Or. Murtadha Alshareifi e-Library Bertram G. Katzung Anthony J. Trevor BASIC & CLINICAL PHARMACOLOGY Sil C3 13th EditionThank You For downloading this eBook For upcoming eBooks, Please join us on facebook at httpsy/wwwfacebook.com/ebooks.drmurtadhalphotos_albumsSCHEDULE OF CONTROLLED DRUGS! SCHEDULE I (Ail nonresearch use illegal under federal Lov.) Flunitrazepam (Rohypnol) Narcotics: Heroin and meny normarieted synthetic narcotics Hallucinogens: LsD MDA, STP, DMT, DET, mescaline, peyote, bfctenine, ibogrine, psilocybin phencyclidine (PCP; veterinary drug nly) Marijuana Methaqualone SCHEDULE IL (Wo telephone prescriptions, no refills)? Opioids: pita Opitm alkaloids and desived phenartireneallsloids: codeine, morphine (Avinea, Kadien, MSContin Roxana), Tnydrocodone and iydrocodone combinations (Zolytiro ER, Hycodan Vicodin Lotta), tydcomorphone ilevci), orymorphone (Exelgs), oxycodone (diydroxycodsinone, a component of Oxycontin, Percodan Percocet, Roxicodone, Tytas) Desigated synthetic drugs. meperidine (Demerol), methadone, levorphanal (Levo-Dromoci), fentcyt Dimegesic, Actiq Fectore), alfetanl (Alfents),” sufetarl (Sufens), remifestan (Ulva), tapertedal yest) Stimulants: Coca leaves and coesine Amphetamines: Amphetamine complex (Biphetamin®), Amphetamine sults (Adderal), Dextroemphetamine (Dexedkine,Procentra), Lisdexenfetamine (Vyvanse), Methamphetamine (Desorya), Methyhenidate Ritalin, Concerts, Metin Daytrana, Medadss), Above inmixtes with other conrolled of wontraled drwge Cannabinoids: Nebitone (Ceseme) Depressants: “Amobarbital (Antal) Pertobarbital Nembutal) Secoberbital Geconal) SCHEDULE IT (Prescription must be rewritten ater 6 months of five refills) Opioids: Buprenorphine (Buprenes, Subitex) Mixture of above Buprenorphine and Naloxone (Svbarone) Tia following opioids in combination with one ot more active non-opioid ingredients, provided the emoust does rot exceed that shown: Codsine and dtydrocodene: not to exceed 1800 mg/dL or 90 mg tablet or other dosage wit Oita 500 mal or 25 mg/S mL or other dosage unt (paregpric) Stimulants: Becmphetanine Didcex)Phendimetrazine Bonk) Depressants: Schedule I bebiturtes inmixtures with aoncontroled drugs arin suppository dosage form Beituctes(buaberbital[Butiso],bualtitel Fiorina!) Ketamine (etal) Cannabinoids: Dronsbiool (Marino!) Ambolic Steroiis: Fluorymesterone (Anirary), Metiyiteoserane (Android, Testred, Methtes), Nendalone decanoate (Deca-Duwabolis) Non US, Nendtolone pherpropionate (Duebolis) Non US, Oxandrolone (Oxanckis), Oxymetholone (Andeol-50), Stenazolol (WWinstral), Testolactone (Teslac), Testosterone and its esters SCHEDULE IV (Prescription must be rewriten afer 6 months or five refills; differs from Schedule III in penalties for illega possession) Opioids: Butorphanol (Stadol) Difenorin 1 mg+ atropine 25 meg (Motofex) Pentazocine (Talis) Stimulants: ‘Asmodefirl (Muvigi) Dietiyipropion Temate) notin US Modafinil Provig) Phentermine (Ionamin Adiper-P) Depressants: Bermodiezepines: Alprazolam (Xene), Chlordiezeporide (Litriun), Clonazepam (Klonopis), Clorezepate (CTramens), Diezepan (Valium), Estezolam (ProSom), Flurezepam (Dalmens), Halecepam (Penipan), Lorezepant (Ativet, Midazolam (Versed), Onazepam (eres), Precepam (Centrex), Quizepam (Doral), Temazepam (Restorl) Triezolem (Halcicr) Choral trate Somnote) Eszopicione (Lunests) Lacosanide (Vamped) Meprobamate Equal, Mltown, et) Methobasbital (Meberal) Methohexital Brevitel) Paraldetye Phenobarbital Zaleplon Sonat) Zolpidem (Ambies) SCHEDULE V (As any other nonopioid prescription drug) Codeine: 200 mg100 mL i emerson Dilyécocodeine preparations. 10 mgl00 mL ae ae emer eee ee Se eee eee eee) Etlyimorphine preparations. 100 mg/i00 mL Opium preparations, 109 mg/100 mi esestlt (et) lens (Ce nee eaters]See http: /hrww usdo}.gov/dea/pubs/ scheduling him! for additional details, 2Emergency prescriptions may be telephoned if followed within7 days by a valid written prescription annotated to indicate that it was previously placed by telephone‘a LANGE medical book Basic & Clinical Pharmacology ‘Thirteenth EditionCopyright © 2015 by McGraw-Hill Education All rights reserved Except as permitted under the United States Copyright Act of 1976, no part of this publication may be reproduced or distibuted in any form or by arly means, ot storedine database or retrieval system, without the prior wsitten permission ofthe publisher. 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McGraw-Hill Educetion hes no esponsibility for the content of any information accessed through the work. Under no circumstances shall MGs aw-Hill Education and/or its licensors be liable for any indirect, incidental, special, punitive, consequential or similar damages that result from the use of or inability to use the work, evenif any of them has been advised of the possibility of such damages ‘This Limitation of liability shall apply to any claim or cause whatsoever whether such claim or cause arises in contract, tort or otherwiseContents Preface Axthors section I BASIC PRINCIPLE 1. Intreduction: The Nature of Drugs & Drug Development & Regultion Bertram G. Ketamg MD, PhD Drug Receptors & Pharmacodynamics ‘Mask von Zastrow, MD, PHD 3, Pharmacokinetics & Pharmacodynamics: Rational Desing & the Time Cowse of Drug Action Nicholas H.G. Holford, MB, ChB, FRACP 4, Drug Biotransformation ‘Marie Almira Correia, PhD 5, Pharmacogenomics Jemifer E. Hibma, PharmD, & Kathleen M. Giacomini, PLD section IT AUTONOMIC DRUGS 6, Introduction te Autonomic Pharmacology Bertram G. Ketamg MD, PhD 7. Cholinoceptor- Activ ating & Cholinesterase-Inhibiting Drugs Achilles J. Pappano, PHD 8, Cholineceptor- Blocking Drugs Achilles J. Pappano, PHD 9. Adrenoceptor Agonists & Sympathomimetic Drugs Itelo Biaggjori, MD, & David Robertson MD 10. Adrenoceptor Antagonist Drugs David Robertson, MD, & Italo Biaggioni, MD section IT CARDIOVASCULAR-RENAL DRUGS LL. Antibypertensive Agents Neel L. Benowitz, MD 12. Vasedihtors & the Treatment of Angina Pectoris Bertram G. Ketamg MD, PhD 13. Drugs Used in Heart Failure Bertram G. Ketamg MD, PhD 14, Agents Used in Cardiac ArthythomiasJosephs. Hume, PHD, & Augustus O. Grant, MD, PED 15, Dimetic Agents ReminSem, MD, Devid Pearce, MD, & HerlenE. Ives, MD, PAD section TV DRUGS WITH IMPORTANT ACTIONS ON SMOOTH MUSCLE 16. Histamine, Serotonin, & the Ergot Allaoids Bertram G. Ketamg MD, PhD 17. Vasoactive Peptides IanA Reid PhD 18. The Eicosanoids: Prostaghndins, Thrombexanes, Leukotrienes, & Related Compounds Emer M. Smyth PHD, & Garret A FitsGerald, MD 19. Nitric Oxide ‘Semie R. Jaffrey, MD, PHD 20. Drugs Used in Asthma Josiaa M Gelenter, MD, & Homer A. Boushey, MD section V DRUGS THAT ACT IN THE CENTRAL NERVOUS SYSTEM 21. Intreduetion fo the Pharmacology of CNS Drugs Joba A. Gray, MD, PAD, & Roger A. Nicoll, MD Sedative-Hypnotic Drugs Axthony J. Trevor, PED 23. The Alcohols ‘Susan. Masters, PHD, & Anthony J. Trevor, PD 24. Antiseizure Drugs Roger J. Portes, MD, & Brians. Meldrum, MB, PED 25. General Anesthetics Helge Eilers, MD, & Spencer Yost, MD 26. Local Anesthetics Kenneth Drasner, MD 27. SkeletalMuscle Relaxants ‘Marieke Kruidering Hell, PAD, & Lundy Campbell, MD 28. Pharmacologic Management of Parkinsonism & Other Movement Disonters ‘Michnel J. Aminoff, MD, DSc, FRCP 29. Antipsychotic Agents & Lithium Charles DeBatlista, MD 30. Antidepressant Agents Charles DeBatiista, MD 31. Opioid Agonists & Antagonists ‘Mark A Schumacher, PHD, MD, AllanI. Basbeum, PHD, & Remana K, Naidy MD32. Drugs of Abuse Ctxistian Luischer, MD secon VI DRUGS USED TO TREAT DISEASES OF THE BLOOD, INFLAMMATION, & GOUT 33. Agents Used in Cytopenias; Hematepoietic Growth Factors Temes L. Zehnder, MD 34. Drugs Used in Disorders of Ce James L. Zehnder, MD agulation 35. Agents Used in Dystpidemia ‘Mary. Malloy, MD, & John P. Kene, MD, PhD 36. Nonsteroidal Anti Inflammatery Drugs, Disease-Modifying Antizhe umatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout Nabeel H. Borazen, MD, & Daniel E. Furst, MD secon VIE ENDOCRINE DRUGS 37. Hypothalamic & Pituitary Hormones Roger K. Lang MD, & Haken Calanek, MD 38. Thyreid & Antithyreid Drugs Betty J. Dong PhumD, FASHP, FCCP, & Francis S. Greenspan, MD, FACP 39. Adrenecorticestervids & Adrenocortical Antagonists Gearge P. Clxousos, MD 40. The GonadalHormones & Inhibiters Gearge P. Clxousos, MD 41. Pancreatic Hormones & Antidiabetic Drugs ‘Martha S. Nolte Kennedy, MD, & Umesh Mesharani, MBBS, MRCP (UK) 42. Agents That Affect Bone Mineral Homeostasis Daniel D. Bille, MD, PED