S T O E LT I N G SPharmacology and Physiology inAnesthetic PracticeFIFTH EDITIONShafer_FM.indd 1 9/30/14 1:45 AMShafer_FM.indd 2 9/30/14 1:45 AMS T O E LT I N G SPharmacology and Physiology inAnesthetic PracticeFIFTH EDITIONSteven Shafer, MDProfessor of Anesthesiology, Perioperative and Pain MedicineStanford UniversityPalo Alto, CaliforniaJames P. Rathmell, MDPamela Flood, MD, MAProfessor of Anesthesiology, Perioperative and Pain MedicineStanford UniversityPalo Alto, CaliforniaAQ1Shafer_FM.indd 3 9/30/14 1:45 AMAcquisitions Editor: Brian BrownProduct Development Editor: Nicole DernoskiEditorial Assistant: Lindsay BurgessProduction Project Manager: Alicia JacksonDesign Coordinator: Stephen DrudingIllustration Coordinator: Jennifer ClementsManufacturing Coordinator: Beth WelshMarketing Manager: Daniel DresslerPrepress Vendor: Absolute Service, Inc.Fifh EditionCopyright 2015 Wolters Kluwer HealthCopyright 2006, 1999 Lippincott Williams & WilkinsAll rights reserved. Tis book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearinginthisbookpreparedbyindividualsaspartoftheirocialdutiesasU.S.government employees are not covered by the above-mentioned copyright. To request permission, please contact WoltersKluwerHealthatTwoCommerceSquare,2001MarketStreet,Philadelphia,PA19103,via email at permissions@lww.com, or via our website at lww.com (products and services).9 8 7 6 5 4 3 2 1Printed in China or the United States of AmericaLibrary of Congress Cataloging-in-Publication Data

Tis work is provided as is, and the publisher disclaims any and all warranties, express or implied,includinganywarrantiesastoaccuracy,comprehensiveness,orcurrencyofthecontentof this work.Tisworkisnosubstituteforindividualpatientassessmentbasedonhealthcare professionalsexaminationofeachpatientandconsiderationof,amongotherthings,age,weight, gender,currentorpriormedicalconditions,medicationhistory,laboratorydata,andotherfactors unique to the patient. Te publisher does not provide medical advice or guidance, and this work is merely a reference tool. Healthcare professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments.Given continuous, rapid advances in medical science and health information, independent professionalvericationofmedicaldiagnoses,indications,appropriatepharmaceuticalselections anddosages,andtreatmentoptionsshouldbemadeandhealthcareprofessionalsshouldconsulta variety of sources. When prescribing medication, healthcare professionals are advised to consult the productinformationsheet(themanufacturerspackageinsert)accompanyingeachdrugtoverify, among other things, conditions of use, warnings, and side eects and identify any changes in dosage scheduleorcontradictions,particularlyifthemedicationtobeadministeredisnew,infrequently used, or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work.LWW.comShafer_FM.indd 4 9/30/14 1:45 AMCONTRIBUTORSBihua BieAnesthesiology InstituteCleveland ClinicCleveland, OhioKenneth Cummings, III, MD, MSAssistant Professor of AnesthesiologyAnesthesiology InstituteCleveland ClinicCleveland, OhioHesham Elsharkawy, MD, MScAssistant Professor of AnesthesiologyCleveland Clinic Lerner College of MedicineStaDepartment of Outcomes ResearchAnesthesiology InstituteCleveland ClinicCleveland, OhioPamela Flood, MD, MAProfessor of Anesthesiology, Perioperative and Pain MedicineStanford UniversityPalo Alto, CaliforniaSumeet Goswami, MD, MPHAssociate Professor of AnesthesiologyColumbia University Medical CenterNew York, New YorkDavid A. GrossblattJonathan HastieMaya Jalbout-Hastie, MDAssistant Professor of AnesthesiologyDepartment of AnesthesiologyColumbia University Medical CenterNew York, New YorkBessie KachulisMihir M. KamdarAQ3AQ2AQ2AQ2AQ2Joseph Kwok, MDClinical InstructorDepartment of Anesthesiology and Pain MedicineStanford University School of MedicineStanford, CaliforniaJerrold H. Levy, MDProfessor of AnesthesiologyAssociate Professor of SurgeryCodirectorCardiothoracic Intensive Care UnitDuke University School of MedicineDurham, North CarolinaSansan S. Lo, MDAssistant Professor of AnesthesiologyDivision