Ebook Essentials of pharmacology for anesthesia, pain medicine and critical care: Part 1

(BQ) Part 1 book Essentials of pharmacology for anesthesia, pain medicine and critical care presents the following contents: Pharmacokinetics and pharmacodynamics of anesthetics, principles of total intravenous anesthesia, perioperative considerations in pharmacology, anesthetic induction agents, benzodiazepines and muscle relaxants,...

Essentials of Pharmacology for Anesthesia, Pain

Medicine, and Critical Care

Alan David Kaye Adam M Kaye Richard D Urman

Editors

123

Pain Medicine, and Critical Care

ISBN 978-1-4614-8947-4 ISBN 978-1-4614-8948-1 (eBook)

DOI 10.1007/978-1-4614-8948-1

Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2014948072

© Springer Science+Business Media New York 2015

This work is subject to copyright All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher's location, in its current version, and permission for use must always be obtained from Springer Permissions for use may be obtained through RightsLink at the Copyright Clearance Center Violations are liable to prosecution under the respective Copyright Law

The use of general descriptive names, registered names, trademarks, service marks, etc in this publication does not imply, even in the absence of a specifi c statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use

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Printed on acid-free paper

LSU Interim Hospital

New Orleans , LA

USA

Adam M Kaye, PharmD

Department of Pharmacy Practice

Thomas J Long School of Pharmacy

and Health Sciences

University of the Pacifi c

Stockton , CA

USA

Richard D Urman, MD, MBA Department of Anesthesiology Perioperative and Pain Medicine Brigham and Women’s Hospital Harvard Medical School Boston , MA

USA Ambulatory Care Center Brigham and Women’s Hospital Chestnut Hill , MA

USA Center for Perioperative Management and Medical Informatics

Department of Anesthesiology Perioperative and Pain Medicine Brigham and Women’s Hospital Boston , MA

USA

Adam and I wish to thank our parents, Florence Feldman and Joel Kaye, for their love and support We also want to thank our stepparents, Andrea Kaye and the late Gideon Feldman, along with the Gittelman family for always helping and treating us with love and kindness over our lifetime All three of us wish to thank Dr Jonathan Jahr and Dr Karina Gritsenko, MD, for their extra help in the preparation of this book This book has been the largest project I have undertaken in many decades I wish to dedicate this book to everyone interested to learn about anesthesia and pharmacology

I also wish to dedicate this book to my family: my wife Dr Kim Kaye, my son Aaron, and my daughter Rachel I also wish to thank

my pharmacology and anesthesia mentors,

Dr Alan W Grogono, MD; Dr Philip

J Kadowitz, PhD; and Dr Bobby

D Nossaman, MD, for allowing me to complete my PhD in pharmacology while serving my full-time duties at Tulane Medical Center many years ago

Alan D Kaye, MD, PhD

I would like to dedicate this book to my wife Beth Kaye and daughter Jessica Kaye and thank them from the bottom of my heart for their patience and love I would like to thank James W Blankenship, PhD, Emeritus

Professor, Department of Physiology and Pharmacology, for stimulating my interest while a student at the Thomas J Long School

of Pharmacy and Health Sciences, University

of the Pacifi c Most importantly, I would like

to thank my older and wiser brother Alan Kaye for being my fi rst teacher and best friend

Adam M Kaye, PharmD

This book covers extensive amount of

material highly relevant to the practice of anesthesiology, pain, and critical care

medicine I would like to thank my

colleagues, students, and mentors for

encouraging me to undertake this massive project I hope that current and future

generations of practitioners and trainees will benefi t from my efforts I would like to thank

my wife Zina Matlyuk, MD, for her editorial assistance and advice I wish to dedicate this book to Zina, my daughters Abigail and Isabelle, and my parents Dennis and Tanya Urman

Richard D Urman, MD, MBA

The word pharmacology is derived from the Greek φάρμακον, pharmakon ,

and -λογία, -logia , “study of.” Strangely φάρμακον meant “poison” in classic Greek

but came to mean “drug” in the modern language But what is a drug? It can be described as anything manufactured, natural, or endogenous that exerts some physi-ological cellular Pharmacology is the study of the interactions between a living organism and substances that have an impact on normal or abnormal function The division between food and herbs is somewhat blurred as the latter prepara-tions are not governed by the Food and Drug Administration but rather held to the standards of the food industry where trials of effectiveness and universal testing of safety are not required However, the word “drug” is believed to originate from an old French word “drogue” and later from the Dutch “droge-vate,” which referred to the drying or preserving barrels used to store plants for medicinal use (in other words, drugs and herbs are the same thing) Indeed, today about 30 % of our medi-cines derive directly from herbs, the only difference being that drugs have specifi ed amounts of active ingredients and herbs are not regulated as to content

Some of our earliest medical texts have centered on medicinal therapies The

Yellow Emperor’s Classic of Internal Medicine , collected around 2600 BC, describes

plants and foods that are applicable to the maintenance of health and the treatment

of specifi cally diseased organs Writing in the fi rst century AD, Pedanius Dioscorides (circa 40–90 AD), a Greek physician, pharmacologist, and botanist, authored a 5-volume encyclopedia about some 600 herbal medicines that was the standard ref-erence for 1,500 years During the Renaissance the book was read in Latin, Greek, and Arabic Before that, in the seventh century AD, Paulus Aeginata, also Greek, in

a monumental act of plagiarism (although he does give some acknowledgements), collected all the works of Hippocrates, Galen, Dioscorides, and Aretaeus, among others, and produced seven books, the last of which is over 600 pages long and is devoted entirely to herbal remedies In all of these works, many of the drugs we use today such as opium, aspirin, cannabis, castor oil, mandragora (atropine, scopol-amine), cocaine, physostigmine, and digitalis among many others are listed It is to the efforts of William Withering to understand the effects of this last herb, digitalis, from the purple foxglove, that we see the foundations of pharmacology In his text,