secon VII CHEMOTHERAPEUTIC DRUGS 43, Beta-Lactam & Other Cell Wall. & Membrane-Active Antibiotics Daniel H. Deck, PharmD, & Lisa G. Winston MD 44, Tetracyclines, Macrolides, Clindamycin, Coramphenicel, Streptogramins, & Oxazolilinones Daniel H. Deck, PharmD, & Lisa G. Winston, MD 45, Aminoglycosides & Spectinemycin Daniel H. Deck, PharmD, & Lisa G. Winston MD 46. Sulforamides, Trimethoprim, & Quinolones Daniel H. Deck, PharmD, & Lisa G. Winston, MD 47. Antimycobacterial DrugsDaniel H. Deck, PharmD, & Lisa G. Winston MD 48. Antifungal Agents Don Sheppard, MD, & Harry W. Lampisis, MD 49. Antiviral Agents ‘Sharon Saftin, MD 50. Miscellaneous Antimicrobial Agents; Disinfectants, Antisep tics, & Sterilants Daniel H. Deck, PharmD, & Lisa G. Winston MD 51. Clinical Use of Antimicrobial Agents Horry W. Lampiris, MD, & Daniel S. Madelx, PharmD 52. Antipretozeal Drugs Philip J. Rosenthal, MD 53. Clinical Pharmacology of the Antiheluinthic Drugs Philip J. Rosenthal, MD 54, Cancer Chemotherapy Edward Cia, MD, & AlanC. Sartorelli, PLD 55, Immumepharmacolegy Douglas F. Lake, PHD, & Adciemne D. Briggs, MD section IX TOXICOLOGY 56. Intreduction to Texicology: Occupational & Environmental Daniel T. Teitelbaum, MD 57. Heavy Metal Intoxication & Cheaters ‘Michael J. Kosnett, MD, MPH 58. Management of the Poisoned Patient Kent. Olson MD section X SPECIAL TOPICS 59. Special Aspects of Perinatal & Pediatric Pharmacology Gideon Koren, MD 60. ‘Special Aspects of Geriatric Pharmacology Bertram G. Ketamg MD, PhD 61. Dermatologic Pharmacology Dirk B. Robertson, MD & Howard1. Maibach, MD 62. Drugs Used in the Treatment of Gastrointestinal Diseases KemethR. McQuaid, MD 63. Therapeutic & Toxic Potential of Over-the-Counter Agents RobinL. Corelli, PharmD 64. Dietary Supplements & Herbal Medications Cotta E, Dennehy, PharmD, & Candy Tsowounis, PharmD65. 66. Rational Prescribing & Prescription Writing Paul W.Lofholm, PharmD, & Bertram G. Katzmng MD, PHD Important Drug Interactions & Their Mechanisms JobnR. Horn, PharmD, FCCP Appendix: Vaccines, Immune Globulins, & Other Complex Biologic Products Harry W. Lampiris, MD, & Daniel S. Madelx, PharmD IndexPreface ‘The thicteenth edition ofBasic & Clinical Pharmacology contimues the important changes inaugwreted in the eleventh edition with extensive use of full-color illustrations end expanded coverage of transporters, pharmacogenomics, and new ceugs. Case studies accompany most chapters and answers to questions posed inthe case studies appear at the end of each chapter. As in prior editions, the book is designed to provide a comprehensive, atthoritetive, and readable phermacalogy textbook for students in the health sciences. Frequent revision is necessary to keep pace with the rapid changes in pharmacology and therapeutics, the 2-3 year revision cycle of the printed text is among the shortest in the field end the availability of an online version provides even greater cxrency. The book also offers special featwes that make it e wsefid reference for house officers and practicing clinicians. Information is orginized according to the sequence used in many pharmacology cowses and in integrated curicla: basic principles, autonomic drugs, cardiovascular-renal drugs, drugs with important actions on smooth muscle; central nervous system deugs, drugs used to treat inflammation gout, and diseases of the blood, envlocrine drugs, chemotherapeutic ugg, toricology, and special topics. This sequence builds new information on a foundation of information already assimilated For example, easly presentation of autonomic nervous system pharmacology allows students to integrate the physiology and newoscience they have leerned elsewhere with the pharmacology they are learning and prepares them to ‘understand the autonomic effects of other drugs. This is especially important for the cardiovascular and cexisal nervous system drug goups. However, chapters can be used equally well in courses and curricula that present these topics in a ckfferent sequence. ‘Within each chapter, emphasis is placed on discussion of drug groups and prototypes rather then offering repetitive detail about individual deugs. Selection of the subject matter and the order of its presentation are based on the accumulated experience of teaching this materiel to thousands of medical, pharmacy, dental, podiatry, auxsing and other health science students Major features that make this book particularly usefil in integrated cursicula include sections that specifically addvess the clinical choice and use of drugs in patients and the monitoring of their effects—in other words, clinical pharmacology is an integral part of this text. Lists of the trade and generic names of commercial preparations available are provided at the end of each chapter for easy reference by the house officer or practitioner wsiting a chart arder or prescsiption Significant revisions in this edition indude: + Addition of a chepter on pharmacogenomics, en area of increasingimportance in all aspects of pharmacalogy. The drug development and regdation meterial previously covered in Chapter 5 has been incorporated info Chapter 1 + Acgeneric name-trade name table appears at the conclusion of most chepters, providing a rapid reference for these + Many revised illustrations in full colar provide significartly more information about drug mechanisms and effects end help to clarify impostent concepts + Major revisions of the chapters on sympathomimetic, diuretic, antipsychotic, antidepressant, antidiabetic, anti- inflammatory, end antiviral deugs, prostaglandins, nitic oxide, hypothalamic end pituitary hormones, ceniral nervout system newotransmitters, immunopharmacology, and toxicology. + Continued expansion of the coverage of general concepts relating to newly discovered receptors, receptor mechanisms, and drug tensporters, + Descriptions of important new drugs released through August 2014. An important related educational resowee is Katamg & Trevor's Pharmacology. Exeminstion & Board Review tenth edition (Trevor AJ, Ketamg BG, & Masters SB: McGraw-Hill, 2013). This book provides a succinct review pharmacalogy with appracimetely one thousand sample exeminetion questions and answers. It is especially helpful to students preparing for board-type exeminations. A more highly condensed sauce of information suxteble for review purposes is USMLE Road Map: Pharmacology, second edition (KatamgBG, Trevor AJ: McGraw-Hill, 2006) ‘This edition merks the 32th year of publication of Basic & Clinical Pharmacology. The widespread adoption ofthe first twelve editions indicates that this book fills en important need We believe thatthe thisteerth edition will satisfy this need even more successfully Spanish Portuguese, Itelien, French Indonesian, Japanese, Korean Twhish and Ulzeinia: ‘wenslations ere availeble Translations into other languages are under way, the publisher may be contacted for furtherinformation I wish to acknowledge the prior end confiming efforts of my contributing authors an the major contributions ofthe staff at Lange Medical Publications, Appleton & Lange, and McGraw-Hill, and of ow editors for this edition, Donna Frassetb and Rachel D’Anmucei Hemiquez I also wish to thank Alice Camp and Katharine Ketamg for their expert proofreadin contributions Suggestions and comments sbout Basic & Clinical Pharmacologyare always welcome. They may be sent to me in cere of the publisher. Bowen 6 Keuang,MD, PAD san Banco Decenber 2011Michael J. Aminoff, MD, DSc, FRCP Professor, Department of Newology, University of California, San Francisco AllanI. Basbaum, PHD Professor and Chair, Department of Anatomy and WM. Keck Foundation Center for integrative Newoscience University of Californie, Sen Francisco Neal. Benowitz, MD Professor of Medicine and Bioengineering & Therapeutic Science, University of California, San Francisco, Sa Francisco Italo Biaggioni, MD Professor of Pharmacology, vanderbilt University School of Medicine, Nasnille Daniel D. Bikde, MD, PhD Professor of Medicine, Department of Medicine, and Co-Director, Special Diagnostic and Treatment Unit, Universit of California, SenFrancisco, and veterans Affeirs Medical Center, SanFrancisco NabeelH. Borazan, MD Department of Medicine, University of California, Los Angeles Homer A. Boushey, MD Chief, Astime Clinical Research Center and Division of Allergy & Immunology, Professor of Medicine, Departmer of Medicine, University of California, SenFrancisco Adrienne D. Briggs, MD Clinical Director, Bone Merrow