[eBook] [PDF] Lehne's Pharmacotherapeutics for Advanced Practice Nurses and Physician Assistants 2nd

Lehne's Pharmacotherapeutics for Advanced Practice Nurses and Physician Assistants 2 EDITION

Laura D. Rosenthal, DNP, ACNP, FAANP Associate Professor, College of Nursing University of Colorado, Anschutz Medical Campus Denver, Colorado

Jacqueline Rosenjack Burchum, DNSc, FNPBC, CNE Associate Professor, College of Nursing Department of Advanced Practice and Doctoral Studies University of Tennessee Health Science Center Memphis, Tennessee

Table of Contents Cover image Title Page Copyright Dedication Acknowledgments About the Authors Contributor and Reviewers Preface Laying Foundations in Basic Principles Reviewing Physiology and Pathophysiology Teaching Through Prototypes Using Clinical Reality to Prioritize Content Special Features

Teaching Supplements for Instructors Student Resources Ways to Use This Textbook

Unit I Introduction 1 Prescriptive Authority Abstract What Is Prescriptive Authority? Prescriptive Authority Regulations The Case for Full Prescriptive Authority Prescriptive Authority and Responsibility 2 Rational Drug Selection and Prescription Writing Abstract Responsibility of Prescribing Drug Selection Prescriptions Assistance 3 Promoting Positive Outcomes of Drug Therapy Abstract Medication Education

Monitoring Adherence Managing Medication Therapy Summary

Unit II Basic Principles of Pharmacology 4 Pharmacokinetics, Pharmacodynamics, and Drug Interactions Abstract Pharmacokinetics Pharmacodynamics Drug Interactions 5 Adverse Drug Reactions and Medication Errors Abstract Adverse Drug Reactions Medication Errors 6 Individual Variation in Drug Responses Abstract Body Weight and Composition Age Pathophysiology

Tolerance Placebo Effect Variability in Absorption Genetics and Pharmacogenomics Gender- and Race-Related Variations Comorbidities and Drug Interactions 7 Genetic and Genomic Considerations in Pharmacotherapeutics Abstract Pharmacogenomics Application of Pharmacogenomics Barriers to Pharmacogenomic Application in Practice Implications and Ethics Guidelines

Unit III Drug Therapy Across the Life Span 8 Drug Therapy During Pregnancy and Breastfeeding Abstract Drug Therapy During Pregnancy: Basic Considerations Drug Therapy During Pregnancy: Teratogenesis and Other Risks Drug Therapy During Breastfeeding

9 Drug Therapy in Pediatric Patients Abstract Pharmacokinetics: Neonates and Infants Pharmacokinetics: Children 1 Year and Older Adverse Drug Reactions Dosage Determination Promoting Adherence 10 Drug Therapy in Geriatric Patients Abstract Pharmacokinetic Changes in Older Adults Pharmacodynamic Changes in Older Adults Adverse Drug Reactions and Drug Interactions Promoting Adherence Considerations for End-of-Life Care

Unit IV Peripheral Nervous System Drugs 11 Basic Principles of Neuropharmacology Abstract How Neurons Regulate Physiologic Processes Basic Mechanisms by Which Neuropharmacologic Agents Act

Multiple Receptor Types and Selectivity of Drug Action An Approach to Learning About Peripheral Nervous System Drugs 12 Physiology of the Peripheral Nervous System Abstract Divisions of the Nervous System Overview of Autonomic Nervous System Functions Autonomic Nervous System Regulation of Physiologic Processes Anatomic Considerations Transmitters of the Peripheral Nervous System Receptors of the Peripheral Nervous System Exploring the Concept of Receptor Subtypes Locations of Receptor Subtypes Functions of Cholinergic and Adrenergic Receptor Subtypes Receptor Specificity of the Adrenergic Transmitters Transmitter Life Cycles 13 Muscarinic Agonists and Cholinesterase Inhibitors Abstract Introduction to Cholinergic Drugs Muscarinic Agonists Cholinesterase Inhibitors

14 Muscarinic Antagonists Abstract Introduction to Anticholinergic Drugs Muscarinic Antagonists (Anticholinergic Drugs) 15 Adrenergic Agonists Abstract Mechanisms of Adrenergic Receptor Activation Overview of the Adrenergic Agonists Therapeutic Applications and Adverse Effects of Adrenergic Receptor Activation Properties of Representative Adrenergic Agonists 16 Adrenergic Antagonists Abstract α-Adrenergic Antagonists β-Adrenergic Antagonists 17 Indirect-Acting Antiadrenergic Agents Abstract Centrally Acting α2 Agonists

Unit V Central Nervous System Drugs 18 Introduction to Central Nervous System Pharmacology Abstract Transmitters of the Central Nervous System The Blood–Brain Barrier How Central Nervous System Drugs Produce Therapeutic Effects Adaptation of the Central Nervous System to Prolonged Drug Exposure Development of New Psychotherapeutic Drugs Approaching the Study of Central Nervous System Drugs 19 Drugs for Parkinson Disease Abstract The Pathophysiology Underlying Motor Symptoms Overview of Motor Symptom Management Pharmacology of the Drugs Used for Motor Symptoms Nonmotor Symptoms and Their Management 20 Drugs for Alzheimer Disease Abstract Pathophysiology of Alzheimer Disease

Risk Factors and Symptoms Drugs for Cognitive Impairment 21 Drugs for Seizure Disorders Abstract Generation of Seizures Types of Seizures How Antiseizure Drugs Work Basic Therapeutic Considerations Classification of Antiseizure Drugs Traditional Antiseizure Drugs Newer Antiseizure Drugs Management of Generalized Convulsive Status Epilepticus 22 Drugs for Muscle Spasm and Spasticity Abstract Drugs for Spasticity Drugs for Localized Muscle Spasm Cyclobenzaprine

Unit VI Drugs for Pain 23 Local Anesthetics

Abstract Basic Pharmacology of the Local Anesthetics Properties of Individual Local Anesthetics Clinical Use of Local Anesthetics 24 Opioid Analgesics, Opioid Antagonists, and Nonopioid Centrally Acting Analgesics Abstract Opioid Analgesics Basic Pharmacology of the Opioids Opioid Antagonists Nonopioid Centrally Acting Analgesic—Tramadol Prescribing Opioids for Chronic, Noncancer Pain During a National Opioid Crisis 25 Drugs for Headache Abstract Migraine Headache Cluster Headaches Medication Overuse Headache

Unit VII Psychotherapeutic Drugs 26 Antipsychotic Agents and Their Use in Schizophrenia

Abstract Schizophrenia: Clinical Presentation and Etiology First-Generation (Conventional) Antipsychotics Second-Generation (Atypical) Antipsychotics Depot Antipsychotic Preparations Management of Schizophrenia 27 Antidepressants Abstract Major Depression: Clinical Features, Pathogenesis, and Treatment Overview Drugs Used for Depression Peripartum Depression 28 Drugs for Bipolar Disorder Abstract Characteristics of Bipolar Disorder Treatment of Bipolar Disorder Mood-Stabilizing Drugs Antipsychotic Drugs 29 Sedative-Hypnotic Drugs Abstract

Benzodiazepines Benzodiazepine-Like Drugs Ramelteon: a Melatonin Agonist Suvorexant: an Orexin Antagonist Barbiturates Management of Insomnia Other Hypnotics 30 Management of Anxiety Disorders Abstract Generalized Anxiety Disorder Panic Disorder Obsessive-Compulsive Disorder Social Anxiety Disorder Posttraumatic Stress Disorder 31 Central Nervous System Stimulants and Attention-Deficit/Hyperactivity Disorder Abstract Central Nervous System Stimulants Attention-Deficit/Hyperactivity Disorder

Unit VIII Substance Use Disorders 32 Substance Use Disorders I Abstract Definitions Diagnostic Criteria for Substance Use Disorder Factors That Contribute to Substance Use Disorder Neurobiology of Substance Use Disorders Principles of Substance Use Disorder Treatment Controlled Substances Act 33 Substance Use Disorders II Abstract Basic Pharmacology of Alcohol Alcohol Use Disorder Drugs for Alcohol Use Disorder 34 Substance Use Disorders III Abstract Basic Pharmacology of Nicotine Pharmacologic Aids to Smoking Cessation 35 Substance Use Disorders IV

Abstract Heroin, Oxycodone, and Other Opioids Kratom General Central Nervous System Depressants Psychostimulants Marijuana and Related Preparations Psychedelics Dextromethorphan 3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) Inhalants Anabolic Steroids

Unit IX Drugs That Affect the Heart, Blood Vessels, Blood, and Blood Volume 36 Review of Hemodynamics Abstract Overview of the Circulatory System Regulation of Cardiac Output Regulation of Arterial Pressure 37 Diuretics Abstract

Review of Renal Anatomy and Physiology Introduction to Diuretics Loop Diuretics Thiazides and Related Diuretics Potassium-Sparing Diuretics 38 Drugs Acting on the Renin-Angiotensin-Aldosterone System Abstract Physiology of the Renin-Angiotensin-Aldosterone System Angiotensin-Converting Enzyme Inhibitors Angiotensin II Receptor Blockers Aliskiren, a Direct Renin Inhibitor Aldosterone Antagonists 39 Calcium Channel Blockers Abstract Calcium Channels: Physiologic Functions and Consequences of Blockade Calcium Channel Blockers: Classification and Sites of Action Nondihydropyridines—Verapamil and Diltiazem: Agents That Act on Vascular Smooth Muscle and the Heart Dihydropyridines: Agents That Act Mainly on Vascular Smooth Muscle

40 Vasodilators Abstract Basic Concepts in Vasodilator Pharmacology Pharmacology of Individual Vasodilators 41 Drugs for Hypertension Abstract Basic Considerations in Hypertension Management of Chronic Hypertension Drugs for Hypertensive Disorders of Pregnancy 42 Drugs for Heart Failure Abstract Pathophysiology of Heart Failure Overview of Drugs Used to Treat Heart Failure Digoxin, a Cardiac Glycoside Management of Heart Failure 43 Antidysrhythmic Drugs Abstract Introduction to Cardiac Electrophysiology, Dysrhythmias, and the Antidysrhythmic Drugs Pharmacology of the Antidysrhythmic Drugs

44 Prophylaxis of Atherosclerotic Cardiovascular Disease Abstract Cholesterol Plasma Lipoproteins Role of Low-Density Lipoprotein Cholesterol in Atherosclerosis 2018 American College of Cardiology/American Heart Association Guideline on The Management of Blood Cholesterol Drugs and Other Products Used to Improve Plasma Lipid Levels Monoclonal Antibodies (Proprotein Convertase Subtilisin/Kexin Type 9 [PCSK9] Inhibitors) 45 Drugs for Angina Pectoris Abstract Angina Pectoris: Pathophysiology and Treatment Strategy Organic Nitrates β Blockers Calcium Channel Blockers Ranolazine Treatment Measures 46 Anticoagulant and Antiplatelet Drugs Abstract

Coagulation: Physiology and Pathophysiology Overview of Drugs for Thromboembolic Disorders Anticoagulants Direct Oral Anticoagulants Antiplatelet Drugs 47 Drugs for Deficiency Anemias Abstract Red Blood Cell Development Iron Deficiency Vitamin B12 Deficiency Folic Acid Deficiency

Unit X Drugs for Endocrine Disorders 48 Drugs for Diabetes Mellitus Abstract Diabetes Mellitus: Basic Considerations Insulin Noninsulin Medications for the Treatment of Diabetes 49 Drugs for Thyroid Disorders

Abstract Thyroid Physiology Thyroid Function Tests Thyroid Pathophysiology Thyroid Hormone Preparations for Hypothyroidism Drugs for Hyperthyroidism

Unit XI Women's Health 50 Estrogens and Progestins Abstract The Menstrual Cycle Estrogens Phytoestrogens Selective Estrogen Receptor Modulators Progestins Menopausal Hormone Therapy Drug Therapy for Transgender Women Management of Female Sexual Interest-Arousal Disorder 51 Birth Control Abstract

Effectiveness of Birth Control Methods Selecting a Birth Control Method Oral Contraceptives Combination Contraceptives With Novel Delivery Systems Long-Acting Contraceptives Spermicides Emergency Contraception Drugs for Medical Abortion

Unit XII Men's Health 52 Androgens Abstract Testosterone Clinical Pharmacology of the Androgens Androgen (Anabolic Steroid) Abuse 53 Male Sexual Dysfunction and Benign Prostatic Hyperplasia Abstract Male Sexual Dysfunction Erectile Dysfunction Premature Ejaculation

Benign Prostatic Hyperplasia

Unit XIII Antiinflammatory, Antiallergic, and Immunologic Drugs 54 Review of the Immune System Abstract Introduction to the Immune System Antibody-Mediated (Humoral) Immunity Cell-Mediated Immunity 55 Childhood Immunization Abstract General Considerations Target Diseases Specific Vaccines and Toxoids 56 Antihistamines Abstract Histamine The Two Types of Antihistamines: Histamine-1 Antagonists and Histamine-2 Antagonists 57 Cyclooxygenase Inhibitors

Abstract Mechanism of Action Classification of Cyclooxygenase Inhibitors First-Generation Nonsteroidal Antiinflammatory Drugs Second-Generation Nonsteroidal Antiinflammatory Drugs (Cyclooxygenase-2 Inhibitors, Coxibs) Acetaminophen American Heart Association Statement on Cyclooxygenase Inhibitors in Chronic Pain 58 Glucocorticoids in Nonendocrine Disorders Abstract Review of Glucocorticoid Physiology Pharmacology of Glucocorticoids

Unit XIV Drugs for Bone and Joint Disorders 59 Drug Therapy of Rheumatoid Arthritis Abstract Pathophysiology of Rheumatoid Arthritis Overview of Therapy Nonsteroidal Antiinflammatory Drugs Glucocorticoids

Conventional Disease-Modifying Antirheumatic Drugs Biologic Disease-Modifying Antirheumatic Drugs Targeted Disease-Modifying Antirheumatic Drug: Janus Kinase Inhibitors 60 Drug Therapy for Gout Abstract Pathophysiology of Gout Overview of Drug Therapy Drugs for Acute Gouty Arthritis Drugs for Hyperuricemia (Urate-Lowering Therapy) Pharmacologic Management of Gout 61 Drugs Affecting Calcium Levels and Bone Mineralization Abstract Calcium Physiology Calcium-Related Pathophysiology Drugs for Disorders Involving Calcium and Bone Mineralization Osteoporosis

Unit XV Respiratory Tract Drugs 62 Drugs for Asthma and Chronic Obstructive Pulmonary Disease

Abstract Basic Considerations Antiinflammatory Drugs Bronchodilators Combination Drugs Management of Asthma Management of Chronic Obstructive Pulmonary Disease 63 Drugs for Allergic Rhinitis, Cough, and Colds Abstract Drugs for Allergic Rhinitis Drugs for Cough Cold Remedies: Combination Preparations

Unit XVI Gastrointestinal Drugs 64 Drugs for Peptic Ulcer Disease Abstract Pathogenesis of Peptic Ulcers Overview of Treatment Antibacterial Drugs Histamine-2 Receptor Antagonists

Proton Pump Inhibitors Other Antiulcer Drugs 65 Laxatives Abstract General Considerations Basic Pharmacology of Laxatives Laxative Abuse 66 Other Gastrointestinal Drugs Abstract Antiemetics Drugs for Motion Sickness Antidiarrheal Agents Drugs for Irritable Bowel Syndrome Drugs for Inflammatory Bowel Disease Prokinetic Agents Pancreatic Enzymes Anorectal Preparations

Unit XVII Nutrition and Complementary Therapies 67 Vitamins

Abstract Basic Considerations Fat-Soluble Vitamins Water-Soluble Vitamins 68 Drugs for Weight Loss Abstract Assessment of Weight-Related Health Risk Pathophysiology Overview of Obesity Treatment Weight-Loss Drugs A Note Regarding Drugs for Weight Loss 69 Complementary and Alternative Therapy Abstract Regulation of Dietary Supplements Private Quality Certification Programs Standardization of Herbal Products Adverse Interactions With Conventional Drugs Some Commonly Used Dietary Supplements Harmful Supplements to Avoid

Unit XVIII Therapy of Infectious and Parasitic Diseases 70 Basic Principles of Antimicrobial Therapy Abstract Selective Toxicity Classification of Antimicrobial Drugs Acquired Resistance to Antimicrobial Drugs Selection of Antibiotics Host Factors That Modify Drug Choice, Route of Administration, or Dosage Dosage and Duration of Treatment Therapy With Antibiotic Combinations Prophylactic Use of Antimicrobial Drugs Misuses of Antimicrobial Drugs Monitoring Antimicrobial Therapy 71 Drugs That Weaken the Bacterial Cell Wall I Abstract Introduction to the Penicillins Properties of Individual Penicillins 72 Drugs That Weaken the Bacterial Cell Wall II

Abstract Cephalosporins Carbapenems Other Inhibitors of Cell Wall Synthesis 73 Bacteriostatic Inhibitors of Protein Synthesis Abstract Tetracyclines Macrolides Other Bacteriostatic Inhibitors of Protein Synthesis 74 Aminoglycosides Abstract Basic Pharmacology of the Aminoglycosides Properties of Individual Aminoglycosides 75 Sulfonamide Antibiotics and Trimethoprim Abstract Sulfonamides Trimethoprim Trimethoprim/Sulfamethoxazole 76 Drug Therapy of Urinary Tract Infections

Abstract Organisms That Cause Urinary Tract Infections Specific Urinary Tract Infections and Their Treatment Urinary Tract Antiseptics 77 Drug Therapy for Tuberculosis Abstract Pathogenesis of Tuberculosis Overview of Treatment Treatment of Latent Tuberculosis Vaccination Against Tuberculosis Pharmacology of Individual Antituberculosis Drugs Ethambutol Second-Line Antituberculosis Drugs 78 Miscellaneous Antibacterial Drugs Abstract Fluoroquinolones Additional Antibacterial Drugs 79 Antifungal Agents Abstract

Drugs for Systemic Mycoses Drugs for Superficial Mycoses 80 Antiviral Agents I Abstract Drugs for Infection With Herpes Simplex Viruses and Varicella Zoster Virus Drugs for Cytomegalovirus Infection Drugs for Hepatitis C Drugs for Hepatitis B Drugs for Influenza 81 Antiviral Agents II Abstract 82 Drug Therapy for Sexually Transmitted Diseases Abstract Chlamydia Trachomatis Infections Gonococcal Infections Nongonococcal Urethritis Pelvic Inflammatory Disease Acute Epididymitis Syphilis

Bacterial Vaginosis Trichomoniasis Chancroid Herpes Simplex Virus Infections Proctitis Anogenital Warts 83 Anthelmintics Abstract Classification of Parasitic Worms Helminthic Infestations Drugs of Choice for Helminthiasis

Unit XIX Cancer Therapy 84 Introduction to Immunomodulators Abstract Monoclonal Antibodies “Mabs” Monoclonal Antibodies for Asthma Monoclonal Antibodies for Infectious Disease—Clostridium Difficile Monoclonal Antibodies for Migraine Prevention Common Adverse Reactions to Monoclonal Antibodies

Tyrosine Kinase Inhibitors “Nibs” Proteasome Inhibitors “Mibs” Immunotherapy of the Future 85 Anticancer Drugs for the Nonspecialist Abstract The Role of the Nonspecialist What Is Cancer? Treatment of Cancer Introduction to the Cytotoxic Anticancer Drugs Cytotoxic Agents Hormonal Agents, Targeted Drugs, and Other Noncytotoxic Anticancer Drugs Chemoprevention and Cancer Immunotherapy 86 Pain Management in Patients With Cancer Abstract Pain in Cancer Patients Management Strategy Assessment and Ongoing Evaluation Drug Therapy Nondrug Therapy

Patient Education

Unit XX Drugs for Eyes, Ears, and Skin 87 Drugs for the Eye Abstract Glaucoma Allergic Conjunctivitis Additional Ophthalmic Drugs 88 Drugs for the Skin Abstract Anatomy of the Skin Topical Drug Formulations Acne Sunscreens Drugs for Atopic Dermatitis (Eczema) Agents for Wart Removal Drugs for Miscellaneous Skin Conditions 89 Drugs for the Ear Abstract Otitis Media and Its Management

Otitis Media With Effusion Acute Otitis Externa

Unit XXI Drug Therapy in Acute Care 90 Agents Affecting the Volume and Ion Content of Body Fluids Abstract Disorders of Fluid Volume and Osmolality Acid–Base Disturbances Magnesium Imbalances 91 Management of ST-Segment Elevation Myocardial Infarction Abstract Pathophysiology of STEMI Management of ST-Segment Elevation Myocardial Infarction Complications of STEMI Secondary Prevention of STEMI 92 Drugs for Acute Care Abstract Anesthesia, Neuromuscular Blockers, and Analgesia Cardiology Hematology

Nephrology Appendix A Canadian Drug Information Canadian Drug Legislation Drug Advertising International System of Units Drug Serum Concentrations References Index

Copyright Elsevier 3251 Riverport Lane St. Louis, Missouri 63043 LEHNE'S PHARMACOTHERAPEUTICS FOR ADVANCED PRACTICE NURSES AND PHYSICIAN ASSISTANTS, SECOND EDITION ISBN: 9780-323-55495-4 Copyright © 2021 by Elsevier, Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher's permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notice Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas

contained in the material herein. Previous edition copyrighted 2018. Library of Congress Control Number: 2019940236 Executive Content Strategist: Lee Henderson Senior Content Development Manager: Luke Held Senior Content Development Specialist: Jennifer Wade Publishing Services Manager: Julie Eddy Senior Project Manager: Rachel E. McMullen Design Direction: Renee Duenow Printed in China Last digit is the print number: 9 8

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Dedication In remembrance of Victoria “Vicki” Erickson; a nursing leader, mentor, colleague, and friend. You are missed by many. LDR To my remarkable students. It excites me to know that the future of nursing is in your most capable hands. JRB

Acknowledgments We would like to acknowledge the support of our colleagues at Elsevier, including Lee Henderson, Executive Content Strategist; Jennifer Wade, Senior Content Development Specialist; and Rachel McMullen, Senior Project Manager. Finally, we would like to acknowledge the foundational work by Richard A. Lehne. His dedication to the Lehne Pharmacology series made this text possible.

About the Authors

Laura D. Rosenthal, DNP, ACNP, FAANP, has been a registered nurse since graduating with her Bachelor of Science degree in Nursing from the University of Michigan in 2000. She completed her Master of Science degree in Nursing in 2006 at Case Western Reserve University in Cleveland, Ohio. She finished her nursing education at the University of Colorado, College of Nursing, graduating with her Doctor of Nursing Practice degree in 2011. Her background includes practice in acute care and inpatient medicine. While working as a nurse practitioner at the University of Colorado Hospital, she assisted in developing one of the first fellowships for advanced practice clinicians in hospital medicine. Dr. Rosenthal serves as an associate professor at the University of Colorado, College of Nursing, where she teaches within the undergraduate and graduate programs and serves as the director of the DNP program. She received the Dean's Award for Excellence in Teaching in 2013 and the AANP State Award for Excellence in 2015. In her spare time, Dr. Rosenthal enjoys running, skiing, and fostering retired greyhounds for Colorado Greyhound Adoption.

Jacqueline Rosenjack Burchum, DNSc, FNP-BC, CNE, has been a family nurse practitioner for over 20 years since earning her Masters of Science in Nursing degree in 1996. She completed her Doctor of Nursing Science degree in 2002. As a nurse practitioner, Dr. Burchum's work centers on addressing the needs of vulnerable populations with a special focus on immigrant and refugee populations. Dr. Burchum currently serves as an associate professor for the University of Tennessee Health Science Center (UTHSC) College of Nursing. She is credentialed as a certified nurse educator (CNE) by the National League for Nursing. She is a three-time recipient of the UTHSC Student Government Association's Excellence in Teaching Award and a recipient of the 2014 UT Alumni Association's Outstanding Teacher Award. Dr. Burchum was also the 2016–2017 Faculty Innovation Scholar for the UTHSC Teaching and Learning Center. Dr. Burchum has a special interest in online teaching and program quality. To this end, she serves as an on-site evaluator for the Commission on Collegiate Nursing Education (CCNE), a national agency that accredits nursing education programs. In addition, she is a Master Reviewer for Quality Matters, a program that certifies the quality of online courses. Her favorite activities involve spending time with family. She also enjoys designing and making quilts.

Contributor and Reviewers CONTRIBUTOR Courtney Quiring BSP, BCGP College of Pharmacy and Nutrition University of Saskatchewan Saskatoon, Saskatchewan, Canada

Appendix: Canadian Drug Information REVIEWERS Laurie M. Connors DNP, MS Assistant Professor School of Nursing Vanderbilt University Nashville, Tennessee Abimbola Farinde PharmD Professor of Health Care Administration College of Business Columbian Southern University Orange Beach, Alabama Ashley N. Fort MS, PA-C Assistant Professor PA Program LSUH Shreveport School of Allied Health Professions Shreveport, Louisiana James Graves PharmD Clinical Pharmacist Inpatient Pharmacy University of Missouri Columbia

Columbia, Missouri Margaret Hammersla BSN, MS, PhD, CRNP-A Senior Director, DNP Program; Assistant Professor Organizational Systems and Adult Health University of Maryland School of Nursing Baltimore, Maryland Bradley R. Harrell DNP, APRN, ACNP-BC Assistant Professor Loewenberg College of Nursing The University of Memphis Memphis, Tennessee Robert Hawkes MSPA, PA-C Program Director Master of Physician Assistant Studies Florida Gulf Coast University Ft. Myers, Florida Leslie Jones Higgins PhD, APRN, FNP-BC Professor Graduate Nursing Program Belmont University School of Nursing Nashville, Tennessee Kathleen S. Jordan DNP, MS, FNP-BC, ENP-BC, SANE-P Clinical Assistant Professor School of Nursing The University of North Carolina at Charlotte Nurse Practitioner Emergency Department Mid-Atlantic Emergency Medicine Associates Charlotte, North Carolina Kathy Kemle MS, PA-C, DFAAPA Clinical Assistant Professor Family Medicine Medical Center of Central Georgia/Navicent Health Mercer University School of Medicine Macon, Georgia

Lisa Miklush PhD, RN, CNS Adjunct Graduate Faculty School of Nursing & Human Physiology Gonzaga University Spokane, Washington Mary Alice Momeyer DNP, APRN-CNP Assistant Professor of Clinical Nursing The Ohio State University Columbus, Ohio Patricia Neafsey PhD Professor Emeritus School of Nursing University of Connecticut Storrs, Connecticut Stephanie Neary MPA, MMS, PA-C Instructor, Didactic Coordinator General Internal Medicine, PA Online Program Yale University New Haven, Connecticut Teresa R. Preston MBA, MPAS, PA-C, APWH-PA Associate Professor, Program Director Department of Physician Assistant Studies Christian Brothers University Memphis, Tennessee James Van Rhee MS, PA-C Program Director, Yale Physician Assistant Online Program Yale School of Medicine New Haven, Connecticut Meera K. Shah PharmD Clinical Pharmacist University of Missouri, Kansas City Kansas City, Missouri Paula Denise Silver BS Biology, PharmD Medical Instructor

Medical Assisting/LPN/RN ECPI University, School of Health Science Newport News, Virginia Cynthia Ann Smith DNP, CNN-NP, FNP-BC, APRN, FNKF Nurse Practitioner Renal Consultants, PLLC South Charleston, West Virginia Jennifer K. Sofie DNP, FNP, ANP Associate Clinical Professor College of Nursing Montana State University Bozeman, Montana Laura Steadman EdD, CRNP, MSN, RN Assistant Professor School of Nursing The University of Alabama at Birmingham Birmingham, Alabama Family Nurse Practitioner Adult/Acute Health Chronic Care and Foundations Birmingham, Alabama Mariya Tankimovich DNP, MSN, APRN, FNP-C, CNE Assistant Professor, FNP Track Coordinator for Clinical Education, Simulation, and Advising Graduate Programs UTHealth Houston, Texas Daniel T. Vetrosky PA-C, PhD, DFAAPA Physician Assistant Associate Professor (Ret) Department of Physician Assistant Studies Pat Capps Covey College of Allied Health Professions University of South Alabama Mobile, Alabama Donna Warder DNP, MS, FNP-BC, CNM

Teaching Associate Health Systems Science University of Illinois Chicago College of Nursing Chicago, Illinois Allison White PharmD Pharmacist Kansas City, Missouri Jack A.P. Yensen BSc (Hons), PhD, RN, MN Instructor DNP Program, School of Nursing Samuel Merritt University Oakland, California Lisa M. Young DNP, APRN Assistant Professor College of Nursing and Health Sciences Ashland University Mansfield, Ohio

Preface Pharmacology and pharmacotherapeutics pervade all phases of advanced practice and relate directly to patient care and education. Despite their importance, many students—and even some teachers—are often uncomfortable with these subjects because traditional texts have stressed memorizing rather than understanding. In this text, the guiding principle is to establish further understanding of drugs and their use in patient care. This text has two major objectives: to help you, the advanced practice student, establish a continued knowledge base in the basic science of drugs; and to show you how that knowledge can be applied in clinical practice. The methods by which these goals are achieved are described here.

Laying Foundations in Basic Principles To understand drugs, you need a solid foundation in basic pharmacologic principles. To help you establish that foundation, the book has major chapters on the following topics: basic principles that apply to all drugs (Chapters 4 through 7), basic principles of drug therapy across the life span (Chapters 8 through 10), basic principles of neuropharmacology (Chapter 11), and basic principles of antimicrobial therapy (Chapter 70).

Reviewing Physiology and Pathophysiology To understand the actions of a drug, it is useful to understand the biologic systems that the drug influences. Accordingly, for all major drug families, relevant physiology and pathophysiology are reviewed. In almost all cases, these reviews are presented at the beginning of each chapter rather than in a systems review at the beginning of a unit. This juxtaposition of pharmacology, physiology, and pathophysiology is designed to help you understand how these topics interrelate.

Teaching Through Prototypes Within each drug family, we can usually identify a prototype—that is, a drug that embodies characteristics shared by all members of the group. Because other family members are similar to the prototype, to know the prototype is to know the basic properties of all family members. The benefits of teaching through prototypes can be appreciated with an example. Let's consider the nonsteroidal antiinflammatory drugs (NSAIDs), a family that includes aspirin, ibuprofen (Motrin), naproxen (Aleve), celecoxib (Celebrex), and more than 20 other drugs. Traditionally, information on these drugs is presented in a series of paragraphs describing each drug in turn. When attempting to study from such a list, you are likely to learn many drug names and little else; the important concept of similarity among family members is easily lost. In this text, the family prototype—aspirin—is discussed first and in depth. After this, the small ways in which individual NSAIDs differ from aspirin are pointed out. Not only is this approach more efficient than the traditional approach, it is also more effective, in that similarities among family members are emphasized.

Using Clinical Reality to Prioritize Content This book contains two broad categories of information: pharmacology (i.e., basic science about drugs) and therapeutics (i.e., clinical use of drugs). To ensure that content is clinically relevant, we use evidence-based treatment guidelines as a basis for deciding what to stress and what to play down. Unfortunately, clinical practice is a moving target: when effective new drugs are introduced, and when clinical trials reveal new benefits or new risks of older drugs, the guidelines change—and so we have to work hard to keep this book current. Despite our best efforts, the book and clinical reality may not always agree. Some treatments discussed here will be considered inappropriate before the second edition comes out. Furthermore, in areas where controversy exists, the treatments discussed here may be considered inappropriate by some clinicians right now.

Special Features • Summary of Key Prescribing Considerations: This summary provides guidance for safe prescribing practices and includes

information such as baseline data collection, monitoring needs, identification of high-risk patients, and evaluation for therapeutic effects. • Prototype Drugs: Denoted in teal boxes; these key drugs are easy to locate. • Black Box Warnings: This feature draws the reader's attention to important safety concerns related to contraindications and adverse effects. • Patient Education: These boxes offer important information to provide to patients regarding their therapy. • Patient-Centered Care Across the Life Span: Tables in many chapters highlight care concerns for patients throughout their lives, from infancy to older adulthood. • Canadian trade names are identified by a maple-leaf icon.

Teaching Supplements for Instructors • The Instructor Resources for the first edition are available online and include a Test Bank, a PowerPoint Collection, and an Image Collection.

Student Resources • New online student resources include one case study per textbook section.

Ways to Use This Textbook Thanks to its focus on essentials, this text is especially well suited to serve as the primary text for a course dedicated specifically to pharmacology and pharmacotherapeutics. In addition, the book's focused approach makes it a valuable resource for pharmacologic instruction within an integrated curriculum and for self-directed learning by students, teachers, and practitioners. How is this focus achieved? Four primary techniques are employed: (1)

teaching through prototypes, (2) using standard print for essential information and small print for secondary information, (3) limiting discussion of adverse effects and drug interactions to information that matters most, and (4) using evidence-based clinical guidelines to determine what content to stress. Students often feel that pharmacology is one of the most difficult classes to master. Pharmacotherapeutics can be an unpopular subject because of the vast and rapidly changing area of content. We hope that this book makes the subjects of pharmacology and pharmacotherapeutics easier for you to master and more enjoyable for you to understand by allowing you to focus on the most important, umbrella concepts of pharmacology and pharmacotherapeutics as they relate to the care and safety of patients and the management of their health problems. Laura D. Rosenthal Jacqueline Rosenjack Burchum

UNIT I

Introduction OUTLINE 1 Prescriptive Authority 2 Rational Drug Selection and Prescription Writing 3 Promoting Positive Outcomes of Drug Therapy

1

Prescriptive Authority Abstract Advanced practice providers have a responsibility for selecting, prescribing, monitoring, and optimizing drug therapy as part of their role in managing patient care. The extent to which they can accomplish this as an autonomous practice component is determined by legislation that varies depending on professional licensure, physician affiliation requirements, and state laws. This chapter provides an introduction to prescriptive authority and its impact on advance practice provider practice.

Keywords prescriptive authority; full practice authority; scope of practice; state regulations; scheduled drugs Our purpose in writing this book is to prepare advanced practice providers to provide safe and competent medication therapy to patients. This role requires the ability to select, prescribe, and manage medications. In this chapter we examine issues surrounding prescriptive authority and how those issues affect this fundamental aspect of comprehensive patient care.

What Is Prescriptive Authority? Prescriptive authority is the legal right to prescribe drugs. Full prescriptive authority affords the legal right to prescribe independently and without limitation. Physicians have full prescriptive authority. For nonphysician providers, the degree of prescriptive authority varies. Some have full prescriptive authority; however, for many, prescriptive authority is restricted. Limitations are generally tied to oversight by a doctor of medicine (MD) or doctor of osteopathy (DO) as part of the provider's scope of practice.

Recall that there are two components of prescriptive authority: (1) the right to prescribe independently and (2) the right to prescribe without limitation. The provider who prescribes independently is not subject to rules requiring physician supervision or collaboration. The provider who prescribes without limitation may prescribe any drugs, including controlled drugs, with the exception of schedule I drugs, which have no current medical use. Full practice authority is sometimes interpreted differently for advanced practice registered nurses (APRNs) and physician assistants (PAs) because supervisory requirements vary for the two professions. PAs are required to have an affiliation with a physician in order to practice and prescribe. All PAs, including those in a solo practice, must establish a relationship with physician who serves in a supervisory or collaborative role and who can be reached by telephone or other means of telecommunication. (See PA State Laws and Regulations available at https://www.aapa.org/download/28349 for additional information.) If the PA–physician arrangement does not limit drugs that may be prescribed and if the law allows the PA to prescribe schedule II to V drugs, the PA may enjoy a type of quasi-full prescriptive authority. Indeed, some have referred to this as full prescriptive authority; however, the issue of being affiliated to a physician still applies. Hence PAs do not have the legal right to prescribe without the PA–physician arrangement. Even for those in solo practice, there is always the possibility of dissolution of the PA–physician arrangement. In the event this occurs, the PA must affiliate with another physician or physician group to continue prescribing. Whether APRNs possess full prescriptive authority depends on their legal right to prescribe without a supervisory or collaborative requirement. APRNs are educated to practice and prescribe independently without supervision; however, some state laws require that they practice in collaboration with or under the supervision of a physician. In these situations, some physicians limit the types of drugs that the APRN can prescribe. State laws may place additional restrictions with regard to controlled drugs. Table 1.1 provides prescriptive authority status for APRNs. Table 1.2 provides prescriptive authority status for PAs. Information regarding the right to prescribe controlled drugs is available at http://www.deadiversion.usdoj.gov/drugreg/practioners. TABLE 1.1

CNM, Certified nurse midwife; CNP, certified nurse practitioner; CNS, clinical nurse specialist; CRNA, certified registered nurse anesthetist. Source: State Boards of Nursing; November 2018.

TABLE 1.2 Physician Assistants Prescriptive Authority by State State

Scheduled Drugs

Required Physician Affiliation for Practice

AL

II–V

Supervisory

AK

II–V

Collaborative

AZ

II–V

Supervisory

AR

III–V

Supervisory

CA

II–V

Supervisory

CO

II–V

Supervisory

CT

II–V

Supervisory

DE

II–V

Supervisory

FL

II–V

Supervisory

GA

III–V

Supervisory

HI

III–V

Supervisory

ID

II–V

Supervisory

IL

II–V

Collaborative

IN

II–V

Supervisory

IA

II–V

Supervisory

KS

II–V

Supervisory

KY

No

Supervisory

LA

II–V

Supervisory

ME

II–V

Supervisory

MD

II–V

Supervisory

MA

II–V

Supervisory

MI

II–V

Participatinga

MN

II–V

Supervisory

MS

II–V

Supervisory

MO

III–V

Supervisory

MT

III–V

Supervisory

NE

II–V

Supervisory

NV

II–V

Collaborative

NH

II–V

Supervisory

NJ

II–V

Supervisory

NM

II–V

Varies according to practice

NY

II–V

Supervisory

NC

II–V

Supervisory

ND

II–V

Supervisory

OH

II–V

Supervisory

OK

II–V

Supervisory

OR

II–V

Supervisory

PA

II–V

Supervisory

RI

II–V

Supervisory

SC

II–V

Supervisory

SD

II–V

Supervisory

TN

II–V

Supervisory

TX

III–V

Supervisory

UT

II–V

Supervisory

VT

II–V

Supervisory

VA

II–V

Supervisory

WA

II–V

Supervisory

WV

III–V

Collaborative

WI

II–V

Supervisory

WY

II–V

Supervisory

a

Physician assistants (PAs) are required to have a PA–physician relationship that is detailed in a written practice agreement. Drug Enforcement Agency. Mid-level practitioners—controlled substance authority by discipline within state; 2018. https://www.deadiversion.usdoj.gov/drugreg/practioners/mlp_by_state.pdf. Source: American Medical Association. Physician assistant scope of practice; 2018. Available at: https://www.ama-assn.org/sites/ama-assn.org/files/corp/media-browser/public/arc-public/statelaw-physician-assistant-scope-practice.pdf.

Prescriptive Authority Regulations Prescriptive authority is determined by state law. As a result of differences from state to state, advanced practice providers may have full prescriptive authority in some states yet face significant restrictions in other states. The stark differences particularly affect providers who serve in locum tenens staffing positions or who have practices in two contiguous states. The regulation of prescriptive authority is under the jurisdiction of a health professional board. This may be the State Board of Nursing, the State Board of Medicine, or the State Board of Pharmacy, as determined by each state. Although the federal government controls drug regulation, it has no control over prescriptive authority. However, several organizations have appealed for changes that would place scope of practice and prescriptive authority under federal regulation in an effort to expand prescriptive authority and the scope of practice of advanced practice providers. For example, National Academy of Medicine (formerly the Institute of Medicine or IOM) advocated for federal regulation in their report, The Future of Nursing: Focus on Scope of Practice. After noting problems with the “patchwork of state regulations,” they wrote: The federal government has a compelling interest in the regulatory environment for health care professions because of its responsibility to patients covered by federal programs. … Equally important is the responsibility to all American taxpayers who fund the care provided under these programs to ensure that their tax dollars are spent efficiently. … Scope-of-practice regulations in all states should reflect the full extent not only of nurses but of each profession's education and training. (http://www.nationalacademies.org/hmd/~/media/Files/Report%20Files/2010/TheFuture-of-

These findings echo the dire circumstances reported in the 2013 Department of Health and Human Services report, Projecting the Supply and Demand for Primary Care Practitioners through 2020, which concluded that full utilization of nurse practitioners and PAs can reduce the physician shortage. In this scenario, in which physician demands are excessive, requiring oversight for other providers may be untenable. To adequately meet the demands for future health care needs, APRNs and PAs will need broader practice privileges than some states currently allow. This includes an imperative to afford full prescriptive authority.

Prescriptive Authority and Responsibility The possession of full prescriptive authority requires a somber responsibility. Whether you are reading this book as a student or as a practicing provider, it is essential to recognize the full obligation this requires. The safe and competent practice of prescribing and managing medications requires a sound understanding of drugs and the conditions that they are used to manage. It is our goal to help you lay that foundation. In the coming chapters, you will read about rational drug selection, writing prescriptions, and promoting positive outcomes. Then we will delve into the heart of pharmacology through a study of pharmacokinetics and pharmacodynamics as we prepare you for the study of individual drug categories.

2

Rational Drug Selection and Prescription Writing Abstract There are many different issues to acknowledge when writing a prescription. Important considerations include cost, current practice guidelines, medication interactions, side effects, and the need for monitoring. In addition to the process of choosing appropriate therapy, there are specific ways to construct a prescription, which will be discussed in this chapter.

Keywords prescribing; prescriptions; prescribing assistance; nurse practitioner; prescriptive authority

Responsibility of Prescribing As a practitioner, you will assume great responsibility when caring for patients. The ability to prescribe medications is both a privilege and a burden. Although you may be familiar with many drugs through your previous practice as a registered nurse or other member of the health care field, giving medications and prescribing medications are two very different things. There are many different issues to consider when writing a prescription, many of which we discuss in this chapter or in the previous chapter regarding prescriptive authority. The best way to keep your patients (and yourself) safe is to be prudent and deliberate in your decision-making process. Have a documented provider– patient relationship with the person for whom you are prescribing. Do not prescribe medications for family or friends or for yourself. Document a thorough

history and physical examination in your records. Include any discussions you have with the patient regarding risk factors, side effects, or therapy options. Have a documented plan regarding drug monitoring or titration, if applicable. If you consult additional providers, note that you did so. Finally, use the references provided in the following box to assist in safely and rationally choosing one medication over another.

Drug Selection Cost The cost of medications in the United States has risen steeply within the past 10 years. Increasing cost is related to multiple factors, including corporate competition. It is also noted that one of the reasons people do not adhere to their prescribed medication regimen is its excessive cost. Often we are so concerned with obtaining the right diagnosis and making our patient well that we overlook key pieces of information, including patient financial status. When patients cannot afford the drug you prescribe, they may not get well, even though they want to be compliant. It is of critical importance that providers ask patients if they have difficulty obtaining their medication because it is cost prohibitive. If you find that your patient is having difficulty purchasing the prescribed medications, consider changing pharmacies or drug regimens. The cost of a drug can vary widely between pharmacies, even within the same city. Many corporations have created generic $4 lists or special prescription programs that allow patients to fill their medications for a reasonable cost. In addition, all health plans through the ACA are required to include prescription drug coverage, although these vary greatly. As a prescriber, you need to be familiar with the local resources for medication assistance and low-cost medications.

Guidelines When in doubt, follow current guidelines for the treatment of a particular disease or symptom. Almost all medical and nursing societies have published guidelines, including the American Heart Association, the American College of Cardiology, the Infectious Diseases Society of America, and the American Diabetes Association. It is the provider's responsibility to keep abreast of new recommendations or changes in guidelines and to incorporate these into their prescribing practices. Although closely following the guidelines is desirable, we

must always take into account that our patients may not fit well into these guidelines and that individualized care is always best. In these cases, it is important to document the rationale for deviating from standard of care.

Availability Every facility and pharmacy provides drugs according to a formulary. This formulary is selected by a panel of pharmacists and providers and may be subject to following guidelines created by regulatory agencies, such as the Centers for Medicare and Medicaid Services (CMS). The formulary may also depend on regional and national drug supplies, drug costs and available rebates, and the presence of generic medications on the market. In short, the drug you want may not be available in your facility or at a specific pharmacy. This can affect your choice in medications. Become familiar with the formulary where you are employed, and know that it can change over time. Often there are substitutes or similar medications you can order in place of what you originally intended. For example, omeprazole may be indicated for the treatment of erosive esophagitis, but the formulary contains esomeprazole instead.

Interactions As noted throughout this text, there are very few medications that do not interact with either another medication or a food. Polypharmacy greatly increases the risk for interactions. Some of these interactions are negligible, but some can have life-threatening consequences. It is of crucial importance to ask the patient about all current drugs, including over-the-counter (OTC) medications and other herbal preparations. Many patients do not consider OTC or alternative pharmaceuticals as “medications” and may not mention them unless you ask specifically. When adding a new medication to a patient regimen, check for significant interactions. There are many resources that allow checks for interactions between multiple medications or foods at one time. If there is a low-risk interaction identified, you may find it acceptable to discuss this with your patient, document the conversation, and then prescribe the medication. If there is a relative or absolute contraindication to the proposed drug combination, it is best to choose an alternative if at all possible.

Side Effects All drugs have side effects. Some are adverse, and some may be beneficial. In addition, one patient may experience adverse effects to a medication, whereas another patient may not. It is important to note the pertinent side effects for each medication and to ask your patients about presence of symptoms after initiating, stopping, or changing a medication dose. When assessing the risk-to-benefit ratio of a medication, one must consider the severity of the side effects. If a patient started on a new antihypertensive medication has a decreased blood pressure, and therefore improvement in hypertension, but experiences fainting, a decrease in dose or a different medication should be considered.

