”—to istration to its site of action. Finally, a practical drug should be avoid meeting the Food and Drug Administration (FDA) stan- inactivated or excreted from the body at a reasonable rate so that dards described in the second part of this chapter. Conversely, its actions will be of appropriate duration. lack of understanding of basic scientific principles in biology and Drugs may be solid at room temperature (eg, aspirin, atro- statistics and the absence of critical thinking about public health pine), liquid (eg, nicotine, ethanol), or gaseous (eg, nitrous oxide). issues have led to rejection of medical science by a segment of the These factors often determine the best route of administration. public and to a common tendency to assume that all adverse drug The most common routes of administration are described in effects are the result of malpractice. Chapter 3, Table 3–3. The various classes of organic compounds— General principles that the student should remember are carbohydrates, proteins, lipids, and smaller molecules—are all rep- (1) that all substances can under certain circumstances be toxic; resented in pharmacology. As noted above, oligonucleotides, in the (2) that the chemicals in botanicals (herbs and plant extracts, form of small segments of RNA, have entered clinical trials and are “nutraceuticals”) are no different from chemicals in manufactured on the threshold of introduction into therapeutics. drugs except for the much greater proportion of impurities in A number of useful or dangerous drugs are inorganic elements, botanicals; and (3) that all dietary supplements and all therapies eg, lithium, iron, and heavy metals. Many organic drugs are weak promoted as health-enhancing should meet the same standards of acids or bases. This fact has important implications for the way efficacy and safety as conventional drugs and medical therapies. they are handled by the body, because pH differences in the vari- That is, there should be no artificial separation between scientific ous compartments of the body may alter the degree of ionization medicine and “alternative” or “complementary” medicine. Ideally, of weak acids and bases (see text that follows). all nutritional and botanical substances should be tested by the same types of randomized controlled trials (RCTs) as synthetic Drug Size compounds. The molecular size of drugs varies from very small (lithium ion, molecular weight [MW] 7) to very large (eg, alteplase [t-PA], a protein of MW 59,050). However, most drugs have molecular I GENERAL PRINCIPLES OF weights between 100 and 1000. The lower limit of this narrow PHARMACOLOGY range is probably set by the requirements for specificity of action. To have a good “fit” to only one type of receptor, a drug molecule THE NATURE OF DRUGS must be sufficiently unique in shape, charge, and other properties to prevent its binding to other receptors. To achieve such selective In the most general sense, a drug may be defined as any sub- binding, it appears that a molecule should in most cases be at least stance that brings about a change in biologic function through 100 MW units in size. The upper limit in molecular weight is its chemical actions. In most cases, the drug molecule interacts determined primarily by the requirement that drugs must be able as an agonist (activator) or antagonist (inhibitor) with a specific to move within the body (eg, from the site of administration to target molecule that plays a regulatory role in the biologic system. the site of action). Drugs much larger than MW 1000 do not dif- This target molecule is called a receptor. The nature of recep- fuse readily between compartments of the body (see Permeation, tors is discussed more fully in Chapter 2. In a very small number in following text). Therefore, very large drugs (usually proteins) of cases, drugs known as chemical antagonists may interact must often be administered directly into the compartment where directly with other drugs, whereas a few drugs (osmotic agents) they have their effect. In the case of alteplase, a clot-dissolving interact almost exclusively with water molecules. Drugs may be enzyme, the drug is administered directly into the vascular synthesized within the body (eg, hormones) or may be chemicals compartment by intravenous or intra-arterial infusion. not synthesized in the body (ie, xenobiotics). Poisons are drugs that have almost exclusively harmful effects. However, Paracelsus Drug Reactivity & Drug-Receptor Bonds (1493–1541) famously stated that “the dose makes the poison,” Drugs interact with receptors by means of chemical forces or meaning that any substance can be harmful if taken in the wrong bonds. These are of three major types: covalent, electrostatic, and dosage. Toxins are usually defined as poisons of biologic origin, ie, hydrophobic. Covalent bonds are very strong and in many cases synthesized by plants or animals, in contrast to inorganic poisons not reversible under biologic conditions. Thus, the covalent bond such as lead and arsenic. formed between the acetyl group of acetylsalicylic acid (aspirin) and cyclooxygenase, its enzyme target in platelets, is not readily The Physical Nature of Drugs broken. The platelet aggregation–blocking effect of aspirin lasts To interact chemically with its receptor, a