An Account of the Foxglove , Withering relates how he achieved the potion from an

old lady in Shropshire and sent samples to his colleagues to gauge under which circumstances the extract would relieve lower extremity edema and other signs of heart failure

One of the frightening experiences the new resident in anesthesia has is tering the sometimes bewildering array of medications that can take patients to the door of death and then (hopefully) bring them back With an aging population come more comorbidities and the risk of drug interactions increases Ever-increasing complexity of machines, requirements for monitoring, and mandated data collec-tion all add to the stress of the perioperative period The ability to turn to a concise yet easy to read comprehensive text on the drugs we use daily is something to be treasured and an immense help for the practitioner In this, the latest of a long line

encoun-of pharmaceutical texts, Drs Kaye and Urman are to be congratulated on gathering together such a wide range of authors from many different venues and perspectives

The coverage of topics within Essentials of Pharmacology is indeed encyclopedic

It is my hope that this book will allow practitioners of anesthesia to embrace the topic of pharmacology and thus gain confi dence in the knowledge that their patients will be cared for appropriately and safely

New York , NY , USA Elizabeth A M Frost , MD

Foreword

In many academic papers that we have read and written over the years, drugs are described in abstract and theoretical ways These drugs might possess novel mecha-nisms or improved duration of activity These agents might be less toxic or possess reduced side effects Clearly, drugs dramatically affect our life spans, including our quality of life As the years have gone by, we have a much greater appreciation for their wonders

It was not long ago that our life spans were much shorter Tens of thousands of people died due to plague, an organism easily treated with sulfonamides It is an astonishing fact that dysentery was the single greatest cause of death of Confederate and Union soldiers during our epic Civil War Some of our greatest fi gures in history had shortened lives related to what we would now consider very treatable states George Washington probably died of acute bacterial epiglottis The poet Lord Byron died prematurely from an epileptic seizure Harry Houdini probably died from acute appendicitis Arthur Ashe died, in part, from transmission of the human immune defi ciency virus Thousands of people die each year from NSAID-mediated silent gastrointestinal bleeding

Principally during the last 50 years, we have dramatically increased our standing of disease states, and the technology to detect these states has also grown signifi cantly Drug development has resulted in an increasing longevity, reduced pain, and enhanced quality of life On a daily basis in every community, an anesthe-siologist is called to a code with a patient appearing lifeless and without hope and delivers atropine, epinephrine, sodium bicarbonate, and calcium, and the patient is ultimately rescued and stabilized These drug-mediated miracles are commonplace and routine in our practices

In the last decade, we have seen complete cataloging of the entire human genome and an increase in drug targets from fi ve hundred to well over one thousand No longer is it a guaranteed death sentence to have human immune defi ciency virus, many types of cancers, or sepsis There is now new hope in drug targeting for vas-cular atherosclerosis, diabetes mellitus, cardiomyopathy, many cancers, and even Alzheimer’s disease We fi nd ourselves constantly at a new beginning with drugs, including in our fi elds of anesthesia and pain medicine Structural activity

relationships and complex three-dimensional analyses of therapeutic targets have produced further advances Freudenberg received a patent for a cyclodextrin struc-ture in 1953; while, in 2014, we appreciate the role of a cyclodextrin-structured agent, sugammadex, in neuromuscular drug reversal Forty years ago, we fi rst iden-tifi ed an opiate receptor In recent years, we have made substantial increases in understanding of endogenous opiates and subgroup opioid receptors throughout the body With these understandings, our future will ultimately see better targeting agents for acute and chronic pain states It is an exciting time fi lled with hope in modern medicine and in our fi eld Anesthesia has never been safer, thanks, in part,

to drug development

In this book, we have attempted to cover all pharmacological considerations in the fi eld of anesthesiology in a slightly different way The fi rst section of the book covers basic drugs, including an introduction, mechanisms, drug class, structure, drug interactions, side effects, black box warnings, and clinical pearls The second section looks at pharmacological considerations in each anesthesia-related subspe-cialty The third section is timely and describes interesting and provocative current topics that directly infl uence how we practice anesthesiology The fi nal section is devoted to new vistas in many aspects of both anesthesiology and pain management

History affords us lessons and clues to be better prepared for our present and futures We must remain critical about expectations regarding quality and standard-ization of our drugs in order to maintain appropriate bioavailability and therapeutic outcomes An appreciation of current black box warnings in the United States is given a special focus in this book We must be leaders as many people within our hospitals suddenly are fi nding it their business to infl uence our practices and deci-sion making It is a golden age for drugs, and we should continue to improve the quality of life on this planet Let us all be up to the challenge one patient at a time New Orleans , LA , USA Alan David Kaye , MD, PhD, DABA, DABPM, DABIPP Stockton , CA , USA Adam M Kaye , PharmD, FASCP, FCPhA Boston , MA , USA Richard D Urman , MD, MBA, CPE