of Cardiothoracic AnesthesiaColumbia UniversityNew York, New YorkKamal Maheshwari, MDSta AnesthesiologistRegional Anesthesia and Acute Pain ManagementDepartment of Outcomes ResearchCleveland ClinicCleveland, OhioJillian A. Maloney, MDDepartment of AnesthesiologyMayo ClinicPhoenix, ArizonaSteven Miller, MDAssistant ProfessorDepartment of AnesthesiologyColumbia University Medical CenterNew York-Presbyterian HospitalNew York, New YorkVivek K. Moitra, MDAssociate Professor of AnesthesiologyDepartment of AnesthesiologyDivision of Critical CareColumbia University Medical CenterNew York, New York vShafer_FM.indd 5 9/30/14 1:45 AMSteven Shafer, MDProfessor of Anesthesiology, Perioperative and Pain MedicineStanford UniversityPalo Alto, CaliforniaJack S. Shanewise, MD, FASEProfessor of AnesthesiologyColumbia University Medical CenterNew York, New YorkPeter Slinger, MD, FRCPCProfessor of AnesthesiologyUniversity of TorontoToronto, CanadaSarah C. Smith, MDAssistant Professor of AnesthesiologyDivision of Cardiothoracic AnesthesiologyDepartment of AnesthesiologyColumbia University Medical CenterNew York, New YorkJessica Spellman, MDAssistant Professor of AnesthesiologyDepartment of AnesthesiologyDivision of Adult Cardiothoracic AnesthesiologyColumbia University Medical CenterNew York, New YorkRobert K. Stoelting, MDEmeritus Professor and ChairDepartment of AnesthesiaIndiana University School of MedicineIndianapolis, IndianaHui Yang, MD, PhDAnesthesiology InstituteCleveland ClinicCleveland, OhioviContributorsTeresa A. Mulaikal, MDAssistant Professor of AnesthesiologyColumbia University Medical CenterDivisions of Cardiothoracic and Critical Care Medicine,Department of AnesthesiologyColumbia University Medical CenterNew York, New YorkMichael J. Murray, MD, PhDConsultantDepartment of AnesthesiologyMayo ClinicPhoenix, ArizonaProfessor of AnesthesiologyMayo Medical SchoolScottsdale, ArizonaMohamed A. Naguib, MD, MSc, FFARCSIProfessor of AnesthesiologyCleveland Clinic Lerner College of MedicineFacultyDepartment of General AnesthesiologyCleveland ClinicCleveland, OhioPeatrossJames Ramsay, MDProfessor of AnesthesiologyDepartment of Anesthesia and Perioperative CareUniversity of CaliforniaSan Francisco, CaliforniaJames P. Rathmell, MDCarl E. RosowAQ2AQ1AQ2Shafer_FM.indd 6 9/30/14 1:45 AM viiMyjourneywithPharmacologyandPhysiologyinAnes-thetic Practice began in the early 1980s with what seemed an impossible dream, a single-author anesthesia textbook de-voted to the daily application of principles of pharmacology andphysiologyinthecareofpatients.Manyyellowtablets later (my computer skills were in their infancy), an under-standing family, residents and faculty in the Department of AnesthesiaatIndianaUniversitySchoolofMedicine,and theunwaveringsupportandencouragementofaspecial friend and publisher, the rst edition of Pharmacology and Physiology in Anesthetic Practice appeared in the fall of 1986.Teacceptanceofthetextbookbystudents,trainees, andpractitionersovertheyearshasbeenincrediblyre-wardingtomepersonallyandservedasthestimulusto create revisions for the next three editions with Simon C. Hillier,MB,ChBjoiningmeasacoeditorforthefourth edition that appeared in 2006.It is clearly time for a new edition and a new approach ifPharmacologyandPhysiologyinAnestheticPracticeis goingtocontinuetomeetitsoriginalgoalofproviding anin-depthbutconciseandcurrentpresentationofthose aspectsofpharmacologyandphysiologythatarerelevant eitherdirectlyorindirectlytotheperioperativeanesthetic management of patients.Inthisregard,Icouldnotbemorepleasedandhon-oredthatDrs.JamesP.Rathmell,StevenShafer,and Pamela Flood agreed to act as coeditors of a multi authored fhedition.Teiruniqueexpertiseandaccesstorecog-nized authorities in the wide and expanding areas of phar-macologyandphysiologythatimpacttheperioperative care of patients is clearly evident in this fh edition.On behalf of myself and all our past (and future) read-ers, I thank the new coeditors and their authors for keep-ing Stoeltings Pharmacology and Physiology in Anesthetic Practice