drug molecule must long after free acetylsalicylic acid has disappeared from the blood- have the appropriate size, electrical charge, shape, and atomic stream (about 15 minutes) and is reversed only by the synthesis composition. Furthermore, a drug is often administered at a of new enzyme in new platelets, a process that takes several days. 4 SECTION I Basic Principles Other examples of highly reactive, covalent bond-forming drugs TABLE 1–1 Dissociation constants (Kd) of the include the DNA-alkylating agents used in cancer chemotherapy enantiomers and racemate of carvedilol. to disrupt cell division in the tumor. Electrostatic bonding is much more common than covalent ` Receptors a Receptors Form of Carvedilol (Kd, nmol/L1) (Kd, nmol/L) bonding in drug-receptor interactions. Electrostatic bonds vary from relatively strong linkages between permanently charged R(+) enantiomer 14 45 ionic molecules to weaker hydrogen bonds and very weak induced S(−) enantiomer 16 0.4 dipole interactions such as van der Waals forces and similar R,S(±) enantiomers 11 0.9 phenomena. Electrostatic bonds are weaker than covalent bonds. 1 The Kd is the concentration for 50% saturation of the receptors and is inversely Hydrophobic bonds are usually quite weak and are probably proportionate to the affinity of the drug for the receptors. important in the interactions of highly lipid-soluble drugs with Data from Ruffolo RR et al: The pharmacology of carvedilol. Eur J Clin Pharmacol the lipids of cell membranes and perhaps in the interaction of 1990;38:S82. drugs with the internal walls of receptor “pockets.” The specific nature of a particular drug-receptor bond is of less Finally, because enzymes are usually stereoselective, one drug practical importance than the fact that drugs that bind through enantiomer is often more susceptible than the other to drug- weak bonds to their receptors are generally more selective than metabolizing enzymes. As a result, the duration of action of one drugs that bind by means of very strong bonds. This is because enantiomer may be quite different from that of the other. Simi- weak bonds require a very precise fit of the drug to its receptor larly, drug transporters may be stereoselective. if an interaction is to occur. Only a few receptor types are likely Unfortunately, most studies of clinical efficacy and drug elimina- to provide such a precise fit for a particular drug structure. Thus, tion in humans have been carried out with racemic mixtures of drugs if we wished to design a highly selective short-acting drug for a rather than with the separate enantiomers. At present, only a small particular receptor, we would avoid highly reactive molecules that percentage of the chiral drugs used clinically are marketed as the form covalent bonds and instead choose a molecule that forms active isomer—the rest are available only as racemic mixtures. As a weaker bonds. result, most patients receive drug doses of which 50% is less active or A few substances that are almost completely inert in the inactive. Some drugs are currently available in both the racemic and chemical sense nevertheless have significant pharmacologic the pure, active isomer forms. However, proof that administration of effects. For example, xenon, an “inert” gas, has anesthetic effects the pure, active enantiomer decreases adverse effects relative to those at elevated pressures. produced by racemic formulations has not been established. Drug Shape Rational Drug Design The shape of a drug molecule must be such as to permit binding to Rational design of drugs implies the ability to predict the appro- its receptor site via the bonds just described. Optimally, the drug’s priate molecular structure of a drug on the basis of information shape is complementary to that of the receptor site in the same way about its biologic receptor. Until recently, no receptor was known that a key is complementary to a lock. Furthermore, the phenom- in sufficient detail to permit such drug design. Instead, drugs enon of chirality (stereoisomerism) is so common in biology that were developed through random testing of chemicals or modifica- more than half of all useful drugs are chiral molecules; that is, they tion of drugs already known to have some effect. However, the can exist as enantiomeric pairs. Drugs with two asymmetric centers characterization of many receptors during the past three decades have four diastereomers, eg, ephedrine, a sympathomimetic drug. has changed this picture. A few drugs now in use were developed through molecular design based on knowledge of the three- In most cases, one of these enantiomers is much more potent than dimensional structure of the receptor site. Computer programs its mirror image enantiomer, reflecting a better fit to the receptor are now available that can iteratively optimize drug structures molecule. If one imagines the receptor site to be like a glove into to fit known receptors. As more becomes known about receptor which the drug molecule must fit to bring about its effect, it is structure, rational drug design will become more common. clear why a “left-oriented” drug is more effective in binding to a left-hand receptor than its “right-oriented” enantiomer. The more active enantiomer at one type of receptor site may Receptor Nomenclature