Preface

Part I Basic Pharmacologic Principles

1 Pharmacokinetics and Pharmacodynamics of Anesthetics 3Patrick Chan and James A Uchizono

2 A Review of Mechanisms of Inhalational Anesthetic Agents 49Elizabeth A.M Frost

3 Pharmacokinetics, Pharmacodynamics, and Physical Properties

of Inhalational Agents 61Hanjo Ko, Alan David Kaye, and Richard D Urman

4 Principles of Total Intravenous Anesthesia 73Basavana Gouda Goudra and Preet Mohinder Singh

5 Perioperative Considerations in Pharmacology 87Angela Vick, Amaresh Vydyanathan, Tarang Safi ,

and Karina Gritsenko

Part II Drug Classes

6 Anesthetic Induction Agents 103

David Hirsch, Charles Fox, and Alan David Kaye

7 Analgesics: Opiate Agonists, Mixed Agonists/Antagonists,

and Antagonists for Acute Pain Management 113

Orlando J Salinas and Christopher K Merritt

8 Analgesics: Opioids for Chronic Pain Management

and Surgical Considerations 125

Roy Esaki and Alex Macario

9 Nonopioid Analgesic and Adjunct Drugs 147

Mary Bekhit, Kaveh Navab, Andrew Ghobrial, and Tod Aust

10 Benzodiazepines and Muscle Relaxants 167

Joyce C Lo and Alan David Kaye

11 Pharmacology of Local Anesthetics 179

Neesa Patel and Alireza Sadoughi

12 Neuromuscular Blockers 195

Gabriel Goodwin and Vilma Joseph

13 Reversal Agents 205

Andrew Sim and Angela Vick

14 Drugs Acting on the Autonomic Nervous System 219

John Pawlowski

15 Antihypertensives, Diuretics, and Antidysrhythmics 235

Ryan Field

16 Peripheral Vasodilators 257

Ratan K Banik and Jay S Berger

17 Nitric Oxide and Pulmonary Vasodilators 275

Michelle Schlunt

18 Asthma and COPD Agents 295

Alexis Appelstein and Mabel Chung

19 Hormones, Part 1: Thyroid and Corticosteroid Hormones 313

Joe C Hong

20 Hormones Part 2: Insulin and Other Glucose- Controlling

Medications 327

Kumar Vivek, Shamantha Reddy, and Justo Gonzalez

21 Antacids, Gastrointestinal Prokinetics,

and Proton Pump Inhibitors 345

Sunitha Kanchi Kandadai and Mark V Boswell

22 Histamine Modulators 365

Michael Yarborough and Judy G Johnson

23 Central Nervous System Stimulants 381

Eric S Hsu

24 Anticoagulant Drugs 397

Subarna Biswas, Jun Sasaki, and Michelle Braunfeld

25 Hemostatic Agents 415

John S McNeil and M Dustin Boone

26 Blood, Blood Products, and Substitutes 421

Molly Chung, Laura Mayer, Hamid Nourmand, Michelle You,

and Jonathan S Jahr

Contents

27 Antipyretics: Acetaminophen, Arachidonic Acid Agents,

and COX1 and COX2 Inhibitors 433

My Tu, Karina Gritsenko, Boleslav Kosharskyy,

and Naum Shaparin

28 Antiemetic Agents 445

Aaron M Fields

29 Antiepileptic Agents 453

Angelika Kosse and Heesung Kang

30 Neuropharmacologic Agents for Neurologic Conditions 485

Maria Bustillo and Tricia Vecchione

31 Chemotherapeutic Agents 503

Adrienne B Warrick, Karina Gritsenko, and Melinda Aquino

32 Antimicrobial Agents 525

Rebecca Johnson, Richard Lancaster, and Timothy Ku

33 Herbal Medications and Vitamin Supplements 549

Philip Gregory, Andrew Abe, and Darren Hein

34 Minerals and Electrolytes 563

Amit Prabhakar, Alan David Kaye, and Amir Baluch

35 Disinfection Agents and Antiseptics 573

Valeriy Kozmenko, Rudolph R Gonzales Jr., James Riopelle,

and Alan David Kaye

36 Psychopharmacologic Agents and Psychiatric

Drug Considerations 581

Charles Fox, Alan David Kaye, and Henry Liu

37 Cocaine, Methamphetamine, MDMA, and Heroin 595

Ethan O Bryson

Part III Clinical Subspecialties

38 Cardiac Surgery 609

Henry Liu, Hong Yan, Ming Chen, Mingbing Chen, Charles Fox,

and Alan David Kaye

39 The Intensive Care Unit 645

Brian O’Gara and Shahzad Shaefi

40 Enteral and Parenteral Nutrition 661

Jillian Redgate and Sumit Singh

41 Obstetrics 677

Laura Mayer, Richard Hong, and Jeff Bernstein

42 Pediatrics 697

Vanessa Ng, Karina Gritsenko, and Rebecca Lintner

43 Neurologic Surgery 707

Allison Spinelli and Robyn Landy

44 Liver Disease and Liver Transplantation 719

Gundappa Neelakanta and Victor Xia

Part IV Special Topics

45 Black Box FDA Warnings and Legal Implications 741

Meghan Lane-Fall

46 Drug-Induced QT Prolongation 753

Elizabeth A Valentine, Alan David Kaye, Jackie V Abadie,

and Adam M Kaye

47 Drugs and Cancer Propagation 767

Amit Prabhakar, Alan David Kaye, and Richard D Urman

48 Lipid-Lowering Agents 783

Scott D Friedman and Brian McClure

49 Serotonin Syndrome 797

Julie A Gayle, Jacqueline Volpi Abadie, Adam M Kaye,

and Alan David Kaye

Part V New Vistas in Pharmacology

50 Novel Psychoactive Substances: Synthetic Cathinones

and Cannabinoid Receptor Agonists 811

Ethan O Bryson

51 New Vistas in Anesthetics, IV Induction Agents 819

John Pawlowski

52 New Vistas in Neuromuscular Blockers 827

Matthew T Murrell and John J Savarese

53 Patient-Controlled Analgesia: The Importance of Effector

Site Pharmacokinetics 837

Pamela P Palmer and Mike A Royal

54 Understanding Anesthesia-Induced Memory Loss 847

Agnieszka A Zurek and Beverley A Orser

55 Novel Targets of Current Analgesic Drug Development 859

Jeffrey A Katz and Honorio T Benzon

Index 875

Contents

Alexis Appelstein , DO Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine ,

Bronx , NY , USA

Melinda Aquino , MD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine – Yeshiva University , Bronx , NY , USA

Tod Aust , MD Department of Anesthesiology , David Geffen School

of Medicine at UCLA , Los Angeles , CA , USA

Amir Baluch , MD Metropolitan Anesthesia Consultants , Dallas , TX , USA

Ratan K Banik , MD, PhD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine ,