Transplant Progrem, Banner Good Samaritan Hospital, Phoenix Hakan Calomak, MD Department of Medicine, University of California, San Francisco Lundy Campbell, MD Professos, Department of Anesthesiology and Perioperative Medicine, University of C lifornia San Francisco, Schoo of Medicine, San Francisco George P. Chrouses, MD Professor & Chair, First Department of Pediatrics, Athens University Medical School, Athens Eéward Chu, MD Professor of Medicine end Pharmacology & Chemical Biology, Chief, Division of Hematology-oncology, Deptt, Director, University of Pittsburgh Cancer institute, University of Pittsburgh School of Medicine, Pittsburgh Robin L. Corelli, PharmD Clinical Professor, Department of Clinical Pharmacy, School of Pharmacy, University of Californie, Sen Francisco Maria Almira Correia, PAD Professor of Phamacology, Pharmaceutical Chemistry and Biopharmaceutical Sciences, Department of Celluler & Molecular Pharmacology, University of California, San Francisco (Charles DeBattista, MDProfessor of Psychiatry and Behavioral Sciences, Stenford University School of Medicine, Stanford Daniel H. Deck, PharmD Associate Clinical Professor, School of Phumacy, University of California, Sen Francisco, infectious Disease Clinical Pharmacist, Sen Francisco General Hospital CathiE. Dennehy, PharmD Professor, Department of Clinical Pharmacy, University of Californie, Sen Francisco School of Pharmacy Betty J. Dong, PharmD, FASHP, FCCP Professor of Clinical Phimacy and Clinical Professor of Family and Community Medicine, Department of Clinice Pharmacy and Department of Family and Community Medicine, Schools of Pharmacy and Medicine, University o California, San Francisco Kenneth Drasner, MD Profesor of Anesthesie and Perioperative Care, University of California, SanFrancisco Helge Eilers, MD Professor of Anesthesia end Perioperative Case, University of California, SanFrencisco Ganet A. FitzGerald, MD Chis, Department of Pharmacology, Director, institute for Translational Medicine and Therapeutics, Perelman choc. of Meckcine at the University of Permsyivenia, Philadelphie Daniel E. Furst, MD Carl M. Pearson Professor of Rheumatology, Director, Rheunetology Clinical Research Center, Department 0 Rheunatology, University of California, Los Angeles Joshua M. Galanter, MD Department of Medicine, University of California, San Francisco Augustus ©. Grant, MD, PAD Professor of Medicine, Cardiovascular Division, Duke University Medical Center, Durham Jon A. Gray, MD, PhD Assistant Professor, Department of Neurology, Center for Newoscience, University of California, Davis Francis S, Greenspan, MD, FACP. Clinical Professor Emeritus of Medicine and Radiology and Chief, Thyroid Clinic, Division of Endocrinole Department of Medicine, University of California, San Francisco Nichols H. G. Holford, MB, ChB, FRACP Professos, Department of Pharmacology and Clinical Pharmacology University of Aucldand Medical School ‘Avekland John R. Horn, PharmD, FCCP Professor of Phamacy, School of Pharmacy, University of Washingon; Associate Director of Pharmacy Services Department of Medicine, University of Washington Medicine, Seattle Joseph. Hume, PhD Emeritus Chairmen of Pharmacology and Professor of Pharmacology & Physiology, University of Nevade School « Medicine, Reno, NV 89557 HarhnE. es, MD, PhD Professor Emeritus of Medicine, Department of Medicine, University of California, SanFrensisco Samie R. Jaffrey, MD, PHD Associate Professor of Pharmacology, Department of Pharmacology, Cornell University Weill Medical College, New‘York City Joln P. Kane, MD, PhD Professor of Medicine, Department of Medicine, Professor of Biochemistry and Biophysics, Associste Director Cardiovascular Research Institute, University of California, San Francisco Bertram G. Katzung, MD, PAD Professor Emeritus, Department of Cellular & Molecuiar Pharmacology, University of California, San Francisco Gideon Koren MD, FRCPC, FACMT Director, The Motherisk Program Professor of Pediatrics, Pharmacology, Pharmacy end Medical Genetics Th University of Toronto; Professor of Medicine, Pediatrics end PlysiclogyPhamacology and the ivey Chair ix Molecular Toxicology The University of Western ortario Michael J. Kosnett, MD, MPH Associste Clinical Professor of Medicine, Division of Clinical Pharmacology and Toxicology, University Colorado Health Sciences Center, Denver Marieke Kruidering-Hall, PhD Academy Chair in Pharmacology Education, Associate Professor, Department of Cellular end Molecule Pharmacology, University of Californie, San Francisco Doughs F. Lake, PhD Associate Professor, The Biodesigninstitute, Arizona Stete University, Tempe Hany W. Lampiris, MD Professor of Clinical Medicine, UCSF, Interim Chief, ID Section Medical Service, San Francisco VA Medict Center Paul W. Lofholm, PharmD Clinical Professor of Pharmacy, School of Pharmacy, University of Californie, Sen Francisco (Clistian Liischer, MD Departments of Basic and Clincial Newosciences, Medical Faculty, University Hospitel of geneva, Geneva Switzerland Daniel S. Maddix, PharmD ‘Associate Clinical Professor of Pharmacy, University of California, Sen Francisco Howard I, Maibach, MD. Professor of Dermatology, Depertnent of Dermatology, University of Californie, San Francisco Mary J. Malley, MD Clinical Professor of Pediatrics and Medicine, Departments of Pediatics end Medicine, Cardiovascuier researc! institute, University of California, San Francisco ‘Susan B. Masters, PhD Associate Dean School of Medicine; Professor of Pharmacology Department of Cellier & Molecular Pharmacology, University of California, SanFrancisco KennethR. MeQuaid, MD Professor of Clinical Medicine, University of California, San Francisco; Chief of Gastroenterology, San Francise veterans Affairs Medical Center Brian S. Meldrum, MB, PhD Professor Emeritus, GKT School of Medicine, Guy's Campus, LondonRamana K. Naidu, MD Department of Anesthesia and Perioperative Care, University of California, SenFransisco Roger A. Nicoll, MD Professor of Pharmacology andl Physiology, Departments of Cellular & Molecular Pharmacology and Physiology University of Californie, Sen Francisco ‘Martha S. Nolte Kennedy, MD Clinical Professor, Department of Medicine, University of California, San Francisco Kent R. Olson, MD Clinical Professor, Departments of Medicine and Pharmacy, University of California, San Francisco, Medica Director, SanFrancisco Division, Californie Poison Contral System Achilles J. Pappane, PhD Professor Emeritus, Department of Cell Biology and Calhom Cardiology Center, University of Connecticut Healt Center, Farmington Roger J. Porter, MD Adjunct Professor of Newology, University of Pemsyivania, Philedelpbie, Adjunct Professor of Pharmacology Uniformed Services University of the Health Sciences, Bethesda Ian A. Reid, PAD Professor Emeritus, Department of Physiology, University of California, San Francisco David Robertson, MD Elton Yates Professor of Medicine, Pharmacology end Newology vanderbilt University, Director, Clinical & ‘Translational Research enter, vanderbilt institute for Clinical end Translational Research, Nashwille Dirk B. Robertson, MD Professor of Clinicel Dermatology, Department of Dermatology, Emory University School of Medicine, Atlanta Philp J. Rosenthal, MD Professor of Medicine, University of Celiforie, Sen Francisco, San Francisco Genesal Hospitel ‘Stephen M. Resenthal, MD Professor of Pediatrics, Associate Program Director, Pediatric Endocrinology, Director, Pediattic Entlocrimy ouipatient Services, University of Califor, San Francisco Sharon Safrin, MD Associste Clinical Professor, Department of Medicine, University of California, Sen Francisco, President, Safti Clinical Research, Abn C. Sartorelli, PHD Alfred Gilman Professor of Pharmacology, Depasiment of Pharmacology, Yale University School of Medicine, New Haven, Mark A. Schumacher, PhD, MD Professor, Department of Anesthesia and Perioperative Care, University of California, San Francisco Don Sheppart, MD Associste Professor, Departments of Microbiology and immunology and Medicine, McGill University, Progen Director, McGill Royal College Training Program in Medical Microbiology and infectious Diseases, Montreal EmerM. Smyth, PhD Associate Professor, Department of Pharmacology, University of Pemsyivania School of Medicine, Philedelphia Daniel T. Teitebaum, MDAdjunct Professor of occupetional and Environmental Health, Colorado School of Public Health, Denver, Coloradc end Adjunct Professor, Civil and Environmental Engineering Colorado