not be more active at another receptor type, eg, a type that may be The spectacular success of newer, more efficient ways to identify responsible for some other effect. For example, carvedilol, a drug and characterize receptors (see Chapter 2) has resulted in a variety that interacts with adrenoceptors, has a single chiral center and of differing, and sometimes confusing, systems for naming them. thus two enantiomers (Table 1–1). One of these enantiomers, the This in turn has led to a number of suggestions regarding more (S)(–) isomer, is a potent β-receptor blocker. The (R)(+) isomer rational methods of naming receptors. The interested reader is is 100-fold weaker at the β receptor. However, the isomers are referred for details to the efforts of the International Union of approximately equipotent as α-receptor blockers. Ketamine is an Pharmacology (IUPHAR) Committee on Receptor Nomenclature intravenous anesthetic. The (+) enantiomer is a more potent anes- and Drug Classification (reported in various issues of Pharma- thetic and is less toxic than the (–) enantiomer. Unfortunately, the cological Reviews and elsewhere) and to Alexander SP et al: The drug is still used as the racemic mixture. Concise Guide to PHARMACOLOGY 2015/16: Overview.  CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation 5 Br J Pharmacol 2015;172:5729. The chapters in this book mainly inactive state (or some state other than the acetylcholine-activated use these sources for naming receptors. state). These agents reduce the effects of acetylcholine and similar molecules in the body (Figure 1–2B), but their action can be over- come by increasing the dosage of agonist. Some antagonists bind DRUG-BODY INTERACTIONS very tightly to the receptor site in an irreversible or pseudoirre- versible fashion and cannot be displaced by increasing the agonist The interactions between a drug and the body are conveniently concentration. Drugs that bind to the same receptor molecule but divided into two classes. The actions of the drug on the body are do not prevent binding of the agonist are said to act allosterically termed pharmacodynamic processes (Figure 1–1); the principles and may enhance (Figure 1–2C) or inhibit (Figure 1–2D) the of pharmacodynamics are presented in greater detail in Chapter 2. action of the agonist molecule. Allosteric inhibition is not usually These properties determine the group in which the drug is classi- overcome by increasing the dose of agonist. fied, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease. The actions B. Agonists That Inhibit Their Binding Molecules of the body on the drug are called pharmacokinetic processes and Some drugs mimic agonist drugs by inhibiting the molecules are described in Chapters 3 and 4. Pharmacokinetic processes gov- responsible for terminating the action of an endogenous ago- ern the absorption, distribution, and elimination of drugs and are nist. For example, acetylcholinesterase inhibitors, by slowing the of great practical importance in the choice and administration of a destruction of endogenous acetylcholine, cause cholinomimetic particular drug for a particular patient, eg, a patient with impaired effects that closely resemble the actions of cholinoceptor agonist renal function. The following paragraphs provide a brief introduc- molecules even though cholinesterase inhibitors do not bind or tion to pharmacodynamics and pharmacokinetics. 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 of exogenous agonists. Most drugs must bind to a receptor to bring about an effect. However, at the cellular level, drug binding is only the first in a C. Agonists, Partial Agonists, and Inverse Agonists sequence of steps: Figure 1–3 describes a useful model of drug-receptor interaction. Drug (D) + receptor-effector (R) → drug-receptor-effector As indicated, the receptor is postulated to exist in the inactive, complex → effect nonfunctional form (Ri) and in the activated form (Ra). Ther- D + R → drug-receptor complex → effector molecule → effect modynamic considerations indicate that even in the absence of D + R → D-R complex → activation of coupling molecule → any agonist, some of the receptor pool must exist in the Ra form effector molecule → effect some of the time and may produce the same physiologic effect as agonist-induced activity. This effect, occurring in the absence Inhibition of metabolism of endogenous activator → increased of agonist, is termed constitutive activity. Agonists have a much activator action on an effector molecule → increased effect higher affinity for the Ra configuration and stabilize it, so that a Note that the final change in function is accomplished by an large percentage of the total pool resides in the Ra–D fraction and effector mechanism. The effector may be part of the receptor a large effect is produced. The recognition of constitutive activity molecule or may be a separate molecule. A very large number may depend on the receptor density, the concentration of cou- of receptors communicate with their effectors through coupling pling molecules (if a coupled system), and the number of effectors molecules, as described in Chapter 2. in the system. Many agonist drugs, when administered at concentrations A. Types of Drug-Receptor Interactions sufficient to saturate