current with the times and fullling the dream I had more than 30 years ago.Robert K. Stoelting, MDFOREWORDShafer_FM.indd 7 9/30/14 1:45 AMShafer_FM.indd 8 9/30/14 1:45 AM ixPREFACE TO THE FIFTH EDITIONRobertStoeltingisamongthebestwritersinourspe-cialty. His signature textbook, Pharmacology and Physiol-ogyinAnestheticPractice,resonatedwithresidentsand youngfaculty,includingus,becauseitwasexceptionally wellwritten.Dr.Stoeltingsclearprosesuccinctlycov-eredthedrugswewereusinginourdailypractice.His explanationsofphysiologywereintuitiveandsensible. Everychapterinthersteditionsspokewiththesame voice,reectingthemanyyearsheinvestedinasingle-authored textbook. Even though Dr. Hillier joined him as coauthor of the fourth edition, the text always resonated as a single voice.Whenrstapproachedaboutrevisingthetextbook, weturneddowntheproject.Itseemedimpossibleto reproduce the clarity of the Stoeltings work. However, the optionforthepublisherwastotransformPharmacology andPhysiologyin AnestheticPracticeintoaconventional multiauthored textbook. Tat felt like sacrilege, reducing oneofthereveredtextsinourspecialtytoametoo multiauthored textbook. We agreed to take on the task.It took a half decade longer than expected. Too much had changed in the 30 years since Dr. Stoelting produced his initial textbook to simply revise the chapters. Te text-bookrequiredacompletereorganization.Everychapter was nearly completely rewritten.Tejobwastoomuchforonepersonoreventhree. Wechoseahybridmodel,inwhichasmallnumberof authors oversaw major blocks. Te nal editing was done bytwoeditors,FloodandRathmell,toapproximatethe single voice that distinguished the rst four editions.We have to acknowledge the eorts of our publishers Brian Brown and Nicole Dernoski, who never gave up on us during the 7 years it took to produce this textbook. Te nal book reects their dedication to Dr. Stoeltings text-book. Tey knew he had created a gem. Tey were deter-mined to keep it polished.WeareproudtobringthefheditionofDr. Stoeltingstextbooktoanesthesiologyresidents,clini-cians,andinvestigators.Tenamehasbeenchanged, forever, to reect where this started. It is now Stoeltings PharmacologyandPhysiologyinAnestheticPractice. Makingnopretenseofreproducingtheelegantwriting of Dr. Stoeltings original textbook, we have tried to cap-turethecurrentstate-of-the-artinanestheticpharma-cology and physiology.Is everything in this book correct? No. Te authors of eachchapterhaveimperfectunderstanding;knowledge changesandmistakeshappen.Wikipediabrilliantlyad-dressesthisbyallowingreaderswhocatcherrorstox them.WecantimplementtheWikipediaapproachin atextbook,butwecancomeclosebyinvitingyou,the readercompulsiveenoughtoreadthePreface,tobring anyerrors,corrections,orsuggestionstoourattention. Tee-mailaddressisStoeltingSuggestions@gmail.com. We invite our readers to become peer reviewers, point-ingouterrors,out-of-datereferences,drugsnolonger used,ormissingcontentrelevanttopharmacologyand physiology in anesthesia practice. In this manner, readers will become collaborators for all future editions.Tisfheditionisourtributetotheprofoundcon-tributiontoeducationandclinicalpracticemadeby Dr. Stoelting with his now eponymous textbook.Steven Shafer, MDJames P. Rathmell, MDPamela Flood, MDShafer_FM.indd 9 9/30/14 1:45 AMShafer_FM.indd 10 9/30/14 1:45 AM xiContributorsvForewordviiPreface to the Fifh EditionixPART I:Basic Principles of Physiology and Pharmacology1 Basic Principles of Physiology. . . . . . . . . .1Pamela Flood Steven Shafer2Basic Principles of Pharmacology . . . . . .11Pamela Flood Steven ShaferPART II:Neurologic System3Neurophysiology. . . . . . . . . . . . . . . . . . . .45Pamela Flood Steven Shafer4Inhaled Anesthetics . . . . . . . . . . . . . . . . . .98Pamela Flood Steven Shafer5 Intravenous Sedatives andHypnotics. . . . . . . . . . . . . . . . . . . . . . . . .160James P. Rathmell Carl E. Rosow6Pain Physiology. . . . . . . . . . . . . . . . . . . .204Hui Yang Bihua Bie Mohamed A. Naguib7Opioid Agonists and Antagonists.. . . . .217Kenneth Cummings, III Mohamed A. Naguib8 Centrally