School of Mines, Golden, Colorado Anthony J. Trevor, PhD Professor Emeritus, Department of Cellular & Molecuiar Pharmacology, University of California, San Francisco Candy Tsoureunis, PharmD Professor of Clinical Pharmacy, Medication outcomes Center, University of California, Sen Francisco School 0 Phamacy Markvon Zastrow, MD, PhD Professos, Departments of Peychiaty and Cellular & Molecular Pharmacology University of Celifornia, Se: Francisco Lisa G. Winston, MD Associate Professor, Department of Medicine, Division of infectious Diseases, University of California, Se: Francisco; Hospital Epidemiologst, Sen Francisco General Hospital Spencer Yest, MD. Professos, Department of Anesthesia and Perioperstive Care, University of Californie, Sen Francisco, Medica Director, UCSF-Mt. Zion ICU, Chief of Anesthesia, UCSF-Mt Zion Hospital James L. Zehnder, MD Professor of Pathology and Medicine, Pathology Departmest, Stenford University School of Medicine, Stanford368 SAS AYCHAPTER 1 Introduction: the Nature of Drugs & Drug Development & Regulation Bertram G. Katzung, MD, PhD” A 26-year-old man is brought by fitends to the emergency department of the city hospital because he has been. tbebaving strangely for several days. A lmown user of methamphetamine, he has not eaten or slept in 48 hows, He tireatened to shoot one of lis friends because he believes ths fiend is ploting agnnst him. On admission the man is extemely agitated, appears to be underweight, and is unable to give a coherent history. He has to be restrained to prevent him fom walling out ofthe emergency depastinent and info affic on the sect. His blood pressure is 160/100 sum Hg hast rate 100, temperature 39°C, end respirations 30/nin His arms show evidence of mamuerous intravenous injections The reminder of his plysical examination is wxemarkable, After evaluation the manis gven a sedative, fluids, a diretic, and anmorivm chloride parenterally. What isthe purpose of the ammonium chloride? Pharmacology cen be defined as the study of substances thet interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. These substances may be chemicals administered to achieve a beneficial therapeutic effect on some process within the patient or for their toxic effects on regulstory processes in parasites infecting the patient. Such deliberate therapeutic applications may be considered the proper role of medical pharmacology, whichis often defined as the science of substances wsed to prevent, chagnose, and teat disease. Toxicology is the branch of pharmacology thet deals with the undesirable effects of chemicals on living systems, from individual cells to humans to complex ecosystems (Figwe 1-1). The nature of drugs—their physical properties and ther interactions with biological systems—is discussed in part I of this chapter. The development of new ceugs and their regulation by government agencies are discussed in pert ILChemical 3 Paton E 2 intended Unintended Other © target targets: organisms tissues g & $ Food chain & Therapeutc E ofiocts z More ‘organisms Medical pharmacology Environmental and toxicology toxicology FIGURE 1-1 Major areas of study in pharmacology. The actions of chemicals canbe divided into two lerge domains. The first eft side) is that of medicel pharmacology and toxicology, whichis simed at understanding the actions of drugs as chemicals onindkvidual organisms, especially humans and domestic animals. Both beneficial and toxic effects are included. Pharmacokinetics deals with the absorption, distribution end elimination of drugs. Pharmacodynamics concerns the actions of the chemicel on the organism. The second domein (sight side) is that of environmental taxicology, whichis concemned with the effects of chemicals on all organisms and their survival in groups and as species. THE HISTORY OF PHARMACOLOGY Prehistoric people undoubtedly recoguized the beneficial or toxic effects of meny plant and animel materials. Eesly written records list remedies of many types, including a few that are sll recognized as useful drugs today. Most, however, were worthless or actuelly harmfid. In the lest 1500 yeers, sporadic attempts were made to introduce rational methods into medicine, but none was successful owingto the dominance of systems of thought thet purported to explein all of biclogy and disease without the need for experimentation and observation These schools promulgated bizerre notions such es the idea that disease was caused by excesses of bile or blood in the body, that wounds could be heeled by applying salve to the ‘weepon that caused the wound, and so on ‘Around the end of the 17th century, and following the exemple of the physical sciences, reliance on observation and experimentation began to seplace theorizing in medicine. As the velue of these methods in the study of disease became cleer, physicians in Great Britein end on the Continent began to apply them to the effects of traditional deugs used in their own practices, Ths materia medica—the science of drug preperation and the medical uses of deugs—began to develop as the precursor to pharmacology However, any real understanding of the mechanisms of action of drugs was prevented by the absence of methods for purifying active agents from the crude materials that were available and—even more—by the lack of methods for testinghypotheses about the nature of drug actions. In the Iote 18th and early 19th centuries, Frangois Magendie, and his student Claude Berard began to develop the methods of experimental physiology and pharmacology. Advances in chemistry end the further development of physiology in the 18th 19th, and early 20th centuries Inid the foundation needed for understanding how drugs work at the organ and tissue levels. Paradoxically, real advances in basic pharmacology dtxing this time were accompanied by an outburst of ‘unscientific cleims by memfactwers and marketers of worthless “petent medicines.” Not until the concepts of reticnal therepeutics, especielly that of the controled clinical trial, were reintroduced into medicine—only about 60 years agp— dit become possible to accurately eveluate therapeutic claims. Asound the same time, « major expansion of research efforts in all areas of biology began As new concepts end new techniques were introduced, information accumulated about drug action and the biologic substrate of that action, the drugreceptor. During the last half-century, many findamentelly new drug goups and new members of old goups were introduced, The last tree decades have seen an even more rapid growth of information and understanding of the molectier ‘basis for drug ection The molecular mechanisms of ection of many drugs have now been idenfified end mmerous seceptors have been isolated, structurally characterized, and cloned. In fact, the use of seceptor identificetion methods (Gescribed inChepter 2) has led to the discovery of many orphan receptors—receptors for which no ligand has been Giscovered and whose function can only be surmised Studies ofthe local molectler environment of receptors have shown that receptors and effectors do not function in isolation, they are strongly influenced by other receptors end by compenion seguletory proteins Pharmacogenomics—the relation ofthe individual's genatic mekeup to his or her response to specific drugs—is close to becoming en importart part of therapeutics (see Chapter 5). Decoding of the genomes of many species—from bacteria to Inmens—has led to the recognition of unsuspected relationships between receptor families and the ways that receptor proteins have evolved. Discovery that small segments of RNA cen interfere with protein synthesis with extreme selectivity ings led to investigation of small intenfering RNAs (siRNAs) and micro-RNAs (miRNAs) es therepevtic agents Similesly, short mucleotide chains celled antisense oligonucleotides (ANOs), syrtinesized to be complementary to natural RNA or DNA, ceninterfere with the readout of genes and the transcription of RNA. These iniracellar targets may provide the nex major wave of advances in therapeutics ‘Te extension of scientific principles into everyday therapeutics is still going on, although the medicetion-consuning public is sill exposed to vast amounts of inaccurate, incomplete, or unscientific information regarding the pharmecologe effects of chemicals, This has semited in the irrational use of innumerable expensive, ineffective, end sometimes harmfid remedies and the growth of e inge “alternative health cere” industry. Unfortunately, manipulation