Bronx , NY , USA

Mary Bekhit , MD Department of Anesthesiology , Ronald Reagan UCLA Medical Center , Los Angeles , CA , USA

Honorio T Benzon , MD Department of Anesthesiology ,

Northwestern University Feinberg School of Medicine , Chicago , IL , USA

Jay S Berger , MD, PhD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine ,

Bronx , NY , USA

Jeff Bernstein Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Subarna Biswas , MD Department of Surgery , UCLA Medical Center ,

Los Angeles , CA , USA

M Dustin Boone , MD Department of Anesthesia , Harvard Medical School , Boston , MA , USA

Department of Anesthesia, Critical Care and Pain Medicine ,

Beth Israel Deaconess Medical Center , Boston , MA , USA

Mark V Boswell , MD, PhD, MBA Department of Anesthesiology

and Perioperative Medicine , University of Louisville School of Medicine ,

Louisville , KY , USA

Michelle Braunfeld UCLA Department of Anesthesiology ,

David Geffen School of Medicine at UCLA , Los Angeles , CA , USA

Ethan O Bryson , MD Departments of Anesthesiology and Psychiatry ,

The Mount Sinai School of Medicine , New York , NY , USA

Maria Bustillo , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Patrick Chan , PharmD, PhD Department of Pharmacy Practice and

Administration , Western University of Health Sciences , Pomona , CA , USA

Ming Chen , MD Department of Anesthesiology , Hubei Women and Children’s Hospital , Wuhan , China

Mingbing Chen , MD Department of Anesthesiology , Tulane University Medical Center , New Orleans , LA , USA

Mabel Chung , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Molly Chung , MD Department of Anesthesiology , David Geffen School

of Medicine at UCLA, Ronald Reagan UCLA Medical Center ,

Los Angeles , CA , USA

Roy Esaki , MD, MS Department of Anesthesiology, Perioperative

and Pain Medicine , Stanford University School of Medicine , Stanford ,

CA , USA

Ryan Field , MD Department of Anesthesiology and Perioperative Care ,

School of Medicine, University of California–Irvine , Irvine , CA , USA

Aaron M Fields , MD Department of Anesthesiology , Tripler Army Medical Center , Honolulu , HI , USA

Charles Fox , MD Department of Anesthesiology , LSU Health Science

Center Shreveport , Shreveport , LA , USA

Scott D Friedman , MD Department of Anesthesiology , Tulane University School of Medicine , New Orleans , LA , USA

Contributors

Elizabeth A M Frost , MD Department of Anesthesiology ,

Icahn School of Medicine at Mount Sinai , New York , NY , USA

Julie A Gayle , MD Department of Anesthesiology , Louisiana State University Health Sciences Center , New Orleans , LA , USA

Andrew Ghobrial , MD Department of Anesthesiology , David Geffen School

of Medicine at UCLA , Los Angeles , CA , USA

Rudolph R Gonzales Jr , RN, MSN, CNOR, CRCST, CHL Sterile Processing Services, North Texas Veterans Administration Health Care System ,

Department of Anesthesiology and Critical Care Medicine ,

Hospital of the University of Pennsylvania , Philadelphia , PA , USA

Philip Gregory , PharmD Center for Drug Information

and Evidence-Based Practice , Creighton University , Omaha , NE , USA

Karina Gritsenko , MD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine,

Yeshiva University , Bronx , NY , USA

Department of Family and Social Medicine , Montefi ore Medical Center,

Albert Einstein College of Medicine, Yeshiva University , Bronx , NY , USA

Darren Hein , PharmD Center for Drug Information and Evidence-Based Practice , Creighton University , Omaha , NE , USA

David Hirsch , MD Department of Anesthesiology , Tulane Medical Center , New Orleans , LA , USA

Joe C Hong , MD UCLA Department of Anesthesiology ,

Ronald Reagan UCLA Medical Center , Los Angeles , CA , USA

Richard Hong Department of Anesthesiology ,

Ronald Reagan UCLA Medical Center , Los Angeles , CA , USA

Eric Hsu , MD Anesthesiology Pain Medicine Center ,

UCLA–School of Medicine, University of California , Los Angeles , USA

Jonathan S Jahr , MD Department of Anesthesiology ,

David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center , Los Angeles , CA , USA

Sunitha Kanchi Kandadai , MD Department of Anesthesiology

and Perioperative Medicine , University of Louisville School of Medicine ,

Louisville , KY , USA

Heesung Kang , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine of Yeshiva University , Bronx , NY , USA

Jeffrey A Katz , MD Department of Anesthesiology ,

Northwestern University Feinberg School of Medicine , Chicago , IL , USA

Adam M Kaye , PharmD Thomas J Long School of Pharmacy

and Health Sciences , University of the Pacifi c , Stockton , CA , USA

Alan David Kaye , MD, PhD Department of Anesthesiology ,

Tulane Medical Center , New Orleans , LA , USA

Department of Anesthesiology , Louisiana State University Health Sciences Center , New Orleans , LA , USA

Hanjo Ko , MD Department of Anesthesiology and Perioperative Medicine , Brigham and Women’s Hospital , Boston , MA , USA

Boleslav Kosharskyy , MD Department of Anesthesiology ,

Albert Einstein School of Medicine – Yeshiva University,

Montefi ore Medical Center , Bronx , NY , USA

Angelika Kosse , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine of Yeshiva University , Bronx , NY , USA

Valeriy Kozmenko , MD Department of Anesthesiology ,

Louisiana State University Health Sciences Center , New Orleans , LA , USA

Timothy Ku , MD Department of Anesthesiology , Tulane Medical Center ,

New Orleans , LA , USA

Richard Lancaster , MD Department of Anesthesiology , Tulane Medical Center , New Orleans , LA , USA