Allergies At times, guidelines may suggest a particular drug for a specific ailment. Unfortunately, your patient may have an allergy to that medication or class of drug. It is of critical importance to determine the type of reaction and to document in the patient's chart. Then, selection of an appropriate drug may begin. In the case of severe allergy, such as anaphylaxis or swelling of the face, these drugs are absolutely contraindicated, but in the case of the patient who experienced vomiting or other similar reactions, the drug may be used again if necessary. The desired choice would be to use an alternate medication that is just as effective. For example, a patient with pyelonephritis who is allergic to penicillin can benefit from a fluoroquinolone instead.

Hepatic and Renal Function Many drugs are metabolized and eliminated by the liver and kidneys. If these systems are impaired, this can lead to increased adverse effects and possible medication overdose. Frequently, drugs have special decreased doses or different dosing schedules for patients with hepatic or renal impairment. This is known as hepatic dosing or renal dosing. Despite the known safety of decreasing doses in some drugs, if there is a different option available, it is prudent to choose a different medication. For example, morphine sulfate is highly metabolized by the kidneys. For patients with renal impairment, morphine can be used to treat pain, but the better choice would be fentanyl because fentanyl does not require a dose reduction in patients with renal impairment. Although some drugs are safe to

give or can be used with caution in patients with hepatic or renal dysfunction, other drugs are contraindicated in these patients and must be avoided at all costs.

Need for Monitoring Some drugs require frequent monitoring at initiation or throughout the duration of treatment. Examples of these medications include warfarin, lithium, opioids, and immunosuppressive therapies (tacrolimus, sirolimus). When levels of these drugs are not within therapeutic range, serious patient harm can occur. If a patient does not have the ability to attend frequent laboratory appointments, cannot take their medications reliably, or is not easily reachable by phone or electronically, it may be best to try and avoid these medications if possible.

Special Populations Populations that deserve special mention when thinking about medications include pregnant or nursing mothers, and older adults. These populations are addressed in depth in Unit III, Drug Therapy Across the Life Span. In addition, Life Span Tables are present in many of the chapters throughout the text to alert you to special considerations.

Prescriptions Necessities When writing any prescription, there are key elements that must be present to compose a complete prescription. An example of a common template for a written prescription is provided in Fig. 2.1. These elements include the following:

Common Example of a Written Prescription. DEA, U.S. Drug Enforcement Administration, DAW, dispense as written; NPI, National Provider Identifier. FIG. 2.1

• Prescriber name, license number, and contact information • Prescriber U.S. Drug Enforcement Administration (DEA) number, if applicable • Patient name and date of birth • Patient allergies • Name of medication • Indication of medication (e.g., atenolol for hypertension) • Medication strength (e.g., 25 mg, 500 mg/mL) • Dose of medication and frequency (e.g., 12.5 mg once daily) • Number of tablets or capsules to dispense • Number of refills If using an electronic medical record (EMR) to complete prescriptions, many of these elements will be mandatory for the provider, although many will already be completed by the EMR, including prescriber name and contact information. It is important to note the indication for the medication because many drugs are used for more than one purpose. This allows for the patient as well as other providers to understand your intent for prescribing this particular drug.

Types of Prescriptions Telephone A common and convenient way to create a new prescription or prescription refill is by telephone. A prescription can be called in to a pharmacy by you or a specified designee. This is often done by leaving a message with the correct information. Although this is a different way of prescribing, the necessities remain the same (see earlier section “Necessities”). Certain medications cannot be prescribed or refilled by telephone. These include medications within the schedule II category. Patients must have a written prescription for these medications. The only exception to this rule is during an emergency. In this case a telephone order can be used for a limited amount of medication, but a written prescription must be presented to the pharmacy within 7 days.

Written Providers have been writing prescriptions in the United States since the 1700s. Patients even received scripts during Prohibition in the 1920s to purchase alcohol for medicinal use (Fig. 2.2). Interestingly enough, these paper scripts did not look much different than they do nowadays. This is because the required elements for a complete prescription have not changed over the years. Although health care is making the transition to electronic prescriptions, many providers still use written scripts to prescribe medication. Written prescriptions, like telephone calls or electronic scripts, contain all the necessary elements as described earlier in this chapter. Although all the correct prompts for information may be prepopulated on your script, there are still some important points to consider. If you use a script with a different provider name or a generic script, make sure your name and contact information are printed legibly on the paper. Write all prescriptions in ink or indelible pencil. Avoid abbreviations such as U (units), MSO4 (morphine), or QD (daily) because these can increase errors and are therefore no longer acceptable. For a list of abbreviations to avoid, see Table 2.1.

FIG. 2.2

Prohibition Era Prescription for Alcohol.

TABLE 2.1 Abbreviations and Figures to Avoid Do Not Use

Preferred

U

Units

IU

International units

QD

Daily

QOD

Every other day

Trailing zero (X.0 mg)

Never trail (X mg)

Lack of leading zero (.X mg)

Always lead with a zero before a decimal point (0.X mg)

MS, MSO4, MgSO4

Morphine sulfate, magnesium sulfate

AS, AD, AU

Left ear, right ear, both ears

OS, OD, OU

Left eye, right eye, both eyes

In addition, never write prescriptions on presigned scripts or presign blank scripts for other providers or staff. Although this may seem like a convenient way to ensure availability to patients at all times, it is ultimately an unsafe practice. Finally, many facilities provide tamper-resistant scripts, and some states

require their use, especially in the prevention of substance misuse and abuse. A few tamper-resistant security features include Hidden Message Technology, which appears when the script is copied on a copy machine; Anti-Copy Coin Rub, which appears when rubbed with a coin; and distinctive security backgrounds. To learn more about these features, visit http://rxsecurityfeatures.com/.

E-Prescribing With the advent of the EMR, many pharmacies currently have capabilities to accept electronic prescriptions. In fact, CMS provides incentives for using an EMR to prescribe medications. This program, called Meaningful Use, is thought to contribute to increased patient safety and improved patient outcomes. Using an EMR allows the provider to select a specific, patient-selected pharmacy. After the correct medication information is entered, the prescription is automatically sent to the selected pharmacy. This is beneficial because there is direct transmission of information, making error less likely. In addition, the prescription can be ready for the patient when the patient leaves the facility—the patient does not need to drop off the paper script and then wait for a medication fill. Prior to the advent of Two-Factor Authentication software, limitations to eprescribing included scheduled medications. Currently, many companies like Duo, Nexmo, and OneLogin provide an extra layer of security through use of a smartphone to verify identity at the time of prescribing. These programs are incorporated into the EMR, allowing electronic prescribing of scheduled medications directly to the pharmacy. Unfortunately, many health care organizations still do not have a functional EMR, and many pharmacies still do not have the software capabilities to process these requests. In these cases, paper prescriptions are still necessary.

Refills There are a few things to consider when refilling a prescription. Questions you should ask yourself include the following:

• Is this a newer medication for this patient? • Am I changing dose or frequency of the medication? • Am I adding new medications to their regimen? • Is the patient having undesired side effects?

• When do I expect to follow up with this patient? • If the patient is requesting a refill by telephone, when was the last time I saw this patient? Do I need to see the patient again before refill? • Is this a schedule II medication? If the answer to any of these questions is “yes,” consider a shorter time between refills (1 to 3 months). The exception to this question is with schedule II medications. These are not eligible for refills and must have a new prescription each renewal period. When changing or adding to current medication regimens, it is prudent to follow up with the patient by phone or in person to assess changes. This time can be used to discuss new or increased side effects, check vital signs, obtain laboratory work, or make further adjustments. When a medication, such as warfarin, requires frequent monitoring with drug levels, an even shorter refill allotment is reasonable. If the patient has been maintained on the current dose of a medication for some time and remains stable, it is likely acceptable to continue to refill that medication for a longer time period (e.g., 12 months).

Assistance Applications for Tablets and Phones This textbook will be paramount in your learning, but it may not be convenient to carry around in the clinical setting. Although we encourage you to use this text to the fullest extent, there are many new applications and websites available to assist providers with safe prescribing (Box 2.1). However, it must be noted that all these tools still require common sense and good judgment on the part of the prescriber. As stated previously, one must take into account the individual patient and multiple other factors, including cost, side effects, and medication formularies. An application can assist you with the basic suggestions in dosing and duration, but ultimately there is no substitute for sound practice. Box 2.1

Helpful Applications and Websites for Safe

Prescribing Websites Epocrates: http://www.epocrates.com/ LexiComp: http://online.lexi.com/action/home Pepid: http://www.pepid.com/ Physicians’ Desk Reference (PDR): http://www.pdr.net/ UptoDate: http://www.uptodate.com/contents/search

Applications for Tablets, Phones Centers for Disease Control and Prevention Antibiotic Guidelines Elsevier Clinical Pharmacology Epocrates Pepid Prescriber's Letter

Collaboration As reflected in this chapter, writing a prescription safely can be complicated. It is strongly encouraged that you use all available resources, including your colleagues. Developing a relationship with your pharmacist can be one of the most helpful and fruitful relationships you cultivate. Because this is their specialty, pharmacists will likely have additional information on formulary and drug interactions as well as suggestions for adequate medication dosing. In some practices, pharmacists are responsible for medication initiation and titration based on standardized protocols. Infectious disease (ID) specialists can also be a helpful resource. Choosing an appropriate antimicrobial agent for a specific infectious process is often difficult for a new practitioner. A local ID specialist can provide guidance on resistance patterns, common local microbial flora, and correct doses, as well as on duration of treatment for specific infections.

3

Promoting Positive Outcomes of Drug Therapy Abstract Promoting positive drug therapy outcomes requires a thoughtful and deliberate proactive approach to medication management. In this chapter we explore ways the provider can improve patient outcomes. Emphasis is placed on monitoring therapy, promoting adherence to therapy, and educating the patient.

Keywords therapy outcomes; medication education; patient teaching; medication monitoring; medication adherence Selecting and prescribing the most appropriate drug (see Chapter 2) is just the first step in providing safe and competent medication therapy. Ensuring positive outcomes requires establishing a medication education plan, monitoring positive and negative patient responses, identifying and addressing issues of nonadherence, and managing the patient's complete medication regimen.

Medication Education Probably no other provider action influences the patient's commitment to carry out a medication plan more than medication education. This not only provides an opportunity to explain the importance of the medication but also allows the provider to dispel rumors about medications that often lead to therapy failures. Moreover, education reduces medication errors by empowering patients with accurate information and clear guidelines.

Medication Education Components There are basic components that should be included when teaching about any new medication. These are (1) medication name, (2) purpose, (3) dosing regimen, (4) administration, (5) adverse effects, (6) any special storage needs, (7) associated laboratory testing, (8) food or drug interactions, and (9) duration of therapy. Each of these is discussed in the following sections.

Medication Name Patients need to know the name of the medication they are taking. Unfortunately, when taking a medication history, we still have patients who refer to medications by their understood purpose (e.g., “blood pressure pill”) rather than by their name. This creates a challenge for the provider who needs to select appropriate therapy. It also increases the risk for medication errors. If we teach patients the medication names, we can avoid this concern. Patients should be encouraged to keep a list of their medications on their person at all times. Both the generic name and the brand (trade) name should be included. This can be especially important for the patient who travels and may be treated by providers unfamiliar with the patient's history. From the patient perspective, knowing the generic name empowers the patient to catch medication errors in the event that two different providers prescribe the same generic drug under different brand names.

Purpose Patients are more likely to participate in activities when they know those activities produce positive outcomes. The same is true of taking medications. Knowing the reason the medication is prescribed propels the patient to follow through with the medication plan because the patient is aware that this action helps achieve the therapeutic goal.

Dosing The dosing regimen, including the drug quantity and number of tablets or millimeters per dose, needs to be reviewed with the patient even though it is written on the prescription label. Doing this ensures that the patient understands how to take the medication and provides an opportunity for the patient to ask questions.

It is important to be specific when explaining the dosing regimen. For example, “four times a day” may be interpreted in various ways by different people. Can the medication be taken every 4 hours for four doses, or does it need to be spaced out evenly to every 6 hours? Does “once a day” mean that it can be taken at any time, or it is better to take the medication in the morning or evening hours? Patients need to know what to do if a dose is accidentally skipped. This is also a good time to explain why drugs should be taken exactly as prescribed.

Administration A common patient concern is whether medication should be taken with or without food. This routine information should be provided for all drugs. Patients also need to be informed of common administration needs that many of us take for granted. For example, suspensions should be shaken (or rolled, if shaking causes foaming) to equally disperse ingredients before administration. Finally, some drugs require a special apparatus for administration. Inhaled drugs are a common example. Patients need to see how these are administered and should be able to repeat a demonstration before leaving with a prescription. Many manufacturers provide a “dummy” device for teaching purposes.

Adverse Effects Some providers and other health care workers hesitate to discuss a drug's potential adverse effects. Some fear that doing so will lead to a patient's refusal to take the medications. Although that concern is understandable and the consequences may well be true, patients have a right to know of potential harms that may result from therapy. Therefore providers are ethically obligated to divulge adverse effects and other risks. That said, often the approach used in discussing these can make a difference in how patients view them. You probably know patients who worry about taking drugs when the product labeling (i.e., package insert) lists dozens of adverse effects. Patients may not know that, for most drugs, most adverse effects occur in less than 1% to 2% of those taking the drug. Most patients are unaware that the long list of adverse effects represents all effects reported during clinical trials, regardless of whether a direct association to the drug is known. Furthermore, labeling does not mention that sometimes the incidence of adverse effects in the placebo group is similarly high. For example, in clinical trials of lovastatin, 1.8% of subjects taking 40 mg reported myalgias; however, 1.7% of subjects taking a placebo also reported

myalgias. When discussing adverse effects, focus on the adverse effects that are common and avoid undue attention on rare and unanticipated effects. If complex effects such as liver injury or pancytopenia may occur, teach patients the signs and symptoms to report. Let patients know that many adverse effects—most commonly nausea and sedation—are usually temporary and go away with continued medication use. In these discussions, it is also beneficial to emphasize benefits over risks. Patients are often willing to endure short-term adverse effects for long-term health improvement.

Storage Storage is an important concern for some drugs. For example, some antibiotic suspensions, insulins, and rectal suppositories need to be refrigerated. Medications such as sublingual nitroglycerin and dabigatran (Pradaxa) need to be stored in their original container to prevent drug breakdown and loss of potency.

Laboratory Testing Laboratory testing is sometimes necessary to determine whether a medication remains safe and effective. For example, liver enzymes may need to be checked periodically for drugs that can cause liver damage. Serum drug levels may need to be checked when maintaining therapeutic levels is challenging. Patients need to know if special testing will be needed. They also need to know why the monitoring is necessary because those who understand the purpose are more likely to adhere to testing schedules. We recommend teaching what, when, where, why, and how when giving instructions (Box 3.1). Box 3.1

Patient Teaching for Drug Monitoring When testing is needed for monitoring, include the following when providing patient teaching. What: What test is needed? Patients like to know what test is needed. Rather than telling them that a blood test is needed, let them know the type of

blood test (e.g., a test of thyroid function or cholesterol levels). When: When is testing required? Testing can disrupt normal routines. Patients need to know, in advance, how often testing is needed so they can make plans. Where: Where will testing take place? In some practices, testing takes place at locations other than the primary clinic. Patients who are unfamiliar with the area need directions to the testing site and where to go after arrival. Why: Why is testing necessary? Testing is often expensive and disruptive to daily lives. These barriers are common reasons that patients miss appointments. If they understand the need for testing, they are more likely to adhere to testing schedules. How: How does the patient prepare for testing? Some tests require special preparation. For example, many blood tests require fasting. If exercise testing is needed, patients should be told to bring comfortable shoes. It is important to let patients know of anything they need to do prior to arrival.

Food or Drug Interactions Many medications interact with certain foods or other drugs (including alcohol and other recreational drugs). Patients need to know of any potential interactions and the consequence of those interactions. They also need to know if the problem with interactions can be solved by taking substances further apart or whether they need to avoid an interacting food or drug for the duration of therapy. For example, antacids may be taken with most drugs as long as administration is separated by 2 hours; however, patients taking metronidazole must avoid alcohol for the duration of therapy.

Duration of Therapy It is important to let the patient know if medication therapy is being prescribed for a short time (e.g., antibiotics for an acute infection) or whether ongoing longterm medication therapy is anticipated (e.g., thyroid hormone therapy for

hypothyroidism). Failure to recognize the need for prolonged therapy is a common reason patients stop medications prematurely when a prescription runs out.

Written Instructions Medication information is notoriously easy to forget, especially for patients taking numerous medications. We recommend accompanying all verbal education with written instructions. For those who are unable to read due to literacy or vision problems, video or audio instructions can be used. The Patient Protection and Affordable Care Act of 2010, Title V, defines health literacy as “the degree to which an individual has the capacity to obtain, communicate, process, and understand basic health information and services to make appropriate health decisions.” Low levels of health literacy can impair a patient’s ability to understand medication instructions. Best practices in developing written patient education materials abound in the literature. Table 3.1 provides a list of those for which there is greatest consensus. An excellent resource for writing patient education materials is available at http://www.cdc.gov/healthliteracy/pdf/Simply_Put.pdf. TABLE 3.1 Best Practices in Developing Written Patient Education Materials Practice

Rationale

Limit content

Focus on main points. Include only the most important-to-know content.

Place important People tend to remember the first things they read and may become information distracted toward the end. first Write in active voice

Active voice is more direct. Passive voice is less dynamic and may be confusing.

Include White space does not contain text or images. White space makes the adequate page feel less cluttered and less overwhelming. white space Use meaningful Illustrations are a useful way to break up text. Select images or illustrations drawings that have a purpose or that reinforce a point in the

handout. Avoid Use common terms in short, simple sentences that patients can easily professional understand. terminology Check for readability

Materials should be written at a lower education level that can be understood by most patients. Information for increasing readability is available at http://www.cdc.gov/healthliteracy/pdf/Simply_Put.pdf

Monitoring As mentioned in Chapter 2, monitoring is an important consideration in medication therapy. Ongoing monitoring of positive and negative patient responses—and acting on those responses in ways that increase benefit or decrease risk—is essential to ensure optimal outcomes. There are three primary reasons for drug monitoring: (1) determining therapeutic dosage, (2) evaluating medication adequacy, and (3) identifying adverse effects. Each of these purposes is discussed in the following sections. Table 3.2 provides some common examples of drugs that require periodic laboratory monitoring. TABLE 3.2 Selected Medications That Require Periodic Laboratory Monitoring Drug or Drug Category

Laboratory Testing Reason for Monitoring

ACEIs and ARBs

Potassium Serum creatinine

These drugs can cause hyperkalemia. Renal perfusion is dependent on angiotensin in some patients; increased creatinine may require change in medication.

Amiodarone

Liver function Thyroid function Pulmonary function and chest

Hepatotoxicity is an adverse effect. Either hypothyroidism or hyperthyroidism may occur. Pulmonary toxicity is not uncommon; effects may be permanent.

radiographs Anticonvulsants

Serum drug levels

Determination of therapeutic dosage is needed. Some have narrow therapeutic index.

Antidiabetic drugs

Serum glucose Hemoglobin A1c

Determination of glucose control is needed.

Digoxin

Digoxin level Serum electrolytes if at risk

The drugs have a narrow therapeutic index. Hypokalemia, hypomagnesemia, and hypocalcemia can increase toxicity risk.

Diuretics, potassiumsparing

Serum electrolytes

Hyperkalemia can reach dangerous levels. Hypocalcemia and hypomagnesemia may occur.

Diuretics, thiazide and loop

Serum electrolytes

Hypokalemia, hypomagnesemia, and hyponatremia are common. Thiazide diuretics can cause hypercalcemia; loop diuretics can cause hypocalcemia.

Lithium

CBC Lithium level Thyroid function Renal function Serum electrolytes

Lithium can cause leukocyte elevation. The drug has a narrow therapeutic index. Both hypothyroidism and hyperthyroidism may occur. Renal damage is a serious adverse effect. Nephrogenic diabetes insipidus may occur; hyponatremia can create complications.

Methotrexate

CBC Liver function Renal function

Pancytopenia, or a decrease of any of the blood cell types, may occur. Hepatotoxicity is an adverse effect. Renal toxicity is an adverse effect.

NSAIDs (longterm use)

CBC Serum creatinine

Anemia may occur, especially if there is bleeding, which may be occult. Prostaglandin inhibition may decrease

Statins

Liver function

renal perfusion, causing injury. Rare but serious liver injury has occurred.

Liver function Creatine kinase Lipid panel

Elevations in liver enzymes may be associated with injury. Creatine kinase can determine whether muscle pain is caused by injury secondary to drug use. Lipids are checked to determine effect.

Thiazolidinediones Liver function

These drugs are associated with a risk for hepatotoxicity.

Thyroid hormone

TSH, T4

Monitoring is needed to optimize therapy.

Warfarin

PT/INR

Monitoring is needed to maintain therapeutic range.

ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CBC, complete blood count; NSAIDs, nonsteroidal antiinflammatory drugs; PT/INR, prothrombin time/international normalized ratio; TSH, thyroid-stimulating hormone; T4, thyroxine.

Determining Therapeutic Dosage Many drugs have a narrow therapeutic index (NTI) (see Chapter 4). Examples include carbamazepine, digoxin, lithium, phenytoin, and theophylline. For these drugs, the difference between an effective dose and a lethal dose is small. To ensure safety, periodic measurement of serum drug levels is needed when drugs with an NTI are prescribed. This not only determines whether the drug is in a therapeutic range but also provides an opportunity for fine-tuning of dosage. If a drug is nearing a toxic level or a subtherapeutic level, the provider will make a dosage adjustment accordingly. How often monitoring is needed varies for each drug. In addition, patient factors such as poor liver or renal function may determine the frequency of drug level monitoring. For some drugs with an NTI, a therapeutic dosage is determined by means other than the serum drug level. Warfarin is a drug that illustrates this method. Instead of ordering a serum warfarin level, optimal dosing is determined by measures of prothrombin time with international normalized ratio (PT/INR).

Evaluating Medication Adequacy

For some drugs, evaluation of effectiveness can be determined easily. For example, if an analgesic is given, effectiveness is determined by asking the patient to rate the pain on a scale of 0 to 10. Similarly, the adequacy of an antihypertensive medication can be evaluated by checking the patient's blood pressure. However, evaluating medication adequacy is not so simple for some conditions. Some conditions do not cause obvious signs or symptoms. Hyperlipidemia is a common example; signs and symptoms often do not appear until after decades of accumulated damage have occurred. Other conditions may be manifested by signs and symptoms that are not easily quantifiable. A common example of this condition is hyperglycemia associated with diabetes. Some people display obvious signs and symptoms when hyperglycemic, whereas for others, the evidence is much more subtle. For conditions such as hyperlipidemia and hyperglycemia, laboratory testing offers a precisely quantifiable measure that can be used to gauge the effectiveness of medication therapy. For example, a hemoglobin A1c level can be used to evaluate glucose control, and lipid panels can used to determine the effectiveness of hyperlipidemia management.

Identifying Adverse Effects One of the most common uses of drug monitoring is that of monitoring for harm. This is a proactive undertaking to identify problems early, before they progress to the point of harm. Many drugs are potentially dangerous. For these, monitoring depends on the type of potential injury. For example, if a drug can cause liver injury, periodic monitoring of liver enzymes (and possibly other tests of liver function) is needed. If a drug can cause bone marrow suppression, periodic monitoring of a complete blood count to assess for anemia, leukopenia, or thrombocytopenia is warranted. In addition, baseline laboratory studies are done before initiating therapy.

Adherence Medication nonadherence costs the U.S. health care system approximately $290 billion each year. It is often directly responsible for disease exacerbations, avoidable hospitalizations, transitioning to long-term (i.e., “nursing home”) care, and premature deaths.

Medication adherence can be defined as the extent to which patients take their medications as prescribed by the provider and agreed to by the patient.a The patient who adheres to the agreed-on medication regimen takes the medication in the prescribed dose at the prescribed frequency for the length of time indicated. In 2013, the National Community Pharmacists Association (NCPA) released Medication Adherence in America: A National Report Card (available at http://www.ncpa.co/adherence/AdherenceReportCard_Full.pdf with yearly progress reports at http://www.ncpanet.org/solutions/adherence-simplify-mymeds). The NCPA report identifies six nonadherent behaviors. They are, in the percentage of frequency, as follows:

• Missed a dose (57%) • Forgot to take a dose (30%) • Did not refill the medication in time (28%) • Took a lower than prescribed dose (22%) • Did not refill the medication (20%) • Stopped taking the medication (14%) The reasons given by patients to explain their nonadherence provide additional insight. Again, in the frequency of occurrence, they are as follows:

• Forgot to take it (42%) • Ran out (34%) • Was away from home (27%) • Was trying to save money (22%) • Didn't like the side effects (21%) • Was too busy (17%) • The medicine wasn't working (17%) • Didn't believe the medicine was necessary (16%) • Didn't like taking the medicine (12%) These documents can offer valuable insight for the health care provider. Moreover, they beg the question, “What could the provider have done differently to address issues of nonadherence proactively?” In examining these, five primary patterns emerge. These are: (1) forgetfulness,

(2) lack of planning, (3) cost, (4) dissatisfaction, and (5) altered dosing. An honest and open discussion that respects both the patient and provider perspectives can be an important facilitator to promoting positive outcomes. Individualized solutions that address the specific patient's concerns are those most likely to be successful.

Forgetfulness The most common reason cited for nonadherence was that the patient simply forgot to take the medication. Studies have demonstrated that medications are easier to remember if they are aligned with common daily activities. For example, morning medications may be taken on first arising (if they should be taken on an empty stomach) or with breakfast (if they should be taken with food). Doing this establishes habits, which are more difficult to forget. Several memory aids are available to help patients remember to take their medications. Drug organizers are probably the most common tool used. If these are filled at the beginning of each week, the patient can tell at a glance if medications have been taken on any given day. Numerous apps are also available for various electronic devices. These can be programmed to alarm or deliver a verbal message when it is time to take a drug. Similarly, digital assistances (e.g., Amazon's Alexa and Google Assistant) can be programmed to alert patients when it is time to take their medications. Some patients have found that medication administration records (MARs), similar to MARs used by nurses in hospitals, can be helpful. An advantage of personalized MARs is the ability to tailor them to meet patient's vision and literacy needs.

Lack of Planning Aligned closely with forgetfulness is the lack of planning. In this category, we include those statements aligned with failure to refill medications whether because the patient was too busy, away from home, or ran out for other reasons. Most pharmacies offer reminder notices, either by email or automated phone calls, as part of their regular services. If being “too busy” is a concern, a pharmacy that offers a home delivery service or a mail delivery service is a viable solution.

Cost As mentioned in Chapter 2, costs should be considered initially when selecting an appropriate drug. When possible, use of generic drugs, drugs on formulary, or drugs that are a part of a discount pharmacy program can reduce out of pocket costs. Sometimes, however, there are no adequate substitutions for a necessary but expensive drug. Fortunately, prescription assistance programs (PAPs), also called patient assistance programs and pharmaceutical assistance programs, are widely available. These offer steeply discounted drugs for those who meet eligibility requirements. There are three sources for PAPs: pharmaceutical companies, government-run programs, and nonprofit organizations. Table 3.3 offers a program sampling. If you do not find what you need here, your likely best resource for reliable information is a local pharmacist. Warn patients to beware of discount cards that are not affiliated with known reputable organizations. Unfortunately, some criminals use applications for fake cards for illegal purposes. TABLE 3.3

Dissatisfaction The issue of dissatisfaction as a reason for nonadherence highlights the need to identify what medications are taken and to discuss any concerns with the patient at each encounter. It is essential to uncover the reason for dissatisfaction (e.g., adverse effects, inconvenient dosing, or a perception that a drug is ineffective). Often the problem can be easily addressed by simple interventions. For example, taking medications with food can reduce adverse effects of nausea and gastrointestinal distress in many instances. Changing to a sustained-release drug may be all that is necessary to address problems with inconvenient dosing. If the patient believes a drug is ineffective, it becomes important to discuss patient expectations of drug therapy and what can be realistically achieved. For some conditions (e.g., obesity), change may come slowly. For others (e.g., hypertension), the medication may cause the patient to feel worse without a perceived benefit. If the drug is truly an important one, this may be a good time to explore with the patient any consequences of not taking the drug and whether the patient is willing to assume those risks. In some instances the patient may decide to assume those risks rather than to take the medication. It is within the patient's right to do so.

Altered Dosing It is concerning that more than 20% of patients in the NCPA report took lower than the prescribed dose. The reasons were not made clear; however, the consequence is this, because a drug must reach a therapeutic level to be effective, a subtherapeutic dose is no better than no dose at all! Furthermore, in the case of certain antimicrobial drugs, subtherapeutic levels may cause harm if the bacteria develop resistance as a result. This finding emphasizes the necessity of not only reviewing which medications are taken at each encounter but also asking whether the medications are taken as prescribed. If dosing is altered, it is imperative to determine how and why, and then to educate the patient regarding how alterations in dosing affect outcomes.

Managing Medication Therapy

In addition to the medication review undertaken at each patient encounter, a more comprehensive and deliberate review is needed periodically (at least annually). This review should be approached with the intent purpose of determining whether there are better options for medication therapy. Inherent questions that must be asked about each drug include the following:

• Is each medication accomplishing its intended purpose? • Is each medication still necessary? • Has the patient's condition changed? • Do adverse effects or risks outweigh the benefits that some drugs provide? • What would happen if some medications were no longer prescribed? • What problems does each medication create for the patient? • Is a medication problem amplified by other drugs the patient is taking? • If a medication is necessary but problematic, are drugs with fewer adverse effects available? • If polypharmacy is an issue, are there ways to decrease the number of medications? • Will a combination drug simplify management? • Is a single drug available (and desirable) for management of two different conditions? Ideally, these reviews should be carried out in collaboration with the patient or patient's family so that nothing is overlooked. Medication regimens can then be optimized to eliminate unnecessary drugs, add new drugs, if necessary, and ultimately improve patient satisfaction with care.

Summary We have examined four opportunities to promote positive outcomes in drug therapy. Patients need adequate drug education to take drugs correctly and to avoid complications associated with therapy. Monitoring provides a method of ensuring safe and effective therapy. Promoting adherence, by addressing

common causes of nonadherence proactively, can ensure ongoing therapy without interruption. Finally, scheduled medication reviews with the intent to optimize medication regimens, based on patient experiences and needs, can help promote positive outcomes. aThe addition of “agreed to by the patient” distinguishes the definition of

medication adherence from medication compliance. The concept of medication compliance has fallen out of favor because it views the provider from the perspective of an authoritarian who dictates treatment rather than a provider who makes decisions that consider the patient's preferences and values.

UNIT II

Basic Principles of Pharmacology OUTLINE 4 Pharmacokinetics, Pharmacodynamics, and Drug Interactions 5 Adverse Drug Reactions and Medication Errors 6 Individual Variation in Drug Responses 7 Genetic and Genomic Considerations in Pharmacotherapeutics

4

Pharmacokinetics, Pharmacodynamics, and Drug Interactions Abstract In order to adequately understand drug actions, reactions, and interactions, we must be aware of the processes that drugs undergo and the mechanisms by which drugs exert their effects. This knowledge has important implications for safe prescribing and drug monitoring. In this chapter, we explore pharmacokinetic and pharmacodynamic processes and how they affect the way people experience drug effects.

Keywords pharmacokinetics; pharmacodynamics; drug interactions; absorption; distribution; metabolism; elimination; half-life; drug receptors

Pharmacokinetics Pharmacokinetics is the study of drug movement throughout the body.a There are four basic pharmacokinetic processes: absorption, distribution, metabolism, and excretion (Fig. 4.1). Absorption is the drug's movement from its site of administration into the blood. Distribution is the drug's movement from the blood to the interstitial space of tissues and from there into cells. Metabolism (biotransformation) is the enzymatically mediated alteration of drug structure. Excretion is the movement of drugs and their metabolites out of the body. The combination of metabolism and excretion is called elimination. The four pharmacokinetic processes, acting in concert, determine the concentration of a

drug at its sites of action.

The Four Basic Pharmacokinetic Processes. Dotted lines represent membranes that must be crossed as drugs move throughout the body. GI, Gastrointestinal. FIG. 4.1

By applying knowledge of pharmacokinetics to drug therapy, we can help maximize beneficial effects and minimize harm. Recall that the intensity of the response to a drug is directly related to the concentration of the drug at its site of action. To maximize beneficial effects, a drug must achieve concentrations that are high enough to elicit desired responses; to minimize harm, we must avoid concentrations that are too high. This balance is achieved by selecting the most appropriate route, dosage, and dosing schedule.

Passage of Drugs Across Membranes All four phases of pharmacokinetics—absorption, distribution, metabolism, and excretion—involve drug movement. To move throughout the body, drugs must cross membranes. Drugs cross membranes as they pass from the site of administration into the bloodstream and, subsequently, as they leave the vascular system to reach the site of action. In addition, drugs must cross membranes to undergo metabolism and excretion. Accordingly, the factors that determine the passage of drugs across biologic membranes have a profound influence on all aspects of pharmacokinetics. Biologic membranes are composed of layers of individual cells. The cells

composing most membranes are very close to one another—so close, in fact, that drugs must usually pass through cells, rather than between them, to cross the membrane. Hence the ability of a drug to cross a biologic membrane is determined primarily by its ability to pass through single cells.

Three Ways to Cross a Cell Membrane The three most important ways by which drugs cross cell membranes are (1) passage through channels or pores, (2) passage with the aid of a transport system, and (3) direct penetration of the membrane. Of the three, direct penetration of the membrane is most common. Channels and Pores Very few drugs cross membranes through channels or pores. The channels in membranes are extremely small and are specific for certain molecules. Consequently, only the smallest of compounds, such as potassium and sodium, can pass through these channels and then only if the channel is the right one. Transport Systems Transport systems are carriers that can move drugs from one side of the cell membrane to the other side. All transport systems are selective. Whether a transporter will carry a particular drug depends on the drug's structure. Transport systems are an important means of drug transit. For example, certain orally administered drugs could not be absorbed unless there were transport systems to move them across the membranes that separate the lumen of the intestine from the blood. A number of drugs could not reach intracellular sites of action without a transport system to move them across the cell membrane. One transporter, known as P-glycoprotein (PGP) or multidrug transporter protein, deserves special mention. PGP is a transmembrane protein that transports a wide variety of drugs out of cells. Direct Penetration of the Membrane For most drugs, movement throughout the body is dependent on the ability to penetrate membranes directly because (1) most drugs are too large to pass through channels or pores and (2) most drugs lack transport systems to help them cross all of the membranes that separate them from their sites of action, metabolism, and excretion. A general rule in chemistry states that “like dissolves like.” Membranes are

composed primarily of lipids; therefore, to directly penetrate membranes, a drug must be lipid soluble (lipophilic).

Polar Molecules and Ions Certain kinds of molecules are not lipid soluble and therefore cannot penetrate membranes. This group consists of polar molecules and ions.

Polar Molecules Polar molecules are molecules that have no net charge; however, they have an uneven distribution of electrical charge. That is, positive and negative charges within the molecule tend to congregate separately from one another. Water is the classic example. As depicted in Fig. 4.2, the electrons (negative charges) in the water molecule spend more time in the vicinity of the oxygen atom than in the vicinity of the two hydrogen atoms. As a result, the area around the oxygen atom tends to be negatively charged, whereas the area around the hydrogen atoms tends to be positively charged. In accord with the “like dissolves like” rule, polar molecules will dissolve in polar solvents (such as water) but not in nonpolar solvents (such as lipids).

Polar molecules. (A) Stippling shows the distribution of electrons within the water molecule. As indicated at the lower right, water’s electrons spend more time near the oxygen atom than near the hydrogen atoms, making the area near the oxygen atom somewhat negative and the area near the hydrogen atoms more positive. (B) Gentamicin is a polar drug. The 2-OH groups of gentamicin attract electrons, thereby causing the area around these groups to be more negative than the rest of the molecule. FIG. 4.2

Ions Ions are defined as molecules that have a net electrical charge (either positive or negative). Except for very small molecules, ions are unable to cross membranes; therefore they must become nonionized to cross from one side to the other. Many drugs are either weak organic acids or weak organic bases, which can exist in charged and uncharged forms. Whether a weak acid or base carries an electrical charge is determined by the pH of the surrounding medium. Acids tend to ionize in basic (alkaline) media, whereas bases tend to ionize in acidic media. Therefore drugs that are weak acids are best absorbed in an acidic environment such as gastric acid because they remain in a nonionized form. When aspirin molecules pass from the stomach into the small intestine, where the environment is relatively alkaline, more of the molecules change to their ionized form. As a result, absorption of aspirin from the intestine is impeded. pH Partitioning (Ion Trapping) Because the ionization of drugs is pH dependent, when the pH of the fluid on one side of a membrane differs from the pH of the fluid on the other side, drug molecules tend to accumulate on the side where the pH most favors their ionization. Accordingly, because acidic drugs tend to ionize in basic media and because basic drugs tend to ionize in acidic media, when there is a pH gradient between two sides of a membrane, the following occur:

• Acidic drugs accumulate on the alkaline side. • Basic drugs accumulate on the acidic side. The process whereby a drug accumulates on the side of a membrane where the pH most favors its ionization is referred to as pH partitioning or ion trapping.

Absorption Absorption is defined as the movement of a drug from its site of administration into the systemic circulation. The rate of absorption determines how soon effects will begin. The amount of absorption helps determine how intense effects will be. Two other terms associated with absorption are chemical equivalence and bioavailability. Drug preparations are considered chemically equivalent if they

contain the same amount of the identical chemical compound (drug). Preparations are considered equal in bioavailability if the drug they contain is absorbed at the same rate and to the same extent. It is possible for two formulations of the same drug to be chemically equivalent while differing in bioavailability. The concept of bioavailability is discussed further in Chapter 6.

Factors Affecting Drug Absorption The rate at which a drug undergoes absorption is influenced by the physical and chemical properties of the drug and by physiologic and anatomic factors at the absorption site. Rate of Dissolution Before a drug can be absorbed, it must first dissolve. Hence the rate of dissolution helps determine the rate of absorption. Drugs in formulations that allow rapid dissolution have a faster onset than drugs formulated for slow dissolution. Surface Area The surface area available for absorption is a major determinant of the rate of absorption. When the surface area is larger, absorption is faster. For this reason, absorption of orally administered drugs is usually greater from the small intestine rather than from the stomach. (Recall that the small intestine, because of its lining of microvilli, has an extremely large surface area, whereas the surface area of the stomach is relatively small.) Blood Flow Drugs are absorbed most rapidly from sites where blood flow is high because blood containing a newly absorbed drug will be replaced rapidly by drug-free blood, thereby maintaining a large gradient between the concentration of drug outside the blood and the concentration of drug in the blood. The greater the concentration gradient, the more rapid absorption will be. Lipid Solubility As a rule, highly lipid-soluble drugs are absorbed more rapidly than drugs whose lipid solubility is low. This occurs because lipid-soluble drugs can readily cross the membranes that separate them from the blood, whereas drugs of low lipid solubility cannot.

pH Partitioning pH partitioning can influence drug absorption. Absorption will be enhanced when the difference between the pH of plasma and the pH at the site of administration is such that drug molecules will have a greater tendency to be ionized in the plasma.

Characteristics of Commonly Used Routes of Administration For each of the major routes of administration—oral (PO), intravenous (IV), intramuscular (IM), and subcutaneous (subQ)—the pattern of drug absorption (i.e., the rate and extent of absorption) is unique. Consequently, the route by which a drug is administered significantly affects both the onset and the intensity of effects. The distinguishing characteristics of the four major routes are summarized in Table 4.1. Additional routes of administration (e.g., topical, transdermal, inhaled) each have unique characteristics that are addressed throughout the book as we discuss specific drugs that use them. TABLE 4.1

Distribution

Distribution is defined as the movement of drugs from the systemic circulation to the site of drug action. Drug distribution is determined by three major factors: blood flow to tissues, the ability of a drug to exit the vascular system, and, to a lesser extent, the ability of a drug to enter cells.

Blood Flow to Tissues In the first phase of distribution, drugs are carried by the blood to the tissues and organs of the body. The rate at which drugs are delivered to a particular tissue is determined by blood flow to that tissue. Because most tissues are well perfused, regional blood flow is rarely a limiting factor in drug distribution. There are two pathologic conditions—abscesses and tumors—in which low regional blood flow can affect drug therapy. An abscess has no internal blood vessels; therefore, because abscesses lack a blood supply, antibiotics cannot reach the bacteria within. Accordingly, if drug therapy is to be effective, the abscess must usually be surgically drained. Solid tumors have a limited blood supply. Although blood flow to the outer regions of tumors is relatively high, blood flow becomes progressively lower toward the core. As a result, it may not be possible to achieve high drug levels deep inside tumors. Limited blood flow is a major reason that solid tumors are resistant to drug therapy.

Exiting the Vascular System After a drug has been delivered to an organ or tissue by blood circulation, the next step is to exit the vasculature. Because most drugs do not produce their effects within the blood, the ability to leave the vascular system is an important determinant of drug actions. Drugs in the vascular system leave the blood at capillary beds. Typical Capillary Beds Most capillary beds offer no resistance to the departure of drugs because, in most tissues, drugs can leave the vasculature simply by passing through pores in the capillary wall. Because drugs pass between capillary cells rather than through them, movement into the interstitial space is not impeded. The exit of drugs from a typical capillary bed is depicted in Fig. 4.3.

Drug Movement at Typical Capillary Beds. In most capillary beds, “large” gaps exist between the cells that compose the capillary wall. Drugs and other molecules can pass freely into and out of the bloodstream through these gaps. As illustrated, lipid-soluble compounds can also pass directly through the cells of the capillary wall. FIG. 4.3

Blood–Brain Barrier The term blood–brain barrier (BBB) refers to the unique anatomy of capillaries in the central nervous system (CNS). As shown in Fig. 4.4, there are tight junctions between the cells that compose the walls of most capillaries in the CNS. These junctions are so tight that they prevent drug passage. Consequently, to leave the blood and reach sites of action within the brain, a drug must be able to pass through cells of the capillary wall. Only drugs that are lipid soluble or have a transport system can cross the BBB to a significant degree.

Drug Movement Across the Blood-Brain Barrier. Tight junctions between cells that compose the walls of capillaries in the central nervous system prevent drugs from passing between cells to exit the vascular system. Consequently, to reach sites of action within the brain, a drug must pass directly through cells of the capillary wall. To do this, the drug must be lipid soluble or be able to use an existing transport system. FIG. 4.4

Recent evidence indicates that, in addition to tight junctions, the BBB has another protective component: PGP. As noted earlier, PGP is a transporter that pumps a variety of drugs out of cells. In capillaries of the CNS, PGP pumps drugs back into the blood and thereby limits their access to the brain. The BBB is not fully developed at birth. As a result, newborns have heightened sensitivity to medicines that act on the brain. Likewise, neonates are especially vulnerable to CNS toxicity. Placental Drug Transfer The membranes of the placenta separate the maternal circulation from the fetal circulation (Fig. 4.5). However, the membranes of the placenta do NOT constitute an absolute barrier to the passage of drugs. The same factors that determine the movement of drugs across other membranes determine the movement of drugs across the placenta. Most drugs cross the placenta via simple diffusion. Lipid-soluble, nonionized compounds readily pass from the maternal bloodstream into the blood of the fetus. In contrast, compounds that are ionized, highly polar, or protein bound are largely excluded—as are drugs that are substrates for the PGP transporter that can pump a variety of drugs out of placental cells into the maternal blood.

Placental Drug Transfer. To enter the fetal circulation, drugs must cross membranes of the maternal and fetal vascular systems. Lipid-soluble drugs can readily cross these membranes and enter the fetal blood, whereas ions and polar molecules are prevented from reaching the fetal blood. FIG. 4.5

Protein Binding Drugs can form reversible bonds with various proteins in the body. Of all the proteins with which drugs can bind, plasma albumin is the most important. Like other proteins, albumin is a large molecule. Because of its size, albumin is too large to leave the bloodstream. Fig. 4.6 depicts the binding of drug molecules to albumin. Note that the drug molecules are much smaller than albumin. As indicated by the two-way arrows, binding between albumin and drugs is reversible. Hence drugs may be bound or unbound (free).

Protein Binding of Drugs. (A) Albumin is the most prevalent protein in plasma and the most important of the proteins to which drugs bind. (B) Only unbound (free) drug molecules can leave the vascular system. Bound molecules are too large to fit through the pores in the capillary wall. FIG. 4.6

Even though a drug can bind albumin, only some molecules will be bound at any moment. The percentage of drug molecules that are bound is determined by the strength of the attraction between albumin and the drug. For example, the attraction between albumin and the anticoagulant warfarin is strong, causing nearly all (99%) of the warfarin molecules in plasma to be bound, leaving only 1% free. On the other hand, the attraction between the antibiotic gentamicin and albumin is relatively weak; less than 10% of the gentamicin molecules in plasma are bound, leaving more than 90% free. An important consequence of protein binding is restriction of drug distribution. Because albumin is too large to leave the bloodstream, drug molecules that are bound to albumin cannot leave either (see Fig. 4.6B). As a result, bound molecules cannot reach their sites of action or undergo metabolism or excretion until the drug–protein bond is broken so that the drug is free to leave the circulation. In addition to restricting drug distribution, protein binding can be a source of drug interactions. As suggested by Fig. 4.6A, each molecule of albumin has only a few sites to which drug molecules can bind. Because the number of binding sites is limited, drugs with the ability to bind albumin will compete with one

another for those sites. As a result, one drug can displace another from albumin, causing the free concentration of the displaced drug to rise, thus increasing the intensity of drug responses. If plasma drug levels rise sufficiently, toxicity can result.

Entering Cells Many drugs produce their effects by binding with receptors located on the external surface of the cell membrane; however, some drugs must enter cells to reach their sites of action, and practically all drugs must enter cells to undergo metabolism and excretion. The factors that determine the ability of a drug to cross cell membranes are the same factors that determine the passage of drugs across all other membranes, namely lipid solubility, the presence of a transport system, or both.