of the legislative process inthe United States has allowed meny substances promoted for health—but not promoted specificelly as “drugs’—to avoid meeting the Food and Drug Administration (FDA) standards described in the secon part ofthis chapter. Conversely, lack of understanding of basic sciestific principles in biology end statistics and the absence of critical thinking ebout public health issues have led to rejection of medicel science by a seguent of the public end to e common tendency to assume that all adverse drug effects are the result of malpractice ‘Two general principles that the student should remember ere (1) that all substances con under certain circumstances be toxic, and the chemicals in botanicals (herbs and plent extracts, “miracetticals”) are no different from chemicals in smanifactured drugs except for the much greeter proportion of impurities in botenicals, and (2) that ell dietary supplements and all therapies promoted as heelth-enhncing should meet the same standards of efficacy and safety as conventional drugs and medical therapies. That is, there should be no artificial separation between scientific medicine and “alternative” oF “complementary” medicine. Ideclly, ell mititional and botenicel substances should be tested by the same rendomized controlled tials (RCTS) as synthetic compounds mi GENERAL PRINCIPLES OF PHARMACOLOGY THE NATURE OF DRUGS Inthe most general sense, a deugmay be defined as any substance thet brings about a change in biologic fimstion through its chemical actions. In most cases, the drug molecule interacts as enagonist (activator) or antagonist (jniubito:) with a specific molecule in the biologic system that plays a cegdatory role, This target molecule is celled axeceptor. The natwe of receptors is discussed more filly in Chapter 2. Ina very smell mauber of cases, drugs Inown as chemical antagonists may interact directly with other drugs, whereas a few drugs (osmotic agents) interact almost exclusively with water molecules. Drug may be synthesized within the body (eg, hoxmones) or may be chemicals not synthesized in the body (ie, xenobiotics, from the Greelexenos, meaning “stranger"). Poisons are drugs that have almost exclusively harmful effects However, Paracelsus (1493-1541) famously stated that “the dose makes the poison” meaning that any substance cen be ‘haumfid if teken in the wrong dosage. Texins are usuelly defined as poisons of biologie origin ie, synthesized by plants or animals, in contrast to inorganic poisons such as lead and arsenic To interact chemically with its receptor, a drug molecule must have the appropriate size, electrical charge, shape, end atomic composition Furthermore, a drugis often administered at « locetion distert from its intended site of action, eg a pill given orally to relieve @ headache. Therefore, a usefti drug must have the necessary properties to be transported fom its site of administration to its site of action Finally, a practical drug should be inactivated or excreted from the body at @ reasonable rate go that its actions will be of appropriate duxation The Physical Nature of Drugs Druge may be solid at room temperate (eg espirin atropine), liquid (eg nicotine, ethano), or gaseous (eg nitrous acide). These factors often determine the best route of adninisration The most common routes of adsunitrtion are described in Tebie 3-3. The various classes of orgarac compounds—cesbotyictes, proteins, lipids, and their constituents—are all represented in pharmacology. As noted above, oligomucleotides, in the form of small seguents of RNA, have entered clinical trials and are onthe threshold of inlroduction into therapeutics, ‘Armmber of useful or dangerous drugs are inorganic elements, eg lithium, iron, and heavy metals. Many organic deuge are weak acids or bases. This fact has important implicetions for the way they are handled by the body, because pH chfferences in the various compartments of the body may alter the degree of iorization of such drugs (see text that follows), Drug Size ‘The molecular size of deuge vasies from very smell (lithium ion MW'7) to very large (eg, alteplese [PA], @ protein of ‘MWY59,050). However, most drugs have molecular weights between 100 and 1000, The lower limit of this narrow range is probably set by the requirements for specificity of action To have « good “fit” to only one type of receptor, a drug molecule must be sufficiently wique in shape, charge, and other properties, to prevent its binding to other receptors. To achieve such selective binding it appears that a molecule should in most cases be at least 100 MWuits in ize. The upper limit in molecular weight is determined primarily by the requiremest that drugs must be able to move within the body (eg, fiom the site of adkintstration to the site of action). Drugs much larger than MW 1000 do not diffuse readily between compertments of the body (see Permeation, in following text). Therefore, very large drugs (usually proteins) must often be administered directly into the compartment where they have their effect. In the case of alteplase, a clot dissolving exzyme, the deugis aduinistered directly into the vascular compartment by intravenous or intre- arterial infusion Drug Reactivity & Drug-Receptor Bonds Drug interact with receptors by means of chemical forces or bonds. These are of three major types covalent, electrostatic, end hydrephobic. Covelent bonds ere very strong end in many cases not reversible under biologie conditions. Tins, the covalent bond formed between the aceiyt goup of aceyiselicylic eci (aspirin) end cyclooxygenase, its eczyme target in platelets, is not readily broken The platelet eggegation-blocking effect of espirin lasts long after fee acetylsalicylic acid has disappeared from the bloodstream (about 15 mimes) end is reversed only by the synthesis of new enzyme in new platelets, a process that takes several days. Other exemples of highly reachve, covalent bond forming drugs include the DNA alivleting agents used in cancer chemotherapy to disrupt cell divisionin the tuner Electrostatic bonding is much more common then cavelent bonding in deugyeceptor inferections. Electrostatic bonds vary from relatively strong linkeges between permanently charged iontc molecules to weaker hydrogen bonds end very week induced dipole interactions such as van der Waals forces and siniler phenomena, Electrostatic bonds are weaker then covalent bonds Hydophobic bonds are unully quite weak and exe probsbly important in th interactions of highly lipid-soluble drugs ‘with the lipids of cell membranes and perhaps inthe interaction of drug with the internal walls of receptor “pockets” The specific nate of a pasticuler deugreceptor bonis of less practical importence then the fect that drugs that bind tough weak bonds to ther receptors are generally:more selective then drugs thet bind by means of very strong bonds. This, is beceuse weak bonds require a very precise fit ofthe deugto its receptor f aninteractionis to occu. Only a few receptor types are likely to provide such e precise Sit for a particular drug structure. Thus, if we wished to design e lnghly selective short-acting drugfor a particular seceptor, we would avoid highly reactive molecules thet form covalent bonds and instead choose a molecule that farms weaker bonds ‘A few substances that are slmost completely inert inthe chemical sense nevertheless have signficent phamecologe effects For exemple, xenon, an"inest” gas, has anesthetic effects et elevated pressures Drug Shape ‘The shape of drug molecule must be such as to permit binding to its receptor site vie the bonds just described. Optimally, the deug's shape is complementary to that of the receptor site in the same way that a key is complementary to a lock Furthermore, the phenomenon of chirality (stereeisemerism) is so common in biology that more than half of ell useful deugs are chiral molecules, that is, they can exist as enantiomeric pairs. Drugs with two asymmetric centers have four chastereomers, eg ephedine, « sympathomimetic drug Inmost cases, one of these enantiomers is much more potent then its sisror image enantiomer, reflecting a better fit to the receptor molecule. If one imagines the receptor site to be like « glove info which the drug molecule must fit to bring about its effect, itis clear why e “left oriented” drugis more effective in ‘bindingto a left-hand receptor thenits “sight-oriented” enantiomer ‘The more active enastiomer at one type of receptor site may not be