Robyn Landy , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Meghan Brooks Lane-Fall , MD, MSHP Department of Anesthesiology and Critical Care , University of Pennsylvania , Philadelphia , PA , USA

Contributors

Rebecca Lintner , MD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine ,

Bronx , NY , USA

Henry Liu , MD Department of Anesthesiology , Tulane Medical Center ,

New Orleans , LA , USA

Joyce C Lo , MD Department of Anesthesiology, Pain, and Perioperative Care , Stanford University School of Medicine , Palo Alto , CA , USA

Alex Macario , MD, MBA Department of Anesthesiology, Perioperative and Pain Medicine , Stanford University School of Medicine , Stanford , CA , USA

Laura Mayer , MD Department of Anesthesiology ,

David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center , Los Angeles , CA , USA

Brian McClure Department of Anesthesiology ,

Tulane University School of Medicine , New Orleans , LA , USA

John S McNeil , MD Department of Anesthesia , Harvard Medical School , Boston , MA , USA

Department of Anesthesia, Critical Care and Pain Medicine ,

Beth Israel Deaconess Medical Center , Boston , MA , USA

Christopher K Merritt , MD Department of Anesthesiology , Louisiana State University , New Orleans , LA , USA

Matthew T Murrell , MD, PhD Department of Anesthesiology ,

Weill Cornell Medical College , New York , NY , USA

Kaveh Navab , MD Department of Anesthesiology ,

David Geffen School of Medicine at UCLA , Los Angeles , CA , USA

Gundappa Neelakanta , MD Department of Anesthesiology ,

Ronald Reagan UCLA Medical Center, David Geffen School of Medicine at UCLA , Los Angeles , CA , USA

Vanessa Ng , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Hamid Nourmand , MD Department of Anesthesiology ,

David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center , Los Angeles , CA , USA

Brian O’Gara , MD Department of Anesthesia , Harvard Medical School ,

Boston , MA , USA

Department of Anesthesia, Critical Care and Pain Medicine ,

Beth Israel Deaconess Medical Center , Boston , MA , USA

Department of Anesthesia , University of Toronto , Toronto , ON , Canada

Pamela P Palmer , MD, PhD AcelRx Pharmaceuticals, Inc , Redwood City ,

CA , USA

Neesa Patel , MD Department of Anesthesiology , UCLA - Santa Monica Medical Center and Orthopedic Hospital , Santa Monica , CA , USA

Department of Anesthesiology , Ronald Reagan UCLA Medical Center ,

Los Angeles , CA , USA

Department of Anesthesiology, David Geffen School of Medicine,

University of California , Los Angeles , CA , USA

John Pawlowski Division of Thoracic Anesthesia ,

Beth Israel Deaconess Medical Center , Boston , MA , USA

Amit Prabhakar , MD, MS Department of Anesthesiology, Louisiana State University Health Sciences Center , New Orleans , LA , USA

Shamantha Reddy , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Jillian Redgate , RD, CNSC Nutrition and Food Services ,

VA Greater Los Angeles Healthcare System , Los Angeles , CA , USA

James Riopelle , MD Department of Anesthesiology ,

Louisiana State University Health Sciences Center , New Orleans , LA , USA

Mike A Royal , MD, MBA, JD AcelRx Pharmaceuticals, Inc ,

Redwood City , CA , USA

Alireza Sadoughi , MD Department of Anesthesiology , UCLA - Santa Monica Medical Center and Orthopedic Hospital , Santa Monica , CA , USA

Department of Anesthesiology, David Geffen School of Medicine,

University of California , Los Angeles , CA , USA

Tarang Safi , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine, Yeshiva University , Bronx , NY , USA

Orlando J Salinas , MD Department of Anesthesiology ,

Louisiana State University , New Orleans , LA , USA

Jun Sasaki , MD UCLA Department of Anesthesiology ,

David Geffen School of Medicine at UCLA , Los Angeles , CA , USA

John J Savarese , MD Department of Anesthesiology ,

Weill Cornell Medical College , New York , NY , USA

Contributors

Michelle Schlunt , MD Department of Anesthesiology , Loma Linda University , Loma Linda , CA , USA

Shahzad Shaefi , MD Department of Anesthesia , Harvard Medical School , Boston , MA , USA

Department of Anesthesia, Critical Care and Pain Medicine ,

Beth Israel Deaconess Medical Center , Boston , MA , USA

Naum Shaparin , MD Department of Anesthesiology ,

Albert Einstein School of Medicine – Yeshiva University, Montefi ore Medical Center , Bronx , NY , USA

Department of Family and Social Medicine , Albert Einstein School

of Medicine – Yeshiva University, Montefi ore Medical Center , Bronx , NY , USA

Andrew Sim , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

Preet Mohinder Singh , MD, DNB Department of Anesthesia ,

All India Institute of Medical Sciences , New Delhi , India

Sumit Singh , MD, UCLA Department of Anesthesiology ,

David Geffen School of Medicine at UCLA , Los Angeles , CA , USA

Nutrition and Food Services, VA Greater Los Angeles Healthcare System,

Los Angeles , CA , USA

Allison Spinelli , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine , Bronx , NY , USA

My Tu , MD Department of Anesthesiology , Albert Einstein School

of Medicine – Yeshiva University, Montefi ore Medical Center , Bronx , NY , USA

James A Uchizono, PharmD, Phd Department of Pharmaceutics and Medicinal Chemistry , University of the Pacifi c , Stockton , CA , USA

Richard D Urman , MD, MBA Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital , Harvard Medical School , Boston , MA , USA

Center for Perioperative Management and Medical Informatics,

Brigham and Women’s Hospital , Boston , MA , USA

Elizabeth Valentine , MD Department of Anesthesiology and Critical Care , Perelman School of Medicine at the University of Pennsylvania , Philadelphia ,