Metabolism Drug metabolism, also known as biotransformation, is defined as the enzymatic alteration of drug structure. Most drug metabolism takes place in the liver.

Hepatic Drug-Metabolizing Enzymes Most drug metabolism that takes place in the liver is performed by the hepatic microsomal enzyme system, also known as the P450 system. The term P450 refers to cytochrome P450, a key component of this enzyme system. It is important to appreciate that cytochrome P450 is not a single molecular entity but rather a group of 12 closely related enzyme families. Three of the cytochrome P450 (CYP) families—designated CYP1, CYP2, and CYP3— metabolize drugs. The other nine families metabolize endogenous compounds (e.g., steroids, fatty acids). Each of the three P450 families that metabolize drugs is composed of multiple forms, each of which metabolizes only certain drugs. To identify the individual forms of cytochrome P450, designations such as CYP1A2, CYP2D6, and CYP3A4 are used to indicate specific members of the CYP1, CYP2, and CYP3 families, respectively.

Therapeutic Consequences of Drug Metabolism Drug metabolism has six possible consequences of therapeutic significance:

• Accelerated renal excretion of drugs • Drug inactivation • Increased therapeutic action • Activation of prodrugs • Increased toxicity • Decreased toxicity Accelerated Renal Drug Excretion The most important consequence of drug metabolism is promotion of renal drug excretion. The kidneys, which are the major organs of drug excretion, are unable to excrete drugs that are highly lipid soluble. Hence, by converting lipid-soluble drugs into more hydrophilic (water-soluble) forms, metabolic conversion can accelerate renal excretion of many agents. Drug Inactivation Drug metabolism can convert pharmacologically active compounds to inactive forms. This is the most common end result of drug metabolism. Increased Therapeutic Action Metabolism can increase the effectiveness of some drugs. For example, metabolism converts codeine into morphine. The analgesic activity of morphine is so much greater than that of codeine that formation of morphine may account for virtually all the pain relief that occurs after codeine administration. Activation of Prodrugs A prodrug is a compound that is pharmacologically inactive as administered and then undergoes conversion to its active form through metabolism. Prodrugs have several advantages; for example, a drug that cannot cross the BBB may be able to do so as a lipid-soluble prodrug that is converted to the active form in the CNS. Increased or Decreased Toxicity By converting drugs into inactive forms, metabolism can decrease toxicity. Conversely, metabolism can increase the potential for harm by converting relatively safe compounds into forms that are toxic. Increased toxicity is illustrated by the conversion of acetaminophen into a hepatotoxic metabolite. It

drug that undergoes rapid hepatic metabolism is often administered parenterally. This permits the drug to temporarily bypass the liver, thereby allowing it to reach therapeutic levels in the systemic circulation before being metabolized. Nutritional Status Hepatic drug-metabolizing enzymes require a number of cofactors to function. In the malnourished patient, these cofactors may be deficient, causing drug metabolism to be compromised. Competition Between Drugs When two drugs are metabolized by the same metabolic pathway, they may compete with each other for metabolism and may thereby decrease the rate at which one or both agents are metabolized. If metabolism is depressed enough, a drug can accumulate to dangerous levels.

Enterohepatic Recirculation As noted earlier and depicted in Fig. 4.7, enterohepatic recirculation is a repeating cycle in which a drug is transported from the liver into the duodenum (through the bile duct) and then back to the liver (through the portal blood). However, it is important to note that only certain drugs are affected. Specifically, the process is limited to drugs that have undergone glucuronidation, a process that converts lipid-soluble drugs to water-soluble drugs by binding them to glucuronic acid. After glucuronidation, these drugs can enter the bile and then pass to the duodenum. In the intestine, some drugs can be hydrolyzed by intestinal β-glucuronidase, an enzyme that breaks the bond between the original drug and the glucuronide moiety, thereby releasing the free drug. Because the free drug is more lipid soluble than the glucuronidated form, the free drug can undergo reabsorption across the intestinal wall, followed by transport back to the liver, where the cycle can start again. Because of enterohepatic recycling, drugs can remain in the body much longer than they otherwise would.

Movement of Drugs After Gastrointestinal (GI) Absorption. All drugs absorbed from sites along the GI tract—stomach, small intestine, and large intestine (but not the oral mucosa or distal rectum)—must go through the liver, through the portal vein, on their way to the heart and then the general circulation. For some drugs, passage is uneventful. Others undergo extensive hepatic metabolism, and still others undergo enterohepatic recirculation, a repeating cycle in which a drug moves from the liver into the duodenum (through the bile duct) and then back to the liver (through the portal blood). As discussed in the text under Enterohepatic Recirculation, the process is limited to drugs that have first undergone hepatic glucuronidation. FIG. 4.7

Excretion Drug excretion is defined as the removal of drugs from the body. Drugs and their metabolites can exit the body in urine, bile, sweat, saliva, breast milk, and expired air. The most important organ for drug excretion is the kidney.

Renal Drug Excretion The kidneys account for the majority of drug excretion. When the kidneys are healthy, they serve to limit the duration of action of many drugs. Conversely, if renal failure occurs, both the duration and intensity of drug responses may increase. Steps in Renal Drug Excretion Urinary excretion is the net result of three processes: (1) glomerular filtration,

(2) passive tubular reabsorption, and (3) active tubular secretion. Glomerular filtration. Renal excretion begins at the glomerulus of the kidney tubule. As blood flows through the glomerular capillaries, fluids and small molecules—including drugs —are forced through the pores of the capillary wall. This process, called glomerular filtration, moves drugs from the blood into the tubular urine. Blood cells and large molecules (e.g., proteins) are too big to pass through the capillary pores and therefore do not undergo filtration. Because large molecules are not filtered, drugs bound to albumin remain in the blood. Passive tubular reabsorption. As depicted in Fig. 4.8, the vessels that deliver blood to the glomerulus return to proximity with the renal tubule at a point distal to the glomerulus. At this distal site, drug concentrations in the blood are lower than drug concentrations in the tubule. This concentration gradient acts as a driving force to move drugs from the lumen of the tubule back into the blood. Because lipid-soluble drugs can readily cross the membranes that compose the tubular and vascular walls, drugs that are lipid soluble undergo passive reabsorption from the tubule back into the blood. In contrast, drugs that are not lipid soluble (ions and polar compounds) remain in the urine to be excreted.

FIG. 4.8

Renal Drug Excretion. MW, Molecular weight.

Active tubular secretion. There are active transport systems in the kidney tubules that pump drugs from the blood to the tubular urine. These pumps have a relatively high capacity and play a significant role in excreting certain compounds. Factors That Modify Renal Drug Excretion

Renal drug excretion varies from patient to patient. Conditions such as chronic renal disease may cause profound alterations. Three other important factors to consider are pH-dependent ionization, competition for active tubular transport, and patient age. pH-dependent ionization. The phenomenon of pH-dependent ionization can be used to accelerate renal excretion of drugs. Recall that passive tubular reabsorption is limited to lipidsoluble compounds. Because ions are not lipid soluble, drugs that are ionized at the pH of tubular urine will remain in the tubule and be excreted. Consequently, by manipulating urinary pH in such a way as to promote the ionization of a drug, we can decrease passive reabsorption back into the blood and can thereby hasten the drug's elimination. This principle has been used to promote the excretion of poisons and medications that have been taken in toxic doses. Competition for active tubular transport. Competition between drugs for active tubular transport can delay renal excretion, thereby prolonging effects. The active transport systems of the renal tubules can be envisioned as motor-driven revolving doors that carry drugs from the plasma into the renal tubules. These “revolving doors” can carry only a limited number of drug molecules per unit of time. Accordingly, if there are too many molecules present, some must wait their turn. Because of competition, if we administer two drugs at the same time and if both drugs use the same transport system, excretion of each will be delayed by the presence of the other. Age. The kidneys of newborns are not fully developed. Until their kidneys reach full capacity (a few months after birth), infants have a limited capacity to excrete drugs. This must be accounted for when medicating an infant. In older adults, renal function often declines. Older adults have smaller kidneys and fewer nephrons. The loss of nephrons results in decreased blood filtration. In addition, vessel changes such as atherosclerosis reduce renal blood flow. As a result, renal excretion of drugs is decreased.

Nonrenal Routes of Drug Excretion In most cases, excretion of drugs by nonrenal routes has minimal clinical significance. However, in certain situations, nonrenal excretion can have

important therapeutic and toxicologic consequences. Breast Milk Some drugs taken by breast-feeding women can undergo excretion into milk. As a result, breastfeeding can expose the nursing infant to drugs. The factors that influence the appearance of drugs in breast milk are the same factors that determine the passage of drugs across membranes. Accordingly, lipid-soluble drugs have ready access to breast milk, whereas drugs that are polar, ionized, or protein bound cannot enter in significant amounts. Other Nonrenal Routes of Excretion The bile is an important route of excretion for certain drugs. Because bile is secreted into the small intestine, drugs that do not undergo enterohepatic recirculation leave the body in the feces. The lungs are the major route by which volatile anesthetics are excreted. Alcohol is partially eliminated by this route. Small amounts of drugs can appear in sweat and saliva. These routes have little therapeutic or toxicologic significance.

Time Course of Drug Responses It is possible to regulate the time at which drug responses start, the time they are most intense, and the time they cease. Because the four pharmacokinetic processes—absorption, distribution, metabolism, and excretion—determine how much drug will be at its sites of action at any given time, these processes are the major determinants of the time course over which drug responses take place.

Plasma Drug Levels In most cases the time course of drug action bears a direct relationship to the concentration of a drug in the blood. Hence, before discussing the time course per se, we need to review several important concepts related to plasma drug levels. Clinical Significance of Plasma Drug Levels Providers frequently monitor plasma drug levels in efforts to regulate drug responses. When measurements indicate that drug levels are inappropriate, these levels can be adjusted up or down by changing dosage size, dosage timing, or

both. The practice of regulating plasma drug levels to control drug responses should seem a bit odd, given that (1) drug responses are related to drug concentrations at sites of action and (2) the site of action of most drugs is not in the blood. More often than not, it is a practical impossibility to measure drug concentrations at sites of action. Experience has shown that, for most drugs, there is a direct correlation between therapeutic and toxic responses and the amount of drug present in plasma. Therefore, although we cannot usually measure drug concentrations at sites of action, we can determine plasma drug concentrations that, in turn, are highly predictive of therapeutic and toxic responses. Accordingly, the dosing objective is commonly spoken of in terms of achieving a specific plasma level of a drug. Two Plasma Drug Levels Defined Two plasma drug levels are of special importance: (1) the minimum effective concentration (MEC) and (2) the toxic concentration. These levels are depicted in Fig. 4.9.

FIG. 4.9

Single-Dose Time Course.

Minimum effective concentration. The MEC is defined as the plasma drug level less than which therapeutic effects will not occur. Hence, to be of benefit, a drug must be present in concentrations

at or greater than the MEC. Toxic concentration. Toxicity occurs when plasma drug levels climb too high. The plasma level at which toxic effects begin is termed the toxic concentration. Doses must be kept small enough so that the toxic concentration is not reached. Therapeutic Range As indicated in Fig. 4.9, there is a range of plasma drug levels, falling between the MEC and the toxic concentration, which is termed the therapeutic range. When plasma levels are within the therapeutic range, there is enough drug present to produce therapeutic responses but not so much that toxicity results. The objective of drug dosing is to maintain plasma drug levels within the therapeutic range. The width of the therapeutic range is a major determinant of the ease with which a drug can be used safely. Drugs that have a narrow therapeutic range are difficult to administer safely. Conversely, drugs that have a wide therapeutic range can be administered safely with relative ease. The principle is the same as that of the therapeutic index discussed in Chapter 3. The therapeutic range is quantified, or measured, by the therapeutic index. Understanding the concept of therapeutic range can facilitate patient care. Because drugs with a narrow therapeutic range are more dangerous than drugs with a wide therapeutic range, patients taking drugs with a narrow therapeutic range are the most likely to require intervention for drug-related complications. The provider who is aware of this fact can focus additional attention on monitoring these patients for signs and symptoms of toxicity.

Single-Dose Time Course Fig. 4.9 shows how plasma drug levels change over time after a single dose of an oral medication. Drug levels rise as the medicine undergoes absorption. Drug levels then decline as metabolism and excretion eliminate the drug from the body. Because responses cannot occur until plasma drug levels have reached the MEC, there is a latent period between drug administration and onset of effects. The extent of this delay is determined by the rate of absorption. The duration of effects is determined largely by the combination of metabolism and excretion. As long as drug levels remain greater than the MEC,

therapeutic responses will be maintained; when levels fall to less than the MEC, benefits will cease. Because metabolism and excretion are the processes most responsible for causing plasma drug levels to fall, these processes are the primary determinants of how long drug effects will persist.

Drug Half-Life Before proceeding to the topic of multiple dosing, we need to discuss the concept of half-life. When a patient ceases drug use, the combination of metabolism and excretion will cause the amount of drug in the body to decline. The half-life of a drug is an index of just how rapidly that decline occurs for most drugs. The concept of half-life does not apply to the elimination of all drugs. A few agents, most notably ethanol (alcohol), leave the body at a constant rate, regardless of how much is present. The implications of this kind of decline for ethanol are discussed in Chapter 32. Drug half-life is defined as the time required for the amount of drug in the body to decrease by 50%. A few drugs have half-lives that are extremely short— on the order of minutes or less. In contrast, the half-lives of some drugs exceed 1 week. Note that, in our definition of half-life, a percentage—not a specific amount— of drug is lost during one half-life. That is, the half-life does not specify, for example, that 2 g or 18 mg will leave the body in a given time. Rather, the halflife tells us that, no matter what the amount of drug in the body may be, half (50%) will leave during a specified period of time (the half-life). The actual amount of drug that is lost during one half-life depends on just how much drug is present: the more drug in the body, the larger the amount lost during one halflife. The concept of half-life is best understood through an example. Morphine provides a good illustration. The half-life of morphine is approximately 3 hours. By definition, this means that body stores of morphine will decrease by 50% every 3 hours—regardless of how much morphine is in the body. If there are 50 mg of morphine in the body, 25 mg (50% of 50 mg) will be lost in 3 hours; if there are only 2 mg of morphine in the body, only 1 mg (50% of 2 mg) will be lost in 3 hours. Note that, in both cases, morphine levels drop by 50% during an interval of one half-life. However, the actual amount lost is larger when total body stores of the drug are higher. The half-life of a drug determines the dosing interval (i.e., how much time separates each dose). For drugs with a short half-life, the dosing interval must be

correspondingly short. If a long dosing interval is used, drug levels will fall to less than the MEC between doses, and therapeutic effects will be lost. Conversely, if a drug has a long half-life, a long time can separate doses without loss of benefits.

Drug Levels Produced With Repeated Doses Multiple dosing leads to drug accumulation. When a patient takes a single dose of a drug, plasma levels simply go up and then come back down. In contrast, when a patient takes repeated doses of a drug, the process is more complex and results in drug accumulation. The factors that determine the rate and extent of accumulation are considered next. Plateau Drug Levels Administering repeated doses will cause a drug to build up in the body until a plateau (steady level) has been achieved. What causes drug levels to reach plateau? If a second dose of a drug is administered before all of the prior dose has been eliminated, total body stores of that drug will be higher after the second dose than after the initial dose. As succeeding doses are administered, drug levels will climb even higher. The drug will continue to accumulate until a state has been achieved in which the amount of drug eliminated between doses equals the amount administered. When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached (Fig. 4.10).

Drug Accumulation With Repeated Administration. The drug has a half-life of 1 day. The dosing schedule is 2 g given once a day on days 1 through 9. Note that plateau is reached at about the beginning of day 5 (i.e., after four half-lives). Note also that, when administration is discontinued, it takes approximately 4 days (four FIG. 4.10

half-lives) for most (94%) of the drug to leave the body.

Time to Plateau When a drug is administered repeatedly in the same dose, plateau will be reached in approximately four half-lives. For the hypothetical agent illustrated in Fig. 4.10, total body stores approached their peak near the beginning of day 5, or approximately 4 full days after treatment began. Because the half-life of this drug is 1 day, reaching plateau in 4 days is equivalent to reaching plateau in four half-lives. As long as dosage remains constant, the time required to reach plateau is independent of dosage size. Put another way, the time required to reach plateau when giving repeated large doses of a particular drug is identical to the time required to reach plateau when giving repeated small doses of that drug. Referring to the drug in Fig. 4.10, just as it took four half-lives (4 days) to reach plateau when a dose of 2 g was administered daily, it would also take four halflives to reach plateau if a dose of 4 g were administered daily. It is true that the height of the plateau would be greater if a 4-g dose were given, but the time required to reach plateau would not be altered by the increase in dosage. To confirm this statement, substitute a dose of 4 g in the previous exercise and see when plateau is reached. Techniques for Reducing Fluctuations in Drug Levels As illustrated in Fig. 4.10, when a drug is administered repeatedly, its level will fluctuate between doses. The highest level is referred to as the peak concentration, and the lowest level is referred to as the trough concentration. The acceptable height of the peaks and troughs will depend on the drug's therapeutic range: the peaks must be kept less than the toxic concentration, and the troughs must be kept greater than the MEC. If there is not much difference between the toxic concentration and the MEC, then fluctuations must be kept to a minimum. Three techniques can be used to reduce fluctuations in drug levels. One technique is to administer drugs by continuous infusion. With this procedure, plasma levels can be kept nearly constant. Another is to administer a depot preparation, which releases the drug slowly and steadily. The third is to reduce both the size of each dose and the dosing interval (keeping the total daily dose constant). For example, rather than giving the drug from Fig. 4.10 in 2-g doses

once every 24 hours, we could give this drug in 1-g doses every 12 hours. With this altered dosing schedule, the total daily dose would remain unchanged, as would total body stores at plateau. However, instead of fluctuating over a range of 2 g between doses, levels would fluctuate over a range of 1 g. Loading Doses Versus Maintenance Doses As discussed previously, if we administer a drug in repeated doses of equal size, an interval equivalent to approximately four half-lives is required to achieve plateau. When plateau must be achieved more quickly, a large initial dose can be administered. This large initial dose is called a loading dose. After high drug levels have been established with a loading dose, plateau can be maintained by giving smaller doses. These smaller doses are referred to as maintenance doses. The claim that use of a loading dose will shorten the time to plateau may appear to contradict an earlier statement, which said that the time to plateau is not affected by dosage size. However, there is no contradiction. For any specified dosage, it will always take about four half-lives to reach plateau. When a loading dose is administered followed by maintenance doses, the plateau is not reached for the loading dose. Rather, we have simply used the loading dose to rapidly produce a drug level equivalent to the plateau level for a smaller dose. To achieve plateau level for the loading dose, it would be necessary to either administer repeated doses equivalent to the loading dose for a period of four half-lives or administer a dose even larger than the original loading dose. Decline From Plateau When drug administration is discontinued, most (94%) of the drug in the body will be eliminated over an interval equal to approximately four half-lives. The time required for drugs to leave the body is important when toxicity develops. If a drug has a short half-life, body stores will decline rapidly, thereby making management of overdose less difficult. However, when an overdose of a drug with a long half-life occurs, toxic levels of the drug will remain in the body for a long time. Additional management may be needed in these instances.

Pharmacodynamics Pharmacodynamics is the study of the biochemical and physiologic effects of drugs on the body and the molecular mechanisms by which those effects are produced. To participate rationally in achieving the therapeutic objective, an

understanding of pharmacodynamics is essential.

Dose–Response Relationships The dose–response relationship (i.e., the relationship between the size of an administered dose and the intensity of the response produced) is a fundamental concern in therapeutics. Dose–response relationships determine the minimal amount of drug needed to elicit a response, the maximal response a drug can elicit, and how much to increase the dosage to produce the desired increase in response.

Basic Features of the Dose–Response Relationship The basic characteristics of dose–response relationships are illustrated in Fig. 4.11. Part A shows dose–response data plotted on linear coordinates. Part B shows the same data plotted on semilogarithmic coordinates (i.e., the scale on which dosage is plotted is logarithmic rather than linear). The most obvious and important characteristic revealed by these curves is that the dose–response relationship is graded. That is, as the dosage increases, the response becomes progressively larger. Because drug responses are graded, therapeutic effects can be adjusted to fit the needs of each patient by raising or lowering the dosage until a response of the desired intensity is achieved.

Basic Components of the Dose-Response Curve. (A) A dose– response curve with dose plotted on a linear scale. (B) The same dose–response relationship shown in A but with the dose plotted on a FIG. 4.11

logarithmic scale. Note the three phases of the dose–response curve: Phase 1, The curve is relatively flat; doses are too low to elicit a significant response. Phase 2, The curve climbs upward as bigger doses elicit correspondingly bigger responses. Phase 3, The curve levels off; bigger doses are unable to elicit a further increase in response. (Phase 1 is not indicated in A because very low doses cannot be shown on a linear scale.)

As indicated in Fig. 4.11, the dose–response relationship can be viewed as having three phases. Phase 1 (see Fig. 4.11B) occurs at low doses. The curve is flat during this phase because doses are too low to elicit a measurable response. During phase 2, an increase in dose elicits a corresponding increase in the response. This is the phase during which the dose–response relationship is graded. As the dose goes higher, eventually a point is reached where an increase in dose is unable to elicit a further increase in response. At this point, the curve flattens out into phase 3.

Maximal Efficacy and Relative Potency Dose–response curves reveal two characteristic properties of drugs: maximal efficacy and relative potency. Curves that reflect these properties are shown in Fig. 4.12.

Dose–Response Curves Demonstrating Efficacy and Potency. (A) Efficacy, or maximal efficacy, is an index of the maximal response a drug can produce. The efficacy of a drug is indicated by the height of its dose–response curve. In this example, meperidine has greater efficacy than pentazocine. Efficacy is an important quality in a drug. (B) Potency is an index of how much drug must be administered to elicit a desired response. In this example, achieving pain relief with meperidine requires higher doses than with morphine. We would say that morphine is more potent than meperidine. Note that, if administered in sufficiently high doses, meperidine can FIG. 4.12

produce just as much pain relief as morphine. Potency is usually not an important quality in a drug.

Maximal Efficacy Maximal efficacy is defined as the largest effect that a drug can produce. Maximal efficacy is indicated by the height of the dose–response curve. The concept of maximal efficacy is illustrated by the dose–response curves for meperidine (Demerol) and pentazocine (Talwin), two morphine-like pain relievers (see Fig. 4.12A). As you can see, the curve for pentazocine levels off at a maximal height less than that of the curve for meperidine. This tells us that the maximal degree of pain relief we can achieve with pentazocine is smaller than the maximal degree of pain relief we can achieve with meperidine. Put another way, no matter how much pentazocine we administer, we can never produce the degree of pain relief that we can with meperidine. Accordingly, we would say that meperidine has greater maximal efficacy than pentazocine. Despite what intuition might tell us, a drug with very high maximal efficacy is not always more desirable than a drug with lower efficacy. Recall that we want to match the intensity of the response to the patient's needs. This may be difficult to do with a drug that produces extremely intense responses. For example, certain diuretics (e.g., furosemide) have such high maximal efficacy that they can cause dehydration. If we want to mobilize only a modest volume of water, a diuretic with lower maximal efficacy (e.g., hydrochlorothiazide) would be preferred. Similarly, in a patient with a mild headache, we would not select a powerful analgesic (e.g., morphine) for relief. Rather, we would select an analgesic with lower maximal efficacy, such as aspirin. Relative Potency The term potency refers to the amount of drug we must give to elicit an effect. Potency is indicated by the relative position of the dose-response curve along the x (dose) axis. The concept of potency is illustrated by the curves in Fig. 4.12B. These curves plot doses for two analgesics—morphine and meperidine—versus the degree of pain relief achieved. As you can see, for any particular degree of pain relief, the required dose of meperidine is larger than the required dose of morphine. Because morphine produces pain relief at lower doses than meperidine, we would say that morphine is more potent than meperidine. That is, a potent drug is one that produces its effects at low doses.

Potency is rarely an important characteristic of a drug. The only consequence of having greater potency is that a drug with greater potency can be given in smaller doses. It is important to note that the potency of a drug implies nothing about its maximal efficacy! Potency and efficacy are completely independent qualities. Drug A can be more effective than drug B even though drug B may be more potent. In addition, drugs A and B can be equally effective even though one may be more potent. As shown in Fig. 4.12B, although meperidine happens to be less potent than morphine, the maximal degree of pain relief that we can achieve with these drugs is identical. A final comment on the word potency is in order. In everyday parlance, people tend to use the word potent to express the pharmacologic concept of effectiveness. That is, when most people say, “This drug is very potent,” what they mean is, “This drug produces powerful effects.” They do not mean, “This drug produces its effects at low doses.” In pharmacology, we use the words potent and potency with the specific and appropriate terminology.

Drug–Receptor Interactions Introduction to Drug Receptors Drugs produce their effects by interacting with other chemicals. Receptors are the special chemical sites in the body that most drugs interact with to produce effects. We can define a receptor as any functional macromolecule in a cell to which a drug binds to produce its effects. However, although the formal definition of a receptor encompasses all functional macromolecules, the term receptor is generally reserved for the body's own receptors for hormones, neurotransmitters, and other regulatory molecules. The other macromolecules to which drugs bind, such as enzymes and ribosomes, can be thought of simply as target molecules rather than as true receptors. Binding of a drug to its receptor is usually reversible. Receptors are activated by interaction with other molecules (Fig. 4.13). Under physiologic conditions, endogenous compounds (neurotransmitters, hormones, other regulatory molecules) are the molecules that bind to receptors to produce a response. When a drug is the molecule that binds to a receptor, all that it can do is mimic or block the actions of endogenous regulatory molecules. By doing so, the drug will either increase or decrease the rate of the physiologic activity normally

controlled by that receptor. Because drug action is limited to mimicking or blocking the body's own regulatory molecules, drugs cannot give cells new functions. In other words, drugs cannot make the body do anything that it is not already capable of doing.b

Interaction of Drugs With Receptors for Norepinephrine. Under physiologic conditions, cardiac output can be increased by the binding of norepinephrine (NE) to receptors (R) on the heart. Norepinephrine is supplied to these receptors by nerves. These same receptors can be acted on by drugs, which can either mimic the actions of endogenous NE (and thereby increase cardiac output) or block the actions of endogenous NE (and thereby reduce cardiac output). FIG. 4.13

Receptors and Selectivity of Drug Action Selectivity, the ability to elicit only the response for which a drug is given, is a highly desirable characteristic of a drug. The more selective a drug is, the fewer side effects it will produce. Selective drug action is possible in large part because drugs act through specific receptors. There are receptors for each neurotransmitter (e.g., norepinephrine [NE], acetylcholine, dopamine); there are receptors for each hormone (e.g., progesterone, insulin, thyrotropin); and there are receptors for all of the other molecules the body uses to regulate physiologic processes (e.g., histamine, prostaglandins, leukotrienes). As a rule, each type of receptor participates in the regulation of just a few processes (Fig. 4.14). If a drug interacts with only one type of receptor, and if that receptor type regulates just a few processes, then the effects of the drug will be limited. Conversely, if a

drug interacts with several different receptor types, then that drug is likely to elicit a wide variety of responses.

The Four Primary Receptor Families. 1, Cell membrane– embedded enzyme. 2, Ligand-gated ion channel. 3, G protein–coupled receptor system (G, G protein). 4, Transcription factor. (See text for details.) FIG. 4.14

How can a drug interact with one receptor type and not with others? In some important ways, a receptor is analogous to a lock and a drug is analogous to a key for that lock: just as only keys with the proper profile can fit a particular lock, only those drugs with the proper size, shape, and physical properties can bind to a particular receptor (Fig. 4.15).

Interaction of Acetylcholine With Its Receptor. (A) Threedimensional model of the acetylcholine molecule. (B) Binding of acetylcholine to its receptor. Note how the shape of acetylcholine closely matches the shape of the receptor. Note also how the positive charges on acetylcholine align with the negative sites on the receptor. FIG. 4.15

Theories of Drug-Receptor Interaction In the discussion that follows, we consider two theories of drug–receptor interaction: (1) the simple occupancy theory and (2) the modified occupancy theory. These theories help explain dose–response relationships and the ability of drugs to mimic or block the actions of endogenous regulatory molecules. Simple Occupancy Theory The simple occupancy theory of drug–receptor interaction states that (1) the intensity of the response to a drug is proportional to the number of receptors occupied by that drug and (2) a maximal response will occur when all available receptors have been occupied. This relationship between receptor occupancy and the intensity of the response is depicted in Fig. 4.16.

Model of Simple Occupancy Theory. The simple occupancy theory states that the intensity of response to a drug is proportional to the number of receptors occupied; maximal response is reached with 100% receptor occupancy. Because the hypothetical cell in this figure has only four receptors, maximal response is achieved when all four receptors are occupied. (Note: Real cells have thousands of receptors.) FIG. 4.16

Although certain aspects of dose–response relationships can be explained by

the simple occupancy theory, other important phenomena cannot. Specifically, there is nothing in this theory to explain why one drug should be more potent than another. In addition, this theory cannot explain how one drug can have higher maximal efficacy than another. That is, according to this theory, two drugs acting at the same receptor should produce the same maximal effect, provided that their dosages were high enough to produce 100% receptor occupancy. However, we have already seen this is not true. As illustrated in Fig. 4.12A, there is a dose of pentazocine greater than which no further increase in response can be elicited. Presumably, all receptors are occupied when the doseresponse curve levels off. However, at 100% receptor occupancy, the response elicited by pentazocine is less than that elicited by meperidine. Simple occupancy theory cannot account for this difference. Modified Occupancy Theory The modified occupancy theory of drug–receptor interaction explains certain observations that cannot be accounted for with the simple occupancy theory. The modified theory ascribes two qualities to drugs: affinity and intrinsic activity. The term affinity refers to the strength of the attraction between a drug and its receptor. Intrinsic activity refers to the ability of a drug to activate the receptor after binding. Affinity and intrinsic activity are independent properties. Affinity. As noted, the term affinity refers to the strength of the attraction between a drug and its receptor. Drugs with high affinity are strongly attracted to their receptors. Conversely, drugs with low affinity are weakly attracted. The affinity of a drug for its receptor is reflected in its potency. Because they are strongly attracted to their receptors, drugs with high affinity can bind to their receptors when present in low concentrations. Because they bind to receptors at low concentrations, drugs with high affinity are effective in low doses. That is, drugs with high affinity are very potent. Conversely, drugs with low affinity must be present in high concentrations to bind to their receptors. Accordingly, these drugs are less potent. Intrinsic activity. The term intrinsic activity refers to the ability of a drug to activate a receptor upon binding. Drugs with high intrinsic activity cause intense receptor activation. Conversely, drugs with low intrinsic activity cause only slight

activation. The intrinsic activity of a drug is reflected in its maximal efficacy. Drugs with high intrinsic activity have high maximal efficacy. That is, by causing intense receptor activation, they are able to cause intense responses. Conversely, if intrinsic activity is low, maximal efficacy will be low as well. It should be noted that, under the modified occupancy theory, the intensity of the response to a drug is still related to the number of receptors occupied. The wrinkle added by the modified theory is that intensity is also related to the ability of the drug to activate receptors after binding has occurred. Under the modified theory, two drugs can occupy the same number of receptors but produce effects of different intensity; the drug with greater intrinsic activity will produce the more intense response.

Agonists, Antagonists, and Partial Agonists As previously noted, when drugs bind to receptors, they can do one of two things: they can either mimic the action of endogenous regulatory molecules or they can block the action of endogenous regulatory molecules. Drugs that mimic the body's own regulatory molecules are called agonists. Drugs that block the actions of endogenous regulators are called antagonists. Like agonists, partial agonists also mimic the actions of endogenous regulatory molecules, but they produce responses of intermediate intensity. Agonists Agonists are molecules that activate receptors. Because neurotransmitters, hormones, and other endogenous regulators activate the receptors to which they bind, all of these compounds are considered agonists. When drugs act as agonists, they simply bind to receptors and mimic the actions of the body's own regulatory molecules. For example, dobutamine is a drug that mimics the action of NE at receptors on the heart, thereby causing heart rate and force of contraction to increase. In terms of the modified occupancy theory, an agonist is a drug that has both affinity and high intrinsic activity. Affinity allows the agonist to bind to receptors, whereas intrinsic activity allows the bound agonist to activate or turn on receptor function. Antagonists Antagonists produce their effects by preventing receptor activation by

endogenous regulatory molecules and drugs. Antagonists have virtually no effects of their own on receptor function. In terms of the modified occupancy theory, an antagonist is a drug with affinity for a receptor but with no intrinsic activity. Affinity allows the antagonist to bind to receptors, but lack of intrinsic activity prevents the bound antagonist from causing receptor activation. Although antagonists do not cause receptor activation, they most certainly do produce pharmacologic effects. Antagonists produce their effects by preventing the activation of receptors by endogenous regulatory molecules. For example, antihistamines are histamine receptor antagonists that suppress allergy symptoms by binding to receptors for histamine, thereby preventing activation of these receptors by histamine released in response to allergens. It is important to note that the response to an antagonist is determined by how much agonist is present. Because antagonists act by preventing receptor activation, if there is no agonist present, administration of an antagonist will have no observable effect; the drug will bind to its receptors, but nothing will happen. On the other hand, if receptors are undergoing activation by agonists, administration of an antagonist will shut the process down, resulting in an observable response. An example is the use of the opioid antagonist naloxone, which is used to block opioid receptors in the event of an opioid overdose. Antagonists can be subdivided into two major classes: (1) noncompetitive antagonists and (2) competitive antagonists. Most antagonists are competitive. Noncompetitive (insurmountable) antagonists. Noncompetitive antagonists bind irreversibly to receptors. The effect of irreversible binding is equivalent to reducing the total number of receptors available for activation by an agonist. Because the intensity of the response to an agonist is proportional to the total number of receptors occupied and because noncompetitive antagonists decrease the number of receptors available for activation, noncompetitive antagonists reduce the maximal response that an agonist can elicit. If sufficient antagonist is present, agonist effects will be blocked completely. Dose–response curves illustrating inhibition by a noncompetitive antagonist are shown in Fig. 4.17A.

Dose–Response Curves in the Presence of Competitive and Noncompetitive Antagonists. (A) Effect of a noncompetitive antagonist on the dose–response curve of an agonist. Note that noncompetitive antagonists decrease the maximal response achievable with an agonist. (B) Effect of a competitive antagonist on the dose–response curve of an agonist. Note that the maximal response achievable with the agonist is not reduced. Competitive antagonists simply increase the amount of agonist required to produce any given intensity of response. FIG. 4.17

Because the binding of noncompetitive antagonists is irreversible, inhibition by these agents cannot be overcome, no matter how much agonist may be available. Although noncompetitive antagonists bind irreversibly, this does not mean that their effects last forever. Cells are constantly breaking down old receptors and synthesizing new ones. Consequently, the effects of noncompetitive antagonists wear off as the receptors to which they are bound are replaced. Because the life cycle of a receptor can be relatively short, the effects of noncompetitive antagonists may subside in a few days. Still, this can be a long time for some functions; therefore these agents are rarely used therapeutically. Competitive (surmountable) antagonists. Competitive antagonists bind reversibly to receptors. As their name implies, competitive antagonists produce receptor blockade by competing with agonists for receptor binding. If an agonist and a competitive antagonist have equal affinity for a particular receptor, then the receptor will be occupied by whichever agent—agonist or antagonist—is present in the highest concentration. If there are more antagonist molecules present than agonist molecules, antagonist molecules will occupy the receptors and receptor activation will be blocked. Conversely, if agonist molecules outnumber the antagonists, receptors will be occupied mainly by the agonist and little inhibition will occur.

Because competitive antagonists bind reversibly to receptors, the inhibition they cause is surmountable. In the presence of sufficiently high amounts of agonist, agonist molecules will occupy all receptors and inhibition will be completely overcome. The dose–response curves shown in Fig. 4.17B illustrate the process of overcoming the effects of a competitive antagonist with large doses of an agonist. Partial Agonists A partial agonist is an agonist that has only moderate intrinsic activity. As a result, the maximal effect that a partial agonist can produce is lower than that of a full agonist. Pentazocine is an example of a partial agonist. As the curves in Fig. 4.12A indicate, the degree of pain relief that can be achieved with pentazocine is much lower than the relief that can be achieved with meperidine (a full agonist). Partial agonists are interesting in that they can act as antagonists as well as agonists. For this reason, they are sometimes referred to as agonists-antagonists. For example, when pentazocine is administered by itself, it occupies opioid receptors and produces moderate relief of pain. In this situation, the drug is acting as an agonist. However, if a patient is already taking meperidine (a full agonist at opioid receptors) and is then given a large dose of pentazocine, pentazocine will occupy the opioid receptors and prevent their activation by meperidine. As a result, rather than experiencing the high degree of pain relief that meperidine can produce, the patient will experience only the limited relief that pentazocine can produce. In this situation, pentazocine is acting as both an agonist (producing moderate pain relief) and an antagonist (blocking the higher degree of relief that could have been achieved with meperidine by itself).

Regulation of Receptor Sensitivity Receptors are dynamic components of the cell. In response to continuous activation or continuous inhibition, the number of receptors on the cell surface can change, as can their sensitivity to agonist molecules. For example, when the receptors of a cell are continually exposed to an agonist, the cell usually becomes less responsive. When this occurs, the cell is said to be desensitized or refractory or to have undergone downregulation. Several mechanisms may be responsible, including destruction of receptors by the cell and modification of receptors such that they respond less fully. Continuous exposure to antagonists has the opposite effect, causing the cell to become hypersensitive (also referred

to as supersensitive). One mechanism that can cause hypersensitivity is synthesis of more receptors.

Drug Responses That Do NOT Involve Receptors Although the effects of most drugs result from drug–receptor interactions, some drugs do not act through receptors. Rather, they act through simple physical or chemical interactions with other small molecules. Common examples of these drugs include antacids, antiseptics, saline laxatives, and chelating agents. Antacids neutralize gastric acidity by direct chemical interaction with stomach acid. The antiseptic action of ethyl alcohol results from precipitating bacterial proteins. Magnesium sulfate, a powerful laxative, acts by retaining water in the intestinal lumen through an osmotic effect. Dimercaprol, a chelating agent, prevents toxicity from heavy metals (e.g., arsenic, mercury) by forming complexes with these compounds. All of these pharmacologic effects are the result of simple physical or chemical interactions and not interactions with cellular receptors.

Interpatient Variability in Drug Responses The dose required to produce a therapeutic response can vary substantially from patient to patient because people differ from one another. In this section we consider interpatient variation as a general issue. The specific kinds of differences that underlie variability in drug responses are discussed in Chapter 6. To promote the therapeutic objective, you must be alert to interpatient variation in drug responses. Because of interpatient variation, it is not possible to predict exactly how an individual patient will respond to medication. The provider who appreciates the reality of interpatient variability will be better prepared to anticipate, evaluate, and respond appropriately to each patient's therapeutic needs. Fig. 4.18 illustrates an example of interpatient variability in response to a drug. Fig. 4.18A represents incremental increases in the milligram dose of drug to elevated gastric pH coupled with the number of patients who had a therapeutic response (pH of 5) at each dose. In Fig. 4.18B, these results are plotted on a frequency distribution curve. We can see from the curve that a wide range of doses is required to produce the desired response in all subjects. For some subjects, a dose of only 100 mg was sufficient to produce the target response.

For other subjects, the therapeutic end point was not achieved until the dose totaled 240 mg.

Interpatient Variation in Drug Responses. (A) Data from tests of a hypothetical acid suppressant in 100 patients. The goal of the study is to determine the dosage required by each patient to elevate gastric pH to 5. Note the wide variability in doses needed to produce the target response for the 100 subjects. (B) Frequency distribution curve for the data in A. The dose at the middle of the curve is termed the ED50—the dose that will produce a predefined intensity of response in 50% of the population. FIG. 4.18

ED50 The dose at the middle of the frequency distribution curve is termed the ED50 (see Fig. 4.18B). (ED50 is an abbreviation for average effective dose.) The ED50 is defined as the dose that is required to produce a defined therapeutic response in 50% of the population. In the case of the drug in our example, the ED50 was 170 mg—the dose needed to elevate gastric pH to a value of 5 in 50% of the 100 people tested. The ED50 can be considered a standard dose and, as such, is frequently the dose selected for initial treatment. After evaluating a patient's response to this standard dose, we can then adjust subsequent doses up or down to meet the patient's needs.

Clinical Implications of Interpatient Variability Interpatient variation has four important clinical consequences. As a provider you should be aware of these implications:

• The initial dose of a drug is necessarily an approximation. Subsequent doses may need to be fine-tuned based on the patient's response. • When given an ED50, some patients will be undertreated, whereas others will have received more drug than they need. Accordingly, when therapy is initiated with a dose equivalent to the ED50, it is especially important to evaluate the response. Patients who fail to respond may need an increase in dosage. Conversely, patients who show signs of toxicity will need a dosage reduction. • Because drug responses are not completely predictable, you must monitor the patient's response for both positive effects and adverse effects to determine whether too much or too little medication has been administered. In other words, dosage should be adjusted on the basis of the patient's response and not just on the basis of clinical guidelines.

Therapeutic Index The therapeutic index is a measure of a drug's safety. The therapeutic index is defined as the ratio of a drug's LD50 to its ED50. (The LD50, or average lethal dose, is the dose that is lethal to 50% of the subjects treated.) A large (or high or wide) therapeutic index indicates that a drug is relatively safe. Conversely, a small (or low or narrow) therapeutic index indicates that a drug is relatively unsafe. The concept of therapeutic index is illustrated by the frequency distribution curves in Fig. 4.19. Part A of the figure shows curves for therapeutic and lethal responses to drug X. Part B shows equivalent curves for drug Y. As you can see in Fig. 4.19A, the LD50 (100 mg) for drug X is much larger than the average therapeutic dose (10 mg). Because this drug's lethal dose is much larger than its therapeutic dose, common sense tells us that the drug should be relatively safe. The safety of this drug is reflected in its high therapeutic index, which is 10. In contrast, drug Y is unsafe. As shown in Fig. 4.19B, the LD50 for drug Y (20 mg) is only twice the average therapeutic dose (10 mg). Hence, for drug Y, a dose

only twice the ED50 could be lethal to 50% of those treated. Clearly, drug Y is not safe. This lack of safety is reflected in its low therapeutic index.

Therapeutic Index. (A) Frequency distribution curves indicating the average effective dose (ED50) and average lethal dose (LD50) for drug X. Because its LD50 is much greater than its ED50, drug X is relatively safe. (B) Frequency distribution curves indicating the ED50 and LD50 for drug Y. Because its LD50 is very close to its ED50, drug Y is not very safe. Also note the overlap between the effectivedose curve and the lethal-dose curve. FIG. 4.19

The curves for drug Y illustrate a phenomenon that is even more important than the therapeutic index. As you can see, there is overlap between the curve for therapeutic effects and the curve for lethal effects. This overlap tells us that the high doses needed to produce therapeutic effects in some people may be large enough to cause death in others. The message here is that, if a drug is to be truly safe, the highest dose required to produce therapeutic effects must be substantially lower than the lowest dose required to produce death.

Drug Interactions

A drug interaction occurs when another substance alters a drug's efficacy, effects, or safety. These are usually the result of interactions with other drugs, food, or supplements.

Drug–Drug Interactions Drug–drug interactions can occur whenever a patient takes two or more drugs. Some interactions are both intended and desired, as when we combine drugs to treat hypertension. In contrast, some interactions are both unintended and undesired.

Consequences of Drug–Drug Interactions When two drugs interact, there are three possible outcomes: (1) one drug may intensify the effects of the other, (2) one drug may reduce the effects of the other, or (3) the combination may produce a new response not seen with either drug alone. Intensification of Effects When one drug intensifies, or potentiates, the effects of the other, this type of interaction is often termed potentiative. Potentiative interactions may be beneficial or detrimental. Increased therapeutic effects. The interaction between sulbactam and ampicillin represents a beneficial potentiative interaction. When administered alone, ampicillin undergoes rapid inactivation by bacterial enzymes. Sulbactam inhibits those enzymes and thereby prolongs and intensifies ampicillin's therapeutic effects. Increased adverse effects. The interaction between aspirin and warfarin represents a potentially detrimental potentiative interaction. Both aspirin and warfarin suppress formation of blood clots; aspirin does this through antiplatelet activity, and warfarin does this through anticoagulant activity. As a result, if aspirin and warfarin are taken concurrently, the risk for bleeding is significantly increased. Reduction of Effects Interactions that result in reduced drug effects are often termed inhibitory. As

with potentiative interactions, inhibitory interactions can be beneficial or detrimental. Inhibitory interactions that reduce toxicity are beneficial. Conversely, inhibitory interactions that reduce therapeutic effects are detrimental. Reduced therapeutic effects. The interaction between propranolol and albuterol represents a detrimental inhibitory interaction. Albuterol is taken by people with asthma to dilate the bronchi. Propranolol, a drug for cardiovascular disorders, can act in the lung to block the effects of albuterol. Hence, if propranolol and albuterol are taken together, propranolol can reduce albuterol's therapeutic effects. Reduced adverse effects. The use of naloxone to treat morphine overdose is an excellent example of a beneficial inhibitory interaction. When administered in excessive dosage, morphine can produce coma, profound respiratory depression, and eventual death. Naloxone blocks morphine's actions and can completely reverse all symptoms of toxicity. Creation of a Unique Response Rarely, the combination of two drugs produces a new response not seen with either agent alone. To illustrate, let's consider the combination of alcohol with disulfiram (Antabuse)], a drug used to treat alcohol use disorder. When alcohol and disulfiram are combined, a host of unpleasant and dangerous responses can result; however, these effects do not occur when disulfiram or alcohol is used alone.