Acting NonopioidAnalgesics. . . . . . . . . . . . . . . . . . . . . . . . .257Hesham Elsharkawy Mohamed A. Naguib9Peripherally Acting Analgesics . . . . . . . .269Hesham Elsharkawy Mohamed A. Naguib 10Local Anesthetics . . . . . . . . . . . . . . . . . . .282Kamal Maheshwari Mohamed A. Naguib 11Neuromuscular Physiology. . . . . . . . . . .314Mohamed A. Naguib 12 Neuromuscular Blocking Drugsand Reversal Agents . . . . . . . . . . . . . . . . .323Mohamed A. Naguib 13 Antiepileptic and Other NeurologicallyActive Drugs . . . . . . . . . . . . . . . . . . . . . . .345Pamela FloodPART III:Circulatory System 14Circulatory Physiology. . . . . . . . . . . . . .365Teresa A. Mulaikal 15Cardiac Physiology. . . . . . . . . . . . . . . . . .392Sumeet Goswami Teresa A. Mulaikal Bessie Kachulis Jack S. Shanewise 16Renal Physiology. . . . . . . . . . . . . . . . . . .418Robert K. Stoelting Jonathan Hastie Jack S. Shanewise 17Intravenous Fluids and Electrolytes. . . .432Jessica Spellman Jack S. Shanewise 18Sympathomimetic Drugs. . . . . . . . . . . .449Sansan S. Lo Jack S. Shanewise 19Sympatholytics .. . . . . . . . . . . . . . . . . . . .474Steven Miller 20Vasodilators. . . . . . . . . . . . . . . . . . . . . . . .501James Ramsay Peatross 21Antiarrhythmic Drugs . . . . . . . . . . . . . . .515James Ramsay 22Diuretics. . . . . . . . . . . . . . . . . . . . . . . . . .533Maya Jalbout-Hastie Jack S. Shanewise 23Lipid-Lowering Drugs . . . . . . . . . . . . . . .542Sarah C. Smith Jack S. ShanewisePART IV:Pulmonary System 24Gas Exchange. . . . . . . . . . . . . . . . . . . . . .549Peter Slinger 25Respiratory Pharmacology . . . . . . . . . . .589Peter Slinger 26AcidBase Disorders . . . . . . . . . . . . . . . .607Peter SlingerCONTENTSShafer_FM.indd 11 9/30/14 1:45 AMPART V:Blood and Hemostasis 27Physiology of Blood and Hemostasis. . .617Jerrold H. Levy 28 Blood Products andBlood Components. . . . . . . . . . . . . . . . .626Jerrold H. Levy 29Procoagulants . . . . . . . . . . . . . . . . . . . . . .640Jerrold H. Levy 30Anticoagulants. . . . . . . . . . . . . . . . . . . . .648Jerrold H. Levy 31 Physiology and Management ofMassive Transfusion. . . . . . . . . . . . . . . . .661Jerrold H. LevyPART VI:Gastrointestinal System and Metabolism 32Gastrointestinal Physiology. . . . . . . . . .669Michael J. Murray 33Metabolism . . . . . . . . . . . . . . . . . . . . . . . .682Michael J. Murray 34Antiemetics . . . . . . . . . . . . . . . . . . . . . . . .692Michael J. Murray David A. Grossblatt 35Gastrointestinal Motility Drugs . . . . . . .699Michael J. Murray Jillian A. Maloney 36Nutrition. . . . . . . . . . . . . . . . . . . . . . . . . .716Michael J. MurrayPART VII:Endocrine System 37Normal Endocrine Function. . . . . . . . . .733Vivek K. Moitra 38Drugs that Alter Glucose Regulation. . . .748Vivek K. Moitra 39 Drugs for the Treatment ofHypothyroidism andHyperthyroidism. . . . . . . . . . . . . . . . . . .758Vivek K. Moitra 40Other Endocrine Drugs. . . . . . . . . . . . . .761Vivek K. MoitraPART VIII:Miscellaneous 41 Antimicrobials, Antiseptics, Disinfectants, and Management of PerioperativeInfection. . . . . . . . . . . . . . . . . . . . . . . . . . .779Pamela Flood 42Chemotherapeutic Drugs . . . . . . . . . . . .802James P. Rathmell Mihir M. Kamdar 43 Drugs Used for Psychopharmacologic Terapy. . . . . . . . . . . . . . . . . . . . . . . . . . .822Joseph Kwok Pamela FloodPART IX:Special Populations 44Physiology of the Newborn. . . . . . . . . . .845Pamela Flood 45 Maternal and Fetal Physiology andPharmacology. . . . . . . . . . . . . . . . . . . . . .850Pamela Flood 46 Physiology and Pharmacology ofthe Elderly . . . . . . . . . . . . . . . . . . . . . . . . .862Pamela Flood 47 Physiology and Pharmacology ofResuscitation. . . . . . . . . . . . . . . . . . . . . . .873Michael J. MurrayDrug Index883Subject Index887xiiContentsShafer_FM.indd 12 9/30/14 1:45 AMQUERIES:AQ1: Please supply authors aliations(s).AQ2: Please supply authors degree(s) and aliations(s).AQ3: Please supply authors degree(s).Shafer_FM.indd 1 9/30/14 1:45 AM