PA , USA

Tricia Vecchione , MD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine ,

Bronx , NY , USA

Angela Vick , MD Department of Anesthesiology , Montefi ore Medical Center, Albert Einstein College of Medicine, Yeshiva University , Bronx , NY , USA

Amaresh Vydyanathan , MD, MS Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine,

Yeshiva University , Bronx , NY , USA

Adrienne B Warrick , MD Department of Anesthesiology ,

Montefi ore Medical Center, Albert Einstein College of Medicine – Yeshiva University , Bronx , NY , USA

Victor Xia , MD Department of Anesthesiology , Ronald Reagan UCLA

Medical Center, David Geffen School of Medicine at UCLA , Los Angeles ,

CA , USA

Hong Yan Department of Anesthesiology , Wuhan Central Hospital ,

Wuhan , China

Michael Yarborough , MD Department of Anesthesiology ,

Tulane Medical Center , New Orleans , LA , USA

Michelle You Department of Anesthesiology , David Geffen School

of Medicine at UCLA, Ronald Reagan UCLA Medical Center ,

Los Angeles , CA , USA

Agnieszka A Zurek Department of Physiology , University of Toronto ,

Toronto , ON , Canada

Contributors

Basic Pharmacologic Principles

Pain Medicine, and Critical Care, DOI 10.1007/978-1-4614-8948-1_1,

© Springer Science+Business Media New York 2015

Introduction

Our understanding of the numerous barriers and cascades that govern drug kinetic and dynamic behavior of clinical response(s) continues to grow in complexity as the inextricable link between pharmacokinetics (PK) and pharmacodynamics (PD) becomes increasingly apparent Colloquially, PK is described as “what the body

Department of Pharmacy Practice and Administration,

Western University of Health Sciences, Pomona, CA, USA

J.A Uchizono, PharmD, PhD

Department of Pharmaceutics and Medicinal Chemistry,

University of the Pacific, Stockton, CA, USA

Contents

Introduction 3 Absorption 5 Volume of Distribution 6 Clearance 7 Metabolism 8 Excretion 8 Elimination Rate Constant and Half-Life 9 Pharmacodynamics 10 Therapeutic Range and Therapeutic Monitoring 11 Drug Tables 12 References 43

does to the drug” and PD is described as “what the drug does to the body.” The key element to those phrases is “what is changing?”: In PK, it is the drug concentration;

in PD, it is the “body” or the physiological and pharmacological systems and cascades that convert drug concentrations into responses More precisely, PK encompasses all of the kinetic processes from the drug released from its dosage form (e.g., i.v., p.o., i.m., extended release) to the delivery of the drug to its site or tissue responsible for initiating the translation of drug concentration/exposure into

a response (shown as the solid arrows in Fig 1.1) And where PK ends, PD begins

by explaining the time-course translation/transduction of drug concentration into a

“biological signal” or “messenger” (e.g., intracellular Ca2+ concentration) that mately leads to the end desired response or effect (e.g., increased pain relief) (shown

ulti-as the broken line arrow in Fig 1.1)

Upon closer examination, PK includes even the kinetics of drug released from the dosage form prior to absorption—such as drug being transferred from syringe to systemic circulation (i.e., i.v bolus) or the complex disintegration, solvation, and dissolution of drug released by an advanced drug delivery system (ADDS) into the gastrointestinal (GI) tract milieu for permeation (passive diffusion and active or facilitated transport) across the GI endothelial barrier to the systemic circulation Additional terms associated with the PK of a drug include absorption, distribution, excretion, and metabolism (see Fig 1.1) A general term describing the sum of drug excretion and metabolism is elimination An even more general PK term, disposi-tion, describes the kinetic time course of drug distribution, excretion, and metabo-lism The input function of drug (e.g., i.v bolus, p.o.) combined with the disposition

Drug dose (IV)

Site of Metabolism

(i.e liver)

Central compartment [drug]

Site of action [drug]

Peripheral (Tissue) compartment [Drug]

Site of excretion (i.e kidneys)

Drug dose

(i.e.PO,

inhalation)

Fig 1.1 The relationship among the pharmacokinetic processes of absorption, distribution,

metabolism, and excretion with the central, peripheral, and site of action compartments

of drug concentrations, dosing intervals, and time to eliminate the drug from the body The primary objective of clinical PK is to maximize efficacy while mini-mizing toxicities, through a process called therapeutic drug monitoring (TDM)

A complete TDM protocol entails monitoring-defined therapeutic endpoints (which include plasma drug concentration if appropriate) and adverse reactions Adjustments of doses can be guided by TDM to provide individualized regi-mens Clinical PK can be affected by numerous covariates, such as age, genetics, gender, race, comorbid disease states, and concomitant medications, resulting in drug interactions These factors should be considered into the dosing regimen for each patient

Absorption

The absorption of a drug is largely dependent on the route of delivery Drugs can be administered by depot type of routes: oral, inhaled, subcutaneous, intramuscular, sublingual, rectal, intraocular, intranasal, vaginal, and transdermal Although intra-venous and intra-arterial technically do have an aspect of absorption (i.e., release of drug from a syringe or i.v./i.a bag), these routes deliver drug directly into the sys-temic circulation and are a special subset of PK input (i.e., instantaneous absorption processes having a bioavailability of 1.0) The physicochemical properties (i.e., solubility, pKa, ionization, polarity, molecular weight, partition coefficient) play a critical role in the absorption of drugs The route of delivery impacts the rate of absorption as well as the extent of absorption Bioavailability is defined as the rate and extent of drug absorption or the percentage or fraction of the parent compound that reaches systemic (plasma) circulation The bioavailability of the same drug in the same patient may be different depending on the route of administration Drug references frequently provide the bioavailabilities of drugs and are typically denoted

as F The extent of absorption, but not the rate, can be described by the parameter area under the curve (AUC) In an acute setting, the rate of absorption, generally k a,

tends to be more important, whereas the extent of absorption tends to be more important in chronic use medications The salt factor (S) is the fraction of a dose that is the active base form of the drug and pragmatically can be viewed as an attenuation of F (e.g., “effective dose” = F*S*dose) Probably, the most frequently

used routes of administration of drugs in anesthesiology are oral, intravenous/intra- arterial, inhaled, and local (epidural, interscalene, etc.)