Basic Mechanisms of Drug–Drug Interactions Drugs can interact through four basic mechanisms: (1) direct chemical or physical interaction, (2) pharmacokinetic interaction, (3) pharmacodynamic interaction, and (4) combined toxicity. Direct Chemical or Physical Interactions Some drugs, because of their physical or chemical properties, can undergo direct interaction with other drugs. Direct physical and chemical interactions usually render both drugs inactive. Direct interactions occur most commonly when drugs are combined in IV

solutions. Frequently, the interaction produces a precipitate; however, direct drug interactions may not always leave visible evidence. Hence you cannot rely on simple inspection to reveal all direct interactions. Because drugs can interact in solution, it is essential to consider and verify drug incompatibilities when ordering medications. The same kinds of interactions that can take place when drugs are mixed together in an IV solution can also occur when incompatible drugs are taken by other routes. However, because drugs are diluted in body water after administration, and because dilution decreases chemical interactions, significant interactions within the patient are much less likely than in IV solutions. Pharmacokinetic Interactions Drug interactions can affect all four of the basic pharmacokinetic processes. That is, when two drugs are taken together, one may alter the absorption, distribution, metabolism, or excretion of the other. Altered absorption. Drug absorption may be enhanced or reduced by drug interactions. There are several mechanisms by which one drug can alter the absorption of another.

• By elevating gastric pH, antacids can decrease the ionization of basic drugs in the stomach, increasing the ability of basic drugs to cross membranes and be absorbed. Antacids have the opposite effect on acidic drugs. • Laxatives can reduce absorption of other oral drugs by accelerating their passage through the intestine. • Drugs that depress peristalsis (e.g., morphine, atropine) prolong drug transit time in the intestine, thereby increasing the time for absorption. • Drugs that induce vomiting can decrease absorption of oral drugs. • Orally administered adsorbent drugs that do not undergo absorption (e.g., cholestyramine) can adsorb other drugs onto themselves, thereby preventing absorption of the other drugs into the blood.

• Drugs that reduce regional blood flow can reduce absorption of other drugs from that region. For example, when epinephrine is injected together with a local anesthetic, the epinephrine causes local vasoconstriction, thereby reducing regional blood flow and delaying absorption of the anesthetic. Altered distribution. There are two principal mechanisms by which one drug can alter the distribution of another: (1) competition for protein binding and (2) alteration of extracellular pH. Competition for protein binding. When two drugs bind to the same site on plasma albumin, coadministration of those drugs produces competition for binding. As a result, binding of one or both agents is reduced, causing plasma levels of free drug to rise. In theory, the increase in free drug can intensify effects. However, because the newly freed drug usually undergoes rapid elimination, the increase in plasma levels of free drug is rarely sustained or significant unless the patient has liver problems that interfere with drug metabolism or has renal problems that interfere with drug excretion. Alteration of extracellular pH. A drug with the ability to change extracellular pH can alter the distribution of other drugs. For example, if a drug were to increase extracellular pH, that drug would increase the ionization of acidic drugs in extracellular fluids (i.e., plasma and interstitial fluid). As a result, acidic drugs would be drawn from within cells (where the pH was less than that of the extracellular fluid) into the extracellular space. Hence the alteration in pH would change drug distribution. The ability of drugs to alter pH and thereby alter the distribution of other drugs can be put to practical use in the management of poisoning. For example, symptoms of aspirin toxicity can be reduced with sodium bicarbonate, a drug that elevates extracellular pH. By increasing the pH outside cells, bicarbonate causes aspirin to move from intracellular sites into the interstitial fluid and plasma, thereby minimizing injury to cells. Altered metabolism.

Altered metabolism is one of the most important—and most complex— mechanisms by which drugs interact. Some drugs increase the metabolism of other drugs, and some drugs decrease the metabolism of other drugs. Drugs that increase the metabolism of other drugs do so by inducing synthesis of hepatic drug-metabolizing enzymes. Drugs that decrease the metabolism of other drugs do so by inhibiting those enzymes. As discussed earlier in this chapter, the majority of drug metabolism is catalyzed by the cytochrome P450 enzymes, which are composed of a large number of isoenzyme families (CYP1, CYP2, and CYP3) that are further divided into specific forms. Five isoenzyme forms are responsible for the metabolism of most drugs: CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Table 4.2 lists major drugs that are metabolized by each isoenzyme and indicates drugs that can inhibit or induce those isoenzymes. TABLE 4.2

This list is not comprehensive. CNS, Central nervous system; HIV, human immunodeficiency virus.

Induction of CYP enzymes. In our discussion of metabolism earlier in the chapter, you learned about induction of CYP enzymes. When it is essential that an inducing agent is taken with another medicine,

dosage of the other medicine may need adjustment. For example, if a woman taking oral contraceptives were to begin taking phenobarbital, induction of drug metabolism by phenobarbital would accelerate metabolism of the contraceptive, thereby lowering its level. If drug metabolism were increased enough, protection against pregnancy would be lost. To maintain contraceptive efficacy, dosage of the contraceptive should be increased. Conversely, when a patient discontinues an inducing agent, dosages of other drugs may need to be lowered. If dosage is not reduced, drug levels may climb dangerously high as rates of hepatic metabolism decline to their baseline (noninduced) values. Inhibition of CYP enzymes. If drug A inhibits the metabolism of drug B, then levels of drug B will rise. The result may be beneficial or harmful. The interactions of cobicistat (a strong CYP3A4 inhibitor) and atazanavir (an expensive drug used to treat HIV infection) provide an interesting case in point. Because cobicistat inhibits CYP3A (the CYP isoenzyme that metabolizes atazanavir), if cobicistat is combined with atazanavir, the plasma level of atazanavir will rise. In this instance, inhibition of CYP3A4 allows us to achieve therapeutic drug levels at lower doses, thereby greatly reducing the cost of treatment. Although inhibition of drug metabolism can be beneficial, as a rule inhibition has undesirable results. That is, in most cases, when an inhibitor increases the level of another drug, the outcome is toxicity. Accordingly, when a patient is taking an inhibitor along with his or her other medicines, you should be alert for possible adverse effects. Unfortunately, because the number of possible interactions of this type is large, keeping track is a challenge. The safest practice is to check for drug interactions in one of the reliable software applications that are widely available. Altered renal excretion. Drugs can alter all three phases of renal excretion: filtration, reabsorption, and active secretion. By doing so, one drug can alter the renal excretion of another. Glomerular filtration can be decreased by drugs that reduce cardiac output: a reduction in cardiac output decreases renal perfusion, which decreases drug filtration at the glomerulus, which in turn decreases the rate of drug excretion. By altering urinary pH, one drug can alter the ionization of another and thereby increase or decrease the extent to which that drug undergoes passive tubular reabsorption. Finally, competition between two drugs for active tubular secretion

can decrease the renal excretion of both agents. Interactions that involve P-glycoprotein. As discussed earlier in this chapter, PGP is a transmembrane protein that transports a wide variety of drugs out of cells, including cells of the intestinal epithelium, placenta, BBB, liver, and kidney tubules. Like P450 isoenzymes, PGP is subject to induction and inhibition by drugs. In fact (and curiously), most of the drugs that induce or inhibit P450 have the same effect on PGP. Drugs that induce PGP can have the following effects on other drugs:

• Reduced absorption—by increasing drug export from cells of the intestinal epithelium into the intestinal lumen • Reduced fetal drug exposure—by increasing drug export from placental cells into the maternal blood • Reduced brain drug exposure—by increasing drug export from cells of brain capillaries into the blood • Increased drug elimination—by increasing drug export from liver into the bile and from renal tubular cells into the urine Drugs that inhibit PGP will have opposite effects. Pharmacodynamic Interactions By influencing pharmacodynamic processes, one drug can alter the effects of another. Pharmacodynamic interactions are of two basic types: (1) interactions in which the interacting drugs act at the same site and (2) interactions in which the interacting drugs act at separate sites. Pharmacodynamic interactions may be potentiative or inhibitory and can be of great clinical significance. Interactions at the same receptor. Interactions that occur at the same receptor are almost always inhibitory. Inhibition occurs when an antagonist drug blocks access of an agonist drug to its receptor. There are many agonist–antagonist interactions of clinical importance. Some reduce therapeutic effects and are therefore undesirable. Others reduce toxicity and are of obvious benefit. The interaction between naloxone and morphine noted earlier in this chapter is an example of a beneficial inhibitory interaction: by blocking access of morphine to its receptors, naloxone can

reverse all symptoms of morphine overdose. Interactions resulting from actions at separate sites. Even though two drugs have different mechanisms of action and act at separate sites, if both drugs influence the same physiologic process, then one drug can alter responses produced by the other. Interactions resulting from effects produced at different sites may be potentiative or inhibitory. The interaction between morphine and diazepam (Valium) illustrates a potentiative interaction resulting from concurrent use of drugs that act at separate sites. Morphine and diazepam are CNS depressants, but these drugs do not share the same mechanism of action. Hence, when these agents are administered together, the ability of each to depress CNS function reinforces the depressant effects of the other. This potentiative interaction can result in profound CNS depression. The interaction between two diuretics—hydrochlorothiazide and spironolactone—illustrates how the effects of a drug acting at one site can counteract the effects of a second drug acting at a different site. Hydrochlorothiazide acts on the distal convoluted tubule of the nephron to increase excretion of potassium. Acting at a different site in the kidney, spironolactone works to decrease renal excretion of potassium. Consequently, when these two drugs are administered together, the potassium-sparing effects of spironolactone tend to balance the potassium-wasting effects of hydrochlorothiazide, leaving renal excretion of potassium at approximately the same level it would have been had no drugs been given at all. Combined Toxicity If drug A and drug B are both toxic to the same organ, then taking them together will cause more injury than if they were not combined. For example, when we treat tuberculosis with isoniazid and rifampin, both of which are hepatotoxic, the potential to cause liver injury is greater than it would be if we used just one of the drugs. As a rule, drugs with overlapping toxicity are not used together. Unfortunately, when treating tuberculosis, the combination is essential.

Clinical Significance of Drug–Drug Interactions Clearly, drug interactions have the potential to affect the outcome of therapy. As a result of drug–drug interactions, the intensity of responses may be increased or reduced. Interactions that increase therapeutic effects or reduce toxicity are

desirable. Conversely, interactions that reduce therapeutic effects or increase toxicity are detrimental. Interactions are especially important for drugs that have a narrow therapeutic range. For these agents, an interaction that produces a modest increase in drug levels can cause toxicity. Conversely, an interaction that produces a modest decrease in drug levels can cause therapeutic failure. Although a large number of important interactions have been documented, many more are yet to be identified. Therefore if a patient develops unusual symptoms, it is wise to suspect that a drug interaction may be the cause— especially because yet another drug might be given to control the new symptoms.

Minimizing Adverse Drug–Drug Interactions We can minimize adverse interactions in several ways. The most obvious is to minimize the number of drugs a patient receives. A second and equally important way to avoid detrimental interactions is to take a thorough drug history. A history that identifies all drugs the patient is taking, including illicit and over-the-counter preparations, allows the provider to adjust the regimen accordingly. Additional measures for reducing adverse interactions include adjusting the dosage when an inducer of metabolism is added to or deleted from the regimen, adjusting the timing of administration to minimize interference with absorption, monitoring for early signs of toxicity when combinations of toxic agents cannot be avoided, and being especially vigilant when the patient is taking a drug with a narrow therapeutic range.

Drug–Food Interactions Coadministration with food can significantly alter the efficacy and safety of some drugs. The primary mechanisms are by decreased or increased absorption and altered metabolism.

Decreased Absorption Food frequently decreases the rate of drug absorption and occasionally decreases the extent of absorption. Reducing the rate of absorption merely delays the onset of effects; peak effects are not lowered. In contrast, reducing the extent of absorption reduces the intensity of peak responses. The interaction between calcium-containing foods and tetracycline antibiotics

is a classic example of food reducing drug absorption. Tetracyclines bind with calcium to form an insoluble and nonabsorbable complex. Hence, if tetracyclines are administered with milk products or calcium supplements, absorption is reduced and antibacterial effects may be lost. High-fiber foods can reduce absorption of some drugs. For example, absorption of digoxin (Lanoxin), used for cardiac disorders, is reduced significantly by wheat bran, rolled oats, and sunflower seeds. This reduced absorption can result in therapeutic failure.

Increased Absorption With some drugs, food increases the extent of absorption. When this occurs, peak effects are heightened. For example, a high-calorie meal more than doubles the absorption of saquinavir (Invirase), a drug for HIV infection. If saquinavir is taken without food, absorption may be insufficient for antiviral activity.

Effects of Food on Drug Metabolism: The Grapefruit Juice Effect Grapefruit juice can inhibit the metabolism of certain drugs, thereby raising their blood levels. Four compounds have been identified as the responsible agents: two furanocoumarins (bergapten and 6′,7′-dihydroxybergamottin) and two flavonoids (naringin and naringenin). This effect is not seen with orange juice; however, other citrus fruits related to grapefruit–Seville oranges, pomelos, and tangelos–contain furanocoumarins. Drug interactions with these fruits have not been adequately tested. Until more is known, these should be treated with the same caution as grapefruit juice. Grapefruit juice raises drug levels mainly by inhibiting CYP3A4 metabolism. CYP3A4 is an isoenzyme of cytochrome P450 found in the liver and the intestinal wall. Inhibition of the intestinal isoenzyme is much greater than inhibition of the liver isoenzyme. By inhibiting CYP3A4, grapefruit juice decreases the intestinal metabolism of many drugs (Table 4.3) and thereby increases the amount available for absorption. As a result, blood levels of these drugs rise, causing peak effects to be more intense. Because inhibition of CYP3A4 in the liver is minimal, grapefruit juice does not usually affect metabolism of drugs after they have been absorbed. Importantly, grapefruit juice has little or no effect on drugs administered intravenously. Why? Because, with IV administration, intestinal metabolism is not involved. Inhibition of CYP3A4

is dose dependent; the more grapefruit juice the patient drinks, the greater the inhibition. TABLE 4.3 Some Drugs Whose Levels Can Be Increased by Grapefruit Juice Potential Consequences of Increased Drug Levels

Drug

Indications

Dihydropyridine CCBs: felodipine, nifedipine, nimodipine, nisoldipine

Hypertension; angina pectoris

Toxicity: flushing, headache, tachycardia, hypotension

Nondihydropyridine CCBs: verapamil

Hypertension; angina pectoris

Toxicity: bradycardia, AV heart block, hypotension, constipation

Statins: atorvastatin, lovastatin, simvastatin (minimal effect on fluvastatin, pravastatin, or rosuvastatin)

Cholesterol reduction

Toxicity: headache, GI disturbances, liver and muscle toxicity

Amiodarone

Cardiac dysrhythmias

Toxicity

Caffeine

Prevents sleepiness

Toxicity: restlessness, insomnia, convulsions, tachycardia

Carbamazepine

Seizures; bipolar disorder

Toxicity: ataxia, drowsiness, nausea, vomiting, tremor

Buspirone

Anxiety

Drowsiness, dysphoria

Triazolam

Anxiety; insomnia

Increased sedation

Midazolam

Induction of anesthesia; conscious sedation

Increased sedation

Saquinavir

HIV infection

Increased therapeutic effect

Cyclosporine

Prevents rejection of

Increased therapeutic effects; if levels rise too

organ transplants

high, renal and hepatic toxicity will occur

Sirolimus and tacrolimus

Prevent rejection of organ transplants

Toxicity

SSRIs: fluoxetine, fluvoxamine, sertraline

Depression

Toxicity: serotonin syndrome

Pimozide

Tourette syndrome

Toxicity: QT prolongation resulting in a lifethreatening ventricular dysrhythmia

Praziquantel

Schistosomiasis

Toxicity

Dextromethorphan

Cough

Toxicity

Sildenafil

Erectile dysfunction

Toxicity

AV, Atrioventricular; CCBs, calcium channel blockers; GI, gastrointestinal; HIV, human immunodeficiency virus; SSRIs, selective serotonin reuptake inhibitors.

Inhibition of CYP3A4 persists after grapefruit juice is consumed, so the problem cannot be easily resolved by scheduling medication hours after drinking the juice. In fact, when grapefruit juice is consumed on a regular basis, inhibition can persist up to 3 days after the last drink. The effects of grapefruit juice vary considerably among patients because levels of CYP3A4 show great individual variation. In patients with very little CYP3A4, inhibition by grapefruit juice may be sufficient to stop metabolism completely. As a result, large increases in drug levels may occur. Conversely, in patients with an abundance of CYP3A4, metabolism may continue more or less normally, despite inhibition by grapefruit juice. The effects of grapefruit juice also vary considerably among CYP3A4 substrates. In one study, coadministration of grapefruit juice produced a 406% increase in blood levels of the calcium channel blocker felodipine (Plendil). For some other drugs metabolized by these isoenzymes, the effects are negligible. The clinical consequences of inhibition may be good or bad. As indicated in Table 4.3, by elevating levels of certain drugs, grapefruit juice can increase the risk for serious toxicity. On the other hand, by increasing levels of two drugs— saquinavir and cyclosporine—grapefruit juice can intensify therapeutic effects to promote positive outcomes.

What should providers do if the drugs they are prescribing can be affected by grapefruit juice? Unless a predictable effect is known or desirable, prudence dictates advising patients to avoid grapefruit juice entirely.

Effects of Food on Drug Toxicity Drug–food interactions sometimes increase toxicity. The most dramatic example is the interaction between monoamine oxidase (MAO) inhibitors and foods rich in tyramine (e.g., aged cheeses, yeast extracts, Chianti wine). If an MAO inhibitor is combined with these foods, blood pressure can rise to a lifethreatening level. To avoid disaster, patients taking MAO inhibitors must be warned about the consequences of consuming tyramine-rich foods and must be given a list of foods to strictly avoid (see Chapter 26). Other drug–food combinations that can increase toxicity include the following:

• Theophylline (an asthma medicine) plus caffeine, which can result in excessive CNS excitation • Potassium-sparing diuretics (e.g., spironolactone) plus salt substitutes, which can result in dangerously high potassium levels • Aluminum-containing antacids (e.g., Maalox) plus citrus beverages (e.g., orange juice), which can result in excessive absorption of aluminum Effects of Food on Drug Action Although most drug–food interactions concern drug absorption or drug metabolism, food may also (rarely) have a direct effect on drug action. For example, foods rich in vitamin K (e.g., broccoli, Brussels sprouts, cabbage) can reduce the effects of warfarin, an anticoagulant. This occurs because warfarin inhibits vitamin K–dependent clotting factors. Accordingly, when vitamin K is more abundant, warfarin is less able to inhibit the clotting factors and therapeutic effects decline.

Timing of Drug Administration With Respect to Meals Prescribing the administration of drugs at the appropriate time with respect to meals is an important part of drug therapy. As discussed, the absorption of some drugs can be significantly decreased by food, and hence these drugs should be

prescribed to be administered on an empty stomach (i.e., at least 1 hour before or 2 hours after a meal). Conversely, the absorption of other drugs can be increased by food, and hence these drugs should be prescribed to be administered with meals. Many drugs cause stomach upset when taken without food. If food does not significantly reduce their absorption, then these drugs should be administered with meals. However, if food does reduce their absorption, then we have a difficult choice: we can administer them with food and thereby reduce stomach upset but also reduce absorption, or we can administer them without food and thereby improve absorption but also increase stomach upset. Unfortunately, the correct choice is not obvious. The best solution, when possible, may be to select an alternative drug that does not upset the stomach.

Drug–Supplement Interactions Dietary supplements (herbal medicines and other nonconventional remedies) create the potential for frequent and significant interactions with conventional drugs. Of greatest concern are interactions that reduce beneficial responses to conventional drugs and interactions that increase toxicity. These interactions occur through the same pharmacokinetic and pharmacodynamic mechanisms by which conventional drugs interact with each other. Unfortunately, reliable information about dietary supplements is largely lacking, including information on interactions with conventional agents. Interactions that have been well documented are discussed as appropriate throughout this text. aFundamental pharmacologic concepts are typically covered in undergraduate

courses; however, experience has demonstrated that a refresher in the basic principles of pharmacokinetics, pharmacodynamics, and drug interactions is usually helpful. Because it is a refresher, the information in this chapter is relatively brief. bThe only exception to this rule is gene therapy. By inserting genes into cells, we

actually can make them do something they were previously incapable of doing.

5

Adverse Drug Reactions and Medication Errors Abstract Medication safety is major and constant concern for providers. Two primary factors that increase the risk for patient harm are adverse drug reactions and medication errors. By becoming knowledgeable about the types of adverse effects, the provider can anticipate their occurrence and minimize potential harm. Similarly, by incorporating measures to reduce medication errors, providers can provide drug therapy that is safer. Taken together, these actions can improve patient outcomes and increase patient satisfaction.

Keywords adverse reaction; side effect; medication error; drug reactions; toxicity; medication reconciliation In this chapter we discuss two related issues of drug safety: (1) adverse drug reactions (ADRs), also known as adverse drug events; and (2) medication errors, a major cause of ADRs. We begin with ADRs and then discuss medication errors.

Adverse Drug Reactions An ADR, as defined by the World Health Organization, is “any noxious, unintended, and undesired effect that occurs at normal drug doses.” Adverse reactions can range in intensity from mildly annoying to life threatening. Among the milder reactions are drowsiness, nausea, itching, and rash. Severe reactions include potentially fatal conditions such as neutropenia, hepatocellular injury, cardiac dysrhythmias, anaphylaxis, and hemorrhage.

Scope of the Problem A 2018 statistical brief by the Agency for Healthcare Research and Quality highlighted a decrease in the occurrence of ADRs for inpatients. These are believed to be the result of intensive efforts to implement system-wide changes to decrease ADRs. For outpatients, however, ADRs have increased. In 2014, more than 1,110,000 outpatients were admitted to hospitals because of ADRs. This represented an increase of 100,000 compared with the year 2010. Box 5.1 lists the most common causes of these ADRs. Many of these incidences were preventable, but fortunately, when drugs are carefully prescribed and when patients are well educated on proper use, many ADRs can be avoided or minimized. Box 5.1

Ranking of Drugs Requiring Hospitalization for Adverse Drug Reactions Antibiotics/anti-infectives (21.6%) Systemic agentsa (13.5%) Hormones (13.3%) Analgesics (13.1%) Hematologic agents (10%) Psychotropic drugs (8.1%) Cardiovascular drugs (6.6%) Water, mineral, and uric acid metabolism drugs (4.9%) Sedatives or hypnotics (3.6%) Anticonvulsants and anti-Parkinson drugs (2.5%) Central nervous system (CNS) depressants and anesthetics (1.9%) Smooth muscle and respiratory drugs (1.3%) CNS drugs not previously identified (1%) Autonomic nervous system drugs (0.7%) Gastrointestinal drugs (0.4%) Eye, skin, and mucous membrane drugs (0.3%) Vaccines (0.1%) Drug not identified (14.4%)

aAnticancer drugs, antiallergy and antiemetic drugs, and other systemic agents.

Adapted from an Agency for Healthcare Research and Quality 2014 examination of hospital admissions in 28 states. See https://www.hcupus.ahrq.gov/reports/statbriefs/sb234-Adverse-Drug-Events.pdf.

Definitions Side Effect A side effect is formally defined as a nearly unavoidable secondary drug effect produced at therapeutic doses. Common examples include drowsiness caused by traditional antihistamines and gastric irritation caused by aspirin. Side effects are generally predictable, and their intensity is dose dependent. Some side effects develop soon after drug use starts, whereas others may not appear until a drug has been taken for weeks or months.

Toxicity The formal definition of toxicity is the degree of detrimental physiologic effects caused by excessive drug dosing. Examples include profound respiratory depression from an overdose of morphine and severe hypoglycemia from an overdose of insulin. Although the formal definition of toxicity includes only those severe reactions that occur when dosage is excessive, in everyday language the term toxicity has come to mean any severe ADR, regardless of the dose that caused it. For example, when administered in therapeutic doses, many anticancer drugs cause neutropenia, thereby putting the patient at high risk for infection. This neutropenia may be called “toxicity” even though it was produced when dosage was therapeutic.

Allergic Reaction An allergic reaction is an immune response. For an allergic reaction to occur, there must be prior sensitization of the immune system. After the immune system has been sensitized to a drug, reexposure to that drug can trigger an allergic response. The intensity of allergic reactions can range from mild itching to severe rash to anaphylaxis. Estimates suggest that less than 10% of ADRs are

of the allergic type. The intensity of an allergic reaction is determined primarily by the degree of sensitization of the immune system, not by drug dosage. Put another way, the intensity of allergic reactions is largely independent of dosage. As a result, a dose that elicits a very strong reaction in one allergic patient may elicit a very mild reaction in another. Furthermore, because a patient's sensitivity to a drug can change over time, a dose that elicits a mild reaction early in treatment may produce an intense reaction later on. Very few medications cause severe allergic reactions. In fact, most serious reactions are caused by just one drug family—the penicillins. Other drugs noted for causing allergic reactions include the nonsteroidal antiinflammatory drugs (e.g., aspirin) and the sulfonamide group of compounds, which includes certain diuretics, antibiotics, and oral hypoglycemic agents.

Idiosyncratic Effect An idiosyncratic effect is defined as an uncommon drug response resulting from a genetic predisposition. An example of an idiosyncratic effect occurs in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an X-linked inherited condition that occurs primarily in people with African and Mediterranean ancestry. When people with G6PD deficiency take drugs such as sulfonamides or aspirin, they develop varying degrees of red blood cell hemolysis, which may become life threatening.

Paradoxical Effect A paradoxical effect is the opposite of the intended drug response. A common example is the excitement that may occur when some children take firstgeneration antihistamines (available over-the-counter as a sleep aid). Similarly, older adults may experience paradoxical excitement when they are given benzodiazepines for sedation.

Iatrogenic Disease An iatrogenic disease is a disease that occurs as the result of medical care or treatment. The term iatrogenic disease is also used to denote a disease produced by drugs. Iatrogenic diseases are nearly identical to naturally occurring diseases. For example, patients taking certain antipsychotic drugs may develop a syndrome

with symptoms that closely resemble those of Parkinson disease.

Physical Dependence Physical dependence is a state in which the body has adapted to drug exposure in such a way that an abstinence syndrome will result if drug use is discontinued. Physical dependence develops during long-term use of certain drugs, such as opioids, alcohol, barbiturates, and amphetamines. The precise nature of the abstinence syndrome is determined by the drug involved. Although physical dependence is usually associated with opioids, these are not the only dependence-inducing drugs. A variety of other centrally acting drugs (e.g., ethanol, barbiturates, amphetamines) can promote dependence. Furthermore, some drugs that work outside the central nervous system can cause physical dependence of a sort. Because a variety of drugs can cause physical dependence of one type or another, and because withdrawal reactions have the potential for harm, patients should be warned against abrupt discontinuation of any medication without first consulting a health professional.

Carcinogenic Effect The term carcinogenic effect refers to the ability of certain medications and environmental chemicals to cause cancers. Fortunately, only a few therapeutic agents are carcinogenic. Ironically, several of the drugs used to treat cancer are among those with the greatest carcinogenic potential. Evaluating drugs for the ability to cause cancer is extremely difficult. Evidence of neoplastic disease may not appear until 20 or more years after initial exposure to a cancer-causing compound.

Teratogenic Effect A teratogenic effect is a drug-induced birth defect. Medicines and other chemicals capable of causing birth defects are called teratogens. Teratogenesis is discussed in Chapter 8.

Organ-Specific Toxicity Many drugs are toxic to specific organs. Common examples include injury to the kidneys caused by amphotericin B (an antifungal drug), injury to the heart caused by doxorubicin (an anticancer drug), injury to the lungs caused by

amiodarone (an antidysrhythmic drug), and injury to the inner ear caused by aminoglycoside antibiotics (e.g., gentamicin). Patients using these drugs should be monitored for signs of developing injury. In addition, patients should be educated about these signs and advised to seek medical attention if they appear. Two types of organ-specific toxicity deserve special comment. These are (1) injury to the liver and (2) altered cardiac function, as evidenced by a prolonged QT interval on the electrocardiogram. Both are discussed next.

Hepatotoxic Drugs As some drugs undergo metabolism by the liver, they are converted to toxic products that can injure liver cells. These drugs are called hepatotoxic drugs. In the United States, drugs are the leading cause of acute liver failure, a rare condition that can rapidly prove fatal. Fortunately, liver failure from using known hepatotoxic drugs is rare, with an incidence of less than 1 in 50,000. (Drugs that cause liver failure more often than this are removed from the market —unless they are indicated for a life-threatening illness.) More than 50 drugs are known to be hepatotoxic. Some examples are listed in Table 5.1. TABLE 5.1 Some Hepatotoxic Drugs Statins and Other Lipid-Lowering Drugs Atorvastatin (Lipitor) Fenofibrate (TriCor, Trilipix, Lipidil EZ) Fluvastatin (Lescol) Gemfibrozil (Lopid) Lovastatin (Mevacor) Niacin (Niaspan, others) Pitavastatin (Livalo) Pravastatin (Pravachol) Rosuvastatin (Crestor) Simvastatin (Zocor) Oral Antidiabetic Drugs Acarbose (Precose, Glucobay) Pioglitazone (Actos) Rosiglitazone (Avandia)

Antiseizure Drugs Carbamazepine (Tegretol) Felbamate (Felbatol) Phenytoin (Dilantin) Valproic acid (Depakene, others) Antifungal Drugs Fluconazole (Diflucan) Griseofulvin (Grifulvin V, Gris-PEG) Itraconazole (Sporanox) Ketoconazole (Nizoral) Terbinafine (Lamisil) Antigout Drugs Allopurinol (Zyloprim) Febuxostat (Uloric) Antidepressant/Antipsychotic Drugs Bupropion (Wellbutrin, Zyban) Duloxetine (Cymbalta) Nefazodone Trazodone Tricyclic antidepressants Antimicrobial Drugs Amoxicillin–clavulanic acid (Augmentin) Erythromycin Minocycline (Minocin) Nitrofurantoin (Macrodantin, Macrobid) Penicillin Trimethoprim-sulfamethoxazole (Septra, Bactrim) Drugs for Tuberculosis Isoniazid Pyrazinamide Rifampin (Rifadin) Immunosuppressants Azathioprine (Imuran) Leflunomide (Arava) Methotrexate (Rheumatrex) Antiretroviral Drugs

Nevirapine (Viramune) Ritonavir (Norvir) Other Drugs Acetaminophen (Tylenol), but only when combined with alcohol or taken in excessive dose Amiodarone (Cordarone) Baclofen (Lioresal, Gablofen) Celecoxib (Celebrex) Diclofenac (Voltaren) Labetalol (Trandate) Lisinopril (Prinivil, Zestril) Losartan (Cozaar) Methyldopa (Aldomet) Omeprazole (Prilosec) Procainamide Tamoxifen (Nolvadex) Testosterone Zileuton (Zyflo)

Combining a hepatotoxic drug with certain other drugs may increase the risk of liver damage. Acetaminophen (Tylenol) is a hepatotoxic drug that can damage the liver when taken in excessive doses. When taken in therapeutic doses, acetaminophen does not usually create a risk for liver injury; however, if the drug is taken with just two or three alcoholic beverages, severe liver injury can result.

QT Interval Drugs The term QT interval drugs—or simply QT drugs—refers to the ability of some medications to prolong the QT interval on the electrocardiogram, thereby creating a risk for serious dysrhythmias. The QT interval is a measure of the time required for the ventricles to repolarize after each contraction. When the QT interval is prolonged (more than 470 ms for postpubertal males or more than 480 ms for postpubertal females), patients can develop a dysrhythmia known as torsades de pointes, which can progress to potentially fatal ventricular fibrillation. More than 100 drugs are known to cause QT prolongation, torsades de pointes, or both. As shown in Table 5.2, QT drugs are found in many drug families. Several QT drugs have been withdrawn from the market because of

deaths linked to their use, and the use of another QT drug—cisapride (Propulsid) —is now restricted. To reduce the risks from QT drugs, the US Food and Drug Administration (FDA) now requires that all new drugs be tested for the ability to cause QT prolongation. TABLE 5.2 Drugs That Prolong the QT Interval, Induce Torsades De Pointes, or Both Cardiovascular: Antidysrhythmics Amiodarone (Cordarone) Disopyramide (Norpace) Dofetilide (Tikosyn) Dronedarone (Multaq) Flecainide (Tambocor) Ibutilide (Corvert) Mexiletine (Mexitil) Procainamide (Procan, Pronestyl) Quinidine Sotalol (Betapace) Cardiovascular: ACE Inhibitors/Calcium Channel Blockers Bepridil (Vascor) Isradipine (DynaCirc) Moexipril Nicardipine (Cardene) Antibiotics Azithromycin (Zithromax) Clarithromycin (Biaxin) Erythromycin Gemifloxacin (Factive) Levofloxacin (Levaquin) Moxifloxacin (Avelox) Ofloxacin (Floxin) Telithromycin Antifungal Drugs Fluconazole (Diflucan) Voriconazole (Vfend) Antidepressants

Amitriptyline (Elavil) Citalopram (Celexa) Desipramine (Norpramin) Doxepin (Sinequan) Escitalopram (Lexapro) Fluoxetine (Prozac) Imipramine (Tofranil) Mirtazapine (Remeron) Protriptyline (Pamelor, Aventyl) Sertraline (Zoloft) Trimipramine (Surmontil) Venlafaxine (Effexor) Antipsychotics Chlorpromazine (Thorazine) Clozapine (Clozaril) Haloperidol (Haldol) Iloperidone (Fanapt) Paliperidone (Invega) Pimozide (Orap) Quetiapine (Seroquel) Risperidone (Risperdal) Thioridazine (Mellaril) Ziprasidone (Geodon) Antiemetics/Antinausea Drugs Dolasetron (Anzemet) Domperidone (Motilium) Droperidol (Inapsine) Granisetron (Kytril) Ondansetron (Zofran) Anticancer Drugs Arsenic trioxide (Trisenox) Eribulin (Halaven) Lapatinib (Tykerb) Nilotinib (Tasigna) Sunitinib (Sutent) Tamoxifen (Nolvadex) Vandetanib (Caprelsa) Vorinostat (Zolinza) Drugs for Attention-Deficit/Hyperactivity Disorder

Amphetamine/dextroamphetamine (Adderall) Atomoxetine (Strattera) Dexmethylphenidate (Focalin) Dextroamphetamine (Dexedrine) Methylphenidate (Ritalin, Concerta) Nasal Decongestants Phenylephrine (Neo-Synephrine, Sudafed PE) Pseudoephedrine (Sudafed) Other Drugs Alfuzosin (Uroxatral) Amantadine (Symmetrel) Chloroquine (Aralen) Cisapride (Propulsid)a Cocaine Felbamate (Felbatol) Fingolimod (Gilenya) Foscarnet (Foscavir) Fosphenytoin (Cerebyx) Galantamine (Razadyne) Halofantrine (Halfan) Indapamide (Lozol) Lithium (Lithobid, Eskalith) Methadone (Dolophine) Midodrine (ProAmatine) Octreotide (Sandostatin) Pasireotide (Signifor) Pentamidine (Pentam, Nebupent) Phentermine (Fastin) Ranolazine (Ranexa) Ritodrine (Yutopar) Salmeterol (Serevent) Saquinavir (Invirase) Solifenacin (Vesicare) Tacrolimus (Prograf) Terbutaline Tizanidine (Zanaflex) Tolterodine (Detrol) Vardenafil (Levitra) a

Restricted availability.

Identifying Adverse Drug Reactions It can be very difficult to determine whether a specific drug is responsible for an observed adverse event because other factors—especially the underlying illness and other drugs being taken—could be the actual cause. To help determine whether a particular drug is responsible, the following questions should be considered:

• Did symptoms appear shortly after the drug was first used? • Did symptoms abate when the drug was discontinued? • Did symptoms reappear when the drug was reinstituted? • Is the illness itself sufficient to explain the event? • Are other drugs in the regimen sufficient to explain the event? If the answers reveal a temporal relationship between the presence of the drug and the adverse event, and if the event cannot be explained by the illness itself or by other drugs in the regimen, then there is a high probability that the drug under suspicion is indeed the culprit. Unfortunately, this process is limited. It can only identify adverse effects that occur while the drug is being used; it cannot identify adverse events that develop years after drug withdrawal. Nor can it identify effects that develop slowly over the course of prolonged drug use.

Adverse Reactions to New Drugs

Preclinical and clinical trials of new drugs cannot detect all of the ADRs that a drug may be able to cause. In fact, about 50% of all new drugs have serious ADRs that are not revealed during phase 1 and phase 3 trials. Because newly released drugs may have as yet unreported adverse effects, you should be alert for unusual responses when prescribing new drugs. If the patient develops new symptoms, it is wise to suspect that the drug may be responsible— even if the symptoms are not described in the literature. It is a good practice to initially check postmarket drug evaluations at www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ucm204091.ht to determine whether serious problems have been reported. If the drug is especially new, however, you may be the first provider to have observed the effect. If you suspect a drug of causing a previously unknown adverse effect, you should report the effect to MedWatch, the FDA Medical Products Reporting

Program. You can file your report online at www.fda.gov/medwatch. Because voluntary reporting by health care professionals is an important mechanism for bringing ADRs to light, you should report all suspected ADRs, even if absolute proof of the drug's complicity has not been established.

Ways to Minimize Adverse Drug Reactions The responsibility for reducing ADRs lies with everyone associated with drug production and use. The pharmaceutical industry must strive to produce the safest medicines possible; the provider must select the least harmful medicine for a particular patient and provide clear instructions for its use; the nurse must evaluate patients for ADRs and educate patients in ways to avoid or minimize harm; and patients and their families must take medication only as directed, watch for signs that an ADR may be developing, and seek medical attention if one appears. When patients are using drugs that are toxic to specific organs, function of the target organ should be monitored. The liver, kidneys, and bone marrow are important sites of drug toxicity. For drugs that are toxic to the liver, the patient should be monitored for signs and symptoms of liver damage (jaundice, dark urine, light-colored stools, nausea, vomiting, malaise, abdominal discomfort, loss of appetite), and periodic tests of liver function (e.g., aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) should be performed. For drugs that are toxic to the kidneys, the patient should undergo routine urinalysis and measurement of serum creatinine or creatinine clearance. For drugs that are toxic to bone marrow, periodic complete blood cell counts are required. Individualizing therapy can reduce adverse effects. When choosing a drug for a patient, the provider must balance the drug's risks and benefits. Drugs that are likely to harm a specific patient should be avoided unless the benefit of the drug exceeds the risk for injury.

Special Alerts and Management Guidelines To decrease harm associated with drugs that cause serious adverse effects, the FDA requires special alerts and management guidelines. These may take the form of a Medication Guide for patients, a boxed warning to alert providers, or a Risk Evaluation and Mitigation Strategy (REMS), which can involve patients,

providers, and pharmacists.

Medication Guides Medication Guides, commonly called MedGuides, are FDA-approved documents created to educate patients about how to minimize harm from potentially dangerous drugs. In addition, a MedGuide is required when the FDA has determined that (1) patient adherence to directions for drug use is essential for efficacy or (2) patients need to know about potentially serious effects when deciding to use a drug. All MedGuides use a standard format that provides information under the following main headings:

• What is the most important information I should know about (name of drug)? • What is (name of drug)? Include a description of the drug and its indications. • Who should not take (name of drug)? • How should I take (name of drug)? Include importance of adherence to dosing instructions, special instructions about administration, what to do in case of overdose, and what to do if a dose is missed. • What should I avoid while taking (name of drug)? Include activities (e.g., driving, sunbathing), other drugs, foods, pregnancy, and breastfeeding. • What are the possible or reasonably likely side effects of (name of drug)? • General information about the safe and effective use of prescription drugs. Additional headings may be added by the manufacturer as appropriate, with the approval of the FDA. MedGuides for all drug products that require one are available online at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm? event=medguide.page.The MedGuide should be provided whenever a prescription is filled, and even when drug samples are handed out.

Boxed Warnings The boxed warning, also known as a black box warning, is the strongest safety warning a drug can carry and still remain on the market. Text for the warning is presented inside a box with a heavy black border. The FDA requires a boxed warning on drugs with serious or life-threatening risks. The purpose of the warning is to alert providers to (1) potentially severe side effects (e.g., lifethreatening dysrhythmias, suicidality, major fetal harm) as well as (2) ways to prevent or reduce harm (e.g., avoiding a teratogenic drug during pregnancy). The boxed warning provides a concise summary of the adverse effects of concern. A boxed warning must appear prominently on the package insert, on the product label, and even in magazine advertising. Drugs that have a boxed warning must also have a MedGuide. An example of a drug with a boxed warning is promethazine (Phenergan). Promethazine is contraindicated in patients less than 2-years-old because it can cause respiratory depression. Additionally, when administered by injection, there is a risk for severe tissue injury and necrosis.

Risk Evaluation and Mitigation Strategies A REMS is simply a plan to minimize drug-induced harm. For most drugs that have a REMS, a MedGuide is all that is needed. For a few drugs, however, the REMS may have additional components. For example, the REMS for the antiacne drug isotretinoin has provisions that pertain to the patient, provider, and pharmacist. This program, known as iPledge, is needed because isotretinoin can cause serious birth defects. The iPledge program was designed to ensure that patients who are pregnant, or may become pregnant, will not have access to the drug. Details of the iPledge program are presented in Chapter 87. All REMS that have received FDA approval can be found online at https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm.

Medication Errors Medication errors are a major cause of morbidity and mortality. According to the National Academy of Medicine (formerly the Institute of Medicine [IOM]), every year medication errors injure at least 1.5 million Americans and kill an estimated 7000. The financial costs are staggering: among hospitalized patients alone, treatment of drug-related injuries costs at least $3.5 billion per year.

What Is a Medication Error? The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm, while the medication is in the control of the healthcare professional, patient, or consumer. Such events may be related to professional practice, healthcare products, procedures, and systems, including prescribing; order communication; product labeling, packaging and nomenclature; compounding; dispensing; distribution; administration; education; monitoring; and use.” Note that, by this definition, medication errors can be made by many people—beginning with workers in the pharmaceutical industry, followed by people in the health care delivery system, and ending with patients and their family members. In this chapter, we focus on medication errors attributed to health care providers. These typically fall into one of the following categories:

Prescribing Practices • Inappropriate drug selection • Error in drug dosage • Lack of clear instructions • Illegible writing Oversight • Failure to keep an up-to-date medication list • Failure to continue or discontinue medications • Absence of medication reconciliation Communication • Inadequate or unclear instructions • Failure to verify drugs that sound alike • Inadequate patient education

Ways to Reduce Medication Errors

Organizations throughout many countries are working to design and implement measures to reduce medication errors. Changes having the most dramatic effect have been those that focused on the National Academy of Medicine recommendations to (1) help and encourage patients and their families to be active, informed members of the health care team, and (2) give health care providers the tools and information needed to prescribe, dispense, and administer drugs as safely as possible. Foremost among these recommendations are requiring electronic prescribing, making drug reference material available electronically, and regulating abbreviations. Implementation of technology to reduce errors has had remarkable success, as well. For example, replacing handwritten medication orders with a computerized order entry system has reduced medication errors by 50%. Using barcode systems that match the patient's armband bar code to a drug barcode has decreased medication errors in some institutions by as much as 85%. Targeted interventions to address provider-related errors can be employed to decrease medication errors by health care providers. These are provided in Table 5.3. TABLE 5.3

ISMP, Institute for Safe Medical Practices.

Incorporating medication reconciliation (Box 5.2) has resulted in decreasing medication errors by 70% and reducing ADRs by 15%. Box 5.2

Medication Reconciliation What Is Medication Reconciliation and When Is It Done? Medication reconciliation is the process of comparing a list of all medications that a patient is currently taking with a list of new medications that are about to be provided. Reconciliation is conducted whenever a patient undergoes a transition in care in which new medications may be ordered or existing orders may be changed. Transitions in care include hospital admission, hospital discharge, moving to a different level of care within a hospital, transfer to

another facility, or discharge home.

How Is Medication Reconciliation Conducted? There are five steps: Step 1. Create a list of current medications. For each drug, include the name, indication, route, dosage size, and dosing interval. For patients entering a hospital, the list would consist of all medications being taken at home, including vitamins, herbal products, and prescription and nonprescription drugs. Step 2. Create a list of all medications to be prescribed in the new setting. Step 3. Compare the medications on both lists. Step 4. Adjust medications based on the comparison. For example, the provider would discontinue drugs that are duplicates or inappropriate and would avoid drugs that can interact adversely. Step 5. When the next transition in care occurs, provide the updated, reconciled list to the patient and the new provider. By consulting the list, the new provider will be less likely to omit a prescribed medication or commit a dosing error and will be less likely to prescribe a new medication that might duplicate or negate the effects of a current medication or interact with a current medication to cause a serious adverse event. Every time a new transition in care occurs, reconciliation should be conducted again.

Does Medication Reconciliation Reduce Medication Errors? Definitely. Approximately 60% of medication errors occur when patients undergo a transition in care. Medication reconciliation can eliminate most of these errors.