more active at another receptor type, eg @ type that may be responsible for some other effect For exemple, carvedilol, a deug thet interacts with ackenoceptors, has a single chisel center end thus two enantiomers (Table 1-1). One of these enantiomers, the (S)(-) isomer, is a potent B-receptor ‘locker. The (R)(#) isomer is 100-fold weaker at the P receptor. However, the isomers are approximately equipotent as a- receptor blockers. Ketamine is an intravenous anesthetic. The (#) enantiomer is a more potent anesthetic and is less toxic ‘thanthe (-) enantiomer, Unfortunately, the drugis still used as the racemic mixtre‘TABLE 1-1 Dissociation constants (K,) of the enantiomers and racemate of carvedilol. ceReceptors Receptors Form of Carvedilol (Ky nmol/L") (Ky nmol/L) (#) enantiomer “4 45 Si) enantiomer 16 04 u 9 "he Kis the concentration for S08 saturation ofthe receptors ands inversely pro- portonateto the affinity ofthe drug forthe receptors. Data fom Ruffolo RR ota The pharmacology of carveiol Eur J Clin Pharmacol 1890:38582, Finglly, because enzymes are usually stereoselective, one drug enaafiomer is often more susceptible than the other to deug metabolizing emzymes, As a result, the duration of ection of one enantiomer may be quite different from that of the other. Similarly, deug transporters may be stereoselective Unfortunately, most studies of clinical efficecy and dug elimination in lumens have been carried out with racemic sixtures of drugs rather then with the separate ensniiomers. At present, only e small percentage of the chirel drugs used clinically are marketed as the active isomer—the rest are available only as racemic mixtwes. As a result, many patients are receiving drug doses of which 50% is less active, inactive, or actively toxic. Some drugs are ctarenily available in both the racemic and the pure, active isomer forms. Unfortunately, the hope that adainistration of the pure, active enastiomer would decrease adverse effects relative to those produced by racemic formulations has not been established. Rational drug design Rational design of dugr implies the ability to predict the appropriate molecular structure of a drug on the basis of information abous its bolog receptor. Uni recently, no receptor was inown in mificient deteil to permit mich dug design Instead, drugs were developed through random testing of chemicals or aiodiication of drugs alzeady Imown to have some effect However, the characterization of many receptors cing the pact three decades has changed th pichae.& fer drugs now in use were developed trough molecular desig based on inowledge of the tres- mensional rructre of the receptor site. Compiter progam are now available that cenitereively optimize drug structres to fit mown receptors. As tore becomes inown about receptor truce, fiona drug designvvill become more common Receptor Nomenclature The spectacular success of newer, more efficient ways to identify and characterize receptors (see Chapter ) harrentedin averiety of differing and sometimes confusing systems for naming them. Thus in tin has led to a rumber of suggestions reguding more rational methods of naming receptors The interested reader isreferred for details to the efforts of the Intentional Union of Pharmacology (UPHAR(Conmittee on Receptor Nomenclate and Drug Classification(reported in various isnies of Phamacologeel Reviews and elsewhere) and to Alerender SPH, Mathie A, Peters JA: Guide t receptors and chamals (GRAC), Sth edition Br J Pharmacol 2011;164(Suppl 1)S1-$324. The chapters in ths book rinly we these sources for mimingreceptors DRUG-BODY INTERACTIONS ‘Tih interactions between a drug end the body are conveniently divided into tro classes. The actions of the drug onthe body are termed pharmacedynamic processes (Figixe I-1); the principles of pharmacodynamics are presented in greater detail inChnpter 2. These properties determine the group in which the deugis clessfied and they play the major role in deciding whether tat group is eppropsiate therapy for « pericer symptom or disease. The actions ofthe body on the drug axe celledpharmacekinetic processes and are described inChapters 3 and 4. Pharmacokinetic processes govern the sbsorption distribution, end elininntion of drugs end are of geet practical importance inthe choice end administration of @ particular drugfor a particular peier, eg a patent withimpeired renal funchon The following paragraphs provide a brief Infrotuctonte pharmecodynaacs and phicmacclanetics Pharmacodynamic Principles Most drugr must bind to « receptor to bring about aneffect However, atthe cellar level, drugbiningis only the firstin a sequence of steps+ Drug(D) + receptor-effector (R) > deugreceptor-effector complex — effect + D+R-— drugreceptor complex —+ effector molecule — effect + D+R—+D-R complex — activation of coupling molecule —> effector molecule — effect + Inhibition of metabolism of endogenous activator —+ increased activator action on an effector molecule — increased effect Note that the final change in function is accomplished by aneffector mechanism. The effector may be part of the receptor molecule or may be e separate molecule. A very large amber of receptors communicate with their effectors through coupling molecules, as described in Chapter 2 A. Types of Drug-Recepter Interactions Agonist drugs bind to and activate the receptor in some fashion which disectly or indirectly brings about the effect Figre 1-24), Receptor activation involves a change in conformation in the cases that have been studied at the molecular structure level. Some receptors incorporate effector machinery in the same molecule, so that drug binding brings sbout the effect cisectly, eg opening of an ion chennel or activation of erzyme activity. Other receptors are linked through one or more intervening coupling molecules to a separate effector molecule. The five major types of drugreceptor-effector coupling systems are discussed in Chapter 2. Pharmacologic antagonist drugs, by binding to a receptor, compete with and prevent ‘binding by other molecules. For example, acetylcholine receptor blockers such as atropine are enfagonists because they revert access of acetylcholine and similar agonist drugs to the acetylcholine receptor site andl they stabilize the receptor in its inactive state (or some state other than the acetylcholine-activated state). These agents reduce the effects of acetylcholine and similer molecules in the body (Figure 1-28), but their action can be overcome by increasing the dosage of agonist Some antagonists bind very tighily to the seceptor site in an irreversible or pseudoisreversible fashion and cannot be displaced by increasing the agonist concestration Drugs that bind to the same receptor molecule but do not prevent binding of the agonist are said to act allesterically and may enhance (Figue 1-20) or inkubit (Figwe 1-20) the action ofthe agonist molecule, Allosteric inkubition is not overcome by increasing the dose of agonistReceptor ————______—> Effects. Drug _~ eo. cs, ™s bo of awn , of am | i ‘Compottive Innit Ailosteric activaior Alster inhibitor FIGURE 1-2 Drugs may interact with receptors in several ways. The effects renting from these interactions ere chagremmed inthe dose-response curves at the sight Drugs that alter the agorist (A) response may activete 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 incsease the efficacy of the agonist or its binding affinity. The ctrve shownseflects enincresse in efficacy, enincsease in affinity would result in a leftward shaft of the B. Agonists that Inhibit their Binding Molecules Some drugs mimic agonist drugs by inlibiting the molecules responsible for terminating the action of an endogenous agonist. For example, acetylcholinesterase inhibitors, by slowing the destruction of endogenous acetylcholine, cause cholinomimetic effects thet closely resemble the actions of cholinoceptor agonist molecules even though cholinesterase inlubitors do not bind or only incidentally bind to cholinoceptors (see Chapter 7). Because they amplify the effects of physiologcally released agonist ligands, their effects are sometimes more selective and less toxic than those of exogenous agonists C. Agonists, Partial agonists, and Laverse agonists Figue 1-3 describes a useful model of deugreceptor interaction As indiceted, the receptor is postulated to exist in the inactive, nonfunctional form (R) and in the activated form (R,). Thermodynamic considerations indicate that even in the absence of ay agonist, some