the receptor pool, can activate their receptor- Agonist drugs bind to and activate the receptor in some fashion, effector systems to the maximum extent of which the system is which directly or indirectly brings about the effect (Figure 1–2A). capable; that is, they cause a shift of almost all of the receptor pool Receptor activation involves a change in conformation in the to the Ra–D pool. Such drugs are termed full agonists. Other cases that have been studied at the molecular structure level. Some drugs, called partial agonists, bind to the same receptors and acti- receptors incorporate effector machinery in the same molecule, so vate them in the same way but do not evoke as great a response, no that drug binding brings about the effect directly, eg, opening of matter how high the concentration. In the model in Figure 1–3, an ion channel or activation of enzyme activity. Other receptors partial agonists do not stabilize the Ra configuration as fully as are linked through one or more intervening coupling molecules full agonists, so that a significant fraction of receptors exists in to a separate effector molecule. The major types of drug-receptor- the Ri–D pool. Such drugs are said to have low intrinsic efficacy. effector coupling systems are discussed in Chapter 2. Pharmaco- Because they occupy the receptor, partial agonists can also prevent logic antagonist drugs, by binding to a receptor, compete with access by full agonists. Thus, pindolol, a β-adrenoceptor partial and prevent binding by other molecules. For example, acetylcho- agonist, may act either as an agonist (if no full agonist is present) line receptor blockers such as atropine are antagonists because or as an antagonist (if a full agonist such as epinephrine is pres- they prevent access of acetylcholine and similar agonist drugs to ent). (See Chapter 2.) Intrinsic efficacy is independent of affinity the acetylcholine receptor site and they stabilize the receptor in its (as usually measured) for the receptor. 6 SECTION I Basic Principles 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 1–2 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 (competitive 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. In the same model, conventional antagonist action can be as benzodiazepines also facilitate the receptor-effector system and explained as fixing the fractions of drug-bound Ri and Ra in cause GABA-like inhibition with sedation as the therapeutic result. the same relative amounts as in the absence of any drug. In this This sedation can be reversed by conventional neutral antagonists situation, no change in activity will be observed, so the drug will such as flumazenil. Inverse agonists of this receptor system cause appear to be without effect. However, the presence of the antago- anxiety and agitation, the inverse of sedation (see Chapter 22). nist at the receptor site will block access of agonists to the receptor Similar inverse agonists have been found for β adrenoceptors, and prevent the usual agonist effect. Such blocking action can be histamine H1 and H2 receptors, and several other receptor systems. termed neutral antagonism. What will happen if a drug has a much stronger affinity for the D. Duration of Drug Action Ri than for the Ra state and stabilizes a large fraction in the Ri–D Termination of drug action can result from several processes. In pool? In this scenario the drug will reduce any constitutive activity, some cases, the effect lasts only as long as the drug occupies the thus resulting in effects that are the opposite of the effects produced receptor, and dissociation of drug from the receptor automatically by conventional agonists at that receptor. Such drugs are termed terminates the effect. In many cases, however, the action may inverse agonists (Figure 1–3). One of the best documented exam- persist after the drug has dissociated because, for example, some ples of such a system is the γ-aminobutyric acid (GABAA) receptor- coupling molecule is still present in activated form. In the case effector (a chloride channel) in the nervous system. This receptor is of drugs that bind covalently to the receptor site, the effect may activated by the endogenous transmitter GABA and causes inhibi- persist until the drug-receptor complex is destroyed and new recep- tion of postsynaptic cells. Conventional exogenous agonists such tors or enzymes are synthesized, as described previously for aspirin.  CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation 7 these endogenous molecules are regulatory molecules. Binding of a Effect drug to a nonregulatory molecule such as plasma albumin will result Ri Ra in no detectable change in the function of the biologic system, so this endogenous molecule can be called an inert binding site. Such D D binding is not completely without significance, however, because it affects the distribution of drug within the body and determines the amount of free drug in the circulation. Both of these factors are of Ri – D Ra – D pharmacokinetic importance (see also Chapter 3). Effect Pharmacokinetic Principles In practical therapeutics, a drug should be able to reach its intended Ra + Da site of action after administration by some convenient route. In many Full agonist cases, the active drug molecule is sufficiently