Should Medication Reconciliation Be Conducted at Discharge? When patients leave a facility, they should receive a single, clear, comprehensive list of all medications they will be taking after discharge. The list should include any medications ordered at the time of discharge, as well as any other medications the patient will be taking, including over-the-counter drugs, vitamins, and herbal products and other nutritional supplements. In addition, the list should include all prescription medications that the patient had been taking at home but had been temporarily discontinued during the episode of care. The discharge list should not include drugs that had been used during the episode of care but are no longer needed. The patient and, with the

patient's permission, the next provider of care should receive the discharge list so that the new provider will be able to continue the reconciliation process. Words that look alike or sound alike are a common source of medication errors (Table 5.4). The Institute for Safe Medical Practices (ISMP) recommends interventions for look-alike drugs (e.g., including brand and generic names when writing prescriptions), but these recommendations do not address sound-alike drugs. When it is necessary to give a verbal order, as in an emergency situation, asking for a verbalization of the order adds an extra layer of safety. TABLE 5.4 Examples of Drugs With Names That Sound Alike or Look Alike Amicar

Omacor

Anaspaz

Antispas

Celebrex

Cerebyx

Clinoril

Clozaril

Cycloserine

Cyclosporine

Depo-Estradiol

Depo-Testadiol

Dioval

Diovan

Estratab

Estratest

Etidronate

Etretinate

Flomax

Volmax

Lamisil

Lamictal

Levoxine

Levoxyl

Lithobid

Lithostat

Lodine

Iodine

Naprelan

Naprosyn

Nasarel

Nizoral

Neoral

Neosar

Nicoderm

Nitroderm

Sarafem

Serophene

Serentil

Seroquel

Tamiflu

Theraflu

Tramadol

Toradol

Trade names are italicized; generic names are not.

Many medication errors result from using error-prone abbreviations, symbols, and dose designations. To address this concern, the ISMP and the FDA together compiled a list of error-prone abbreviations, symbols, and dose designations (Table 5.5) and have recommended against their use. This list includes eight entries (presented at the top of Table 5.5) that have been banned by The Joint Commission (TJC). These banned abbreviations can no longer be used by hospitals and other organizations that require TJC accreditation. The full list is available online at www.ismp.org/tools/errorproneabbreviations.pdf. TABLE 5.5

TJC, The Joint Commission. Adapted from a list compiled by the Institute for Safe Medication Practices. The official TJC list is available at http://www.jointcommission.org/assets/1/18/dnu_list.pdf. The complete ISMP list is available at www.ismp.org/tools/errorproneabbreviations.pdf.

A wealth of information is available on reducing medication errors. See Table

5.6 for some good places to start. TABLE 5.6 Resources on Decreasing Medication Errors Resource

Location

Agency for Healthcare Research and Quality's Patient Safety Network

https://psnet.ahrq.gov

Institute for Safe Medication Practices

www.ismp.org

Institute for Healthcare Improvement Medication Reconciliation Information and Tools

http://www.ihi.org/topics/adesmedicationreconciliation/Pages/default.aspx

National Coordinating www.nccmerp.org Council for Medication Error Reporting and Prevention Institute of Medicine: Preventing Medication Errors

https://www.nap.edu/catalog/11623/preventing-medication-errors

US Food and Drug Administration: Medication Errors Related to Drugs

www.fda.gov/Drugs/DrugSafety/MedicationErrors/default.htm

How to Report a Medication Error You can report a medication error through the Medication Error Reporting

(MER) Program, a nationwide system run by the ISMP. All reporting is confidential and can be done by phone or through the Internet. Details on submitting a report are available at www.ismp.org/orderForms/reporterrortoISMP.asp. The MER Program encourages participation by all health care providers, including pharmacists, nurses, physicians, and students. The objective is not to establish blame, but instead to improve patient safety by increasing our knowledge of medication errors. All information gathered by the MER Program is forwarded to the FDA, the ISMP, and the product manufacturer.

6

Individual Variation in Drug Responses Abstract Prescribing and managing drug therapy would be much simpler if all patients responded to medications in the same way. The reality is that drugs’ effects vary widely among individuals. Factors such as age, gender, body size, genetics and co-morbidities play a large role in individual variation in drug responses. Understanding these factors and anticipating how they affect drug responses can inform prescribing practices and guide wise drug management so that therapy is safer and outcomes are improved.

Keywords variability; drug responses; altered responses; tolerance; placebo effect In this chapter, we discuss the major factors that can cause one patient to respond to drugs differently than another. With this information, you will be better prepared to reduce individual variation in drug responses, thereby maximizing the benefits of treatment and reducing the potential for harm.

Body Weight and Composition The intensity of the response to a drug is determined in large part by the concentration of the drug at its sites of action—the higher the concentration, the more intense the response. Thus body size can be a significant determinant of drug effects. If we give the same dose to a small person and a large person, the drug will achieve a higher concentration in the small person and therefore will produce more intense effects. The potential consequences are that we will produce toxicity in the smaller person and undertreat the larger person. To

compensate for this potential source of individual variation, the size of the patient should be considered when prescribing drug dosage. This is especially important for pediatric patients. Adjustments in dosage are typically based on body surface area because surface area determinations account not only for the patient's weight but also for the patient's relative amount of body adiposity. Because percentage of body fat can change drug distribution, and because altered distribution can change the concentration of a drug at its sites of action, dosage adjustments based on body surface area provide a more precise means of controlling drug responses compared to adjustments based on weight alone.

Age Drug sensitivity varies with age. Infants and older adults are especially sensitive to drugs. In the very young patient, heightened drug sensitivity is the result of organ immaturity. In older adults, heightened sensitivity results largely from decline in organ function. Other factors that affect sensitivity in older adults are the presence of multiple comorbidities and treatment with multiple drugs. The clinical challenge created by heightened drug sensitivity in very young or in older adult patients is the subject of Chapters 9 and 10.

Pathophysiology Physiologic alterations can modify drug responses. Four pathologic conditions, in particular, may have a profound effect: (1) kidney disease, (2) liver disease, (3) acid-base imbalance, and (4) altered electrolyte status.

Kidney Disease Kidney disease can reduce drug excretion, causing drugs to accumulate in the body. If dosage is not lowered, drugs may accumulate to toxic levels. Accordingly, if a patient is taking a drug that is eliminated by the kidneys, and if renal function declines, dosage must be decreased.

Liver Disease Like kidney disease, liver disease can cause drugs to accumulate. This occurs because the liver is the major site of drug metabolism. Therefore if liver function

declines, the rate of metabolism will decline, causing drug levels to climb. Accordingly, to prevent accumulation to toxic levels, the dosage of drugs eliminated through hepatic metabolism must be reduced or discontinued if liver disease develops.

Acid–Base Imbalance By altering pH partitioning (see Chapter 4), changes in acid–base status can alter the absorption, distribution, metabolism, and excretion of drugs. Because of pH partitioning, if there is a difference in pH on two sides of a membrane, a drug will accumulate on the side where the pH most favors its ionization. Because acidic drugs ionize in alkaline media, acidic drugs will accumulate on the alkaline side of the membrane. Conversely, basic drugs will accumulate on the acidic side.

Altered Electrolyte Status Electrolytes (e.g., potassium, sodium, calcium, magnesium, phosphorus) have important roles in cell physiology. Consequently, when electrolyte levels become disturbed, multiple cellular processes can be disrupted. Excitable tissues (nerves and muscles) are especially sensitive to alterations in electrolyte status. Given that disturbances in electrolyte balance can have widespread effects on cell physiology, we might expect that electrolyte imbalances would cause profound and widespread effects on responses to drugs. However, this does not seem to be the case; examples in which electrolyte changes have a significant effect on drug responses are rare. An exception is digoxin in the presence of hypokalemia. When potassium levels are low, the ability of digoxin to induce dysrhythmias is greatly increased. Accordingly, all patients receiving digoxin must undergo regular measurement of serum potassium to ensure that levels remain within a safe range.

Tolerance Tolerance is a decreased responsiveness to a drug as a result of repeated drug administration. Patients who are tolerant to a drug require higher doses to produce effects equivalent to those that could be achieved with lower doses before tolerance developed. There are three categories of drug tolerance: (1)

pharmacodynamic tolerance, (2) metabolic tolerance, and (3) tachyphylaxis.

Pharmacodynamic Tolerance The term pharmacodynamic tolerance refers to the familiar type of tolerance associated with long-term administration of drugs such as morphine and heroin. Pharmacodynamic tolerance is the result of adaptive processes that occur in response to chronic receptor occupation. Because increased drug levels are required to produce an effective response, the minimum effective concentration (MEC) of a drug becomes abnormally high.

Metabolic Tolerance Metabolic tolerance is defined as tolerance resulting from accelerated drug metabolism. This form of tolerance is brought about by the ability of certain drugs (e.g., barbiturates) to induce the synthesis of hepatic drug-metabolizing enzymes, thereby causing rates of drug metabolism to increase. Because of increased metabolism, dosage must be increased to maintain therapeutic drug levels. Unlike pharmacodynamic tolerance, which causes the MEC to increase, metabolic tolerance does not affect the MEC.

Tachyphylaxis Tachyphylaxis is a reduction in drug responsiveness brought on by repeated dosing over a short time. This is unlike pharmacodynamic tolerance and metabolic tolerance, which take days or longer to develop. Transdermal nitroglycerin provides a good example of tachyphylaxis. When nitroglycerin is administered using a transdermal patch, effects are lost in less than 24 hours if the patch is left in place around the clock. As discussed in Chapter 44, the loss of effect results from depletion of a cofactor required for nitroglycerin to act. When nitroglycerin is administered on an intermittent schedule, rather than continuously, the cofactor can be replenished between doses, and no loss of effect occurs.

Placebo Effect A placebo is devoid of intrinsic pharmacologic activity; therefore any response that a patient may have to a placebo is based solely on the patient's psychological

reaction to the idea of taking a medication and not to any direct physiologic or biochemical action of the placebo itself. The primary use of the placebo is as a control preparation during clinical trials. In pharmacology, the placebo effect is defined as the component of a drug response that is caused by psychological factors and not by the biochemical or physiologic properties of the drug. It is widely believed that with practically all medications, some fraction of the total response results from a placebo effect. Although placebo effects are determined by psychological factors and not physiologic responses to the inactive placebo, the presence of a placebo response does not imply that a patient's original pathology was imaginary. Not all placebo responses are beneficial. If a patient believes that a medication is going to be effective, then placebo responses are likely to help promote recovery. Conversely, if a patient is convinced that a particular medication is ineffective or perhaps even harmful, then placebo effects are likely to detract from his or her progress. Because the placebo effect depends on the patient's attitude toward medicine, fostering a positive attitude may help promote beneficial effects. In this regard, it is desirable that all members of the health care team present the patient with an optimistic (but realistic) assessment of the effects that therapy is likely to produce.

Variability in Absorption Both the rate and extent of drug absorption can vary among patients. As a result, both the timing and intensity of responses can be changed.

Bioavailability The term bioavailability refers to the amount of an active drug that reaches the systemic circulation from its site of administration. Different formulations of the same drug can vary in bioavailability. Factors such as tablet disintegration time, enteric coatings, and sustained-release formulations can alter bioavailability and can thereby make drug responses variable. Differences in bioavailability occur primarily with oral preparations rather than parenteral preparations. Fortunately, even with oral agents, when differences in bioavailability do exist between preparations, those differences are usually so small that they lack clinical significance.

Differences in bioavailability are of greatest concern for drugs with a narrow therapeutic range, because with these agents, a relatively small change in drug level can produce a significant change in response: a small decline in drug level may cause therapeutic failure, whereas a small increase in drug level may cause toxicity. Under these conditions, differences in bioavailability could have a significant effect.

Individual Causes of Variable Absorption Individual variations that affect the speed and degree of drug absorption affect bioavailability and can thereby lead to variations in drug responses. Alterations in gastric pH can affect absorption through the pH partitioning effect. For drugs that undergo absorption in the intestine, absorption will be delayed when gastric emptying time is prolonged. Diarrhea can reduce absorption by accelerating the transport of drugs through the intestine. Conversely, constipation may enhance the absorption of some drugs by prolonging the time available for absorption.

Genetics and Pharmacogenomics A patient's unique genetic makeup can lead to drug responses that are qualitatively and quantitatively different from those of the population at large. Adverse effects and therapeutic effects may be increased or reduced. Idiosyncratic responses to drugs may also occur. This topic is explored extensively in Chapter 7.

Gender- and Race-Related Variations Gender- and race-related differences in drug responses are, ultimately, genetically based. However, a general discussion is warranted.

Gender Men and women can respond differently to the same drug. A drug may be more effective in men than in women, or vice versa. Likewise, adverse effects may be more intense in men than in women, or vice versa. Unfortunately, for most drugs, we do not have adequate knowledge about gender-related differences because before 1997, when the FDA pressured drug companies to include women in trials of new drugs, essentially all drug research was done in men.

Since that time, research has demonstrated that significant gender-related differences really do exist. Here are four examples:

• When used to treat heart failure, digoxin may increase mortality in women while having no effect on mortality in men. • Alcohol is metabolized more slowly by women than by men. As a result, a woman who drinks the same amount as a man (on a weight-adjusted basis) will become more intoxicated. • Certain opioid analgesics (e.g., pentazocine, nalbuphine) are much more effective in women than in men. As a result, pain relief can be achieved at lower doses in women. • Quinidine causes greater QT interval prolongation in women than in men. As a result, women given the drug are more likely to develop torsades de pointes, a potentially fatal cardiac dysrhythmia. Although there is still a lack of adequate data related to drug effects in women, information generated by these drug trials, coupled with current and future trials, will permit drug therapy in women to be more rational than is possible today. In the meantime, clinicians must keep in mind that the information currently available may fail to accurately predict responses in female patients. Accordingly, clinicians should remain alert for treatment failures and unexpected adverse effects.

Race In 2005, BiDil, a fixed-dose combination of two vasodilators (isosorbidide dinitrate [ISDN] and hydralazine), became the first drug product approved by the FDA for treatment of a single racial group. Approval was based on results of the African American Heart Failure Trial (A-HeFT), which demonstrated that, in self-described black patients, adding ISDN plus hydralazine to standard therapy of heart failure reduced 1 year mortality by 43%—a very impressive and welcome result. The approval was controversial; however, because populations other than self-described black patients were excluded from clinical trials. Hence, there is no evidence that BiDil will not work just as well (and possibly even better) among some other group.

The greatest concern surrounding race-based therapy has to do with genetic variability. We know there is great diversity within and among racial groups; therefore, a “one fits all” approach based on race is unwise. Still, we can use known associations to guide choices. For example, differences in metabolism between people with East Asian and European heritage are common. The provider can use this knowledge to guide initial dosing (with adjustment, as indicated based on response) if genetic testing is not feasible or warranted.

Comorbidities and Drug Interactions Individuals often have two or more medical conditions or disease processes. When this occurs, drugs taken to manage one condition may complicate management of the other condition. As an example, if a person who has both asthma and hypertension is prescribed a nonselective β-adrenergic antagonist (β blocker) to control blood pressure, this may worsen the patient's asthma symptoms if the dose is sufficient to cause airway constriction. This illustrates the necessity for the provider to consider the whole patient, not only the disease being treated, when selecting drug therapy. Because patients with comorbidities often take multiple medications, there is the increased likelihood of drug interactions. Drug interactions can be an important source of variability. The mechanisms by which one drug can alter the effects of another and the clinical consequences of drug interactions are discussed at length in Chapter 4.

7

Genetic and Genomic Considerations in Pharmacotherapeutics Abstract Key organizations in health care voiced the need for additional education in the field of genomics and pharmacogenomics to improve patient outcomes. Genomics education should be provided for all health professionals, including the areas of patient education, genetic testing and interpretation, and management of appropriate drug therapies. This chapter explores the integration of genetics and genomics into the field of pharmacotherapeutics.

Keywords genetics; genomics; pharmacogenetics; pharmacogenomics Scientists completed sequencing of the human genome in 2003. Since that time, patients have benefited from great advances in the science and technology of genomics. Before we discuss pharmacogenomics in more depth, it is helpful to differentiate between genetics and genomics. The study of genetics has existed since the time of Gregor Mendel and his pea pods in the 1800s. Genetics is the examination of passing genetic traits from one generation to another through human genes. The examination of the effects of genes (through creation of specific proteins) also falls under the study of genetics. As we have found, patients with the same genes may experience different diseases or different expression of disease traits. The National Human Genome Research Institute defines the genome as all of a person's genes. Going further, the study of the genome, as well as how genes interact with each other and the environment, is referred to as genomics. Genomics often involves investigation into diseases, such as asthma, heart disease, and cancer, as these conditions are often the result of complex

interactions between a person's genome and their personal environment. The study of human genomics encompasses many areas of science, including epigenomics, proteomics, microbiomics, and of course, pharmacogenomics. Besides the definitions discussed previously, how does genomics really differ from genetics? As we have found, patients with the same genes may experience different diseases or different expression of disease traits. This phenomenon is due to the variances in where a person lives, what they eat, how much they sleep, how much the work and what they do for work, and, as you can imagine, many other factors. Genomics takes into account a person's environment and lifestyle.

Pharmacogenomics The National Institutes of Health define pharmacogenomics as the study of how genes affect a person's response to drugs. The purpose of pharmacogenomics is to combine the sciences of genomics and pharmacology to provide individualized, targeted, safe drug therapies to patients. Some may include pharmacogenomics within the practice of Personalized Medicine or Precision Medicine, but truly, pharmacogenomics falls under the category of precision medicine. Although the two terms are often used interchangeably, precision medicine refers to a more general approach to finding effective strategies for treatment of similar groups of patients with specific genetic, lifestyle, and environmental factors. The name precision medicine developed from the ideas of personalized medicine. The reason personalized medicine has fallen out of favor is that while providers are treating patients on an individual basis, scientists are not developing novel treatments for every individual on the planet. Although pharmacogenomics is a relatively young science, it has produced significant clinically relevant information—information that can be used to enhance therapeutic effects and reduce harm. A patient's unique genetic makeup can lead to drug responses that are qualitatively and quantitatively different from those of the population at large. Adverse effects and therapeutic effects may be increased or reduced. Idiosyncratic responses to drugs may also occur. Discovery of genetic variants between individuals allows prescribers to select a more appropriate medication for a patient. The US Food and Drug Administration (FDA) lists adverse drug reactions as the fourth leading cause of death in the United States, noting more than 100,000 deaths and 2 million serious adverse drug events each year. As a result, the FDA has more than 150 medications that have pharmacogenomic biomarkers included

in the drug package insert (Fig. 7.1). Of these medications, 38 are required to include pharmacogenetics information on their package inserts. Genetic testing is now done routinely for some drugs. In fact, for a few drugs, such as maraviroc (Selzentry) and trastuzumab (Herceptin), the FDA now requires genetic testing before use, and for a few other drugs, including warfarin (Coumadin) and carbamazepine (Tegretol), genetic testing is recommended but not required.

FIG. 7.1 Warfarin Package

Genomics Education and Competencies Key organizations in health care voiced the need for additional education in the field of genomics and pharmacogenomics to improve patient outcomes. In their 2015 publication, Improving Genetics Education in Graduate and Continuing Health Professional Education, the National Academy of Medicine (NAM), formerly the Institute of Medicine (IOM), stated genomics education should be provided for all health professionals. Providers should possess knowledge in patient education, genetic testing and interpretation, and management of appropriate drug therapies. In September 2011, the American Nurses Association (ANA) published Essential Genetic and Genomic Competencies for Nurses with Graduate Degrees. This document discussed 38 competencies for nurses in the areas of risk assessment and interpretation, genetic education, clinical management, as well as ethical, legal, and social implications. Other strong proponents of genomics education and application include the National Institutes of Nursing Research (NINR) and American Association of Physician Assistants (AAPA). The Society of PAs in Genetics and Genomics (SPAGG) is a significant interest group affiliated with AAPA. Resources for further information surrounding genetics and genomics are located in Table 7.1. TABLE 7.1

Pharmacogenomic and Genetic Resources for Health Care Providers Organization

Resource

Website

Clinical Pharmacogenetics Implementation Consortium (CPIC)

Guidelines to assist providers in using genetic testing to optimize drug therapy

https://epicpgx.org

US Food and Drug Administration (FDA)

Table of http://www.fda.gov/drugs/scienceresearch/researchare Pharmacogenomic Biomarkers in Drug Labeling

Genetics/Genomics Competency Center (G2C2)

Genetics and genomics resource-specific search engine

Genetics in Primary Care Institute (GPCI)

Multiple resources for https://www.aap.org/en-us/advocacy-and-policy/aap-h application into Primary-Care-Institute.aspx primary practice

Personalized Medicine Variety of resources Coalition including tables that link drugs, biomarkers, and indications Pharmacogenomics Knowledgebase (PharmGKB)

https://genomicseducation.net/

http://www.personalizedmedicinecoalition.org/Educa

A wealth of https://www.pharmgkb.org/ information including a listing of drugs having labels with genetic information approved by the FDA and Health Canada

Application of Pharmacogenomics In the discussion that follows, we look at ways in which genetic variations can influence an individual's responses to drugs, and then indicate how

pharmacogenomic tests may be used to guide treatment (Table 7.2). Specifically in pharmacogenomics, we perform testing for gene characteristics related to drug responses. These gene characteristics are also known as biomarkers. The technical definition of a biomarker is a measurable substance that, when present in an organism, indicates the presence of a specific phenomenon. In simple terms, a biomarker tells practitioners about the existence of genetic variation. Not only are biomarkers used to diagnose certain disease processes; they can also be used in pharmacogenomics to determine reaction to drug treatment. As discussed previously, there are many drugs that mention biomarkers in their labels. TABLE 7.2

ADRB1, β1-adrenergic receptor; CCR5, chemokine receptor 5; CYP2C9, 2C9 isozyme of cytochrome P450 (CYP); CYP2C19, 2C19 isozyme of cytochrome P450 (CYP); CYP2D6, 2D6 isozyme of cytochrome P450 (CYP); EGFR, epidermal growth factor receptor; FDA, US Food and Drug Administration; HER2, human epidermal growth factor receptor type 2; HLA-B*1502, human leukocyte antigen B*1502; HLA-B*5701, human leukocyte antigen B*5701; TPMT, thiopurine

methyltransferase; VKORC1, vitamin K epoxide reductase complex 1.

Genetic Variants That Alter Drug Metabolism The most common mechanism by which genetic variants modify drug responses is by altering drug metabolism. These gene-based changes can either accelerate or slow the metabolism of many drugs. The usual consequence is either a reduction in benefits or an increase in toxicity. For drugs that have a high therapeutic index (TI), altered rates of metabolism may have little effect on the clinical outcome. However, if the TI is low or narrow, then relatively small increases in drug levels can lead to toxicity, and relatively small decreases in drug levels can lead to therapeutic failure. In these cases, altered rates of metabolism can be significant. The following examples show how a genetically determined variation in drug metabolism can reduce the benefits of therapy.

• Variants in the gene that codes for cytochrome P450-2D6 (CYP2D6) can greatly reduce the benefits of tamoxifen (Soltamox), a drug used to prevent breast cancer recurrence. To work, tamoxifen must first be converted to its active form— endoxifen—by CYP2D6. Women with an inherited deficiency in the CYP2D6 gene cannot activate the drug well, so they get minimal benefit from treatment. In one study, the cancer recurrence rate in those poor metabolizers was 9.5 times higher than in good metabolizers. Between 8% and 10% of women of European ancestry and up to 40% of Asian descent have gene variants that prevent them from metabolizing tamoxifen to endoxifen. At this time, the FDA neither requires nor recommends testing for variants in the CYP2D6 gene. However, given these numbers, testing is very reasonable and a test kit is available. • Variants of the gene that codes for CYP2C19 can greatly reduce the benefits of clopidogrel (Plavix), a drug that prevents platelet aggregation. Like tamoxifen, clopidogrel is a prodrug that must undergo conversion to an active form. With clopidogrel, the

conversion is catalyzed by CYP2C19. Unfortunately, about 25% of patients produce a variant form of the enzyme—CYP2C19*2. As a result, these people experience a weak antiplatelet response, which places them at increased risk for stroke, myocardial infarction, and other events. People with this genetic variation should use a different antiplatelet drug. • Among Americans of European heritage, about 52% metabolize isoniazid (a drug for tuberculosis) slowly, and 48% metabolize it rapidly. Owing to genetic differences, people of this ancestory may produce two different forms of N-acetyltransferase-2, the enzyme that metabolizes isoniazid. If dosage is not adjusted for these differences, the rapid metabolizers may experience treatment failure and the slow metabolizers may experience toxicity. • About 1 in 14 people of European heritage have a form of CYP2D6 that is unable to convert codeine into morphine, the active form of codeine. As a result, codeine cannot relieve pain in these people. The following examples show how a genetically determined variation in drug metabolism can increase drug toxicity.

• Variants in the gene that codes for CYP2C9 can increase the risk for toxicity from warfarin (Coumadin), an anticoagulant with a narrow TI. Bleeding occurs because (1) warfarin is inactivated by CYP2C9 and (2) patients with altered CYP2C9 genes produce a form of the enzyme that metabolizes warfarin slowly, allowing it to accumulate to dangerous levels. To reduce bleeding risk, the FDA now recommends that patients be tested for variants of the CYP2C9 gene. It should be noted, however, that in this case outcomes using expensive genetic tests are no better than outcomes using cheaper traditional tests, which directly measure the effect of warfarin on coagulation.

• Variants in the gene that codes for thiopurine methyltransferase (TPMT) can reduce TPMT activity and can thereby delay the metabolic inactivation of two thiopurine anticancer drugs: thioguanine (generic only) and mercaptopurine (Purinethol). As a result, in patients with inherited TPMT deficiency, standard doses of thiopurine or mercaptopurine can accumulate to high levels, posing a risk for potentially fatal bone marrow damage. To reduce risk, the FDA recommends testing for TPMT variants before using either drug. Patients who are found to be TPMT deficient should be given these drugs in reduced dosages. • In the United States, about 1% of the population produces a form of dihydropyrimidine dehydrogenase that does a poor job of metabolizing fluorouracil, a drug used to treat cancer. Several people with this inherited difference, while receiving standard doses of fluorouracil, have died from central nervous system injury because of accumulation of the drug to toxic levels.

Genetic Variants That Alter Drug Targets Genetic variations can alter the structure of drug receptors and other target molecules and can thereby influence drug responses. These variants have been documented in normal cells and in cancer cells and viruses. Genetic variants that affect drug targets on normal cells are illustrated by the following two examples:

• Variants in the genes that code for the β1-adrenergic receptor (ADRB1) produce receptors that are hyperresponsive to activation, which can be a mixed blessing. The bad news is that, in people with hypertension, activation of these receptors may produce an exaggerated increase in blood pressure. The good news is that in people with hypertension, blockade of these receptors will therefore produce an exaggerated decrease in blood pressure. Population studies indicate that variant ADRB1 receptors occur more often in people of European ancestry than in

people of African ancestry, which may explain why β blockers work better, on average, against hypertension in people with light skin than in people with dark skin. • The anticoagulant, warfarin works by inhibiting vitamin K epoxide reductase complex 1 (VKORC1). Variant genes that code for VKORC1 produce a form of the enzyme that can be easily inhibited, and hence anticoagulation can be achieved with low warfarin doses. If normal doses are given, anticoagulation will be excessive, and bleeding could result. To reduce risk, the FDA recommends testing for variants in the VKORC1 gene before warfarin is used. Genetic variants that affect drug targets on cancer cells and viruses are illustrated by these three examples. Many of these targets are the focus of immunologic therapy, further discussed with a quickly emerging class of drugs, the biologics, in Chapter 83.

• Trastuzumab (Herceptin), used for breast cancer, only works against tumors that overexpress human epidermal growth factor receptor type 2 (HER2). The HER2 protein, which serves as a receptor for hormones that stimulate tumor growth, is overexpressed in about 25% of breast cancer patients. Overexpression of HER2 is associated with a poor prognosis but also predicts a better response to trastuzumab. Accordingly, the FDA requires a positive test result for HER2 overexpression before trastuzumab is used. • Cetuximab (Erbitux), used mainly for metastatic colorectal cancer, only works against tumors that express the epidermal growth factor receptor (EGFR). All other tumors are unresponsive. Accordingly, the FDA requires evidence of EGFR expression if the drug is to be used. • Maraviroc (Selzentry), a drug for HIV infection, works by binding with a viral surface protein known as chemokine receptor 5 (CCR5), which certain strains of HIV require for entry into

immune cells. HIV strains that use CCR5 are known as being CCR5 tropic. If maraviroc is to be of benefit, patients must be infected with one of these strains. Therefore, before maraviroc is used, the FDA requires that testing be done to confirm that the infecting strain is indeed CCR5 tropic.

Genetic Variants That Alter Immune Responses to Drugs Genetic variants that affect the immune system can increase the risk for severe hypersensitivity reactions to certain drugs. Two examples are as follows:

• Carbamazepine (Tegretol), used for epilepsy and bipolar disorder, can cause life-threatening skin reactions in some patients —specifically patients of Asian ancestry who carry genes that code for an unusual human leukocyte antigen (HLA) known as HLA-B*1502. Although the mechanism underlying toxicity is unclear, a good guess is that interactions between HLA-B*1502 molecules and carbamazepine (or a metabolite) may trigger a cellular immune response. To reduce risk, the FDA recommends that patients of Asian descent be screened for the HLA-B*1502 gene before carbamazepine is used. If the test is positive, carbamazepine should be avoided. • Abacavir (Ziagen), used for HIV infection, can cause potentially fatal hypersensitivity reactions in patients who have a variant gene that codes for HLA-B*5701. Accordingly, the FDA recommends screening for the variant gene before using this drug. If the test is positive, abacavir should be avoided.

Genetic and Pharmacogenomic Testing To perform complete testing, providers must have access to a facility approved to complete accurate laboratory analysis of genetic biomarkers. Blood, saliva, urine, amniotic fluid, tissue, or hair may be used, depending on the test

requirements. Due to the explosive increase in research and technology, there are now more than 70,000 genetic testing products on the market in the United States. About 10 new products enter the market on a daily basis. Many tests are now available in a panel, allowing assessment for multiple biomarkers with one sample. The ability of the public to access genetic testing is increasing. In 2018, the FDA approved the first direct-to-consumer genetic test kit for assessment of breast cancer risk. The test kit, provided by 23andMe, tests for three of the BRCA1 and BRCA2 gene mutations through a saliva sample provided by the consumer. Although this is a step forward in the increasing the availability of genetic testing, the FDA cautions patients and providers about using this test as a definitive guide for treatment. One of the reasons is that the BRCA1 and BRCA2 genes have more than 1000 mutations, and this test only diagnoses 3 “founder” mutations. Shortly after the approval of the 23andMe BRCA test kit, the FDA also approved 23andMe to provide another direct-to-consumer test, the 23andMe Personal Genome Service Pharmacogenetic Report, that provides information about genetic variants that may affect drug metabolism.

Barriers to Pharmacogenomic Application in Practice Lack of Education Because pharmacogenomics is a relatively new and rapidly developing science, many health care providers do not possess the knowledge or comfort to order or interpret testing. In addition, patient education must be incorporated into treatment. How can we educate patients if we do not have the information ourselves? Although there are pockets of valuable resources available on the internet, provider education remains lacking within graduate programs of study.

Financial Cost for Testing Many insurance plans do not cover genetic testing as a preventive option. As precision medicine becomes more prominent, more insurance companies are beginning to pay for all or part of certain tests, especially if recommended by a provider. Costs for genetic tests can vary from $100 to $2000, depending on the

intricacy of the test or test panel.

Implications and Ethics Patients need to know the full implications of testing before undergoing evaluation. Providers must obtain informed consent and educate the patient on the reason for testing, the potential results, and options for treatment based on the results. Providers should also inform patients that they may not have the results of their test for weeks or more. Results of genetic testing must remain confidential, as with any other piece of medical information shared between the provider and patient. The fear of discrimination from employers, insurance companies, or providers is real. In 2008, the Genetic Information Nondiscrimination Act (GINA) was passed. This provides patient protection from discrimination from employers and insurance providers based on genetic information. Although these laws exist, patients are still at risk for discrimination. GINA does not apply to patients receiving care in the military, through the Veteran's Administration, Indian Health Services, or for life or long-term care insurance.

Guidelines Few clinical guidelines exist in the area of pharmacogenomics, as it remains a newer science. Currently, the Clinical Pharmacogenetics Implementation Consortium (CPIC) provides the largest amount of guidelines for clinical practice. As of 2018, CPIC published 35 guidelines on individual medications, including codeine, warfarin, clopidogrel, allopurinol, and others. Each guideline contains commonly tested variants and their effects on specific drugs, and therapy recommendations based on gene variation. The Royal Dutch Association for the Advancement of PharmacyPharmacogenetics Working Group (DPWG) and the Canadian Pharmacogenomics Network for Drug Safety (CPNDS) have also published a number of clinical practice recommendations regarding the use of drug therapy in patients with genetic variation. These guidelines are compiled through PharmGKB and located on their website (see Table 7.1). Clinical practice societies are examining guidelines for their use in specialty practice. As of 2018, the American Psychiatric Association Task Force for Novel Biomarkers and Treatments feels there is a lack of evidence on which to base

clinical guidelines. The National Comprehensive Cancer Network (NCCN) publishes multiple guidelines on the treatment of specific malignancies with pharmacologic therapy based on the genetic variant of the cancer. The American Society of Nephrology (ASN) published their article, Clinical Pharmacogenomics: Applications in Nephrology, in October 2018. This article contained a clinical guidance summary for commonly used drugs within the practice of nephrology. In the future, pharmacogenomic analysis of each patient may allow us to engage in revolutionary personalized medicine that addresses the individual patient's genotype. For the present, however, although many advances have been made in pharmacogenomics knowledge, the science is still relatively new (as science goes). Nevertheless, the rapid expanse of knowledge in this area is astonishing.

UNIT III

Drug Therapy Across the Life Span OUTLINE 8 Drug Therapy During Pregnancy and Breastfeeding 9 Drug Therapy in Pediatric Patients 10 Drug Therapy in Geriatric Patients

8

Drug Therapy During Pregnancy and Breastfeeding Abstract Drug therapy can complicate care for women who are pregnant. Many drugs are teratogens that can cause congenital anomalies. Other drugs can create complications for the pregnancy or for the health of the pregnant woman. Similarly, drug therapy for women who breastfeed can present risks to the infant if drugs are expressed in the milk in sufficient amounts. Understanding the risks that drugs can present to pregnant and breastfeeding women is essential to inform safe prescribing and medication monitoring for these populations.

Keywords pregnancy; breastfeeding; teratogens; teratogenesis; congenital anomalies This chapter addresses drug therapy in women who are pregnant or breastfeeding. The clinical challenge is to provide effective treatment for the patient while avoiding harm to the fetus or nursing infant. Unfortunately, meeting this challenge is confounded by a shortage of reliable data on drug toxicity during pregnancy or breastfeeding.

Drug Therapy During Pregnancy: Basic Considerations Drug use during pregnancy is common: about two-thirds of pregnant patients take at least one medication, and the majority take more. Some drugs are used to treat pregnancy-related conditions, such as nausea, constipation, and

preeclampsia. Some are used to treat chronic disorders, such as hypertension, diabetes, and epilepsy. Still others are used for the management of invasive conditions, such as infectious diseases or cancer. In addition to taking these therapeutic agents, pregnant patients may use drugs of abuse, such as alcohol, cocaine, and heroin. Drug therapy in pregnancy presents a vexing dilemma. In pregnant patients, as in all other patients, the benefits of treatment must balance the risks. Of course, when drugs are used during pregnancy, risks apply to the fetus as well. Unfortunately, most drugs have not been tested during pregnancy. As a result, the risks for most drugs are unknown—hence the dilemma: the provider is obliged to balance risks versus benefits, without always knowing what the risks really are. Despite the imposing challenge of balancing risks versus benefits, drug therapy during pregnancy cannot and should not be avoided. Because the health of the fetus depends on the health of the mother, conditions that threaten the mother's health must be addressed. Chronic asthma is a good example. Uncontrolled maternal asthma is far more dangerous to the fetus than the drugs used to treat it. The incidence of stillbirth is doubled among pregnant patients who do not take medications for asthma control. One of the greatest challenges in identifying drug effects on a developing fetus has been the lack of clinical trials, which, by their nature, would put the developing fetus at risk. Current research often focuses on comparing histories of women who have had children with and without congenital anomalies. An early example was the National Birth Defects Prevention Study (http://www.nbdps.org), which examined births from 1997 to 2011. More recently, the Birth Defects Study to Evaluate Pregnancy Exposures (http://www.cdc.gov/ncbddd/birthdefects/bd-steps.html) began collecting data on children born in January 2014 and beyond. Additionally, there are several pregnancy registries in which a woman who needs to take a drug while pregnant can enroll. This allows researchers to monitor pregnancy outcomes associated with a drug. The US Food and Drug Administration (FDA) provides a list of pregnancy exposure registries at http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm Although some studies are devoted to a single drug and its effect on pregnancy and the fetus, many study multiple drugs.

Physiologic Changes During Pregnancy Pregnancy brings on physiologic changes that can alter drug disposition. Changes in the kidney, liver, and gastrointestinal (GI) tract are of particular interest. Because of these changes, a compensatory change in dosage may be needed. By the third trimester, renal blood flow is doubled, causing a large increase in the glomerular filtration rate. As a result, there is accelerated clearance of drugs that are eliminated by glomerular filtration. Elimination of lithium, for example, is increased by 100%. To compensate for accelerated excretion, dosage must be increased. For some drugs, hepatic metabolism increases during pregnancy. Three antiseizure drugs—phenytoin, carbamazepine, and valproic acid—provide examples. Tone and motility of the bowel decrease in pregnancy, causing intestinal transit time to increase. Because of prolonged transit, there is more time for drugs to be absorbed. In theory, this could increase levels of drugs whose absorption is normally poor. Similarly, there is more time for the reabsorption of drugs that undergo enterohepatic recirculation, possibly resulting in a prolongation of drug effects. In both cases, a reduction in dosage might be needed.

Placental Drug Transfer The factors that determine drug passage across the membranes of the placenta are the same factors that determine drug passage across all other membranes. Accordingly, drugs that are lipid soluble cross the placenta easily, whereas drugs that are ionized, highly polar, or protein bound cross with difficulty. Nonetheless, for practical purposes, the provider should assume that any drug taken during pregnancy will reach the fetus.

Adverse Reactions During Pregnancy Not only are pregnant patients subject to the same adverse effects as nonpregnant patients, but they may also suffer effects unique to pregnancy. For example, when heparin (an anticoagulant) is taken by pregnant patients, it can cause osteoporosis, which in turn can cause compression fractures of the spine. The use of prostaglandins (e.g., misoprostol), which stimulate uterine

contraction, can cause abortion. Conversely, the use of aspirin near term can suppress contractions in labor. In addition, aspirin increases the risk for serious bleeding. Drugs taken during pregnancy can adversely affect the patient as well as the fetus. Regular use of dependence-producing drugs (e.g., heroin, barbiturates, alcohol) during pregnancy can result in the birth of a drug-dependent infant. If the newborn's dependence is not supported with drugs, a withdrawal syndrome will ensue. Symptoms include shrill crying, vomiting, and extreme irritability. The neonate should be weaned from dependence by giving progressively smaller doses of the drug on which he or she is dependent. Additionally, certain pain relievers used during delivery can depress respiration in the neonate. The infant must be closely monitored until respiration is normal. The drug effect of greatest concern is teratogenesis. This is the production of congenital anomalies (also known as birth defects) in the fetus.

Drug Therapy During Pregnancy: Teratogenesis and Other Risks The term teratogenesis is derived from teras, the Greek word for monster. Translated literally, teratogenesis means to produce a monster. Consistent with this derivation, we usually think of congenital anomalies in terms of gross malformations, such as cleft palate, clubfoot, and hydrocephalus.

Incidence and Causes of Congenital Anomalies The incidence of major structural abnormalities (e.g., abnormalities that are life threatening or require surgical correction) is between 1% and 3%. Half of these are obvious and are reported at birth. The other half involve internal organs (e.g., heart, liver, GI tract) and are not discovered until later in life or at autopsy. The incidence of minor structural abnormalities is unknown, as is the incidence of functional abnormalities (e.g., growth delay, intellectual disabilities). Congenital anomalies have multiple causes, including genetic predisposition, environmental chemicals, and drugs. Genetic factors account for about 25% of all congenital anomalies. Of the genetically based anomalies, Down syndrome is the most common. Less than 1% of all congenital anomalies are caused by drugs. For most congenital anomalies, the cause is unknown.

Teratogenesis and Stage of Development Fetal sensitivity to teratogens changes during development; thus the effect of a teratogen is highly dependent on when the drug is given. As shown in Fig. 8.1, development occurs in three major stages: the preimplantation/presomite period (conception through week 2), the embryonic period (weeks 3 through 8), and the fetal period (week 9 through term). During the preimplantation/presomite period, teratogens act in an all-or-nothing fashion. That is, if the dose is sufficiently high, the result is death of the conceptus. Conversely, if the dose is sublethal, the conceptus is likely to recover fully.

FIG. 8.1 Effects of teratogens at various stages of development of the fetus. CNS, Central nervous system. (From Moore K, Persaud TVN, Torchia M. The Developing Human: Clinically Oriented Embryology. 9th ed. Philadelphia: Elsevier; 2012, with permission.)

Gross malformations are produced by exposure to teratogens during the embryonic period (roughly the first trimester). This is the time when the basic shape of internal organs and other structures is being established. Because the fetus is especially vulnerable during the embryonic period, pregnant patients must take special care to avoid teratogen exposure during this time. Teratogen exposure during the fetal period (i.e., the second and third trimesters) usually disrupts function rather than gross anatomy. Of the developmental processes that occur in the fetal period, growth and development

of the brain are especially important. Disruption of brain development can result in learning deficits and behavioral abnormalities.

Identification of Teratogens For the following reasons, human teratogens are extremely difficult to identify:

• The incidence of congenital anomalies is generally low. • Animal tests may not be applicable to humans. • Prolonged drug exposure may be required. • Teratogenic effects may be delayed. • Behavioral effects are difficult to document. • Controlled experiments cannot be done in humans. As a result, only a few drugs are considered proven teratogens. Drugs whose teratogenicity has been documented (or at least is highly suspected) are listed in Table 8.1. However, it is important to note that lack of proof of teratogenicity does not mean that a drug is safe—it only means that the available data are insufficient to make a definitive judgment. Conversely, proof of teratogenicity does not mean that every exposure will result in a congenital anomaly. In fact, with most teratogens, the risk for malformation after exposure is only about 10%. TABLE 8.1

The absence of a drug from this table does not mean that the drug is not a teratogen. CNS, Central nervous system; HMG CoA, 3-hydroxy-3methylglutaryl coenzyme A; NSAIDs, nonsteroidal antiinflammatory drugs.

To prove that a drug is a teratogen, three criteria must be met:

• The drug must cause a characteristic set of malformations. • The drug must act only during a specific window of vulnerability (e.g., weeks 4 through 7 of gestation). • The incidence of malformations should increase with increasing dosage and duration of exposure. Obviously, we cannot do experiments on humans to determine whether a drug

meets these criteria. The best we can do is systematically collect and analyze data on drugs taken during pregnancy in the hope that useful information on teratogenicity will be revealed. Studies in animals may be of limited value, in part because teratogenicity may be species specific. That is, drugs that are teratogens in laboratory animals may be safe in humans. Conversely, and more important, drugs that fail to cause anomalies in animals may later prove teratogenic in humans. The most notorious example is thalidomide. In studies with pregnant animals, thalidomide was harmless; however, when pregnant patients took thalidomide, about 30% had babies with severe malformations. The take-home message is this: lack of teratogenicity in animals is not proof of safety in humans. Accordingly, we cannot assume that a new drug is safe for use in human pregnancy just because it has met FDA requirements based on tests done in pregnant animals. Some teratogens act quickly, whereas others require prolonged exposure. Thalidomide represents a fast-acting teratogen: a single dose can cause malformation. In contrast, alcohol (ethanol) must be taken repeatedly in high doses if gross malformation is to result. (Lower doses of alcohol may produce subtle anomalies.) Because a single exposure to a rapid-acting teratogen can produce obvious malformation, they are easier to identify than slow-acting teratogens. Teratogens that produce delayed effects are among the hardest to identify. The best example is diethylstilbestrol, an estrogenic substance that causes vaginal cancer in female offspring 18 years or so after they were born. Teratogens that affect behavior may be nearly impossible to identify. Behavioral changes are often delayed and therefore may not become apparent until the child goes to school. By this time, it may be difficult to establish a correlation between drug use during pregnancy and the behavioral deficit. Furthermore, if the deficit is subtle, it may not even be recognized. Although we have been discussing the effect of teratogens, it is important to note that drug-related effects are not limited to the distortions of gross anatomy caused by teratogens. Drugs may also include neurobehavioral and metabolic anomalies. For example, benzodiazepines taken late in pregnancy may cause hypoglycemia and respiratory complications along with a hypotonic state that is commonly called floppy infant syndrome. The aminoglycoside streptomycin provides another example. Although the teratogen risk of aminoglycosides is low, children born to women taking streptomycin have been born with congenital deafness. Some drugs taken by pregnant women may be dangerous

(e.g., the anticoagulant warfarin has been associated with fetal hemorrhage) or life threatening (e.g., misoprostol, a drug taken to protect the stomach of people taking nonsteroidal antiinflammatory drugs) can cause a spontaneous abortion.

US Food and Drug Administration Pregnancy Risk Categories In 1979, the FDA established a system for classifying drugs according to their probable risks to the fetus. According to this system, drugs can be put into one of five risk categories: A, B, C, D, and X (Table 8.2). Although this rating system is helpful, it is far from ideal. For example, some drugs that were placed in Category B—to indicate animal reproduction studies—do not indicate risk, and may not have undergone an adequate type or number of studies to adequately determine risk. Because of problems and confusion with the rating system, the FDA decided to phase it out over a period that will end in 2020. Nevertheless, because these categories are frequently referenced in recent pre-2020 literature, it is wise for the provider to have some familiarity with these categories. TABLE 8.2 US Food and Drug Administration Pregnancy Risk Categories Category Category Description A

Remote risk for fetal harm: Controlled studies in women have been done and have failed to demonstrate a risk for fetal harm during the first trimester, and there is no evidence of risk in later trimesters

B

Slightly more risk than A: Animal studies show no fetal risk, but controlled studies have not been done in women. or Animal studies do show a risk for fetal harm, but controlled studies in women have failed to demonstrate a risk during the first trimester, and there is no evidence of risk in later trimesters

C

Greater risk than B: Animal studies show a risk for fetal harm, but no controlled studies have been done in women. or No studies have been done in women or animals

D

Proven risk for fetal harm: Studies in women show proof of fetal damage, but the potential benefits of use during pregnancy may be acceptable

despite the risks (e.g., treatment of life-threatening disease for which safer drugs are ineffective). A statement on risk will appear in the WARNINGS section of drug labeling X

Proven risk for fetal harm: Studies in women or animals show definite risk for fetal abnormality. or Adverse reaction reports indicate evidence of fetal risk. The risks clearly outweigh any possible benefit. A statement on risk will appear in the CONTRAINDICATIONS section of drug labeling

Pregnancy Risk Categories became obsolete in 2020.