of the receptor pool must exist in the R, form some of the time and may produce the same physiologe effect as agonistinduced activity. This effect, occuring in the absence of agonist, is termed constitutive activity. Agonists have a much higher affinity for the R, configration end stabilize it, so that e large percentage of the total pool resides in the R-D fraction and a large effect is produced. The recognition of constitutive activity may depend on the receptor density, the concentration of coupling molecules (if a coupled system), and the muuber of effectors in the system.Full agonist Ry +Dpa Partial agonist Ri+ Dan “Antagonist Response activity Inverse agonist Log Dose FIGURE 1-3 A model of drug receptor interaction The receptor is able to assume two conformations Inthe Ry conformation, itis inactive and produces no effect, even when combined witha drugmolecule Inthe R, conformation, the receptor can activate downstream mechanisms thet produce a small observable effect, evenin the ebsence of drug (Constitutive activity). Inthe absence of deugs, the to isoforms are in ecualibrivm, and the R, form is favored Conventional fil agonist drugs have a much higher affinity for the R, conformation, and mass action tau favors the formation of the R,-D complex with a much larger observed effect. Partial egorists have anintermediate affinity for bothR, andR, forms. Conventional antagonists, accordingtto this hypothesis, have equel affinity for both receptor forms and maintain the same level of constitutive activity. Inverse agonists, on the other bend, have a much bigher affinity for the Ry form, reduce constitutive activity, and may produce « contrasting physiologic result Many agonist drugs, when administered at concentrations méficient to satwate the receptor pool, can activate their receptor-effector systems to the maximun extent of which the system is capable, that is, they cause a shift of almost all of the receptor pool to the R,-D pool. Such drugs are termed full agonists. Other drugs, calledpartial agonists, bind to the same receptors and activate them in the seme way but do not evoke as gest @ response, no metter how high the concentration In the model inFigue 1-3, partial agonists do not stabilize the R, configuration es fully es full agonists, so that a significent fraction of receptors exists in the RD pool. Such drugs are said to have low intrinsic efficacy. Thus, pindolol, « f-advenoceptor partial agonist, may act either as en agonist (iF no fll agonist is presess) or as an antagonist (if @ full agonist such as epinephrine is presenf). (See Chapter 2) Intrinsic efficacy is independent of affinity (as usually measwed) for the receptor. Inthe same model, conventional antagonist action cen be explained as fixing the fractions of drug bowd R, and R, in the same relative amounts as in the absence of any drug In this situation, no change in activity will be observed, so the drug will appear to be without effect However, the presence of the antagonist at the receptor site will block access of agonists to the receptor and prevent the usual agonist effect. Such blocking action cen be termed neutral antagenism. ‘What will happen if a drug has a much stronger affinity for the R than for the R, state and stabilizes e large fraction in the RD pool? Inthis scenario the drugwill reduce eny conslituive activity, tas resuitingin effects that are the opposite of the effects produced by conventional agonists at that receptor. Such drugs are termed inverse agonists (Figure 1-3). One of the best documented exemples of suche system is the y-aminobubynic acid (GABA,) receptor effector (a chloride chame!) inthe nervous system, This receptor is activated by the endogenous transnitter GABA and causes inhibition of postsynaptic cells. Conventional exogenous agonists such ax berzodiezepines also facilitate the receptor-effector system and causeGABA like inbibition with sedation as the therapeutic remit. This sedation can be reversed by conventional neutral antagonists such as unazenil, Inverse agonists of this receptor system cause anciety and agitation, the inverse of sedation (see Chapter 22), Similar inverse agonists have been found for f ackenoceptors, histamine Hy and Hy receptors, and severel other receptor systems, 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 es the drug occupies the receptor, and dissociation of drug from the receptor automatically terminates the effect. In many cases, however, the ackonmay persist after the drughas dissociated because, for example, some couplingmolecul is still present in activated form. Inthe case of deugs that bind covalently tothe receptor site, the effect may persist wil the drug receptor complex is destroyed andnew receptors or exymes are synthesized, as described previously for aspirin In addition many receptor-effector systems incorporate desensitization mechanisms for preventing excessive activation when agonist molecules confine to be present for lang periods, (See Chaapter ? for additional details) E. Receptors and Inert Binding Sites To function as a receptor, an endogenous molecuie must first be selective in choosing ligands (drug molecuies) to bind, and second, it must change its function upon binding in such a way thet the function of the biologge system (cell, tissue, ete) is altered The selectivity characteristic is required to avoid constant activation of the receptar by promiscuous binding of many different ligands. The ability to change fmction is clearly necessary ifthe ligand is to cause « pharmacologe effect ‘The body contains a vast array of molecules that ere capable of binding drugs, however, ancl not all of these endogenous molecules are regdetory molecules, Binding of « dugto « noncegulstory molectie such as plasma albumin will result inno detectable change in the function of the biologc system, so this endogenous molecule can be called aninert binding site. ‘Such binding is not completely without sigaficence, however, beceuse it affects the distribution of drug within the body and determines the amount of free drugin the cisculation Both of these factors are of pharmacokinetic importance (see also Chapter 3), Pharmacokinetic Principles In practical therapeutics, « drug should be able to reach its intended site of action after administration by some convenient route. In many cases, the active drug molecuie is sufficiently lipid-soluble and stable to be given as such In some cases, however, aninactive prectxsor chemical thet is readily absorbed and distributed must be administered and then converted to the active drug by biologic processes—inside the body Such a prectxsor chemical is called apredrug. In only # few situations is it possible to apply a deug directly to its target tissue, eg by topical application of an axti- inflemmatory agent to inflamed skin or mucous membrane. Most often, a drugis administered into one body compartmert, eg the gu, and must mave toits site of actionin another compartment, eg the brainin the case of en astiseizwe medication. ‘This requises that the drug be absorbed into the blood from its site of administration and distributed to its site of action, permeating through the various barriers that seperate these compartments. For a drug given orally to produce an effect in the central nervous system, these barriers include the tissues that make up the well of the infesting, the walls of the capillaries that perfuse the gut, end the blood-brain bersier, the walls of the capillaries that pesfuse the brain Finally, after ‘ringng about its effect, a drug should be eliminated at « reasonable rate by metabolic inactivation, by excretion from the ‘body, of by a combination ofthese processes A.Permeation Drug permeation proceeds by several mechanisms. Passive diffusionin en aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too Laxge to diffuse readkly GFigue 14). Drugvehicles can be very important in facilitating transport and permeation, eg by encapsulating the active agest in liposomes and in regulating release, as in slow release preparations. Newer methods of facilitating transport of ceugs by coupling them to nanoparticles are under investigationLumen| Interstitium) FIGURE 1-4 Mechanisms of drug permestion Drugs may diffuse passively through aqueous channels in the intercellular junctions (eg tight jmctions, A), or through Lipid cell membranes (B). Drugs with the appropriate characteristics may be ‘wensported by cestiers into or out of cells (C). Very impermeant drugs may also bind to cell suface receptors (dask binding sites), be engulfed by the cell membrane (endocytosis), and then released inside the cell or expelled via the ‘membrane-Limited vesicles out ofthe cell into the extracellular space (exocytosis, D). 