The absolute bioavailability, F, is determined by comparing the availability for

any given extravascular (e.v.) route of administration measured against an i.v point

of reference of availability of the drug administered intravenously (Eq 1.1):

1 Pharmacokinetics and Pharmacodynamics of Anesthetics

numer-of the drug affect the drug’s ability to partition from lipid to aqueous phases, and therefore, F Food, drug interactions, and gastrointestinal (GI) motility can all affect

drug solubility and absorption First-pass metabolism, which is pre- systemic olism of the drug, can occur in the GI tract and the liver prior to reaching systemic circulation All of these factors can affect F and the route will sometimes dictate the countersalt needed, thus affecting S, as well.

metab-For inhaled anesthetics, three major factors influencing absorption are ity in the blood, alveolar blood flow, and the partial pressure gradient between alveolar gas and venous blood The solubility of inhaled anesthetics in blood is described by blood/gas partition coefficients (Table 1.1) The inhaled anesthetics are absorbed almost completely and rapidly through the lungs A lower blood/gas partition coefficient indicates a more rapid onset and dissipation of anesthetic action

Volume of Distribution

The volume of distribution Vd is a PK parameter characterizing the extent of drug distribution into the tissue from the blood The physicochemical properties of a drug, plasma protein binding, and tissue binding influence Vd It has also been termed apparent volume of distribution because it does not correlate with an actual

physiological volume compartment in the human body, but rather, it is the inferred volume in which the drug appears to be dissolved It is inferred because as Eq 1.2 shows, the clinician knows the dose given and Cp (drug plasma concentration) is measured; the Vd is inferred or calculated from the two values of dose and Cp The lower limit for nearly all drugs is 3 L or the actual average volume of human plasma

As the apparent or inferred volume of distribution increases in size, the tion begins to focus on the distribution of drug into extravascular tissues The appar-ent or inferred Vd can be calculated using Eq 1.2:

interpreta-Table 1.1 Partition coefficients of commonly used inhaled anesthetics

Vd

i vDoseCp

If the plasma concentration Cp of a drug is small immediately following a single- bolus dose, this generally indicates substantial drug permeation into the tissue(s), and the resultant Vd is >40–80 L, indicating extensive distribution into the tissue In contrast, if Vd is small (close to 3 L), a large fraction of the drug is assumed to reside

in the blood plasma, thus suggesting a little amount of drug has permeated into the extravascular tissue(s) While Vd provides insight as to whether the drug is residing

in the blood or tissue, its value does not determine which specific tissue ment the drug permeates into

compart-Vd is useful in determining the loading dose necessary to achieve a targeted Cp The usual loading dose equation is Loading Dose = Vd × Cptarget For drugs that have

a large Vd, a greater loading dose is necessary to achieve the targeted Cp Drugs with

a small Vd require a reduced loading dose to obtain the targeted Cp

As shown in Table 1.1, the inhaled anesthetics have high brain/blood, muscle/blood, and fat/blood partition coefficients In particular, most inhaled anesthetics distribute extensively into the fat tissues

Clearance

Clearance is an independent PK parameter quantifying the rate the body is able to eliminate a drug More specifically, clearance is the volume of blood that is com-pletely cleared of the drug per unit time The units are in volume/time, usually liters per hour (L/h) or milliliters per minute (mL/min) While the liver is primarily responsible for drug metabolism and the kidneys are primarily responsible for par-ent drug and metabolite excretion (filtration and secretion), other routes of elimina-tion include the chemical decomposition, feces, skin, and lungs Hepatic metabolism and elimination are components of drug clearance Total clearance is characterized

by Eq 1.3:

ClTotal=ClHepatic+ClRenal+ClOther (1.3)Total clearance ClTotal is used in most dose calculations without taking into account the specific route of elimination Clearance is an important parameter because it controls the steady-state concentration Cpss as shown in Eq 1.4:

Cl

ss =( )( )(S F /t)

(1.4)

S is the salt factor, F is the bioavailability, and tau ( τ) is the dosing interval.

1 Pharmacokinetics and Pharmacodynamics of Anesthetics

Metabolism

Drug metabolism occurs primarily in the liver, though metabolism can also occur at other sites such as the gastrointestinal wall, kidneys, and blood-brain barrier Metabolism can be characterized as phase I or phase II reactions Phase I reactions include oxidation, epoxidation, dealkylation, and hydroxylation reactions catalyzed

by the cytochrome P450 enzyme system A majority of the cytochrome P450 enzymes reside in the microsomes of hepatocytes where it metabolizes the highest number of substrates (chemical, drugs, and pollutants) in the body Phase II reac-tions are glucuronidation and sulfation processes

Many drug interactions involve the cytochrome P450 enzyme system Certain drugs, termed inducers, may increase the activity of specific cytochrome P450 iso-zymes, leading to increased metabolism of drugs which are substrates of that par-ticular isozyme The reduction in plasma concentration of the drug substrates may lead to decreased therapeutic effects Other drugs are inhibitors of cytochrome P450 enzymes, decreasing the metabolism of drugs that are substrates The increase in substrate plasma concentration may result in not only enhanced pharmacological effects but also enhanced toxicological effects Clinicians are encouraged to con-sider dosing adjustments based on known drug interactions to achieve therapeutic effects while minimizing adverse reactions

Excretion

Excretion frequently refers to the irreversible clearance of a drug typically through the kidneys The three major physiological processes occurring in the kidneys gov-erning renal excretion are glomerular filtration, active secretion, and reabsorption The glomerular filtration of an adult patient may be estimated by the Cockcroft- Gault equation [3] (Eq 1.5):