US Food and Drug Administration Pregnancy and Lactation Labeling Rule

In December 2014, the FDA issued the Pregnancy and Lactation Labeling Rule (PLLR) providing new guidance for labeling. The PLLR requires three sections for labeling: (1) pregnancy, (2) lactation, and (3) females and males of reproductive potential. These are further divided into subsections containing specified content (Table 8.3). The full report is available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc TABLE 8.3

Adapted from U.S. Department of Health and Human Services, Food and Drug Administration. (2015, June). Appendix A: Organization and Format for Pregnancy, Lactation, and Females and Males of Reproductive Potential Subsections. Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription Drug and Biological Products—Content and Format. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm450636.pdf

Minimizing Drug Risk During Pregnancy A first step in decreasing drug risk during pregnancy is to develop a comprehensive list of current drugs used. It is crucial to include not only prescription drugs but also over-the-counter and nutritional supplements, as well as recreational drug use, at every visit. A drug as common as vitamin A is dangerous when taken in excess. Vitamin A can cause craniofacial anomalies and central nervous system, cardiac, and thymus abnormalities.

If pregnancy status is unknown and a high-risk drug is recommended for management of a condition, a pregnancy test should be performed before prescribing. As noted, some disease states (e.g., epilepsy, asthma, diabetes) pose a greater risk to fetal health than the drugs used for treatment. However, even with these disorders, in which drug therapy reduces the risk for disease-induced fetal harm, we must still take steps to minimize harm from drugs. Accordingly, drugs that pose a high risk for danger to the developing embryo or fetus should be discontinued, and safer alternatives substituted. Sometimes the use of a high-risk drug is unavoidable. Some anticancer drugs, for example, are highly toxic to the developing fetus, yet cannot be ethically withheld from the pregnant patient. If a patient elects to use such drugs, termination of pregnancy should be considered. Reducing the risk for dangerous drug effects also applies to female patients who are not pregnant because approximately 50% of pregnancies are unintended. Accordingly, if a patient of reproductive age is taking a teratogenic medication, she should be educated about the teratogenic risk as well as the necessity of using at least one reliable form of birth control.

Responding to Teratogen Exposure When a pregnant patient has been exposed to a known teratogen, the first step is to determine exactly when the drug was taken and exactly when the pregnancy began. If drug exposure was not during the period of organogenesis (i.e., weeks 3 through 8), the patient should be reassured that the risk of drug-induced malformation is minimal. What should be done if the exposure did occur during organogenesis? First, a reference (such as FDA-approved prescribing information for the drug) should be consulted to determine the type of malformation expected. Next, at least two ultrasound scans should be done to assess the extent of injury. If the malformation is severe, termination of pregnancy should be considered. If the malformation is minor (e.g., cleft palate), it may be correctable by surgery, either shortly after birth or later in childhood.

Drug Therapy During Breastfeeding Drugs taken by lactating patients can be excreted in breast milk. Although nearly all drugs can enter breast milk, the extent of entry varies greatly. The factors that

determine entry into breast milk are the same factors that determine passage of drugs across membranes. Accordingly, drugs that are lipid soluble enter breast milk readily, whereas drugs that are ionized, highly polar, or protein bound tend to be excluded. If drug concentrations in milk are high enough, a pharmacologic effect can occur in the infant, raising the possibility of harm. To address concerns about drug risks for breastfed infants and children, the US National Library of Medicine created the LactMed database. (See https://toxnet.nlm.nih.gov/newtoxnet/lactmed.htm) LactMed is a comprehensive searchable site that provides the most current information on prescription and nonprescription drugs and their effects on breastfed infants and children. Unfortunately, relatively little systematic research has been done on many drugs. As a result, although a few drugs are known to be hazardous (Table 8.4), the possible danger posed by many others remains undetermined. TABLE 8.4

Fortunately, most drugs detected in milk are in concentrations that are too low to cause harm. Still, prudence is in order: if the nursing patient can avoid drugs

that may pose a risk, she should. Moreover, when these drugs must be used, steps should be taken to minimize risk. These include the following:

• Dosing immediately after breastfeeding (to minimize drug concentrations in milk at the next feeding) • Avoiding drugs that have a long half-life • Avoiding sustained-release formulations • Choosing drugs that tend to be excluded from milk • Choosing drugs that are least likely to affect the infant (Table 8.5) TABLE 8.5 Drugs of Choice for Breastfeeding Patients Drug Category

Drugs and Drug Groups of Choice

Comments

Analgesic drugs

Acetaminophen, ibuprofen, flurbiprofen, ketorolac, mefenamic acid, sumatriptan, morphine

Sumatriptan may be given for migraine. Morphine may be given for severe pain

Anticoagulant drugs

Warfarin, acenocoumarol , heparin (unfractionated)

Among breastfed infants whose mothers were taking warfarin, the drug was undetectable in plasma, and bleeding time was not affected. The large molecular size of unfractionated heparin decreases the amount excreted in breast milk. Furthermore, it is not bioavailable from the GI tract, so heparin in breast milk is not systemically absorbed

Antidepressant

Sertraline,

Fluoxetine (Prozac) may be given

drugs

paroxetine, TCAs

if other SSRIs are ineffective; however, caution is needed because levels are higher in breast milk than levels of other SSRIs. Infant risk with TCAs cannot be ruled out; however, no significant adverse effects have been reported

Antiepileptic drugs

Carbamazepine, phenytoin, valproic acid

The estimated level of exposure to these drugs in infants is less than 10% of the therapeutic dose standardized by weight

Antihistamines (histamine-1 blockers)

Loratadine, fexofenadine

First-generation antihistamines are associated with irritability or sedation and may decrease milk supply

Antimicrobial drugs

Penicillins, Avoid chloramphenicol and cephalosporins, tetracycline aminoglycosides, macrolides

β-adrenergic antagonists

Labetalol, metoprolol, propranolol

Angiotensin-converting enzyme inhibitors and calcium channel– blocking agents are also considered safe

Endocrine drugs

Propylthiouracil, insulin, levothyroxine

The estimated level of exposure to propylthiouracil in breastfeeding infants is less than 1% of the therapeutic dose standardized by weight; thyroid function of the infant is not affected

Glucocorticoids

Prednisolone and prednisone

The amount of prednisolone the infant would ingest in breast milk is less than 0.1% of the therapeutic dose standardized by weight

This list is not exhaustive. Cases of overdoses of these drugs must be assessed on an individual basis. GI, Gastrointestinal; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.

• Avoiding drugs that are known to be hazardous (see Table 8.4) • Using the lowest effective dosage for the shortest possible time • Abandoning plans to breastfeed if a necessary drug is known to be harmful to the child

9

Drug Therapy in Pediatric Patients Abstract Children respond differently to drugs than do other populations. This is especially true for neonates and infants who have altered pharmacokinetics due to organ system immaturity. To complicate matters, providers are challenged by inadequate clinical trials to inform safe prescribing practices for many necessary drugs. Knowing the risks and anticipating variations in drug responses are necessary to provide a foundation for safe prescribing and medication management for this vulnerable population.

Keywords pediatric patients; organ immaturity; body surface area; pharmacokinetic alterations; drug reactions Young patients respond differently to drugs than do the rest of the population. Most differences are quantitative. Specifically, younger patients are more sensitive to drugs than adult patients, and they show greater individual variation. Drug sensitivity in the very young results largely from organ system immaturity. Because of heightened drug sensitivity, they are at increased risk for adverse drug reactions. In this chapter we discuss the physiologic factors that underlie heightened drug sensitivity in pediatric patients and ways to promote safe and effective drug use. Pediatrics covers all patients up to age 16 years. Because of ongoing growth and development, pediatric patients in different age groups present different therapeutic challenges. Traditionally, the pediatric population is subdivided into six groups:

• Premature infants (less than 36 weeks gestational age) • Full-term infants (36 to 40 weeks gestational age)

• Neonates (first 4 postnatal weeks) • Infants (postnatal weeks 5 to 52) • Children (1 to 12 years) • Adolescents (12 to 16 years) Not surprisingly, as young patients grow older, they become more like adults physiologically, and hence more like adults with regard to drug therapy. Conversely, the very young—those younger than 1 year, and especially those younger than 1 month—are very different from adults. If drug therapy in these patients is to be safe and effective, we must account for these differences. Managing pediatric drug therapy is made even more difficult by insufficient drug information. To address this deficit, the US Food and Drug Administration (FDA) Safety and Innovation Act of 2012 permanently reauthorized two laws previously enacted by Congress to promote drug research in children: the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). Additionally, in 2012, the National Academies of Medicine (formerly the Institutes of Medicine [IOM]), published a synopsis of findings from previous research conducted under the BPCA and PREA. This report is available at http://nationalacademies.org/hmd/reports/2012/safe-and-effective-medicinesfor-children.aspx. As more studies are done, the gaps in our knowledge will shrink. In the meantime, we must still treat children with drugs—even though we lack the information needed to prescribe rationally. Similar to drug therapy during pregnancy, providers must try to balance benefits and risks, without precisely knowing what the benefits and risks really are.

Pharmacokinetics: Neonates and Infants Pharmacokinetic factors determine the concentration of a drug at its sites of action and hence determine the intensity and duration of responses. If drug levels are elevated, responses will be more intense. If drug elimination is delayed, responses will be prolonged. Because the organ systems that regulate drug levels are not fully developed in very young patients, they are at risk for both drug effects that are unusually intense and prolonged. By accounting for pharmacokinetic differences in the very young, we can increase the chances that drug therapy will be both effective and safe. Fig. 9.1 illustrates how drug levels differ between infants and adults after

administration of doses adjusted for body weight. When a drug is administered intravenously, levels decline more slowly in the infant than in the adult. As a result, drug levels in the infant remain above the minimum effective concentration (MEC) longer than in the adult, thereby causing effects to be prolonged. When a drug is administered subcutaneously, not only do levels in the infant remain above the MEC longer than in the adult, but these levels also rise higher, causing effects to be more intense as well as prolonged. From these illustrations, it is clear that adjustment of dosage for infants on the basis of body size alone is not sufficient to achieve safe results.

Comparison of Plasma Drug Levels in Adults and Infants. (A) Plasma drug levels after intravenous injection. Dosage was adjusted for body weight. Note that plasma levels remain above the minimum effective concentration (MEC) much longer in the infant. (B) Plasma drug levels after subcutaneous injection. Dosage was adjusted for body weight. Note that both the maximal drug level and the duration of action are greater in the infant. FIG. 9.1

If small body size is not the major reason for heightened drug sensitivity in infants, what is? The increased sensitivity of infants is due largely to the immature state of five pharmacokinetic processes: (1) drug absorption, (2) protein binding of drugs, (3) exclusion of drugs from the central nervous system (CNS) by the blood-brain barrier, (4) hepatic drug metabolism, and (5) renal drug excretion.

Absorption

Oral Administration Gastrointestinal physiology in the infant is very different from that in the adult. As a result, drug absorption may be enhanced or impeded, depending on the physicochemical properties of the drug involved. Gastric emptying time is both prolonged and irregular in early infancy, and then gradually reaches adult values by 6 to 8 months. For drugs that are absorbed primarily from the stomach, delayed gastric emptying enhances absorption. On the other hand, for drugs that are absorbed primarily from the intestine, absorption is delayed. Because gastric emptying time is irregular, the precise effect on absorption is not predictable. Gastric acidity is very low 24 hours after birth and does not reach adult values for 2 years. Because of low acidity, absorption of acid-labile drugs is increased.

Intramuscular Administration Drug absorption after intramuscular injection in the neonate is slow and erratic. Delayed absorption is due in part to low blood flow through muscle during the first days of postnatal life. By early infancy, absorption of intramuscular drugs becomes more rapid than in neonates and adults.

Transdermal Absorption Drug absorption through the skin is more rapid and complete in infants than in older children and adults. The stratum corneum of the infant's skin is very thin, and blood flow to the skin is greater in infants than in older patients. Because of this enhanced absorption, infants are at increased risk for toxicity from topical drugs.

Distribution Protein Binding Binding of drugs to albumin and other plasma proteins is limited in the infant because (1) the amount of serum albumin is relatively low, and (2) endogenous compounds (e.g., fatty acids, bilirubin) compete with drugs for available binding sites. Consequently, drugs that ordinarily undergo extensive protein binding in adults undergo much less binding in infants. As a result, the concentration of free levels of such drugs is relatively high in the infant, thereby intensifying the effects. To ensure that the effects are not too intense, dosages in infants should

be reduced. Protein-binding capacity reaches adult values within 10 to 12 months.

Blood–Brain Barrier The blood–brain barrier is not fully developed at birth. As a result, drugs and other chemicals have relatively easy access to the CNS, making the infant especially sensitive to drugs that affect CNS function. Accordingly, all medicines employed for their CNS effects (e.g., morphine, phenobarbital) should be given in reduced dosage. Dosage also should be reduced for drugs used for actions outside the CNS if those drugs are capable of producing CNS toxicity as a side effect.

Hepatic Metabolism The drug-metabolizing capacity of newborns is low. As a result, neonates are especially sensitive to drugs that are eliminated primarily by hepatic metabolism. When these drugs are used, dosages must be reduced. The capacity of the liver to metabolize many drugs increases rapidly about 1 month after birth and approaches adult levels a few months later. Complete maturation of the liver develops by 1 year.

Renal Excretion Renal drug excretion is significantly reduced at birth. Renal blood flow, glomerular filtration, and active tubular secretion are all low during infancy. Because the drug-excreting capacity of infants is limited, drugs that are eliminated primarily by renal excretion must be given in reduced dosage or at longer dosing intervals, or both. Adult levels of renal function are achieved by 1 year.

Pharmacokinetics: Children 1 Year and Older By age 1 year, most pharmacokinetic parameters in children are similar to those in adults. Therefore drug sensitivity in children older than 1 year is more like that of adults than that of the very young. Although pharmacokinetically similar to adults, children do differ in one important way: they metabolize drugs faster than adults. Drug-metabolizing capacity is markedly elevated until age 2 years

and then gradually declines. A further sharp decline takes place at puberty, when adult values are reached. Because of enhanced drug metabolism in children, an increase in dosage or a reduction in dosing interval may be needed for drugs that are eliminated by hepatic metabolism.

Adverse Drug Reactions Like adults, pediatric patients are subject to adverse reactions when drug levels rise too high. In addition, pediatric patients are vulnerable to unique adverse effects related to organ system immaturity and to ongoing growth and development. Among these age-related effects are growth suppression (caused by glucocorticoids), discoloration of developing teeth (caused by tetracyclines), and kernicterus (caused by sulfonamides). Table 9.1 presents a list of drugs that can cause unique adverse effects in pediatric patients of various ages. These drugs should be avoided in patients whose age puts them at risk. TABLE 9.1 Adverse Drug Reactions Unique to Pediatric Patients Drug

Adverse Effect

Androgens

Premature puberty in males; reduced adult height from premature epiphyseal closure

Aspirin and other Severe intoxication from acute overdose (acidosis, hyperthermia, salicylates respiratory depression); Reye syndrome in children with chickenpox or influenza Chloramphenicol Gray syndrome (neonates and infants) Fluoroquinolones Tendon rupture Glucocorticoids

Growth suppression with prolonged use

Hexachlorophene Central nervous system toxicity (infants) Nalidixic acid

Cartilage erosion

Phenothiazines

Sudden infant death syndrome

Promethazine

Pronounced respiratory depression in children younger than 2 years

Sulfonamides

Kernicterus (neonates)

Tetracyclines

Staining of developing teeth

Dosage Determination Because of the pharmacokinetic factors discussed previously, dosage selection for pediatric patients can be challenging. Selecting a dosage is especially difficult in the very young because pharmacokinetic factors are undergoing rapid change. Pediatric doses have been established for a few drugs, but not for most. For drugs that do not have an established pediatric dose, dosage can be extrapolated from adult doses. The method of conversion employed most commonly is based on body surface area (BSA):

Please note that initial pediatric doses—whether based on established pediatric doses or extrapolated from adult doses—are at best an approximation. Subsequent doses must be adjusted on the basis of clinical outcome and plasma drug concentrations. These adjustments are especially important in neonates and younger infants. If dosage adjustments are to be optimal, it is essential that we monitor the patient for therapeutic and adverse responses as a component of optimizing dosage.

Promoting Adherence Achieving accurate and timely dosing requires informed participation of the child's caregiver and, to the extent possible, active involvement of the child as well. Effective education is critical. The following issues should be addressed:

• Dosage size and timing • Route and technique of administration • Duration of treatment • Drug storage • The nature and time course of desired responses • The nature and time course of adverse responses Written instructions should be provided to reinforce verbal instructions. For

techniques of administration that are difficult, a demonstration should be made, after which the child's caregivers should repeat the procedure to ensure they understand. With young children, spills and spitting out are common causes of inaccurate dosing; parents should be taught to estimate the amount of drug lost and to readminister that amount, being careful not to overcompensate. When more than one person is helping medicate a child, all participants should be warned against multiple dosing. Multiple dosing can be avoided by maintaining a drug administration chart. With some disorders—especially infections— symptoms may resolve before the prescribed course of treatment has been completed. Parents should be instructed to complete the full course nonetheless. Additional strategies to promote adherence are presented in Table 9.2. TABLE 9.2

10

Drug Therapy in Geriatric Patients Abstract Prescribing and managing drug therapy for older patients is fraught with challenges. Concerns ranging from altered pharmacokinetics and variable drug sensitivities to multiple co-morbidities complicate decision-making. Added to this are common issues related to medication adherence such as patient confusion, limited financial resources, and the increased severity of adverse effects. The provider who is aware of these challenges and who is prepared to act proactively and intervene promptly will be in the best position to make wise decisions when these problems present in the clinical setting.

Keywords geriatric patients; adverse drug reactions; Beers’ criteria; end-of-life care; medication adherence; polypharmacy; comorbidities Drug use among older adults (those 65 years and older) is disproportionately high. While older adults constitute only 12.8% of the US population, they consume 33% of the nation's prescribed drugs. The reasons for this intensive use of drugs include increased severity of illness, multiple pathologies, and excessive prescribing. Drug therapy in older adults represents a special therapeutic challenge. As a rule, older patients are more sensitive to drugs and they show wider individual variation. In addition, older adults experience more adverse drug reactions (ADRs) and drug–drug interactions. The principal factors underlying these complications are (1) altered pharmacokinetics (secondary to organ system degeneration), (2) multiple and severe illnesses, (3) multidrug therapy, and (4) poor adherence. To help ensure that drug therapy is as safe and effective as possible, individualization of treatment is essential: each patient must be

monitored for desired and adverse responses, and the regimen must be adjusted accordingly. Because older adults often suffer from incurable chronic illnesses, the usual objective is to reduce symptoms and improve quality of life.

Pharmacokinetic Changes in Older Adults The aging process can affect all phases of pharmacokinetics. From early adulthood on, there is a gradual, progressive decline in organ function. This decline can alter the absorption, distribution, metabolism, and excretion of drugs. As a rule, these pharmacokinetic changes increase drug sensitivity (largely from reduced hepatic and renal drug elimination). However, it should be noted that the extent of change varies greatly among patients: pharmacokinetic changes may be minimal in patients who have remained physically fit, whereas they may be dramatic in patients who have aged less fortunately. Accordingly, you should keep in mind that age-related changes in pharmacokinetics are not only a potential source of increased sensitivity to drugs but also a potential source of increased variability. The physiologic changes that underlie alterations in pharmacokinetics are summarized in Table 10.1. TABLE 10.1

Absorption Altered gastrointestinal absorption is not a major factor in drug sensitivity in older adults. As a rule, the percentage of an oral dose that becomes absorbed does not usually change with age. However, the rate of absorption may be slowed (because of delayed gastric emptying and reduced splanchnic blood flow). As a result, drug responses may be somewhat delayed. Gastric acidity is reduced in older adults and may alter the absorption of certain drugs. For example, some drug formulations require high acidity to dissolve, and hence their absorption may be reduced.

Distribution

Four major factors can alter drug distribution in older adults: (1) increased percentage of body fat, (2) decreased percentage of lean body mass, (3) decreased total body water, and (4) reduced concentration of serum albumin. The increase in body fat seen in older adults provides a storage depot for lipidsoluble drugs (e.g., propranolol). As a result, plasma levels of these drugs are reduced, causing a reduction in responses. Because of the decline in lean body mass and total body water, water-soluble drugs (e.g., ethanol) become distributed in a smaller volume than in younger adults. As a result, the concentration of these drugs is increased, causing effects to be more intense. Although albumin levels are only slightly reduced in healthy older adults, these levels can be significantly reduced in older adults who are malnourished. Because of reduced albumin levels, sites for protein binding of drugs decrease, causing levels of free drug to rise. Accordingly, drug effects may be more intense.

Metabolism Rates of hepatic drug metabolism tend to decline with age. The principal reasons are reduced hepatic blood flow, reduced liver mass, and decreased activity of some hepatic enzymes. Because liver function is diminished, the half-lives of certain drugs may be increased, thereby prolonging responses. Responses to oral drugs that ordinarily undergo extensive first-pass metabolism may be enhanced because fewer drugs are inactivated before entering the systemic circulation. However, it is important to note that the degree of decline in drug metabolism varies greatly among individuals. As a result, we cannot predict whether drug responses will be significantly reduced in any particular patient.

Excretion Renal function, and hence renal drug excretion, undergoes progressive decline beginning in early adulthood. Drug accumulation secondary to reduced renal excretion is the most important cause of ADRs in older adults. The decline in renal function is the result of reductions in renal blood flow, glomerular filtration rate, active tubular secretion, and number of nephrons. Renal pathology can further compromise kidney function. The degree of decline in renal function varies greatly among individuals. Accordingly, when patients are taking drugs that are eliminated primarily by the kidneys, renal function should be assessed.

In older adults, the proper index of renal function is creatinine clearance, not serum creatinine levels. Creatinine levels do not adequately reflect kidney function in older adults because the source of serum creatinine—lean muscle mass—declines in parallel with the decline in kidney function. Accordingly, creatinine levels may be normal even though renal function is greatly reduced. Although most medication adjustments for renal problems use creatinine clearance, for a few medications the estimated glomerular filtration rate (eGFR) is used. The National Kidney Foundation offers online calculators to determine the creatinine clearance at https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc and the eGFR at https://www.kidney.org/professionals/kdoqi/gfr_calculator.

Pharmacodynamic Changes in Older Adults Alterations in receptor properties may underlie altered sensitivity to some drugs. However, information on such pharmacodynamic changes is limited. In support of the possibility of altered pharmacodynamics is the observation that betaadrenergic blocking agents (drugs used primarily for cardiac disorders) are less effective in older adults than in younger adults, even when present in the same concentrations. Possible explanations for this observation include (1) a reduction in the number of beta receptors and (2) a reduction in the affinity of beta receptors for beta-receptor blocking agents. Other drugs (warfarin, certain central nervous system depressants) produce effects that are more intense in older adults, suggesting a possible increase in receptor number, receptor affinity, or both. Unfortunately, our knowledge of pharmacodynamic changes in older adults is restricted to a few families of drugs.

Adverse Drug Reactions and Drug Interactions ADRs are seven times more common in older adults than in younger adults, accounting for about 16% of hospital admissions among older individuals and 50% of all medication-related deaths. Most of these reactions are dose related, not idiosyncratic. Symptoms in older adults are often nonspecific (e.g., dizziness, cognitive impairment), making identification of ADRs difficult. Furthermore, older adults may be less comfortable revealing alcohol or recreational drug use because of generational taboos in some segments of society. This can confound efforts to identify the source of a new ADR-related

symptom. Perhaps surprisingly, the increase in ADRs seen in older adults is often not the direct result of aging. Rather, multiple factors predispose older patients to ADRs, the most important of which follow:

• Drug accumulation secondary to reduced renal function • Polypharmacy (treatment with multiple drugs) • Greater severity of illness • Presence of comorbidities • Use of drugs that have a low therapeutic index (e.g., digoxin, a drug for heart failure) • Increased individual variation secondary to altered pharmacokinetics • Inadequate supervision of long-term therapy • Poor patient adherence Most ADRs in older adults are avoidable. Measures that can reduce their incidence are presented in Box 10.1. Box 10.1

Measures to Reduce Adverse Drug Reactions in Older Adults • Take a thorough drug history, including over-the-counter medications, herbal remedies, and dietary supplements • Account for the pharmacokinetic and pharmacodynamic changes that occur with aging • Initiate therapy with low doses and titrating upward gradually (“start low and go slow”) • Monitor clinical responses and plasma drug levels to provide a rational basis for dosage adjustment • Employ the simplest medication regimen possible • Monitor for drug–drug interactions and iatrogenic illness

• Periodically review the need for continued drug therapy, and discontinue medications as appropriate • Encourage the patient to dispose of old medications • Take steps to promote adherence • Avoid drugs included in Beers Criteria for Potentially Inappropriate Medication Use in Older Adults (the Beers list) unless benefits outweigh risks.

Synthesizing information on disparate drugs that can cause harm has presented a challenge. A few lists have emerged over the years, but perhaps the most well known are the Beers List and START/STOPP criteria. Both identify drugs that are potentially inappropriate. As with all drug decisions, the provider must weigh benefits and risks. The patient’s individual history must also be taken into account. For example, often patients are started on these medications well before they reach age 65. If the drugs are meeting the patient’s needs and not causing problems, it would be illogical to stop them or reduce their dosage based on age alone. The Beers List identifies drugs with a high likelihood of causing adverse effects in older adults. Accordingly, drugs on this list should generally be avoided in adults older than 65 years except when the benefits are significantly greater than the risks. A partial listing of these drugs appears in Table 10.2. The full list, updated in 2019, is available online at https://onlinelibrary.wiley.com/doi/pdf/10.1111/jgs.15767. TABLE 10.2

ACE, Angiotensin-converting enzyme; CNS, central nervous system; COX-2, cyclooxygenase-2; GI, gastrointestinal; NSAIDs, nonsteroidal antiinflammatory drugs; SNRI, serotonin/norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. Adapted from American Geriatrics Society 2019 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019; 674–694. (Note: The original document lists many drugs in addition to those in this table.)

STOPP stands for Screening Tool of Older People's potentially inappropriate Prescriptions. Like the Beers List, STOPP criteria also identify drugs that may be dangerous if prescribed for older adults. It has an advantage of also considering the economic costs of drug therapy. Additionally, when combined with the

Screening Tool to Alert doctors to Right Treatment (START), the set can be used to promote the selection of appropriate treatment in addition to the avoidance of inappropriate treatment. The article detailing START/STOPP criteria is available at https://academic.oup.com/ageing/article/44/2/213/2812233.

Promoting Adherence Between 26% and 59% of older adult patients fail to take their medicines as prescribed. Some patients never fill their prescriptions, some fail to refill their prescriptions, and some don't follow the prescribed dosing schedule. Nonadherence can result in therapeutic failure (from underdosing or erratic dosing) or toxicity (from overdosing). Of the two possibilities, underdosing with resulting therapeutic failure is by far (90%) the more common. Problems arising from nonadherence account for up to 10% of all hospital admissions, and their management may cost more than $100 billion a year. Multiple factors underlie nonadherence to the prescribed regimen (Box 10.2). Among these are forgetfulness; failure to comprehend instructions (because of intellectual, visual, or auditory impairment); inability to pay for medications; and use of complex regimens (several drugs taken several times a day). All of these factors can contribute to unintentional nonadherence. However, in most cases (about 75%), nonadherence among older adults is intentional. The principal reason given for intentional nonadherence is the patient's conviction that the drug was simply not needed in the dosage prescribed. Unpleasant side effects and expense also contribute to intentional nonadherence. Box 10.2

Factors That Increase Risk for Poor Adherence in Older Adults • Multiple chronic disorders • Multiple prescription medications • Multiple doses per day for each medication • Drug packaging that is difficult to open • Multiple prescribers • Changes in the regimen (addition of drugs, changes in dosage size or

timing) • Cognitive or physical impairment (reduction in memory, hearing, visual acuity, color discrimination, or manual dexterity) • Living alone • Recent discharge from hospital • Low literacy • Inability to pay for drugs • Personal conviction that a drug is unnecessary or the dosage too high • Presence of side effects

Several measures can promote adherence, including the following:

• Simplifying the regimen so that the number of drugs and doses per day is as small as possible • Explaining the treatment plan using clear, concise, verbal and written instructions • Choosing an appropriate dosage form (e.g., a liquid formulation if the patient has difficulty swallowing) • Requesting that the pharmacist label drug containers using a large print size and provide containers that are easy to open by patients with impaired dexterity (e.g., those with arthritis) • Suggesting the use of a calendar, diary, or pill counter to record drug administration • Asking the patient if he or she has access to a pharmacy and can afford the medication • Enlisting the aid of a friend, relative, or visiting health care professional • Monitoring for therapeutic responses, adverse reactions, and plasma drug levels However, it must be noted that the benefits of these measures will be restricted primarily to patients whose nonadherence is unintentional. Unfortunately, these measures are generally inapplicable to the patient whose nonadherence is

intentional. For these patients, intensive education may help.

Considerations for End-of-Life Care End-of-life care poses a set of different concerns regarding the choice of drugs to best meet the needs of older patients. Priority treatment varies as goals shift from disease prevention and management to the provision of comfort measures. Drugs that were once considered important in care (e.g., drugs for cholesterol management) may no longer be relevant and can be discontinued. Drugs that were once considered inappropriate due to patient age (e.g., sedatives) may need to become a predominant feature of care. Table 10.3 explores medication considerations and choices for concerns that patients sometimes encounter near the end of life. Additional information is available at https://www.cancer.gov/about-cancer/advanced-cancer/caregivers/planning/lastdays-hp-pdq#section/_7. The National Academy of Medicine's report Dying in America: Improving Quality and Honoring Individual Preferences Near the End of Life addresses multiple concerns of dying patients and their families, and is available at http://www.nap.edu/read/18748/chapter/1. TABLE 10.3 Pharmacological Considerations for End-of-Life Care Problems Constipation

Considerations Constipation may be opioidinduced; an order for opioids should be accompanied by an order to treat constipation. Stimulants typically cause some degree of abdominal cramping. Drugs specifically formulated for opioidinduced constipation (i.e., methylnaltrexone) are very expensive and may not be warranted if other interventions are

Drug Choice First-line choices are osmotic laxatives (e.g., lactulose, polyethylene glycol). Stimulants with stool softener (e.g., senna with docusate) are second-line choices if abdominal cramping is a concern; otherwise, they may be given as a first-line choice. For those who cannot swallow, bisacodyl rectal suppositories or enemas can provide relief. Methylnaltrexone may be used

effective. Increased fiber may cause constipation if there is insufficient fluid intake

for refractory opioidinduced constipation

Delirium

Delirium may be a manifestation of pain. Delirium may be a manifestation of opioidinduced neurotoxicity. Benzodiazepines may cause a paradoxical agitation but may be helpful if delirium is related to alcohol withdrawal or as an adjunct to antipsychotics. Underlying causes (constipation, urinary retention, infection) should be treated, if identified

Treat with antipsychotics such as haloperidol or olanzapine. Benzodiazepines such as midazolam may be helpful short term to supplement antipsychotics for acute episodes of delirium. Consider adding analgesics (or evaluate adequacy of currently prescribed analgesics). For patients taking opioids (e.g., morphine), changing to a different opioid (e.g., fentanyl) has been helpful.

Dyspnea

Dyspnea may or may not be associated with hypoxemia. Management should consider severity of associated manifestations (e.g., profound fatigue exacerbated by respiratory effort). Bronchodilators may increase anxiety which can further worsen sensation of shortness of breath

Oxygen therapy is indicated if hypoxemia is present. Opioids are a first-line drug choice. Glucocorticoids are often helpful, if not contraindicated. Consider bronchodilators only if dyspnea is associated with bronchospasm

Fatigue

Dexamphetamine has only short- Methylphenidate has demonstrated term benefit due to tolerance; improvement in some studies one study showed that benefit did not extend past 8 days

Nausea and vomiting

Pain

Management should be tailored to the underlying cause

Chemotherapy or radiationinduced N/V: 5-HT3 receptor antagonists (e.g., ondansetron) or neurokinin1 receptor antagonist (e.g., aprepitant) or glucocorticoid (e.g., dexamethasone). Metoclopramide is recommended first line for N/V due to gastroparesis, liver failure and unknown causes. Haloperidol, a dopamine receptor antagonist, is often effective in relieving N/V of unknown causes and is first line for N/V due to bowel obstruction and renal failure. Glucocorticoids may be helpful in treating N/V secondary to brain tumors and bowel obstructions. For N/V of unknown cause, metoclopramide may be supplemented with 5HT3receptor antagonists or dopamine receptor antagonists

Pain associated with conditions such as cancer is often intractable. Concerns about addiction are generally irrelevant at this stage of life, so highly addictive drugs may be employed. Opioids undergo hepatic

Fentanyl is the drug of choice for severe pain in patients with renal and/or hepatic dysfunction. Methadone is a drug of choice for patients with renal dysfunction but without hepatic dysfunction. Schedule medication around the clock rather than prn.

Respiratory secretions “Death Rattle”

metabolism and most undergo renal excretion. As organ failure occurs, opioids may accumulate to toxic levels. TCAs have adverse effects and drug–drug interactions that create complications when used for neuropathic pain

Gabapentin or pregabalin are recommended for management of neuropathic pain. SSRIs and SNRIs also may be helpful

Accumulation of secretions in the airway occurs as the patient nears death (within 2 weeks or less) and ineffective cough progresses to loss of cough reflex and pooling of secretions. Suctioning may be inadequate to relieve this problem. Expert opinion is divided regarding whether treatment is warranted. Many believe that the death rattle does not cause patient distress, but it can be upsetting to families

If drug therapy is desired, anticholinergics are often effective in decreasing secretions. Glycopyrrolate is the anticholinergic of choice due to decreased CNS adverse effects. Some studies have indicated that hyoscyamine is a good choice for this purpose

CNS, Central nervous system; N/V, nausea and vomiting; SNRI, serotonin-norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressants.

UNIT IV

Peripheral Nervous System Drugs OUTLINE 11 Basic Principles of Neuropharmacology 12 Physiology of the Peripheral Nervous System 13 Muscarinic Agonists and Cholinesterase Inhibitors 14 Muscarinic Antagonists 15 Adrenergic Agonists 16 Adrenergic Antagonists 17 Indirect-Acting Antiadrenergic Agents

11

Basic Principles of Neuropharmacology Abstract Prescribing and managing neuropharmacological drugs can be intimidating. By developing an understanding of how neurons regulate physiological processes and how neuropharmacological drugs exploit these processes, coupled with a comprehension of receptor types and drug selectivity, this will become a much less daunting task.

Keywords neuropharmacology; neurotransmitters; drug selectivity; drug receptors; synaptic transmission; selectivity Neuropharmacology can be defined as the study of drugs that alter processes controlled by the nervous system. Neuropharmacologic drugs produce effects equivalent to those produced by the excitation or suppression of neuronal activity. Neuropharmacologic agents can be divided into two broad categories: (1) peripheral nervous system (PNS) drugs and (2) central nervous system (CNS) drugs. The neuropharmacologic drugs constitute a large and important family of therapeutic agents. These drugs are used to treat conditions ranging from depression to epilepsy to hypertension to asthma. The clinical significance of these agents is reflected in the fact that more than 25% of this text is dedicated to them. Because the nervous system participates in the regulation of practically all bodily processes, practically all bodily processes can be influenced by drugs that alter neuronal regulation. By mimicking or blocking neuronal regulation, neuropharmacologic drugs can modify such diverse processes as skeletal muscle

contraction, cardiac output, vascular tone, respiration, gastrointestinal function, uterine motility, glandular secretion, and functions unique to the CNS, such as ideation, mood, and perception of pain. Given the broad spectrum of processes that neuropharmacologic drugs can alter, and given the potential benefits to be gained by manipulating those processes, it is no surprise that neuropharmacologic drugs have widespread clinical applications. We begin our study of neuropharmacology by discussing PNS drugs (Chapters 12 through 17), after which we discuss CNS drugs (Chapters 18 through 22). The principal rationale for this order of presentation is that our understanding of PNS pharmacology is much clearer than our understanding of CNS pharmacology because the PNS is less complex than the CNS, and more accessible to experimentation. By placing our initial focus on the PNS, we can establish a firm knowledge base in neuropharmacology before proceeding to the less definitive and vastly more complex realm of CNS pharmacology.

How Neurons Regulate Physiologic Processes As a rule, if we want to understand the effects of a drug on a particular physiologic process, we must first understand the process itself. Accordingly, if we wish to understand the effects of drugs on neuronal regulation of bodily function, we must first understand how neurons regulate bodily function when drugs are absent. Fig. 11.1 illustrates the basic process by which neurons elicit responses from other cells. The figure depicts two cells: a neuron and a postsynaptic cell. The postsynaptic cell might be another neuron, a muscle cell, or a cell within a secretory gland. As indicated, there are two basic steps—axonal conduction and synaptic transmission—in the process by which the neuron influences the behavior of the postsynaptic cell. Axonal conduction is simply the process of conducting an action potential down the axon of the neuron. Synaptic transmission is the process by which information is carried across the gap between the neuron and the postsynaptic cell. As shown in the figure, synaptic transmission requires the release of neurotransmitter molecules from the axon terminal followed by binding of these molecules to receptors on the postsynaptic cell. As a result of transmitter–receptor binding, a series of events is initiated in the postsynaptic cell, leading to a change in its behavior. The precise nature of the change depends on the identity of the neurotransmitter and the type of cell involved. If the postsynaptic cell is another neuron, it may increase or decrease

its firing rate; if the cell is part of a muscle, it may contract or relax; and if the cell is glandular, it may increase or decrease secretion.

How Neurons Regulate Other Cells. There are two basic steps in the process by which neurons elicit responses from other cells: (1) axonal conduction and (2) synaptic transmission. T, Neurotransmitter. FIG. 11.1

Basic Mechanisms by Which Neuropharmacologic Agents Act Sites of Action: Axons Versus Synapses To influence a process under neuronal control, a drug can alter one of two basic neuronal activities: axonal conduction or synaptic transmission. Most neuropharmacologic agents act by altering synaptic transmission. Only a few alter axonal conduction. This is to our advantage because drugs that alter synaptic transmission can produce effects that are much more selective than those produced by drugs that alter axonal conduction.

Axonal Conduction Drugs that act by altering axonal conduction are not very selective. Recall that the process of conducting an impulse along an axon is essentially the same in all neurons. As a consequence, a drug that alters axonal conduction will affect conduction in all nerves to which it has access. Such a drug cannot produce selective effects. Local anesthetics are drugs that work by decreasing axonal conduction. Because these agents produce nonselective inhibition of axonal conduction, they suppress transmission in any nerve they reach. Hence, although local anesthetics are certainly valuable, their indications are limited.

Synaptic Transmission In contrast to drugs that alter axonal conduction, drugs that alter synaptic transmission can produce effects that are highly selective. This selectivity can occur because synapses, unlike axons, differ from one another. Synapses at different sites employ different transmitters. In addition, for most transmitters, the body employs more than one type of receptor. Hence, by using a drug that selectively influences a specific type of neurotransmitter or receptor, we can alter one neuronally regulated process while leaving most others unchanged. Because of their relative selectivity, drugs that alter synaptic transmission have many uses.

Receptors The ability of a neuron to influence the behavior of another cell depends, ultimately, on the ability of that neuron to alter receptor activity on the target cell. As discussed, neurons alter receptor activity by releasing transmitter molecules, which diffuse across the synaptic gap and bind to receptors on the postsynaptic cell. If the target cell lacked receptors for the transmitter that a neuron released, that neuron would be unable to affect the target cell. The effects of neuropharmacologic drugs, like those of neurons, depend on altering receptor activity. That is, no matter what its precise mechanism of action, a neuropharmacologic drug ultimately works by influencing receptor activity on target cells. This concept is central to understanding the actions of neuropharmacologic drugs. In fact, this concept is so critical to our understanding of neuropharmacologic agents that I will repeat it: the effect of a drug on a neuronally regulated process is dependent on the ability of that drug to directly or indirectly influence receptor activity on target cells.

Steps in Synaptic Transmission To understand how drugs alter receptor activity, we must first understand the steps by which synaptic transmission takes place because it is by modifying these steps that neuropharmacologic drugs influence receptor function. The steps in synaptic transmission are shown in Fig. 11.2.

Steps in Synaptic Transmission. Step 1, Synthesis of transmitter (T) from precursor molecules (Q, R, and S). Step 2, Storage of transmitter in vesicles. Step 3, Release of transmitter: in response to an action potential, vesicles fuse with the terminal membrane and discharge their contents into the synaptic gap. Step 4, Action at receptor: transmitter binds (reversibly) to its receptor on the postsynaptic cell, causing a response in that cell. Step 5, Termination of transmission: transmitter dissociates from its receptor and is then removed from the synaptic gap by (a) reuptake into the nerve terminal, (b) enzymatic degradation, or (c) diffusion away from the gap. FIG. 11.2

Step 1: Transmitter Synthesis For synaptic transmission to take place, molecules of transmitter must be present in the nerve terminal. Hence, we can look on transmitter synthesis as the first step in transmission. In the figure, the letters Q, R, and S represent the precursor molecules from which the transmitter (T) is made.

Step 2: Transmitter Storage After transmitter is synthesized, it must be stored until the time of its release. Transmitter storage takes place within vesicles—tiny packets present in the axon terminal. Each nerve terminal contains a large number of transmitter-filled vesicles.

Step 3: Transmitter Release Release of transmitter is triggered by the arrival of an action potential at the axon terminal. The action potential initiates a process in which vesicles undergo fusion with the terminal membrane, causing release of their contents into the synaptic gap. Each action potential causes only a small fraction of all vesicles present in the axon terminal to discharge their contents.

Step 4: Receptor Binding After release, transmitter molecules diffuse across the synaptic gap and then undergo reversible binding to receptors on the postsynaptic cell. This binding initiates a cascade of events that result in altered behavior of the postsynaptic cell.

Step 5: Termination of Transmission Transmission is terminated by dissociation of transmitter from its receptors, followed by removal of a free transmitter from the synaptic gap. Transmitter can be removed from the synaptic gap by three processes: (1) reuptake, (2) enzymatic degradation, and (3) diffusion. In those synapses where transmission is terminated by reuptake, axon terminals contain “pumps” that transport transmitter molecules back into the neuron from which they were released (Step 5a in Fig. 11.2). After reuptake, molecules of transmitter may be degraded, or they may be packaged in vesicles for reuse. In synapses where transmitter is cleared by enzymatic degradation (Step 5b), the synapse contains large quantities of transmitter-inactivating enzymes. Although simple diffusion away from the synaptic gap (Step 5c) is a potential means of terminating transmitter action, this process is very slow and generally of little significance.

Effects of Drugs on the Steps of Synaptic Transmission As emphatically noted, all neuropharmacologic agents (except local anesthetics) produce their effects by directly or indirectly altering receptor activity. We also noted that the way in which drugs alter receptor activity is by interfering with synaptic transmission. Because synaptic transmission has multiple steps, the process offers several potential targets for drugs. In this section, we examine the specific ways in which drugs can alter the steps of synaptic transmission.

Before discussing specific mechanisms by which drugs can alter receptor activity, we need to understand what drugs can do to receptors in general terms. From the broadest perspective, when a drug influences receptor function, that drug can do just one of two things: it can enhance receptor activation, or it can reduce receptor activation. What do we mean by receptor activation? For our purposes, we can define activation as an effect on receptor function equivalent to that produced by the natural neurotransmitter at a particular synapse. Hence a drug whose effects mimic the effects of a natural transmitter would be said to increase receptor activation. Conversely, a drug whose effects were equivalent to reducing the amount of natural transmitter available for receptor binding would be said to decrease receptor activation. Please note that activation of a receptor does not necessarily mean that a physiologic process will go faster; receptor activation can also make a process go slower. For example, the heart rate will decline when the endogenous neurotransmitter acetylcholine activates cholinergic receptors on the heart; therefore, a drug that mimics acetylcholine at receptors on the heart will cause the heart to beat more slowly. Having defined receptor activation, we are ready to discuss the mechanisms by which drugs, acting on specific steps of synaptic transmission, can increase or decrease receptor activity (Table 11.1). As we consider these mechanisms one by one, their logical associations should become apparent. TABLE 11.1

aReceptor activation is defined as producing an effect equivalent to that produced by the natural

transmitter that acts on a particular receptor. T, Transmitter.

Transmitter Synthesis There are three different effects that drugs are known to have on transmitter synthesis. They can (1) increase transmitter synthesis, (2) decrease transmitter synthesis, or (3) cause the synthesis of transmitter molecules that are more effective than the natural transmitter itself. A drug that increases transmitter synthesis will cause receptor activation to increase. The process is this: as a result of increased transmitter synthesis, storage vesicles will contain transmitter in abnormally high amounts. Hence, when an action potential reaches the axon terminal, more transmitter will be released, and therefore more transmitter will be available to receptors on the postsynaptic cell, causing activation of those receptors to increase. Conversely, a drug that decreases transmitter synthesis will cause the transmitter content of vesicles to decline, resulting in reduced transmitter release and decreased receptor activation. Some drugs can cause neurons to synthesize transmitter molecules whose structure is different from that of normal transmitter molecules. For example, by acting as substrates for enzymes in the axon terminal, drugs can be converted into “super” transmitters (molecules whose ability to activate receptors is greater than that of the naturally occurring transmitter at a particular site). Release of these supertransmitters will cause receptor activation to increase.