lipid-soluble and stable to be given as such. In some cases, however, an inactive precursor chemical that is readily absorbed and distributed must be adminis- Response Ra + Dpa tered and then converted to the active drug by biologic processes— Partial agonist inside the body. Such a precursor chemical is called a prodrug. Ra + Ri In only a few situations is it possible to apply a drug directly to its Ra + Dant + Ri + Dant Antagonist target tissue, eg, by topical application of an anti-inflammatory agent Constitutive activity to inflamed skin or mucous membrane. Most often, a drug is admin- Ri + Di Inverse agonist istered into one body compartment, eg, the gut, and must move to Log Dose its site of action in another compartment, eg, the brain in the case of an antiseizure medication. This requires that the drug be absorbed into the blood from its site of administration and distributed to its FIGURE 1–3 A model of drug-receptor interaction. The hypothetical receptor is able to assume two conformations. In the site of action, permeating through the various barriers that separate Ri conformation, it is inactive and produces no effect, even when these compartments. For a drug given orally to produce an effect combined with a drug molecule. In the Ra conformation, the receptor in the central nervous system, these barriers include the tissues that can activate downstream mechanisms that produce a small observ- make up the wall of the intestine, the walls of the capillaries that per- able effect, even in the absence of drug (constitutive activity). In the fuse the gut, and the blood-brain barrier, the walls of the capillaries absence of drugs, the two isoforms are in equilibrium, and the Ri that perfuse the brain. Finally, after bringing about its effect, a drug form is favored. Conventional full agonist drugs have a much higher should be eliminated at a reasonable rate by metabolic inactivation, affinity for the Ra conformation, and mass action thus favors the by excretion from the body, or by a combination of these processes. formation of the Ra–D complex with a much larger observed effect. Partial agonists have an intermediate affinity for both Ri and Ra forms. A. Permeation Conventional antagonists, according to this hypothesis, have equal affinity for both receptor forms and maintain the same level of Drug permeation proceeds by several mechanisms. Passive dif- constitutive activity. Inverse agonists, on the other hand, have a fusion in an aqueous or lipid medium is common, but active much higher affinity for the Ri form, reduce constitutive activity, and processes play a role in the movement of many drugs, especially may produce a contrasting physiologic result. those whose molecules are too large to diffuse readily (Figure 1–4). Drug vehicles can be very important in facilitating transport and permeation, eg, by encapsulating the active agent in liposomes In addition, many receptor-effector systems incorporate desen- and in regulating release, as in slow release preparations. Newer sitization mechanisms for preventing excessive activation when methods of facilitating transport of drugs by coupling them to agonist molecules continue to be present for long periods. (See nanoparticles are under investigation. Chapter 2 for additional details.) 1. Aqueous diffusion—Aqueous diffusion occurs within the E. Receptors and Inert Binding Sites larger aqueous compartments of the body (interstitial space, cyto- To function as a receptor, an endogenous molecule must first be sol, etc) and across epithelial membrane tight junctions and the selective in choosing ligands (drug molecules) to bind; and second, endothelial lining of blood vessels through aqueous pores that—in it must change its function upon binding in such a way that the some tissues—permit the passage of molecules as large as MW function of the biologic system (cell, tissue, etc) is altered. The 20,000–30,000.∗ See Figure 1–4A. selectivity characteristic is required to avoid constant activation of ∗ the receptor by promiscuous binding of many different ligands. The capillaries of the brain, the testes, and some other tissues are The ability to change function is clearly necessary if the ligand is characterized by the absence of pores that permit aqueous diffusion. They may also contain high concentrations of drug export pumps to cause a pharmacologic effect. The body contains a vast array of (MDR pumps; see text). These tissues are therefore protected or molecules that are capable of binding drugs, however, and not all of “sanctuary” sites from many circulating drugs. 