ClCr is the creatinine clearance in mL/min, the age of the patient is in years, SCr

is the serum creatinine, and IBW is the ideal body weight of the patient in kilograms (kg) For female patients, the resultant ClCr is multiplied by 85 % to account for lower muscle mass typically exhibited by females The Cockcroft-Gault equation utilizes serum creatinine, which is a by-product of muscle metabolism and is freely filtered by the glomerulus Creatinine is not actively secreted nor is it reabsorbed For drugs that are primarily eliminated via the renal route, dose adjustments may be made on the basis of creatinine clearance (ClCr) and are provided by drug package inserts or drug information references

Elimination Rate Constant and Half-Life

The dependent parameter K is a first-order rate constant It is a function of Vd and

Cl K can be described as the percentage or fraction of the amount of drug that is

cleared from the body per unit time The units are typically expressed as 1/h (hr−1)

or 1/min (min−1) As shown in Eq 1.6, K can be viewed as a proportionality constant

between Vd and Cl:

K V

= Cld

(1.6)

A large K value indicates rapid elimination of the drug If two drug

concentra-tions are drawn within the same dosing interval, K can be determined using Eq 1.7 [4]:

steady-Table 1.2 The number of half-lives

and the expected percent of true

percent of drug eliminated

the true steady state Conversely, it would take 3.3 half-lives for a patient to nate 90 % of the drug once the administration of the drug has ceased To note, t1/2

elimi-determines the dosing interval, but Vd and Cl determine the size of the dose

Pharmacodynamics

The time-course conversion of drug concentration (Ce) into a pharmacological effect (response) is pharmacodynamics The biosensor process is the detection of

the drug’s presence, Ce Frequently, the biosensor process is the receptor system on

the cell’s surface The white and black biosensor process rectangles indicate that the

drug (Ce) either stimulates (white) or inhibits (black) the zero-order and first-order constants kin or kout, respectively The biosignal is similar to the second messenger,

in that it directs the end response While the pathway in between the biosignal and

the response can contain nonlinear and time-varying processes (circadian, drug-

induced—such as drug tolerance), it still is the biosignal that is responsible for the

end response Alterations of kin or kout are frequently the sites for the nonlinearities

or time-varying processes This model is known as an “indirect” model and is tively general; the most important aspect of this model is that a change in Cp is not instantaneously realized as a change in response (Fig 1.2) Somewhere along the pathway of D, drug, diffusing out of Cp in to Ce or in the translation of D binding

-A kinase

biosensor process

biosignal

Response

Biosignal (endogenous mediator or S)

Fig 1.2 The indirect model (bottom) is laid over a generic diagram of how cells (top) generally

phosphorylated protein A acts as the biosignal responsible for the end response

Ce and response Typical direct models have the form of E E= ± E

+

0 50

positive cooperativity; when γ < 1, the PD has negative cooperativity; and when

γ = 1, the PD has no cooperativity (see Fig 1.3 for a comparison of γ).

In the more commonly used model, notice that as “dose” or the x-axis changes, the effect or response instantaneously changes Another way to view this relation-ship between “dose” and “response” is to assume that the “dose” or “log (Cp)” has reached steady state or equilibrium before the effect has been measured The direct model can still be used to simulate drug tolerance by either attenuating Emax or increasing EC50 as a function of Cp or Ce The utility of this model cannot be over-stated as it has provided many researchers and clinicians with useful pharmacody-namic insights

Therapeutic Range and Therapeutic Monitoring

Most drugs have established therapeutic ranges Therapeutic ranges are typically expressed as a range of drug plasma concentrations that achieve an optimal effect while minimizing adverse reactions However, drugs that require constant monitor-ing of drug concentrations are ones that have narrow therapeutic ranges, a low threshold for serious adverse reactions, or must reach a minimum plasma concentration to achieve an effect

Fig 1.3 Comparison of three

are kept constant for all three

1 Pharmacokinetics and Pharmacodynamics of Anesthetics

In anesthesiology, the minimum alveolar concentration (MAC; Table 1.3) of inhaled anesthetics is used as the target to achieve the necessary therapeutic effect MAC is the amount of inhaled anesthetic required to inhibit physical movement in response to a noxious stimuli in 50 % of patients [5] MAC values can also be used

to compare the relative potencies between two inhaled anesthetic agents

The continuous monitoring of plasma concentrations of intravenous anesthetics

is not performed due to practicality The half-lives and durations of action of most intravenous anesthetics are relatively short It may take several hours for the labora-tory to determine anesthetic concentrations Therefore, anesthetic concentrations do not provide rapid feedback for clinicians to make necessary adjustments to doses during the course of surgery or medical intervention Thus, monitoring of intrave-nous anesthetics is reliant on the signs and symptoms of anesthesia for the attain-ment of therapeutic efficacy and respiratory depression and blood pressure for toxicology

Table 1.4 summarizes the pharmacokinetic (distribution, metabolism, and renal excretion) and pharmacodynamic properties (onset of action and duration of action)

of various anesthetic agents

Drug Tables (Tables 1.5 and 1.6 )

The mechanism of action, indications, contraindications, cautions, pregnancy gory, clinical pearls, dosing options, drug interactions, and side effects of com-monly-used anesthetic agents are presented in Table 1.5 Lidocaine, with its numerous routes of delivery and dosing options, are presented in Table 1.6

cate-Table 1.3 Minimal alveolar concentration of commonly used inhaled anesthetics

adipose tissue; 6–12 times blood

brain, within 30 s; redistrib

T Drug name, mechanism of action, indication

Contraindication, caution, pre

anesthesia obtained within 7–10 min

antiarrhythmics, dolasetron, droperidol, fluconazole, fluox

Drug name, mechanism of action, indication

Contraindication, caution, pre