Transmitter Storage Drugs that interfere with transmitter storage will cause receptor activation to decrease. This occurs because disruption of storage depletes vesicles of their transmitter content, thereby decreasing the amount of transmitter available for release.

Transmitter Release Drugs can either promote or inhibit transmitter release. Drugs that promote release will increase receptor activation. Conversely, drugs that inhibit release will reduce receptor activation. The amphetamines represent drugs that act by promoting transmitter release. Botulinum toxin, in contrast, acts by inhibiting

transmitter release.

Receptor Binding Many drugs act directly at receptors. These agents can (1) bind to receptors and cause activation, (2) bind to receptors and thereby block receptor activation by other agents, or (3) bind to receptor components and thereby enhance receptor activation by the natural transmitter at the site. In the terminology introduced in Chapter 4, drugs that directly activate receptors are called agonists, whereas drugs that prevent receptor activation are called antagonists. The direct-acting receptor agonists and antagonists constitute the largest and most important groups of neuropharmacologic drugs. (There is no single name or category for drugs that bind to receptors to enhance natural transmitter effects.) Examples of drugs that act directly at receptors are numerous. Drugs that bind to receptors and cause activation include morphine (used for its effects on the CNS), epinephrine (used mainly for its effects on the cardiovascular system), and insulin (used for its effects in diabetes). Drugs that bind to and block receptors to prevent their activation include naloxone (used to treat overdose with opioid drugs), antihistamines (used to treat allergic disorders), and metoprolol (used to treat hypertension, angina pectoris, and cardiac dysrhythmias). Benzodiazepines are excellent examples of drugs that bind to receptors and thereby enhance the actions of a natural transmitter. Drugs in this family, which includes diazepam (Valium) and related agents, are used to treat anxiety, seizure disorders, and muscle spasms.

Termination of Transmitter Action Drugs can interfere with the termination of transmitter action by two mechanisms: (1) blockade of transmitter reuptake and (2) inhibition of transmitter degradation. Drugs that act by either mechanism will increase transmitter availability, thereby causing receptor activation to increase.

Multiple Receptor Types and Selectivity of Drug Action As we discussed in Chapter 4, selectivity is one of the most desirable qualities a drug can have. A selective drug can alter a specific disease process while leaving

other physiologic processes largely unaffected. Many neuropharmacologic agents display a high degree of selectivity. This selectivity is possible because the nervous system works through multiple types of receptors to regulate processes under its control. The relationship between multiple receptor types and selective drug action is illustrated by Mort and Merv, whose unique physiologies are depicted in Fig. 11.3. Let's begin with Mort. Mort can perform four functions: he can pump blood, digest food, shake hands, and empty his bladder. All four functions are under neuronal control, and in all cases, that control is exerted by activation of the same type of receptor (designated A).

Multiple Drug Receptors and Selective Drug Action. All of the Mort organs are regulated through activation of type A receptors. Drugs that affect type A receptors on one organ will affect type A receptors on all other organs. Hence, selective drug action is impossible. Merv has four types of receptors (A, B, C, and D) to regulate his four organs. A drug that acts at one type of receptor will not affect the others. Hence, selective drug action is possible. FIG. 11.3

As long as Mort remains healthy, having only one type of receptor to regulate his various functions is no problem. Selective physiologic regulation can be achieved simply by sending impulses down the appropriate nerves. When there is a need to increase cardiac output, impulses are sent down the nerve to his heart; when digestion is needed, impulses are sent down the nerve to his stomach; and so forth. Although having only one receptor type is no disadvantage when all is well, if

Mort gets sick, having only one receptor type creates a therapeutic challenge. Let's assume he develops heart disease and we need to provide a drug that will help increase cardiac output. To stimulate cardiac function, we need to administer a drug that will activate receptors on his heart. Unfortunately, because the receptors on his heart are the same as the receptors on his other organs, a drug that stimulates cardiac function will stimulate his other organs, too. Consequently, any attempt to improve cardiac output with drugs will necessarily be accompanied by side effects. These will range from silly (compulsive handshaking) to embarrassing (enuresis) to hazardous (gastric ulcers). Please note that these undesirable effects are the direct result of Mort having a nervous system that works through just one type of receptor to regulate all organs. That is, the presence of only one receptor type has made selective drug action impossible. Now let's consider Merv. Although Merv appears to be Mort's twin, Merv differs in one important way: whereas all functions in Mort are regulated through just one type of receptor, Merv employs different receptors to control each of his four functions. Because of this simple but important difference, the selective drug action that was impossible with Mort can be achieved easily with Merv. We can, for example, selectively enhance cardiac function in Merv without risking the side effects to which Mort was predisposed. This can be done simply by administering an agonist agent that binds selectively to receptors on the heart (type A receptors). If this medication is sufficiently selective for type A receptors, it will not interact with receptor types B, C, or D. Hence, function in structures regulated by those receptors will be unaffected. Note that our ability to produce selective drug action in Merv is made possible because his nervous system works through different types of receptors to regulate function in his various organs. The message from this example is clear: the more types of receptors we have to work with, the greater our chances of producing selective drug effects.

An Approach to Learning About Peripheral Nervous System Drugs To understand any particular PNS drug, you need three types of information: (1) the type (or types) of receptor through which the drug acts; (2) the normal response to activation of those receptors; and (3) what the drug in question does to receptor function (i.e., does it increase or decrease receptor activation?).

Armed with these three types of information, you can predict the major effects of any PNS drug. (Information about PNS function is reviewed in Chapter 12.) An example will illustrate this process. Let's consider the drug named isoproterenol. The first information we need is the identity of the receptors at which isoproterenol acts. Isoproterenol acts at two types of receptors, named β1and β2-adrenergic receptors. Next, we need to know the normal responses to activation of these receptors. The most prominent responses to activation of β1 receptors are increased heart rate and increased force of cardiac contraction. The primary responses to activation of β2 receptors are bronchial dilation and elevation of blood glucose levels. Finally, we need to know whether isoproterenol increases or decreases the activation of β1 and β2 receptors. At both types of receptor, isoproterenol causes activation. Armed with these three primary pieces of information about isoproterenol, we can now predict the principal effects of this drug. By activating β1 and β2 receptors, isoproterenol can elicit three major responses: (1) increased cardiac output (by increasing heart rate and force of contraction), (2) dilation of the bronchi, and (3) elevation of blood glucose. From this example, you can see how easy it is to predict the effects of a PNS drug. Accordingly, I strongly encourage you to take the approach suggested when studying these agents. That is, for each PNS drug, you should learn (1) the identity of the receptors at which that drug acts, (2) the normal responses to activation of those receptors, and (3) whether the drug increases or decreases receptor activation.

12

Physiology of the Peripheral Nervous System Abstract To safely and competently prescribe and manage drugs that affect the peripheral nervous system, it is necessary to understand the peripheral nervous system physiology. The value of this is in knowing that drugs activate adrenergic, muscarinic, and nicotinic receptors in the same manner as endogenous neurotransmitters. Thus by knowing which receptors drugs target, drug effects are relatively easy to predict.

Keywords autonomic nervous system; adrenergic; cholinergic; parasympathetic; sympathetic; neurotransmitters; synapse; receptor; specificity To understand peripheral nervous system (PNS) drugs, it is necessary to first understand the PNS. The purpose of this chapter is to help you develop that understanding. Because the ultimate goal of this book concerns pharmacology—and not physiology—the discussion is limited to those aspects of PNS physiology that have a direct bearing on the ability to understand drugs.

Divisions of the Nervous System The nervous system has two main divisions, the central nervous system (CNS) and the peripheral nervous system. The PNS has two major subdivisions: (1) the somatic motor system, and (2) the autonomic nervous system. The autonomic nervous system is further subdivided into the parasympathetic nervous system and the sympathetic nervous system. The somatic motor system controls

voluntary movement of muscles. The two subdivisions of the autonomic nervous system regulate many involuntary processes. The autonomic nervous system is the principal focus of this chapter. The somatic motor system is also considered, but discussion is brief.

Overview of Autonomic Nervous System Functions The autonomic nervous system has three principal functions: (1) regulation of the heart, (2) regulation of secretory glands (salivary, gastric, sweat, and bronchial glands), and (3) regulation of smooth muscles (muscles of the bronchi, blood vessels, urogenital system, and gastrointestinal [GI] tract). These regulatory activities are shared between the sympathetic and parasympathetic divisions of the autonomic nervous system.

Functions of the Parasympathetic Nervous System The parasympathetic nervous system performs seven regulatory functions that have particular relevance to drugs. Specifically, stimulation of appropriate parasympathetic nerves causes the following:

• Slowing of heart rate • Increased gastric secretion • Emptying of the bladder • Emptying of the bowel • Focusing the eye for near vision • Constricting the pupil • Contracting bronchial smooth muscle Just how the parasympathetic nervous system elicits these responses is discussed later in the section “Functions of Cholinergic Receptor Subtypes.” From the previous discussion we can see that the parasympathetic nervous system is concerned primarily with what might be called the “housekeeping” chores of the body (digestion of food and excretion of wastes). In addition, the system helps control vision by constricting the pupil and conserves energy by

reducing cardiac work. Therapeutic agents that alter parasympathetic nervous system function are used primarily for their effects on the GI tract, bladder, and eye. Occasionally, these drugs are also used for effects on the heart and lungs. A variety of poisons act by mimicking or blocking effects of parasympathetic stimulation. Among these are insecticides, nerve gases, and toxic compounds found in certain mushrooms and plants.

Functions of the Sympathetic Nervous System The sympathetic nervous system has three main functions:

• Regulating the cardiovascular system • Regulating body temperature • Implementing the acute stress response (commonly called a “fight-or-flight” reaction) The sympathetic nervous system exerts multiple influences on the heart and blood vessels. Stimulation of sympathetic nerves to the heart increases cardiac output. Stimulation of sympathetic nerves to arterioles and veins causes vasoconstriction. Release of epinephrine from the adrenal medulla results in vasoconstriction in most vascular beds and vasodilation in certain others. By influencing the heart and blood vessels, the sympathetic nervous system can achieve three homeostatic objectives:

• Maintenance of blood flow to the brain • Redistribution of blood flow during exercise • Compensation for loss of blood, primarily by causing vasoconstriction The sympathetic nervous system helps regulate body temperature in three ways: (1) By regulating blood flow to the skin, sympathetic nerves can increase or decrease heat loss. By dilating surface vessels, sympathetic nerves increase blood flow to the skin and thereby accelerate heat loss. Conversely, constricting cutaneous vessels conserves heat. (2) Sympathetic nerves to sweat glands promote the secretion of sweat, thereby helping the body cool. (3) By inducing

piloerection (erection of hair), sympathetic nerves can promote heat conservation. When we are faced with an acute stress-inducing situation, the sympathetic nervous system orchestrates the fight-or-flight response, which consists of the following:

• Increasing heart rate and blood pressure • Shunting blood away from the skin and viscera and into skeletal muscles • Dilating the bronchi to improve oxygenation • Dilating the pupils (perhaps to enhance visual acuity) • Mobilizing stored energy, thereby providing glucose for the brain and fatty acids for muscles Many therapeutic agents produce their effects by altering functions under sympathetic control. These drugs are used primarily for effects on the heart, blood vessels, and lungs. Agents that alter cardiovascular function are used to treat hypertension, heart failure, angina pectoris, and other disorders. Drugs affecting the lungs are used primarily for asthma.

Autonomic Nervous System Regulation of Physiologic Processes To understand how drugs influence processes under autonomic control, we must first understand how the autonomic nervous system itself regulates those activities. The basic mechanisms by which the autonomic nervous system regulates physiologic processes are discussed in the following sections.

Patterns of Innervation and Control Most structures under autonomic control are innervated by sympathetic nerves and parasympathetic nerves. The relative influence of sympathetic and parasympathetic nerves depends on the organ under consideration. In many organs that receive dual innervation, the influence of sympathetic nerves opposes that of parasympathetic nerves. For example, in the heart, sympathetic nerves increase the heart rate, whereas parasympathetic nerves slow

the heart rate. In some organs that receive nerves from both divisions of the autonomic nervous system, the effects of sympathetic and parasympathetic nerves are complementary rather than opposite. For example, in the male reproductive system, erection is regulated by parasympathetic nerves, whereas ejaculation is controlled by sympathetic nerves. If attempts at reproduction are to succeed, cooperative interaction of both systems is needed. A few structures under autonomic control receive innervation from only one division. The principal example is blood vessels, which are innervated exclusively by sympathetic nerves. In summary, there are three basic patterns of autonomic innervation and regulation:

• Innervation by both divisions of the autonomic nervous system in which the effects of the two divisions are opposed • Innervation by both divisions of the autonomic nervous system in which the effects of the two divisions are complementary • Innervation and regulation by only one division of the autonomic nervous system

Feedback Regulation Feedback regulation is a process that allows a system to adjust itself by responding to incoming information. Practically all physiologic processes are regulated at least in part by feedback control. Fig. 12.1 depicts a feedback loop typical of those used by the autonomic nervous system. The main elements of this loop are (1) a sensor, (2) an effector, and (3) neurons connecting the sensor to the effector. The purpose of the sensor is to monitor the status of a physiologic process. Information picked up by the sensor is sent to the CNS (spinal cord and brain), where it is integrated with other relevant information. Signals (instructions for change) are then sent from the CNS along nerves of the autonomic system to the effector. In response to these instructions, the effector makes appropriate adjustments in the process. The entire procedure is called a reflex.

FIG. 12.1

Feedback Loop of the Autonomic Nervous System.

Baroreceptor Reflex From a pharmacologic perspective, the most important feedback loop of the autonomic nervous system is one that helps regulate blood pressure. This system is referred to as the baroreceptor reflex. (Baroreceptors are receptors that sense blood pressure.) This reflex is important to us because it frequently opposes our attempts to modify blood pressure with drugs. Feedback (reflex) control of blood pressure is achieved as follows: (1) Baroreceptors located in the carotid sinus and aortic arch monitor changes in blood pressure and send this information to the brain. (2) In response, the brain sends impulses along nerves of the autonomic nervous system, instructing the heart and blood vessels to behave in a way that restores blood pressure to normal. Accordingly, when blood pressure falls, the baroreceptor reflex causes vasoconstriction and increases cardiac output. Both actions help bring blood pressure back up. Conversely, when the blood pressure rises too high, the baroreceptor reflex causes vasodilation and reduces cardiac output, thereby causing the blood pressure to drop. The baroreceptor reflex is discussed in greater detail in Chapter 36.

Autonomic Tone Autonomic tone is the steady, day-to-day influence exerted by the autonomic nervous system on a particular organ or organ system. Autonomic tone provides a basal level of control over which reflex regulation is superimposed. When an organ is innervated by both divisions of the autonomic nervous system, one division—either sympathetic or parasympathetic—provides most of

the basal control, thereby obviating conflicting instruction. Recall that, when an organ receives nerves from both divisions of the autonomic nervous system, those nerves frequently exert opposing influences. If both divisions were to send impulses simultaneously, the resultant conflicting instructions would be counterproductive (like running heating and air conditioning simultaneously). By having only one division of the autonomic nervous system provide the basal control to an organ, conflicting signals are avoided. The branch of the autonomic nervous system that controls organ function most of the time is said to provide the predominant tone to that organ. In most organs, the parasympathetic nervous system provides the predominant tone. The vascular system, which is regulated almost exclusively by the sympathetic nervous system, is the principal exception.

Anatomic Considerations Although a great deal about the anatomy of the PNS is known, very little of this information contributes to an understanding of PNS drugs. The few details that do pertain to pharmacology are shown in Fig. 12.2.

FIG. 12.2 The Basic Anatomy of the Parasympathetic and Sympathetic Nervous Systems and the Somatic Motor System.

Parasympathetic Nervous System

Pharmacologically relevant aspects of parasympathetic anatomy are shown in Fig. 12.2. Note that there are two neurons in the pathway leading from the spinal cord to organs innervated by parasympathetic nerves. The junction (synapse) between these two neurons occurs within a structure called a ganglion. (A ganglion is simply a mass of nerve cell bodies.) The neurons that go from the spinal cord to the parasympathetic ganglia are called preganglionic neurons, whereas the neurons that go from the ganglia to effector organs are called postganglionic neurons. The anatomy of the parasympathetic nervous system offers two general sites at which drugs can act: (1) the synapses between preganglionic neurons and postganglionic neurons, and (2) the junctions between postganglionic neurons and their effector organs.

Sympathetic Nervous System Pharmacologically relevant aspects of sympathetic nervous system anatomy are illustrated in Fig. 12.2. As you can see, these features are nearly identical to those of the parasympathetic nervous system. Like the parasympathetic nervous system, the sympathetic nervous system employs two neurons in the pathways leading from the spinal cord to organs under its control. As with the parasympathetic nervous system, the junctions between those neurons are located in ganglia. Neurons leading from the spinal cord to the sympathetic ganglia are termed preganglionic neurons, and neurons leading from ganglia to effector organs are termed postganglionic neurons. The medulla of the adrenal gland is a feature of the sympathetic nervous system that requires comment. Although not a neuron per se, the adrenal medulla can be looked on as the functional equivalent of a postganglionic neuron of the sympathetic nervous system. (The adrenal medulla influences the body by releasing epinephrine into the bloodstream, which then produces effects much like those that occur in response to the stimulation of postganglionic sympathetic nerves.) Because the adrenal medulla is similar in function to a postganglionic neuron, the nerve leading from the spinal cord to the adrenal gland is commonly referred to as a preganglionic neuron, even though there is no ganglion in this pathway. As with the parasympathetic nervous system, drugs that affect the sympathetic nervous system have two general sites of action: (1) the synapses between preganglionic and postganglionic neurons (including the adrenal medulla), and (2) the junctions between postganglionic neurons and their effector organs.

Somatic Motor System Pharmacologically relevant anatomy of the somatic motor system is depicted in Fig. 12.2. Note that there is only one neuron in the pathway from the spinal cord to the muscles innervated by somatic motor nerves. Because this pathway contains only one neuron, peripherally acting drugs that affect somatic motor system function have only one site of action: the neuromuscular junction (i.e., the junction between the somatic motor nerve and the muscle).

Transmitters of the Peripheral Nervous System The PNS employs three neurotransmitters: acetylcholine, norepinephrine, and epinephrine. Any given junction in the PNS uses only one of these transmitter substances. A fourth compound—dopamine—may also serve as a PNS transmitter, but this role has not been demonstrated conclusively. To understand PNS pharmacology, it is necessary to know the identity of the transmitter employed at each of the junctions of the PNS. This information is shown in Fig. 12.3. As indicated, acetylcholine (ACh) is the transmitter employed at most junctions of the PNS. ACh is the transmitter released by (1) all preganglionic neurons of the parasympathetic nervous system, (2) all preganglionic neurons of the sympathetic nervous system, (3) all postganglionic neurons of the parasympathetic nervous system, (4) all motor neurons to skeletal muscles, and (5) most postganglionic neurons of the sympathetic nervous system that go to sweat glands.

Transmitters Employed at Specific Junctions of the Peripheral Nervous System. (1) All preganglionic neurons of the parasympathetic and sympathetic nervous systems release acetylcholine as their transmitter. (2) All postganglionic neurons of the parasympathetic nervous system release acetylcholine as their transmitter. (3) Most postganglionic neurons of the sympathetic nervous system release norepinephrine as their transmitter. (4) Postganglionic neurons of the sympathetic nervous system that innervate sweat glands release acetylcholine as their transmitter. (5) Epinephrine is the principal transmitter released by the adrenal medulla. (6) All motor neurons to skeletal muscles release acetylcholine as their transmitter. FIG. 12.3

Norepinephrine is the transmitter released by practically all postganglionic neurons of the sympathetic nervous system. The only exceptions are the postganglionic sympathetic neurons that go to sweat glands, which employ ACh as their transmitter. Epinephrine is the major transmitter released by the adrenal medulla. (The adrenal medulla also releases some norepinephrine.)

Receptors of the Peripheral Nervous System The PNS works through several different types of receptors. Understanding these receptors is central to understanding PNS pharmacology. All effort that you invest in learning about these receptors now will be rewarded as we discuss PNS

drugs in later chapters. Much of what follows is based on the information in Fig. 12.3.

Primary Receptor Types: Cholinergic Receptors and Adrenergic Receptors There are two basic categories of receptors associated with the PNS: cholinergic receptors and adrenergic receptors. Cholinergic receptors are defined as receptors that mediate responses to ACh. These receptors mediate responses at all junctions where ACh is the transmitter. Adrenergic receptors are defined as receptors that mediate responses to epinephrine (adrenaline) and norepinephrine. These receptors mediate responses at all junctions where norepinephrine or epinephrine is the transmitter.

Subtypes of Cholinergic and Adrenergic Receptors Not all cholinergic receptors are the same; likewise, not all adrenergic receptors are the same. For each of these two major receptor classes there are receptor subtypes. There are three major subtypes of cholinergic receptors, referred to as nicotinicN, nicotinicM, and muscarinic.a There are four major subtypes of adrenergic receptors, referred to as α1, α2, β1, and β2. In addition to the four major subtypes of adrenergic receptors, there is another adrenergic receptor type, referred to as the dopamine receptor. Although dopamine receptors are classified as adrenergic, these receptors do not respond to epinephrine or norepinephrine. Rather, they respond only to dopamine, a neurotransmitter found primarily in the CNS.

Exploring the Concept of Receptor Subtypes The concept of receptor subtypes is important and potentially confusing. In this section we discuss what a receptor subtype is and why receptor subtypes matter.

What Is a Receptor Subtype? Receptors that respond to the same transmitter but nonetheless are different from

one another are called receptor subtypes. For example, peripheral receptors that respond to ACh can be found (1) in ganglia of the autonomic nervous system, (2) at neuromuscular junctions, and (3) on organs regulated by the parasympathetic nervous system. However, even though all of these receptors can be activated by ACh, there is clear evidence that the receptors at these three sites are, in fact, different from one another. Hence, although all of these receptors belong to the same major receptor category (cholinergic), they are sufficiently different as to constitute distinct receptor subtypes.

How Do We Know That Receptor Subtypes Exist? Historically, our knowledge of receptor subtypes came from observing responses to drugs. In fact, were it not for drugs, receptor subtypes might never have been discovered. Table 12.1 illustrates the types of drug responses that led to the realization that receptor subtypes exist. These data summarize the results of an experiment designed to study the effects of a natural transmitter (ACh) and a series of drugs (nicotine, muscarine, d-tubocurarine, and atropine) on two tissues: skeletal muscle and ciliary muscle. (The ciliary muscle is the muscle responsible for focusing the eye for near vision.) Although skeletal muscle and ciliary muscle both contract in response to ACh, these tissues differ in their responses to drugs. In the discussion that follows, we examine the selective responses of these tissues to drugs and see how those responses reveal the existence of receptor subtypes. TABLE 12.1

At synapses on skeletal muscle and ciliary muscle, ACh is the transmitter employed by neurons to elicit contraction. Because both types of muscle respond to ACh, it is safe to conclude that both muscles have receptors for this substance. Because ACh is the natural transmitter for these receptors, we would classify them as cholinergic. What do the effects of nicotine on skeletal muscle and ciliary muscle suggest? There are four possible conclusions: (1) Because skeletal muscle contracts in response to nicotine, we can conclude that skeletal muscle has receptors at which nicotine can act. (2) Because ciliary muscle does not respond to nicotine, we can tentatively conclude that ciliary muscle does not have receptors for nicotine. (3) Because nicotine mimics the effects of ACh on skeletal muscle, we can conclude that nicotine may act at the same skeletal muscle receptors where ACh acts. (4) Because both skeletal and ciliary muscle have receptors for ACh, and because nicotine appears to act only at the ACh receptors on skeletal muscle, we can tentatively conclude that the ACh receptors on skeletal muscle are different from the ACh receptors on ciliary muscle. What do the responses to muscarine suggest? The conclusions that can be drawn are exactly parallel to those drawn for nicotine. They are that (1) ciliary muscle has receptors that respond to muscarine, (2) skeletal muscle may not have receptors for muscarine, (3) muscarine may be acting at the same receptors on ciliary muscle where ACh acts, and (4) the receptors for ACh on ciliary muscle may be different from the receptors for ACh on skeletal muscle. The responses of skeletal muscle and ciliary muscle to nicotine and muscarine suggest but do not prove that the cholinergic receptors on these two tissues are different. However, the responses of these two tissues to d-tubocurarine and

atropine, both of which are receptor blocking agents, eliminate any doubts as to the presence of cholinergic receptor subtypes. When both types of muscle are pretreated with d-tubocurarine and then exposed to ACh, the response to ACh is blocked in skeletal muscle but not in ciliary muscle. Tubocurarine pretreatment does not reduce the ability of ACh to stimulate ciliary muscle. Conversely, pretreatment with atropine selectively blocks the response to ACh in ciliary muscle—but atropine does nothing to prevent ACh from stimulating receptors on skeletal muscle. Because tubocurarine can selectively block cholinergic receptors in skeletal muscle (whereas atropine can selectively block cholinergic receptors in ciliary muscle), we can conclude with certainty that the receptors for ACh in these two types of muscle must be different. The data just discussed illustrate the essential role of drugs in revealing the presence of receptor subtypes. If ACh were the only probe that we had, all that we would have been able to observe is that both skeletal muscle and ciliary muscle can respond to this agent. This simple observation would provide no basis for suspecting that the receptors for ACh in these two tissues were different. It is only through the use of selectively acting drugs that the presence of receptor subtypes was initially revealed. Today, the technology for identifying receptors and their subtypes is extremely sophisticated—not that studies like the one just discussed are no longer of value. In addition to performing traditional drug-based studies, scientists are now cloning receptors using DNA hybridization technology. As you can imagine, this allows us to understand receptors in ways that were unthinkable in the past.

How Can Drugs Be More Selective Than Natural Transmitters at Receptor Subtypes? Drugs achieve their selectivity for receptor subtypes by having structures that are different from those of natural transmitters. The relationship between structure and receptor selectivity is illustrated in Fig. 12.4. Drawings are used to represent drugs (nicotine and muscarine), receptor subtypes (nicotinic and muscarinic), and ACh (the natural transmitter at nicotinic and muscarinic receptors). From the structures shown, we can easily imagine how ACh is able to interact with both kinds of receptor subtypes, whereas nicotine and muscarine can interact only with the receptor subtypes whose structure is complementary to their own. By synthesizing chemicals that are structurally related to natural transmitters, pharmaceutical chemists have been able to produce drugs that are more selective

for specific receptor subtypes than are the natural transmitters that act at those sites.

Drug Structure and Receptor Selectivity. The relationship between structure and receptor selectivity is shown. The structure of acetylcholine allows this transmitter to interact with both receptor subtypes. In contrast, because of their unique structures, nicotine and muscarine are selective for the cholinergic receptor subtypes whose structure complements their own. FIG. 12.4

Why Do Receptor Subtypes Exist and Why Do They Matter? The physiologic benefits of having multiple receptor subtypes for the same transmitter are not immediately obvious. In fact, as noted previously, were it not for drugs, we probably wouldn't know that receptor subtypes existed at all. Although receptor subtypes are of uncertain physiologic relevance, from the viewpoint of therapeutics, they are invaluable. The presence of receptor subtypes makes possible a dramatic increase in drug selectivity. For example, thanks to the existence of subtypes of cholinergic receptors (and the development of drugs selective for those receptor subtypes), it is possible to influence the activity of certain cholinergic receptors (e.g., receptors of the neuromuscular junction) without altering the activity of all other cholinergic receptors (e.g., the cholinergic receptors found in all autonomic ganglia and all target organs of the parasympathetic nervous system). Were it not for the existence of receptor subtypes, a drug that acted on cholinergic receptors

at one site would alter the activity of cholinergic receptors at all other sites. Clearly, the existence of receptor subtypes for a particular transmitter makes drug actions possible, which are much more selective than could be achieved if all of the receptors for that transmitter were the same. (Recall our discussion of Mort and Merv in Chapter 11.)

Locations of Receptor Subtypes Because many of the drugs discussed in later chapters are selective for specific receptor subtypes, knowledge of the sites at which specific receptor subtypes are located will help us predict which organs a drug will affect. Accordingly, in laying our foundation for studying PNS drugs, it is important to learn the sites at which the subtypes of adrenergic and cholinergic receptors are located. This information is shown in Fig. 12.5. You will find it helpful to master the content of this figure before proceeding. (In the interest of minimizing confusion, subtypes of adrenergic receptors in Fig. 12.5 are listed simply as α and β rather than as α1, α2, β1, and β2. The locations of all four subtypes of adrenergic receptors are discussed in the section that follows.)

Locations of Cholinergic and Adrenergic Receptor Subtypes. (1) NicotinicN receptors are located on the cell bodies of all postganglionic neurons of the parasympathetic and sympathetic FIG. 12.5

nervous systems. NicotinicN receptors are also located on cells of the adrenal medulla. (2) NicotinicM receptors are located on skeletal muscle. (3) Muscarinic receptors are located on all organs regulated by the parasympathetic nervous system (i.e., organs innervated by postganglionic parasympathetic nerves). Muscarinic receptors are also located on sweat glands. (4) Adrenergic receptors—α, β, or both —are located on all organs (except sweat glands) regulated by the sympathetic nervous system (i.e., organs innervated by postganglionic sympathetic nerves). Adrenergic receptors are also located on organs regulated by epinephrine released from the adrenal medulla. ACh, Acetylcholine.

Functions of Cholinergic and Adrenergic Receptor Subtypes Knowledge of receptor function is essential for understanding PNS drugs. By knowing the receptors at which a drug acts, and by knowing what those receptors do, we can predict the major effects of any PNS drug. Tables 12.2 and 12.3 show the pharmacologically relevant functions of PNS receptors. Table 12.2 summarizes responses elicited by the activation of cholinergic receptor subtypes. Table 12.3 summarizes responses to the activation of adrenergic receptor subtypes. You should master Table 12.2 before studying cholinergic drugs (Chapters 13 and 14.) You should master Table 12.3 before studying adrenergic drugs (Chapters 15 to 17). If you master these tables in preparation for learning about PNS drugs, you will find the process of learning the pharmacology relatively simple. Conversely, if you attempt to study the pharmacology without first mastering the appropriate table, you are likely to meet with frustration. TABLE 12.2

aAlthough sweating is due primarily to stimulation of muscarinic receptors by acetylcholine, the

nerves that supply acetylcholine to sweat glands belong to the sympathetic nervous system rather than the parasympathetic nervous system. bCholinergic receptors on blood vessels are not associated with the nervous system.

TABLE 12.3

Functions of Cholinergic Receptor Subtypes Table 12.2 shows the pharmacologically relevant responses to activation of the three major subtypes of cholinergic receptors: nicotinicN, nicotinicM, and muscarinic. Responses to cholinergic receptor activation can be grouped into three major categories based on the subtype of receptor involved:

• Activation of nicotinicN (neuronal) receptors promotes ganglionic transmission at all ganglia of the sympathetic and parasympathetic nervous systems. In addition, activation of nicotinicN receptors promotes release of epinephrine from the adrenal medulla.

• Activation of nicotinicM (muscle) receptors causes contraction of skeletal muscle. • Activation of muscarinic receptors, which are located on target organs of the parasympathetic nervous system, elicits an appropriate response from the organ involved. Specifically, muscarinic activation causes (1) increased glandular secretions (from pulmonary, gastric, intestinal, and sweat glands), (2) contraction of smooth muscle in the bronchi and GI tract, (3) slowing of the heart rate, (4) contraction of the sphincter muscle of the iris, resulting in miosis (reduction in pupillary diameter), (5) contraction of the ciliary muscle of the eye, causing the lens to focus for near vision, (6) dilation of blood vessels, and (7) voiding of the urinary bladder (by causing contraction of the detrusor muscle [which forms the bladder wall] and relaxation of the trigone and sphincter muscles [which block the bladder neck when contracted]). Muscarinic cholinergic receptors on blood vessels require additional comment. These receptors are not associated with the nervous system in any way. That is, no autonomic nerves terminate at vascular muscarinic receptors. It is not at all clear as to how, or even if, these receptors are activated physiologically. However, regardless of their physiologic relevance, the cholinergic receptors on blood vessels do have pharmacologic significance because drugs that are able to activate these receptors cause vasodilation, which in turn causes blood pressure to fall.

Functions of Adrenergic Receptor Subtypes Adrenergic receptor subtypes and their functions are shown in Table 12.3.

α1 Receptors α1 receptors are located in the eyes, blood vessels, male sex organs, prostatic capsule, and bladder (trigone and sphincter). Ocular α1 receptors are present on the radial muscle of the iris. Activation of

these receptors leads to mydriasis (dilation of the pupil). α1 receptors are present on veins and on arterioles in many capillary beds. Activation of α1 receptors in blood vessels produces vasoconstriction. Activation of α1 receptors in the sexual apparatus of males causes ejaculation. Activation of α1 receptors in smooth muscle of the bladder (trigone and sphincter) and prostatic capsule causes contraction.

α2 Receptors α2 receptors of the PNS are located on nerve terminals (see Table 12.3) and not on the organs innervated by the autonomic nervous system. Because α2 receptors are located on nerve terminals, these receptors are referred to as presynaptic or prejunctional. The function of these receptors is to regulate transmitter release. As depicted in Table 12.3, norepinephrine can bind to α2 receptors located on the same neuron from which the norepinephrine was released. The consequence of this norepinephrine–receptor interaction is suppression of further norepinephrine release. Hence, presynaptic α2 receptors can help reduce transmitter release when too much transmitter has accumulated in the synaptic gap. Drug effects resulting from activation of peripheral α2 receptors are of minimal clinical significance. α2 receptors are also present in the CNS. In contrast to peripheral α2 receptors, central α2 receptors are therapeutically relevant. We will consider these receptors in later chapters.

β1 Receptors β1 receptors are located in the heart and the kidney. Cardiac β1 receptors have great therapeutic significance. Activation of these receptors increases heart rate, force of contraction, and velocity of impulse conduction through the atrioventricular node. Activation of β1 receptors in the kidney causes release of renin into the blood. Because renin promotes synthesis of angiotensin, a powerful vasoconstrictor, activation of renal β1 receptors is a means by which the nervous system helps elevate blood pressure. (The role of renin in the regulation of blood pressure is discussed in depth in Chapter 38.)

β2 Receptors β2 receptors mediate several important processes. Activation of β2 receptors in the lung leads to bronchial dilation. Activation of β2 receptors in the uterus causes relaxation of uterine smooth muscle. Activation of β2 receptors in arterioles of the heart, lungs, and skeletal muscles causes vasodilation (an effect opposite to that of α1 activation). Activation of β2 receptors in the liver and skeletal muscle promotes glycogenolysis (breakdown of glycogen into glucose), thereby increasing blood levels of glucose. In addition, activation of β2 receptors in skeletal muscle enhances contraction.

Dopamine Receptors In the periphery, the only dopamine receptors of clinical significance are located in the vasculature of the kidney. Activation of these receptors dilates renal blood vessels, enhancing renal perfusion. In the CNS, receptors for dopamine are of great therapeutic significance. The functions of these receptors are discussed in Chapters 19 and 26.

Receptor Specificity of the Adrenergic Transmitters The receptor specificity of adrenergic transmitters is more complex than the receptor specificity of ACh. Whereas ACh can activate all three subtypes of cholinergic receptors, not every adrenergic transmitter (epinephrine, norepinephrine, dopamine) can interact with each of the five subtypes of adrenergic receptors. Receptor specificity of adrenergic transmitters is as follows: (1) epinephrine can activate all α and β receptors, but not dopamine receptors, (2) norepinephrine can activate α1, α2, and β1 receptors, but not β2 or dopamine receptors, and (3) dopamine can activate α1, β1, and dopamine receptors. (Note that dopamine itself is the only transmitter capable of activating dopamine receptors.) Receptor specificity of the adrenergic transmitters is shown in Table 12.4. TABLE 12.4

Receptor Specificity of Adrenergic Transmitters

Arrows indicate the range of receptors that the transmitters can activate. Knowing that epinephrine is the only transmitter that acts at β2 receptors can serve as an aid to remembering the functions of this receptor subtype. Recall that epinephrine is released from the adrenal medulla—not from neurons—and that the function of epinephrine is to prepare the body for fight or flight. Accordingly, because epinephrine is the only transmitter that activates β2 receptors, and because epinephrine is released only in preparation for fight or flight, times of fight or flight will be the only occasions on which β2 receptors will undergo significant physiologic activation. As it turns out, the physiologic changes elicited by β2 activation are precisely those needed for success in the fight-orflight response. Specifically, activation of β2 receptors will (1) dilate blood vessels in the heart, lungs, and skeletal muscles, thereby increasing blood flow to these organs, (2) dilate the bronchi, thereby increasing oxygenation, (3) increase glycogenolysis, thereby increasing available energy, and (4) relax uterine smooth muscle, thereby preventing delivery (a process that would be inconvenient for a pregnant woman preparing to fight or flee). Accordingly, if you think of the physiologic requirements for success during fight or flight, you will have a good picture of the responses that β2 activation can cause.

Transmitter Life Cycles In this section we consider the life cycles of ACh, norepinephrine, and epinephrine. Because a number of drugs produce their effects by interfering with specific phases of the transmitters’ life cycles, knowledge of these cycles helps us understand drug actions.

Life Cycle of Acetylcholine The life cycle of ACh is depicted in Fig. 12.6. The cycle begins with synthesis of ACh from two precursors: choline and acetylcoenzyme A. After synthesis, ACh is stored in vesicles and later released in response to an action potential. After

release, ACh binds to receptors (nicotinicN, nicotinicM, or muscarinic) located on the postjunctional cell. Upon dissociating from its receptors, ACh is destroyed almost instantaneously by acetylcholinesterase (AChE), an enzyme present in abundance on the surface of the postjunctional cell. AChE degrades ACh into two inactive products: acetate and choline. Uptake of choline into the cholinergic nerve terminal completes the life cycle of ACh. Note that an inactive substance (choline), and not the active transmitter (ACh), is taken back up for reuse.

Life Cycle of Acetylcholine. Transmission is terminated by enzymatic degradation of acetylcholine (ACh) and not by the uptake of intact ACh back into the nerve terminal. Acetyl CoA, Acetylcoenzyme A; AChE, acetylcholinesterase. FIG. 12.6

Therapeutic and toxic agents can interfere with the ACh life cycle at several points. Botulinum toxin inhibits ACh release. A number of medicines and poisons act at cholinergic receptors to mimic or block the actions of ACh. Several therapeutic and toxic agents act by inhibiting AChE, thereby causing ACh to accumulate in the junctional gap.

Life Cycle of Norepinephrine The life cycle of norepinephrine is depicted in Fig. 12.7. As indicated, the cycle begins with synthesis of norepinephrine from a series of precursors. The final step of synthesis takes place within vesicles, where norepinephrine is then stored

before release. After release, norepinephrine binds to adrenergic receptors. Norepinephrine can interact with postsynaptic α1 and β1 receptors (but not with β2 receptors) and with presynaptic α2 receptors. Transmission is terminated by reuptake of norepinephrine back into the nerve terminal. (Note that the termination process for norepinephrine differs from that for ACh, whose effects are terminated by enzymatic degradation rather than reuptake.) After reuptake, norepinephrine can undergo one of two fates: (1) uptake into vesicles for reuse, or (2) inactivation by monoamine oxidase (MAO), an enzyme found in the nerve terminal.

Life Cycle of Norepinephrine. Note that transmission mediated by norepinephrine (NE) is terminated by the reuptake of NE into the nerve terminal and not by enzymatic degradation. Be aware that although postsynaptic cells may have α1, β1, and β2 receptors, NE can only activate postsynaptic α1 and β1 receptors; physiologic activation of β2 receptors is done by epinephrine. DA, Dopamine; MAO, monoamine oxidase. FIG. 12.7

Practically every step in the life cycle of norepinephrine can be altered by therapeutic agents. We have drugs that alter the synthesis, storage, and release of norepinephrine; we have drugs that act at adrenergic receptors to mimic or block the effects of norepinephrine; we have drugs, such as cocaine and tricyclic

antidepressants, that inhibit the reuptake of norepinephrine (and thereby intensify transmission); and we have drugs that inhibit the breakdown of norepinephrine by MAO, causing an increase in the amount of transmitter available for release.

Life Cycle of Epinephrine The life cycle of epinephrine is much like that of norepinephrine—although there are significant differences. The cycle begins with synthesis of epinephrine within chromaffin cells of the adrenal medulla. These cells produce epinephrine by first making norepinephrine, which is then converted enzymatically to epinephrine. (Because sympathetic neurons lack the enzyme needed to convert norepinephrine to epinephrine, epinephrine is not produced in sympathetic nerves.) After synthesis, epinephrine is stored in vesicles to await release. When released, epinephrine travels through the bloodstream to target organs throughout the body, where it can activate α1, α2, β1, and β2 receptors. Termination of epinephrine actions is accomplished primarily by hepatic metabolism, and not by uptake into nerves. aEvidence indicates that muscarinic receptors, like nicotinic receptors, come in

subtypes. Five have been identified. Of these, only three—designated M1, M2, and M3—have clearly identified functions. At this time, practically all drugs that affect muscarinic receptors are nonselective. Accordingly, because our understanding of these receptors is limited, and because drugs that can selectively alter their function are few, we will not discuss muscarinic receptor subtypes further in this chapter. However, we will discuss them in Chapter 14, in the context of drugs for overactive bladder.

13

Muscarinic Agonists and Cholinesterase Inhibitors Abstract The parasympathetic nervous system controls physiological responses of multiple body systems. Muscarinic agonists directly activate receptors of the parasympathetic nervous system; therefore, it is not surprising that they have a wide range of both therapeutic and adverse effects. Additionally, cholinesterase inhibitors indirectly affect receptor activation by increasing the availability of acetylcholine. By examining characteristics of both types of muscarinic agonists and applying these to the management of common conditions, a clearer understanding can be developed as a foundation for using these drugs in practice.

Keywords muscarinic agonists; cholinesterase inhibitors; parasympathetic nervous system; parasympathomimetics; myasthenia gravis; urinary retention; Alzheimer disease

Introduction to Cholinergic Drugs Cholinergic drugs are agents that influence the activity of cholinergic receptors. Most of these drugs act directly at cholinergic receptors, where they either mimic or block the actions of acetylcholine. The remainder—the cholinesterase inhibitors—activate cholinergic receptors indirectly by preventing the breakdown of acetylcholine. The cholinergic drugs have both therapeutic and toxicologic significance. Therapeutic applications are limited but valuable. The toxicology of cholinergic

drugs is extensive, encompassing such agents as nicotine, insecticides, and compounds designed for chemical warfare. There are six categories of cholinergic drugs. These categories are muscarinic agonists, muscarinic antagonists, cholinesterase inhibitors, ganglionic stimulating agents, ganglionic blocking agents, and neuromuscular blocking agents. The muscarinic antagonists, ganglionic blocking agents, and neuromuscular blocking agents (commonly referred to as anticholinergic agents) are discussed in Chapter 14. The muscarinic agonists selectively mimic the effects of acetylcholine at muscarinic receptors. The cholinesterase inhibitors prevent the breakdown of acetylcholine by acetylcholinesterase. As a result, more acetylcholine remains available to activate cholinergic receptors. Ganglionic stimulating agents selectively mimic the effects of acetylcholine at nicotinicN (neuronal) receptors of autonomic ganglia. These drugs have little therapeutic value beyond the use of nicotine in smoking cessation programs (see Chapter 34). Ganglionic blocking agents, represented by mecamylamine, selectively block ganglionic nicotinicN receptors. Neuromuscular blocking agents, represented by d-tubocurarine and succinylcholine, selectively block the effects of acetylcholine at nicotinicM (muscle) receptors at the neuromuscular junction (NMJ). Ganglionic and neuromuscular blocking agents are used in specialty settings and are beyond the scope of this text. Table 13.1 is your key to understanding the cholinergic drugs. It lists the three major subtypes of cholinergic receptors (muscarinic, nicotinicN, and nicotinicM) and indicates the following for each receptor type: (1) location, (2) responses to activation, (3) drugs that produce activation (agonists), and (4) drugs that prevent activation (antagonists). This information, along with the detailed information on cholinergic receptor function summarized in Table 12.2 in Chapter 12, provides the information you need to predict the actions of cholinergic drugs. TABLE 13.1

aThe doses of nicotine needed to activate nicotinic receptors of the neuromuscular junctions are M

much higher than the doses needed to activate nicotinicN receptors in autonomic ganglia.

An example will demonstrate the combined value of Tables 13.1 and 12.2. Let's consider bethanechol. As shown in Table 13.1, bethanechol is a selective agonist at muscarinic cholinergic receptors. Referring to Table 12.2, we see that activation of muscarinic receptors can produce the following: ocular effects (miosis and ciliary muscle contraction), slowing of heart rate, bronchial constriction, urination, glandular secretion, stimulation of the gastrointestinal (GI) tract, and vasodilation. Because bethanechol activates muscarinic receptors, the drug is capable of eliciting all of these responses. Therefore, by knowing which receptors bethanechol activates (from Table 13.1), and by knowing what those receptors do (from Table 12.2), you can predict the kinds of responses you might expect bethanechol to produce. Next we will examine the muscarinic agonists, cholinesterase inhibitors, and muscarinic antagonists. The muscarinic agonists and antagonists produce their effects through direct interaction with muscarinic receptors. The muscarinic agonists cause receptor activation; the antagonists produce receptor blockade. Like the muscarinic agonists, another group of drugs—the cholinesterase inhibitors—can also cause receptor activation, but they do so by an indirect mechanism.