8 SECTION I Basic Principles Lumen Interstitium A B C D FIGURE 1–4 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 be released inside the cell or expelled via the membrane-limited vesicles out of the cell into the extracellular space (exocytosis, D). Aqueous diffusion of drug molecules is usually driven by the too insoluble in lipid to diffuse passively through membranes, eg, concentration gradient of the permeating drug, a downhill move- peptides, amino acids, and glucose. These carriers bring about ment described by Fick’s law (see below). Drug molecules that are movement by active transport or facilitated diffusion and, unlike bound to large plasma proteins (eg, albumin) do not permeate passive diffusion, are selective, saturable, and inhibitable. Because most vascular aqueous pores. If the drug is charged, its flux is also many drugs are or resemble such naturally occurring peptides, influenced by electrical fields (eg, the membrane potential and— amino acids, or sugars, they can use these carriers to cross mem- in parts of the nephron—the transtubular potential). branes. See Figure 1–4C. Many cells also contain less selective membrane carriers that 2. Lipid diffusion—Lipid diffusion is the most important are specialized for expelling foreign molecules. One large family limiting factor for drug permeation because of the large number of such transporters binds adenosine triphosphate (ATP) and of lipid barriers that separate the compartments of the body. is called the ABC (ATP-binding cassette) family. This family Because these lipid barriers separate aqueous compartments, the includes the P-glycoprotein or multidrug resistance type 1 lipid:aqueous partition coefficient of a drug determines how (MDR1) transporter found in the brain, testes, and other tis- readily the molecule moves between aqueous and lipid media. In sues, and in some drug-resistant neoplastic cells (Table 1–2). the case of weak acids and weak bases (which gain or lose electri- Similar transport molecules from the ABC family, the multidrug cal charge-bearing protons, depending on the pH), the ability to resistance-associated protein (MRP) transporters, play impor- move from aqueous to lipid or vice versa varies with the pH of the tant roles in the excretion of some drugs or their metabolites medium, because charged molecules attract water molecules. The into urine and bile and in the resistance of some tumors to ratio of lipid-soluble form to water-soluble form for a weak acid chemotherapeutic drugs. Several other transporter families have or weak base is expressed by the Henderson-Hasselbalch equation been identified that do not bind ATP but use ion gradients to (described in the following text). See Figure 1–4B. drive transport. Some of these (the solute carrier [SLC] family) are particularly important in the uptake of neurotransmitters 3. Special carriers—Special carrier molecules exist for many across nerve-ending membranes. The latter carriers are discussed substances that are important for cell function and too large or in more detail in Chapter 6. TABLE 1–2 Some transport molecules important in pharmacology. Transporter Physiologic Function Pharmacologic Significance NET Norepinephrine reuptake from synapse Target of cocaine and some tricyclic antidepressants SERT Serotonin reuptake from synapse Target of selective serotonin reuptake inhibitors and some tricyclic antidepressants VMAT Transport of dopamine and norepinephrine into Target of reserpine and tetrabenazine adrenergic vesicles in nerve endings MDR1 Transport of many xenobiotics out of cells Increased expression confers resistance to certain anticancer drugs; inhibition increases blood levels of digoxin MRP1 Leukotriene secretion Confers resistance to certain anticancer and antifungal drugs MDR1, multidrug resistance protein-1; MRP1, multidrug resistance-associated protein-1; NET, norepinephrine transporter; SERT, serotonin reuptake transporter; VMAT, vesicular monoamine transporter.  CHAPTER 1 Introduction: The Nature of Drugs & Drug Development & Regulation 9 4. Endocytosis and exocytosis—A few substances are so large For example, pyrimethamine, an antimalarial drug, undergoes the or impermeant that they can enter cells only by endocytosis, the following association-dissociation process: process by which the substance is bound at a cell-surface recep- tor, engulfed by the cell membrane, and carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released into the cytosol by breakdown of the vesicle membrane, Figure 1–4D. This process is responsible for the transport of vitamin B12, complexed with a binding protein Note that the protonated form of a weak acid is the neutral, (intrinsic factor) across the wall of the gut into the blood. Simi- more lipid-soluble form, whereas the unprotonated form of a weak larly, iron is transported into hemoglobin-synthesizing red blood base is the neutral form. The law of mass action requires that these cell precursors in association with the protein transferrin. Specific reactions move to the left in an acid environment (low pH, excess receptors for the binding proteins must be present for this process protons available) and to the right in an alkaline environment. The to work. Henderson-Hasselbalch equation relates the ratio of protonated to The reverse process (exocytosis) is responsible for the secretion unprotonated weak acid or weak base to the molecule’s pKa and of many substances from cells. For example, many neurotransmit- the pH of the medium as follows: ter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cyto- plasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contents into the extracellular space (see Chapter 6). This equation applies to both acidic and basic drugs. Inspec- tion confirms that the lower the pH relative to the pKa, the greater B. Fick’s Law of Diffusion will be the fraction of drug in the protonated form. Because the The passive flux of molecules down a concentration gradient is uncharged form is the more lipi