1. Aqueous diffusion—Aqueous diffusion occurs within the Lerger aqueous compartments of the body (interstitial space, cytosol, te) and across epithelial memlorane tight junctions andthe endothelial lining of blood vessels through equeots ‘pores that—in some tissues—permit the passage of molecules as large as MW'20,000-30,000.* See Figare 1~1A. Aqueous diffusion of drugmolecules is usually driven by the concentretion gradient ofthe permeating drug, « dowsizll movement described by Fick’ slew (see below). Drugmolecties tht are bow to lerge plasme proteins (eg, slbumis) do not permeste most vasculer aqueous pores Ifthe drugis charged, ts fix is also influenced by elechical fields (eg the membrane potential end—in pests of the neplron—the trenstubuler potential. Lipid diffusion—Lipid diffusionis the most important limiting factor for drug permeation because ofthe lerge mumber of lipid barriers that separate the compartments ofthe body. Because these lip bersiers separate aqueous compartments, the lpil:aqueous partition coefficient of « drug determines how readily the malecule moves between ‘aqueous end lipid mecha. Inthe case of weak acids and week: bases (which gain or lose electical charge-beesing ‘protons, depending onthe pH), the ability to move from aqueous to ipid or vice verse vasies with the pH of the medium, because charged molecules attract water molectles, The ratio of lipid-soluble form to wates- soluble form for ‘weak acid ot weak base is expressed by the Henderson Hesselbalch equation (described the following text). See Figure 1B. 3. Special carsiers—Special carer molecules exist for many substances thet are important for cell function and too lerge oF too insoluble in ipid to diffuse pessively trough membranes, eg peptides, amino acids, and guucose. These carriers ‘bring ebout movement by active transport o facilitated diffusion and, wie passive diffusion, are selective, seturable, snd inhibiteble, Because many drugs are or resemble such natwally occuring peptides, emino acids, or sugars, they can. ‘use these casriers to cross membranes. See Figure !~IC. Many cells also contain ess selective membrane cessiers that are specielized for expelling foreignmolecules. One ‘erge family of such transporters binds adenosine triphosphate (ATP) end is celled the ABC (ATP-binding cassette) family. This femily includes the P-glycepretein or multidrug resistance type 1 (MDRI) transporter four inthe ‘oeein testes, and other tissues, andin some ceugresistent neoplastic cells, Table 1-2. Similer transport molecules from. the ABC fenuly, the multidrug resistance-associated protein (MRP) transporters, play important roles inthe excretion of some drugs or theix metabolites into wine and bile endin the resistence of some tumors to chemotherapeutic drugs Several other transporter families have been dertified that do nat bind ATP but use ion gadients to dive transport Some ofthese (the solute cersier [SLC] family) axe particulerly important inthe uptake of sewotensntters across nerve-ending membranes. The latter casters are discussed in more detel in Chapter 6 ‘TABLE 1-2 Some transport molecules important in pharmacology.Transparter Physiologic Function Pharmacclagic Significance Ne Norepinepline euptake fom srapse Taget of cocaine and some ec anidepressants str Serotonin reuptake om synapse get of selective sertonin eupale ihr: and ve eye aatdepresarts war TWanspetef dopamine and norepinephrine. Targetcfrespine and erabenazine aderagicvesclesin neve endings ont ‘Tanepet of many enobots ov of cl Increased expan cones redtance to cen antcancer dag Inhibition increases blood eves of digo ae Leahotion secretin Confers resiance to cera anticance and antifungal drugs OM mulcrupresizance prot: AMP, mobi eitanceauocited prt: NET ncepnepivne warp SRT, serotonin muah Vanpore YMA wear ‘mona aspen 4. Endocytosis and execytosis—A few substances are so large or impermeent thet they can enter cells only by endocytosis, the process by which the substance is bound et a cell-suface receptor, engulfed by the cell membrane, end carried into the cell by pinching off of the newly formed vesicle inside the membrane. The substance can then be released inside the cytosol by breakdown of the vesicle membrane, Figwe 11D. This process is responsible for the tvansport of viteminB,., complexed with a binding protein (intrinsic factos) across the Wall of the gut into the blood. Similarly, izonis transported into hemog)obin-sythesizing red blood cell precrsors in association with the protein twansfersin Specific receptors for the transport proteins must be present for this process to work. ‘The reverse process (exocytosis) is responsible for the secretion of many substances from cells. For example, meny newotvansnitter substances are stored in membrane-bound vesicles innerve endings to protect them from metabolic destruction in the cytoplasm. Appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion ofits contents into the extracellular space (see Claapter 6) B. Fick's Law of Diffusion ‘The passive fluc of molecules down e concentration gradient is given by Fick’ s lew. Flux molecules per unit time) = ‘Area x Permeability coefficient =e) « Thickness, where C, is the higher concentration C, is the lower concentration, area is the crose-sectional area of the diffusion path, permesbility coefficient is e measwe of the mobility of the drug molecules in the medium of the diffusion path, end ‘thickness is the lengih of the diffusion path Inthe case of lipid diffusion, the lipid aqueous partition coefficient is « mejor determinant of mobility of the drug because it determines how readily the drug enters the lipid membrane from the aqueous medun, C. Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch equation ‘The electrostatic charge of an ionized molecule attracts water dipoles and remits in a poles, relatively water-soluble end lipidinsoluble complex. Because lipid diffusion depends on relatively high lipid solubility, ionization of drugs may markedly reduce their ability to permeate membranes. A very large percentage of the drugs in use are week acids or weak ‘bases; Table 1-3 lists some examples. For drugs, a weak acid is best defined as e neutral molecule that cen reversibly issociste into an anion (a negatively charged molecule) ancl « proton a hydrogenior). For example, espisin dissociates as follows _H,0,COOH = C,H,0,C00- + H Neutra Aspirin Proton aspirin anion ‘TABLE 1-3 Ionization constants of some commen drugs.rug rug Weakba Weakbases (cont) os ‘utero Gabaramol 9 toprcterano a6 R opal 4123 Luseaine 19 as Aprencll 96 Neraaninot us Arie ar Methadone a Amodaone 66 Netumphetmice 100 Ariphetarine oa ettidops 105 opine or eroprcol 08 Suphacine a) Nosphine 19 Chlordaeposide 46 eating 1937 Chloroquine 105 94 Nerepinepne a8 Corphenamine ez Pentarcine 18 Chiopromanne 93 Fhenyephine 98 48 Conine & Fhyostigmine i9i8 2292 Cocaine as Plocaine to 18 Codee os Pndeok a6 a cystane a frocahamie 92 Phenobasital “ Desiramioe 402 frocaine 0 Prenjoin a3 Diazepam 30 omehasne 9 Fopythiouscl =k Diphenindanine aa Fropritaal oa See acd 30 Dptenoxyiate nm Fevdoephedine 98 Sulsirine “6 prow 96 Fyimethamine 1073) Ssipcine 8a Epineptine sr unine asad Theophyine 88 figotamine a Seopeiamine a Tolbutide a Fugherasne aa Stree aq23 Warfarin 50 Hycatnine a Testing iat tnipenine 85 Tonio 95. Ta tht pa whch th anette oie andrei rms ea ‘More tan ore eae go. "wdc ptt Aweak base canbe defined as a neutral molecuie that can form a cation (a positively charged molecule) by combining with « proton For example, pyrimethamine, an antimalarial drug wadergpes the following association dissociation process Gy,Hy CINSNH,* = C,,H, CIN,NH, + HE Pyrimethamine Neutral Proton ‘cation pyrimethamine [Note that the protonated form of a weak acid is the nevirel, more lipid-soluble form, whereas the unprotonated form of @ ‘weak base is the neutral form The lew of mass action requires that these reactions move to the left in an acid environment (low pH, excess protons available) end to the right in an alkaline environment. The Hendesson-Hesselbalch equatior telates the ratio of protonated to unprotonsted week acid or weak base to the molecule’s pK, and the pH of the medium as follows (Protonated) rene = PK, pH (Unprotonated)