Muscarinic Agonists The muscarinic agonists bind to muscarinic receptors and thereby cause receptor activation. Because nearly all muscarinic receptors are associated with the parasympathetic nervous system, responses to muscarinic agonists closely resemble those produced by stimulation of parasympathetic nerves. Accordingly, muscarinic agonists are also known as parasympathomimetic agents.

Bethanechol Bethanechol (Urecholine, Duvoid ) embodies the properties that typify all muscarinic agonists and will serve as our prototype for the group.

Mechanism of Action Bethanechol is a direct-acting muscarinic agonist. The drug binds reversibly to muscarinic cholinergic receptors to cause activation. At therapeutic doses, bethanechol acts selectively at muscarinic receptors, having little or no effect on nicotinic receptors, either in ganglia or in skeletal muscle.

Pharmacologic Effects Bethanechol can elicit all of the responses typical of muscarinic receptor activation. Accordingly, we can readily predict the effects of bethanechol by knowing the information on muscarinic responses summarized in Table 12.2. The principal structures affected by muscarinic activation are the heart, exocrine glands, smooth muscles, and eyes. Muscarinic agonists act on the heart to cause bradycardia (decreased heart rate) and on exocrine glands to increase sweating, salivation, bronchial secretions, and secretion of gastric acid. In smooth muscles of the lungs and GI tract, muscarinic agonists promote contraction. The result is constriction of the bronchi and increased tone and motility of GI smooth muscle. In the bladder, muscarinic activation causes contraction of the detrusor muscle and relaxation of the trigone and sphincter; the result is bladder emptying. In vascular smooth muscle, these drugs cause relaxation; the resultant vasodilation can produce hypotension. Activation of muscarinic receptors in the eyes has two effects: (1) miosis (pupillary constriction) and (2) contraction of the ciliary muscle, resulting in accommodation for near vision. (The ciliary muscle, which is attached to the lens, focuses the eyes for near vision by altering lens curvature.) Pharmacokinetics. Bethanechol is available for oral administration. Effects begin in 30 to 60 minutes and persist for about 1 hour. Because bethanechol is a quaternary ammonium compound that always carries a positive charge, the drug crosses membranes poorly. As a result, only a small fraction of each dose is absorbed. Additional information on pharmacokinetics of bethanechol and other muscarinic agonists is provided in Table 13.2.

TABLE 13.2

h, Hour(s); UK, unknown.

Preparations, dosage, and administration. Preparation and dosing of bethanechol and other muscarinic agonists is provided in Table 13.3. TABLE 13.3

Therapeutic Uses Although bethanechol can produce a broad spectrum of pharmacologic effects, the drug is approved only for urinary retention. Urinary retention. Bethanechol relieves urinary retention by activating muscarinic receptors of the urinary tract. Muscarinic activation relaxes the trigone and sphincter muscles and increases voiding pressure by contracting the detrusor muscle, which composes the bladder wall. It is approved to treat urinary retention in postoperative and postpartum patients and to treat retention secondary to neurogenic atony of the bladder. The drug should not be used to treat urinary retention caused by physical obstruction of the urinary tract because increased

pressure in the tract in the presence of blockage could cause injury. Gastrointestinal uses. Bethanechol has been used off-label to treat gastroesophageal reflux. Benefits may result from increased esophageal motility and increased pressure in the lower esophageal sphincter. Bethanechol can help treat disorders associated with GI paralysis. Benefits derive from increased tone and motility of GI smooth muscle. Specific applications are adynamic ileus, gastric atony, and postoperative abdominal distention. Bethanechol should not be given if physical obstruction of the GI tract is present, because in the presence of blockage, increased propulsive contractions might result in damage to the intestinal wall.

Patient-Centered Care Across the Life Span Muscarinic Agonists Life Stage

Patient Care Concerns

Childre Safety and effectiveness in children has not been established for n bethanechol and cevimeline. Pregna nt wo me n

It is unknown whether bethanechol or cevimeline cause fetal harm. Reproduction studies in animals suggest that cevimeline may decrease implantation.

Breastf It is unknown whether bethanechol or cevimeline are excreted in breast eedi milk. As a cautionary measure, manufacturers recommend that nursing ng be discontinued while taking these drugs. wo me n Older adu lts

Because older patients may have decreased cardiac, hepatic, or renal function, care must be taken to evaluate risks on an individual basis.

Adverse Effects In theory, bethanechol can produce the full range of muscarinic responses as side effects. However, with oral dosing, side effects are relatively rare. Cardiovascular system. Bethanechol can cause hypotension (secondary to vasodilation) and bradycardia. Accordingly, the drug is contraindicated for patients with low blood pressure or low cardiac output. Gastrointestinal system. At usual therapeutic doses, bethanechol can cause excessive salivation, increased secretion of gastric acid, abdominal cramps, and diarrhea. Higher doses can cause involuntary defecation. Bethanechol is contraindicated in patients with gastric ulcers because stimulation of acid secretion could intensify gastric erosion, causing bleeding and possibly perforation. The drug is also contraindicated for patients with intestinal obstruction and for those recovering from recent surgery of the bowel. In both cases, the ability of bethanechol to increase the tone and motility of intestinal smooth muscle could result in rupture of the bowel wall. Urinary tract. Because of its ability to contract the bladder detrusor and thereby increase pressure within the urinary tract, bethanechol can be hazardous to patients with urinary tract obstruction or weakness of the bladder wall. In both groups, elevation of pressure within the urinary tract could rupture the bladder. Accordingly, bethanechol is contraindicated for patients with either disorder. Exacerbation of asthma. By activating muscarinic receptors in the lungs, bethanechol can cause bronchoconstriction. Accordingly, the drug is contraindicated for patients with latent or active asthma. Of course, it stands to reason that muscarinic agonists may also complicate other respiratory disorders. Dysrhythmias in patients with hyperthyroidism. Bethanechol is contraindicated for people with hyperthyroidism. If given to patients with this condition, bethanechol may increase heart rate to the point of

initiating a dysrhythmia. (Note that increased heart rate is opposite to the effect that muscarinic agonists have in most patients.) The mechanism of dysrhythmia induction is explained here. When patients with hyperthyroidism are given bethanechol, their initial cardiovascular responses are like those of anyone else: bradycardia and hypotension. In reaction to hypotension, the baroreceptor reflex attempts to return blood pressure to normal. Part of this reflex involves the release of norepinephrine from sympathetic nerves that regulate heart rate. In patients who do not have hyperthyroidism, norepinephrine release serves to increase cardiac output and thus helps restore blood pressure. However, in patients, norepinephrine can induce cardiac dysrhythmias. The reason for this unusual response is that, in patients with hyperthyroidism, the heart is exquisitely sensitive to the effects of norepinephrine, and hence relatively small amounts can cause stimulation sufficient to elicit a dysrhythmia.

Summary of Key Prescribing Considerations Bethanechol Therapeutic Goal: Treatment of nonobstructive urinary retention. Baseline Data: Vital signs, urination trends (times and amounts) Monitoring: Intake and output. Observe for signs of excessive muscarinic response (abnormal salivation, sweating, urinary urgency, bradycardia, and hypotension). Identifying High-Risk Patients: Bethanechol is contraindicated for patients with peptic ulcer disease, urinary tract obstruction, intestinal obstruction, coronary insufficiency, hypotension, asthma, and hyperthyroidism. Evaluating Therapeutic Effects: Absence of bladder distension or suprapubic discomfort. Adequate urinary output. Minimizing Adverse Effects: Taking on an empty stomach can help reduce nausea and vomiting. Treat excessive muscarinic stimulation with atropine and supportive measures.

Other Muscarinic Agonists

Cevimeline Actions and uses. Cevimeline (Evoxac) is a derivative of acetylcholine with actions much like those of bethanechol. The drug is indicated for relief of xerostomia (dry mouth) in patients with Sjögren syndrome, an autoimmune disorder. Xerostomia, left untreated, can lead to multiple complications, including periodontal disease, dental caries, altered taste, oral ulcers and candidiasis, and difficulty eating and speaking. Cevimeline relieves dry mouth by activating muscarinic receptors on residual healthy tissue in salivary glands, thereby promoting salivation. Because it stimulates salivation, cevimeline may also benefit patients with xerostomia induced by radiation therapy for head and neck cancer, although the drug is not approved for this use. Cevimeline has also been used to manage keratoconjunctivitis sicca (inflammation of the cornea and conjunctiva) and dry eye. It increases tear production, which can help relieve discomfort associated with these conditions. Adverse effects. Adverse effects result from activating muscarinic receptors and hence are similar to those of bethanechol. The most common effects are excessive sweating, nausea, rhinitis, and diarrhea. There is also an increased incidence of urinary tract infections (UTIs). To compensate for fluid loss caused by sweating and diarrhea, patients should increase fluid intake. Like bethanechol, cevimeline promotes miosis (constriction of the pupil) and may also cause blurred vision. Both actions can make driving dangerous, especially at night. Activation of cardiac muscarinic receptors can reduce heart rate and slow cardiac conduction. Accordingly, cevimeline should be used with caution in patients with a history of heart disease. Because muscarinic activation increases airway resistance, cevimeline is contraindicated for patients with uncontrolled asthma and should be used with caution in patients with controlled asthma, chronic bronchitis, or chronic obstructive pulmonary disease (COPD). Cevimeline is also contraindicated for people with both narrow-angle glaucoma and iritis. Drug interactions. Cevimeline can intensify cardiac depression caused by β blockers because both drugs decrease heart rate and cardiac conduction.

Beneficial effects of cevimeline can be antagonized by drugs that block muscarinic receptors. Among these are atropine, tricyclic antidepressants (e.g., imipramine), antihistamines (e.g., diphenhydramine), and phenothiazine antipsychotics (e.g., chlorpromazine).

Pilocarpine Pilocarpine is a muscarinic agonist used mainly for topical therapy of glaucoma, an ophthalmic disorder characterized by elevated intraocular pressure (IOP) with subsequent injury to the optic nerve. The basic pharmacology of pilocarpine and its use in glaucoma are discussed in Chapter 87. In addition to its use in glaucoma, oral pilocarpine is approved for treatment of dry mouth resulting from Sjögren syndrome or from salivary gland damage caused by radiation therapy of head and neck cancer. For these applications, pilocarpine is available under the trade name Salagen. It may also be given to manage dry mouth secondary to head and neck cancer. At lower doses, the principal adverse effect is sweating. However, if dosage is excessive, pilocarpine can produce the full spectrum of muscarinic effects.

Toxicology of Muscarinic Agonists Sources of Muscarinic Poisoning Muscarinic poisoning can result from overdose with two kinds of medications: (1) direct-acting muscarinic agonists (e.g., bethanechol, pilocarpine) and (2) indirect-acting cholinomimetics (e.g., cholinesterase inhibitors; discussed later). Muscarinic poisoning can also occur following ingestion of certain mushrooms (e.g., Inocybe and Clitocybe spp.).

Symptoms Manifestations of muscarinic poisoning result from excessive activation of muscarinic receptors. Prominent symptoms are (1) respiratory (bronchospasm and excessive bronchial secretions), (2) cardiovascular (bradycardia and hypotension), (3) GI (profuse salivation, nausea and vomiting, abdominal pain, diarrhea, and fecal incontinence), (4) genitourinary (excessive urination and urinary incontinence), (5) integumentary (diaphoresis), and (5) visual (lacrimation and miosis). Severe poisoning can produce cardiovascular collapse. (Mnemonics for muscarinic poisoning are presented in Box 13.1.)

Box 13.1

Muscarinic (Cholinergic) Toxicity Muscarinic (cholinergic) toxicity can be caused by either muscarinic agonists or cholinesterase inhibitors. Some common mnemonics can help you to identify this potentially dangerous condition.

Mnemonic 1: Dumbels Diaphoresis/Diarrhea Urination Miosis Bradycardia/Bronchospasm/Bronchorrhea Emesis Lacrimation Salivation

Mnemonic 2: Sludge and the Killer Bs Salivation Lacrimation Urination Diaphoresis/Diarrhea Gastrointestinal cramping Emesis Bradycardia Bronchospasm Bronchorrhea

Treatment Management is direct and specific: administer atropine (a selective muscarinic blocking agent) and provide supportive therapy. By blocking access of muscarinic agonists to their receptors, atropine can reverse most signs of toxicity.

Prototype Drugs Cholinergic Agents Muscarinic Agonists Bethanechol (Urecholine, Duvoid) Cholinesterase Inhibitors Pyridostigmine (Mestinon, Regonol) Muscarinic Antagonist Atropine (AtroPen, others)

Patient Education Muscarinic Agonists and Cholinesterase Inhibitors Advise patients to take these drugs 1 h before meals or 2 h after meals to decrease incidence of nausea and vomiting. Inform patients about manifestations of muscarinic excess and advise them to seek medical treatment if they occur.

Cholinesterase Inhibitors Cholinesterase inhibitors are drugs that prevent the degradation of acetylcholine by acetylcholinesterase (also known simply as cholinesterase). Cholinesterase inhibitors are also known as anticholinesterase drugs. By preventing the breakdown of acetylcholine, cholinesterase inhibitors increase the amount of acetylcholine available to activate receptors, thus enhancing cholinergic action. Because cholinesterase inhibitors do not bind directly with cholinergic receptors, they are viewed as indirect-acting cholinergic agonists. Use of cholinesterase inhibitors results in transmission at all cholinergic junctions (muscarinic, ganglionic, and neuromuscular), so these drugs can elicit a broad spectrum of responses. Because they lack selectivity, cholinesterase inhibitors are limited to only a few therapeutic applications: treatment of myasthenia gravis (MG), glaucoma, Alzheimer disease, Parkinson disease dementia, and poisoning by muscarinic antagonists. In specialty areas, they are used to reverse competitive (nondepolarizing) neuromuscular blockade. Applications of individual agents are

shown in Table 13.4. TABLE 13.4

aAlso used for Parkinson disease dementia.

IM, Intramuscular; IV, intravenous; PO, oral; subQ, subcutaneous.

There are two basic categories of cholinesterase inhibitors: (1) reversible inhibitors and (2) irreversible inhibitors. The reversible inhibitors produce effects of moderate duration, and the irreversible inhibitors produce effects of long duration.

Patient-Centered Care Across the Life Span Cholinesterase Inhibitors Life Stage

Considerations or Concerns

Childr en

Safety has not been established. As with all patients, benefits must be considered relative to risks.

Pregn When given for myasthenia gravis, cholinesterase inhibitors may be ant necessary during pregnancy and during labor. Neonatal myasthenia W gravis has occurred, but this effect is transient. om

en Breast It is unknown whether cholinesterase inhibitors are excreted in sufficient amounts in breast milk to cause harm to nursing infants. Of note, women fee with myasthenia gravis may have difficulty breast-feeding due to fatigue. din g W om en Older Older adults are the greatest recipients of cholinesterase inhibitors Ad prescribed for dementia associated with Alzheimer Disease. Doses may ult need lowered if renal function is decreased. s

Reversible Cholinesterase Inhibitors Pyridostigmine Pyridostigmine (Mestinon, Regonol) typifies the reversible cholinesterase inhibitors and will serve as our prototype for the group. Pyridostigmine is the drug of choice for management of MG. It is also approved for reversal of nondepolarizing muscle relaxants. Pyridostigmine contains a quaternary nitrogen atom and hence always carries a positive charge. Because of this charge, pyridostigmine cannot readily cross membranes, including those of the GI tract, blood–brain barrier, and placenta. Consequently, pyridostigmine is absorbed poorly after oral administration and has minimal effects on the brain and fetus. Mechanism of action. Pyridostigmine and the other reversible cholinesterase inhibitors act as substrates for cholinesterase. As indicated in Fig. 13.1, the normal function of cholinesterase is to break down acetylcholine into choline and acetic acid. (This process is called a hydrolysis reaction because of the water molecule involved.) The overall reaction between acetylcholine and cholinesterase is extremely fast. As a result, one molecule of cholinesterase can break down a huge amount of acetylcholine in a very short time.

FIG. 13.1

Hydrolysis of Acetylcholine by Cholinesterase.

The reaction between pyridostigmine and cholinesterase is much like the reaction between acetylcholine and cholinesterase. The only difference is that cholinesterase splits pyridostigmine more slowly than it splits acetylcholine. Hence, after pyridostigmine becomes bound to cholinesterase, the drug remains in place for a relatively long time. Because cholinesterase remains bound until it finally succeeds in degrading pyridostigmine, less cholinesterase is available to catalyze the breakdown of acetylcholine. As a result, more acetylcholine is available to activate cholinergic receptors. Pharmacologic effects. By decreasing breakdown of acetylcholine, pyridostigmine and the other cholinesterase inhibitors make more acetylcholine available, and this can intensify transmission at virtually all junctions where acetylcholine is the transmitter. In sufficient doses, cholinesterase inhibitors can produce skeletal muscle stimulation, ganglionic stimulation, activation of peripheral muscarinic receptors, and activation of cholinergic receptors in the central nervous system (CNS). However, when used therapeutically, cholinesterase inhibitors usually affect only muscarinic receptors on organs and nicotinic receptors of the NMJ. Ganglionic transmission and CNS function are usually unaltered. Muscarinic responses. Muscarinic effects of the cholinesterase inhibitors are identical to those of the direct-acting muscarinic agonists. By preventing breakdown of acetylcholine, cholinesterase inhibitors can cause bradycardia, bronchial constriction, urinary urgency, increased glandular secretions, increased tone and motility of GI smooth muscle, miosis, and focusing of the lens for near vision. Neuromuscular effects. The effects of cholinesterase inhibitors on skeletal muscle are dose dependent. At therapeutic doses, these drugs increase force of contraction. In contrast, toxic doses reduce force of contraction. Contractile force is reduced because excessive

amounts of acetylcholine at the NMJ keep the motor end plate in a state of constant depolarization, causing depolarizing neuromuscular blockade. Central nervous system effects. Effects on the CNS vary with drug concentration. Therapeutic levels can produce mild stimulation, whereas toxic levels depress the CNS, including the areas that regulate respiration. However, keep in mind that for CNS effects to occur, the inhibitor must first penetrate the blood–brain barrier, which some cholinesterase inhibitors can do only when present in very high concentrations. Pharmacokinetics. Pharmacokinetics of pyridostigmine and other cholinesterase inhibitors is provided in Table 13.5. TABLE 13.5

h, Hour(s); UK, unknown.

Preparation and dosage. Preparation and dosage of pyridostigmine and other cholinesterase inhibitors are provided in Table 13.6. TABLE 13.6

ER, Extended release; IM, intramuscular; IR, immediate release; IV, intravenous; subQ, subcutaneous.

Therapeutic uses. MG is a major indication for pyridostigmine and several other reversible cholinesterase inhibitors. Treatment of MG is discussed separately. Adverse effects Excessive muscarinic stimulation. Accumulation of acetylcholine at muscarinic receptors can result in excessive salivation, increased gastric secretions, increased tone and motility of the GI tract, urinary urgency, bradycardia, sweating, miosis, and spasm of accommodation (focusing of the lens for near vision). If necessary, these responses can be suppressed with atropine. Neuromuscular blockade. If administered in toxic doses, cholinesterase inhibitors can cause accumulation of acetylcholine in amounts sufficient to produce depolarizing neuromuscular blockade. Paralysis of the respiratory muscles can be fatal. Precautions and contraindications. Most of the precautions and contraindications regarding the cholinesterase inhibitors are the same as those for the direct-acting muscarinic agonists. These include obstruction of the GI tract, obstruction of the urinary tract, peptic ulcer

disease, asthma, coronary insufficiency, and hyperthyroidism. Drug interactions. The effects of cholinesterase inhibitors at muscarinic receptors are opposite to those of atropine (and all other muscarinic antagonists). Consequently, cholinesterase inhibitors can be used to overcome excessive muscarinic blockade caused by atropine. Conversely, atropine can be used to reduce excessive muscarinic stimulation caused by cholinesterase inhibitors.

Summary of Key Prescribing Considerations Pyridostigmine Therapeutic Goal: Treatment of myasthenia gravis Baseline Data: Heart rate, blood pressure, ECG. Determine the extent of neuromuscular dysfunction by assessing muscle strength, fatigue, ptosis, and ability to swallow. Monitoring: Heart rate, blood pressure. Recheck ECG if bradycardic or for patient reports of palpitations, chest pain, shortness of breath. Additionally, monitor and record (1) times of drug administration; (2) times at which fatigue occurs; (3) state of muscle strength, ptosis, and ability to swallow; and (4) signs of excessive muscarinic stimulation. Titrate dose based on these observations. Monitor for myasthenic crisis (extreme muscle weakness, paralysis of respiratory muscles), which can occur when cholinesterase inhibitor dosing is insufficient. Manage with respiratory support and increased dosage. (Be certain to distinguish myasthenic crisis from cholinergic crisis. This is done by observing for signs of excessive muscarinic stimulation, which will accompany cholinergic crisis but not myasthenic crisis.) Identifying High-Risk Patients: Cholinesterase inhibitors are contraindicated for patients with mechanical obstruction of the intestine or urinary tract. Exercise caution in patients with peptic ulcer disease, bradycardia, asthma, or hyperthyroidism. For patients with decreased renal function, start with low-dose therapy. Evaluating Therapeutic Effects: Assess for increased strength and muscle control.

Minimizing Adverse Effects: For minor effects, common nursing measures (e.g., adequate lighting to address decreased night vision due to miosis and more frequent linen changes to address discomfort due to sweating) are adequate. Cholinergic crisis can result from cholinesterase inhibitor overdose. Manifestations are skeletal muscle paralysis (from depolarizing neuromuscular blockade) and signs of excessive muscarinic stimulation (e.g., excessive salivation, sweating, bradycardia, urinary incontinence). Manage with mechanical ventilation and atropine.

Other Reversible Cholinesterase Inhibitors Neostigmine. Neostigmine (Bloxiverz, Prostigmin ) has pharmacologic effects much like those of other cholinesterase inhibitors. Because neostigmine carries a positive charge, the drug is poorly absorbed after oral administration; hence oral formulations have been discontinued in the United States, although they remain available in some other countries. After it is absorbed, neostigmine can reach sites of action at the NMJ and peripheral muscarinic receptors but it cannot cross the blood-brain barrier to affect the CNS. Neostigmine is widely available as a generic drug. Formulations marketed as branded drugs are not used interchangably. Prostigmin is approved in Canada for management of MG. Bloxiverz is used to reverse the actions of nondepolarizing neuromuscular blockade after surgery; however, this use is beyond the scope of this book. Physostigmine. The basic pharmacology of physostigmine is essentially the same as that of neostigmine. In contrast to neostigmine, physostigmine is not a quaternary ammonium compound and hence does not carry a charge. Because physostigmine is uncharged, physostigmine readily crosses membranes, whereas neostigmine does not. As a result of this important difference, although their pharmacology is the same, their uses are very different. Because physostigmine can cross the blood–brain barrier, it is the drug of choice for treating poisoning by atropine and other drugs that cause muscarinic blockade, including antihistamines and phenothiazine antipsychotics—but not

tricyclic antidepressants, owing to a risk for causing seizures and cardiotoxicity. Physostigmine counteracts antimuscarinic poisoning by causing acetylcholine to build up at muscarinic junctions. The accumulated acetylcholine competes with the muscarinic blocker for receptor binding and thereby reverses receptor blockade. Edrophonium. Edrophonium (Enlon, Tensilon ) has pharmacologic effects much like those of pyridostigmine. It is noteworthy for its very brief duration of action. Edrophonium is also unique in that it is indicated for diagnosis, but not treatment, of MG. In current practice, though, edrophonium is not commonly used for this purpose because better and more accurate testing is now available. Drugs for Alzheimer disease. Three cholinesterase inhibitors—donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon)—are approved for management of Alzheimer disease, and one of them—rivastigmine—is also approved for dementia of Parkinson disease. With all three, benefits derive from inhibiting cholinesterase in the CNS. The pharmacology of these drugs is discussed in Chapter 20.

Irreversible Cholinesterase Inhibitors The irreversible cholinesterase inhibitors have only one indication: treatment of glaucoma. For that indication, only one drug—echothiophate (Phospholine Iodide)—is available. The use of echothiophate for glaucoma is discussed in Chapter 87. The limited indications for irreversible cholinesterase inhibitors is in large part because these agents are highly toxic. During World War II, huge quantities of irreversible cholinesterase inhibitors were produced for possible use as nerve agents but were never deployed. Today, there is concern that these agents might be employed as weapons of terrorism.

Basic Pharmacology All irreversible cholinesterase inhibitors contain an atom of phosphorus. Because of this phosphorus atom, the irreversible inhibitors are known as organophosphate cholinesterase inhibitors. Almost all irreversible cholinesterase inhibitors are highly lipid soluble. As a

result, these drugs are readily absorbed from all routes of administration. They can even be absorbed directly through the skin. Easy absorption, coupled with high toxicity, is what makes these drugs good insecticides—and gives them potential as agents of chemical warfare. After they are absorbed, the organophosphate inhibitors have ready access to all tissues and organs, including the CNS. Mechanism of action. The irreversible cholinesterase inhibitors bind to the active center of cholinesterase, preventing the enzyme from hydrolyzing acetylcholine. Although these drugs can be split from cholinesterase, the splitting reaction is extremely slow. Hence, under normal conditions, their binding to cholinesterase can be considered irreversible. Because binding is irreversible, effects persist until new molecules of cholinesterase can be synthesized. Although we normally consider the bond between irreversible inhibitors and cholinesterase permanent, this bond can, in fact, be broken. To break the bond and reverse the inhibition of cholinesterase, we must administer pralidoxime, a cholinesterase reactivator. Pharmacologic effects. The irreversible cholinesterase inhibitors produce essentially the same spectrum of effects as the reversible inhibitors. The principal difference is that responses to irreversible inhibitors last a long time, whereas responses to reversible inhibitors are brief.

Toxicology of Cholinesterase Inhibitors Sources of Poisoning Poisoning by organophosphate cholinesterase inhibitors is a common occurrence. Cholinesterase inhibitors are employed primarily as insecticides. Agricultural workers have been poisoned by accidental ingestion of organophosphate insecticides and by absorption of these lipid-soluble compounds through the skin. In addition, because organophosphate insecticides are readily available to the public, poisoning may occur accidentally or from attempted homicide or suicide. As mentioned previously, exposure could also occur if these drugs were used as instruments of warfare or terrorism.

Symptoms Toxic doses of irreversible cholinesterase inhibitors produce excessive muscarinic, nicotinic, and CNS effects. This condition, known as a cholinergic crisis, is characterized by excessive muscarinic stimulation and depolarizing neuromuscular blockade. Overstimulation of muscarinic receptors results in profuse secretions from salivary and bronchial glands, involuntary urination and defecation, laryngospasm, and bronchoconstriction. Prominent nicotinic effects reflect nicotinic activity at NMJs, resulting in muscle weakness, fasciculations, cramps, and twitching. Neuromuscular blockade can result in paralysis, followed by death from apnea. CNS effects may range from anxiety and confusion to delirium. Convulsions of CNS origin precede paralysis and apnea.

Treatment Pharmacologic treatment involves giving atropine to reduce muscarinic stimulation, giving pralidoxime to reverse inhibition of cholinesterase (primarily at the NMJ), and giving a benzodiazepine such as diazepam to suppress convulsions. Respiratory depression from cholinesterase inhibitors cannot be managed with drugs. Rather, treatment consists of mechanical ventilation with oxygen. Pralidoxime. Pralidoxime is a specific antidote to poisoning by the irreversible (organophosphate) cholinesterase inhibitors; the drug is not effective against poisoning by reversible cholinesterase inhibitors. In poisoning by irreversible inhibitors, benefits derive from causing the inhibitor to dissociate from the active center of cholinesterase. Reversal is most effective at the NMJ. Pralidoxime is much less effective at reversing cholinesterase inhibition at muscarinic and ganglionic sites. Furthermore, because pralidoxime is a quaternary ammonium compound, it cannot cross the blood–brain barrier and therefore cannot reverse cholinesterase inhibition in the CNS. To be effective, pralidoxime must be administered soon after organophosphate poisoning has occurred.

Use of Cholinesterase Inhibitors in Practice: Myasthenia Gravis Pathophysiology

MG is a neuromuscular disorder characterized by fluctuating muscle weakness and a predisposition to rapid fatigue. Common symptoms include ptosis (drooping eyelids), difficulty swallowing, and weakness of skeletal muscles. Patients with severe MG may have difficulty breathing owing to weakness of the muscles of respiration. Symptoms of MG result from an autoimmune process in which the patient's immune system produces antibodies that attack nicotinicM receptors on skeletal muscle. As a result, the number of functional receptors at the NMJ is reduced by 70% to 90%, causing muscle weakness.

Treatment with Cholinesterase Inhibitors Beneficial effects. Reversible cholinesterase inhibitors (e.g., pyridostigmine) are the mainstay of therapy. By preventing acetylcholine inactivation, anticholinesterase agents can intensify the effects of acetylcholine released from motor neurons, increasing muscle strength. Cholinesterase inhibitors do not cure MG. Rather, they only produce symptomatic relief, so patients usually need therapy lifelong. When working with patients with MG, keep in mind that muscle strength may be insufficient to permit swallowing. Accordingly, you should assess the ability to swallow before prescribing oral medications. If the patient is unable to swallow water, parenteral medication must be substituted for oral medication. Side effects. Because cholinesterase inhibitors can inhibit acetylcholinesterase at any location, these drugs will cause acetylcholine to accumulate at muscarinic junctions as well as at NMJs. If muscarinic responses are excessive, atropine may be given to suppress them. However, atropine should not be employed routinely because the drug can mask the early signs (e.g., excessive salivation) of overdose with anticholinesterase agents. Dosage adjustment. In the treatment of MG, establishing an optimal dosage for cholinesterase inhibitors can be a challenge. Dose determination is accomplished by administering a small initial dose followed by additional small doses until an optimal level of muscle function has been achieved. Important signs of improvement include increased ease of swallowing and increased ability to raise

the eyelids. You can help establish a correct dosage by having the patient or family keep records of (1) times of drug administration, (2) times at which fatigue occurs, (3) the state of muscle strength before and after drug administration, and (4) signs of excessive muscarinic stimulation. To maintain optimal responses, patients must occasionally modify the dose themselves. To do this, they must be taught to recognize signs of undermedication (ptosis, difficulty in swallowing) and signs of overmedication (excessive salivation and other muscarinic responses). Patients may also need to modify a dose in anticipation of exertion. For example, they may find it necessary to take supplementary medication 30 to 60 minutes before activities such as eating or shopping. It is important to recognize that lack of clinical improvement with pyridostigmine may indicate either an underdose or overdose. It is important to monitor for signs of toxicity before increasing the dose.

Myasthenic Crisis and Cholinergic Crisis Myasthenic crisis. Patients who are inadequately medicated may experience myasthenic crisis, a state characterized by extreme muscle weakness caused by insufficient acetylcholine at the NMJ. Left untreated, myasthenic crisis can result in death from paralysis of the muscles of respiration. A cholinesterase inhibitor (e.g., neostigmine) is used to relieve the crisis. Cholinergic crisis. As noted previously, overdose with a cholinesterase inhibitor can produce cholinergic crisis. Like myasthenic crisis, cholinergic crisis is characterized by extreme muscle weakness or frank paralysis. In addition, cholinergic crisis is accompanied by signs of excessive muscarinic stimulation. Treatment consists of respiratory support plus atropine. The offending cholinesterase inhibitor should be withheld until muscle strength has returned. Distinguishing myasthenic crisis from cholinergic crisis. Because myasthenic crisis and cholinergic crisis share similar symptoms (muscle weakness or paralysis) but are treated very differently, it is essential to distinguish between them. A history of medication use or signs of excessive muscarinic stimulation are usually sufficient to permit a differential diagnosis. If

these clues are inadequate, the provider may elect to administer a challenging dose of edrophonium, an ultrashort-acting cholinesterase inhibitor. If edrophonium-induced elevation of acetylcholine levels alleviates symptoms, the crisis is myasthenic. Conversely, if edrophonium intensifies symptoms, the crisis is cholinergic. Because the symptoms of cholinergic crisis will be made even worse by edrophonium and could be life-threatening, atropine and oxygen should be immediately available whenever edrophonium is used for this test. For this reason, and because cholinergic crisis is relatively rare for patients with MG, the use of edrophonium for this purpose is controversial.

Patient Education Cholinesterase Inhibitors for Myasthenia Gravis • It may be helpful to take this drug before engaging in activities that create difficulty. Depending on the patient’s condition, this challenging activities may range from eating to carrying out activities of daily living to more strenuous tasks. • If a dose is missed, patients should, not take an extra dose the next time it is scheduled. Stress the importance of not taking more drug more than prescribed because high doses can cause serious complications. • Have the patient report difficulty breathing, drooling, vomiting, diarrhea, excessive sweating, or the new onset of other problems. • Because of the possibility of experiencing either myasthenic crisis or cholinergic crisis, patients with MG should keep a list of medications and dosages with them at all times. They should also be encouraged to wear a Medic Alert bracelet or some other form of identification to inform emergency medical personnel of their condition in the event that they become unable to communicate.

14

Muscarinic Antagonists Abstract The parasympathetic nervous system controls physiological responses of multiple body systems. Muscarinic antagonists (the most common type of anticholinergic drug) modulate these responses by blocking muscarinic receptors. These drugs have a wide range of both therapeutic and adverse effects. An understanding of the effects of muscarinic receptor stimulation can be used to predict the effects when those receptors are blocked, thus providing a foundation for safe practice when prescribing and managing conditions using these drugs.

Keywords anticholinergic drugs; muscarinic antagonists; antimuscarinic poisoning; atropine; overactive bladder

Introduction to Anticholinergic Drugs Anticholinergic drugs are agents that block the activity of cholinergic receptors. These drugs act directly at cholinergic receptors, where they block the actions of acetylcholine. There are three categories of anticholinergic drugs. These categories are muscarinic antagonists, ganglionic blocking agents, and neuromuscular blocking agents. Of the three, muscarinic antagonists are the most commonly used. Although muscarinic antagonist is the more specific term, these are more often called simply anticholinergic drugs. The muscarinic antagonists, represented by atropine, selectively block the effects of acetylcholine (and other muscarinic agonists) at muscarinic receptors. Ganglionic blocking agents selectively block ganglionic nicotinicN receptors.

Neuromuscular blocking agents selectively block the effects of acetylcholine at nicotinicM (muscle) receptors at the neuromuscular junction (NMJ). Ganglionic and neuromuscular blocking agents are used in specialty settings and are beyond the scope of this text. We recommend the same approach to learning muscarinic antagonists as we advised for the muscarinic agonists (Chapter 13). Table 14.1 is your key to understanding the anticholinergic drugs. It lists the three major subtypes of cholinergic receptors (muscarinic, nicotinicN, and nicotinicM) and indicates for each receptor type the (1) location, (2) responses to activation, (3) drugs that prevent activation (antagonists). This information, along with the detailed information on cholinergic receptor function summarized in Table 12.2 in Chapter 12, provides the information you need to predict the actions of anticholinergic drugs. TABLE 14.1

Patient-Centered Care Across the Life Span Anticholinergic Drugs Life Patient Care Concerns Stage Child Anticholinergics have a prominent role in the management of respiratory re conditions in childhood. Administration by inhalation decreases systemic n effects. There is no contraindication to systemic use due to age, but due to numerous adverse effects, benefits should be weighed against risk. Preg n

Oxybutynin is relatively safe when taken during pregnancy; however, due to a lack of sufficient animal studies and clinical trials, the full risk of most of

a nt w o m e n

these drugs is unknown. Caution is recommended with a strong consideration of whether benefits derived are worth potential risks.

Brea Anticholinergics may inhibit lactation in some women, resulting in decreased st production of breast milk. Due to a lack of studies, full risks of fe breastfeeding are unknown. If decisions to breastfeed are made, monitor e the infant to identify possible anticholinergic effects. di n g w o m e n Olde Anticholinergic drugs have been designated as potentially inappropriate for r use in geriatric patients. They can cause confusion, blurred vision, a tachycardia, urinary retention, and constipation. Many of these complicate d preexisting conditions (e.g., urinary retention secondary to benign ul prostatic hyperplasia) and increase the risk for other conditions (e.g., ts narrow-angle glaucoma risk secondary to pupil dilation and heat-related illness secondary to hyperthermia and impaired sweating mechanisms).

Prototype Drugs Anticholinergic Agents Muscarinic Antagonist Atropine (AtroPen, others)

Muscarinic Antagonists (Anticholinergic Drugs) Muscarinic antagonists competitively block the actions of acetylcholine at

muscarinic receptors. Because most muscarinic receptors are located on structures innervated by parasympathetic nerves, the muscarinic antagonists are also known as parasympatholytic drugs. Additional names for these agents are antimuscarinic drugs, muscarinic blockers, and anticholinergic drugs. The term anticholinergic can be a source of confusion and requires comment. This term is unfortunate in that it implies blockade at all cholinergic receptors. However, as normally used, the term anticholinergic only denotes blockade of muscarinic receptors. Therefore, when a drug is characterized as being anticholinergic, you can take this to mean that it produces selective muscarinic blockade—and not blockade of all cholinergic receptors. In this chapter, the terms muscarinic antagonist and anticholinergic agent are used interchangeably.

Atropine Atropine (AtroPen, others) is the best-known muscarinic antagonist and will serve as our prototype for the group. The actions of all other muscarinic blockers are much like those of this drug. Atropine is found naturally in a variety of plants, including Atropa belladonna (deadly nightshade) and Datura stramonium (also known as Jimson weed, stinkweed, and devil's apple). Because of its presence in A. belladonna, atropine is referred to as a belladonna alkaloid.

Mechanism of Action Atropine produces its effects through competitive blockade at muscarinic receptors. Like all other receptor antagonists, atropine has no direct effects of its own. Rather, all responses to atropine result from preventing receptor activation by endogenous acetylcholine (or by drugs that act as muscarinic agonists). At therapeutic doses, atropine produces selective blockade of muscarinic cholinergic receptors. However, if the dose is sufficiently high, the drug will produce some blockade of nicotinic receptors, too. It is important to note that not all muscarinic receptors are equally sensitive to blockade by atropine and most other anticholinergic drugs: at some sites, muscarinic receptors can be blocked with relatively low doses; whereas at other sites, much higher doses are needed. Table 14.2 indicates the sequence in which specific muscarinic receptors are blocked as the dose of atropine is increased. TABLE 14.2

aDoses of atropine that are high enough to dilate the bronchi or decrease gastric acid secretion

will also affect all other structures under muscarinic control. As a result, atropine and most other muscarinic antagonists are not very desirable for treating peptic ulcer disease or asthma.

Pharmacologic Effects Because atropine acts by causing muscarinic receptor blockade, its effects are opposite to those caused by muscarinic activation. Accordingly, we can readily predict the effects of atropine by knowing the normal responses to muscarinic receptor activation (see Table 12.2) and by knowing that atropine will reverse those responses. Like the muscarinic agonists, the muscarinic antagonists exert their influence primarily on the heart, exocrine glands, smooth muscles, and eyes. Heart. Atropine increases heart rate. Because activation of cardiac muscarinic receptors decreases heart rate, blockade of these receptors will cause heart rate to increase. Exocrine glands. Atropine decreases secretion from salivary glands, bronchial glands, sweat glands, and the acid-secreting cells of the stomach. Note that these effects are opposite to those of muscarinic agonists, which increase secretion from exocrine glands. Smooth muscle. By preventing activation of muscarinic receptors on smooth muscle, atropine

causes relaxation of the bronchi, decreased tone of the urinary bladder detrusor, and decreased tone and motility of the GI tract. In the absence of an exogenous muscarinic agonist (e.g., bethanechol), muscarinic blockade has no effect on vascular smooth muscle tone because there is no parasympathetic innervation to muscarinic receptors in blood vessels. Eyes. Blockade of muscarinic receptors on the iris sphincter causes mydriasis (dilation of the pupil). Blockade of muscarinic receptors on the ciliary muscle produces cycloplegia (relaxation of the ciliary muscle), thereby focusing the lens for far vision. Central nervous system. At therapeutic doses, atropine can cause mild CNS excitation. Toxic doses can cause hallucinations and delirium, which can resemble psychosis. Extremely high doses can result in coma, respiratory arrest, and death.

Pharmacokinetics Atropine may be administered topically (to the eye), and parenterally (IM, IV, and subQ routes). The drug is rapidly absorbed after administration and distributes to all tissues, including the CNS. Peak effect occurs in 30 minutes to an hour. Atropine has a half-life of approximately 3 hours but may be as long as 10 to 17 hours in older patients. Elimination is by a combination of hepatic metabolism and urinary excretion.

Therapeutic Uses Except for ophthalmic formulations, atropine is used short term (typically one dose or repeated dosing within a short period of time). It is approved for use prior to surgery, as an antidote to anticholinesterase poisoning, and for treatment of sinus bradycardia and atrioventricular (AV) block. It may be used off-label to treat other conditions; these are discussed next. Preanesthetic medication. The cardiac effects of atropine can help during surgery. Procedures that stimulate baroreceptors of the carotid body can initiate reflex slowing of the heart, resulting in profound bradycardia. Because this reflex is mediated by muscarinic

receptors on the heart, pretreatment with atropine can prevent a dangerous reduction in heart rate. Certain anesthetics irritate the respiratory tract and thereby stimulate secretion from salivary, nasal, pharyngeal, and bronchial glands. If these secretions are sufficiently profuse, they can interfere with respiration. By blocking muscarinic receptors on secretory glands, atropine can help prevent excessive secretions. Fortunately, modern anesthetics are much less irritating. The availability of these new anesthetics has greatly reduced the use of atropine for this purpose during anesthesia. Disorders of the eyes. By blocking muscarinic receptors in the eyes, atropine can cause mydriasis and paralysis of the ciliary muscle. Both actions can be of help during eye examinations and ocular surgery. The ophthalmic uses of atropine and other muscarinic antagonists are discussed in Chapter 87. Bradycardia. Atropine can accelerate heart rate in certain patients with bradycardia. Heart rate is increased because blockade of cardiac muscarinic receptors reverses parasympathetic slowing of the heart. Intestinal hypertonicity and hypermotility. By blocking muscarinic receptors in the intestine, atropine can decrease both the tone and motility of intestinal smooth muscle. This can be beneficial in conditions characterized by excessive intestinal motility, such as mild dysentery and diverticulitis. When taken for these disorders, atropine can reduce both the frequency of bowel movements and associated abdominal cramps. Peptic ulcer disease. Because it can suppress secretion of gastric acid, atropine has been used to treat peptic ulcer disease. Unfortunately, when administered in doses that are strong enough to block the muscarinic receptors that regulate secretion of gastric acid, atropine also blocks most other muscarinic receptors (see Table 14.2). Therefore, the use of atropine in treatment of ulcers is associated with a broad range of antimuscarinic side effects (dry mouth, blurred vision, urinary retention, constipation, and so on). Because of these side effects, atropine is reserved for rare cases in which symptoms cannot be relieved with preferred medications

(e.g., antibiotics, histamine-2 receptor antagonists, proton pump inhibitors). Asthma. By blocking bronchial muscarinic receptors, atropine can promote bronchial dilation, thereby improving respiration in patients with asthma. Unfortunately, in addition to dilating the bronchi, atropine also causes drying and thickening of bronchial secretions—effects that can be harmful to patients with asthma. Furthermore, when given in the doses needed to dilate the bronchi, atropine causes a variety of antimuscarinic side effects (see Table 14.2). Because of the potential for harm, and because superior medicines are available, atropine is rarely used for asthma. Biliary colic. Biliary colic is characterized by intense abdominal pain brought on by passage of a gallstone through the bile duct. In some cases, atropine may be combined with analgesics such as morphine to relax biliary tract smooth muscle, thereby helping alleviate discomfort. Muscarinic agonist poisoning. As mentioned in Chapter 13, atropine is a specific antidote to poisoning by agents that activate muscarinic receptors. By blocking muscarinic receptors, atropine can reverse all signs of muscarinic poisoning. An atropine autoinjector (Atropen) is approved for use in people exposed to the irreversible cholinesterase inhibitor nerve agents or insecticides discussed previously (Box 14.1). Box 14.1

AtroPen for Cholinesterase Inhibitor Poisoning The AtroPen is a prefilled autoinjector indicated for intramuscular treatment of poisoning with an organophosphate cholinesterase inhibitor (nerve agent or insecticide). Four strengths are available: 0.25 and 0.5 mg (for children weighing <40 pounds), 1 mg (for children 40–90 pounds), and 2 mg (for adults and children >90 pounds). The AtroPen should be used immediately on exposure or if exposure is strongly suspected. Injections are administered into the lateral thigh, directly through clothing, if necessary.

Dosing is determined by symptom severity and weight. Dose by weight is as follows: • <6.8 kg (<15 lb): administer 0.25 mg/dose • 6.8–18 kg (15–40 lb): administer 0.5 mg/dose • 18–41 kg (40–90 lb): administer 1 mg/dose • >41 kg (>90 lb): administer 2 mg/dose Multiple doses are often required. If symptoms are severe, three weightbased doses should be administered rapidly. If symptoms are mild, one dose should be given; if severe symptoms develop afterward, additional doses can be given up to a maximum of three doses.

Adverse Effects Most adverse effects of atropine and other anticholinergic drugs are the direct result of muscarinic receptor blockade. Accordingly, these effects can be predicted from your knowledge of muscarinic receptor function. Xerostomia. Blockade of muscarinic receptors on salivary glands can inhibit salivation, thereby causing dry mouth. Not only is this uncomfortable; it also can impede swallowing and can promote tooth decay, gum problems, and oral infections. Patients should be informed that dryness can be alleviated by sipping fluids, chewing sugar-free gum, and using salivary stimulants (citrus-flavored or tart sugarless candies, maltose lozenges). If these do not provide adequate relief, oral moisturizers (saliva substitutes) such as Biotene dry mouth spray and XyliMelts are available over-the-counter. Owing to increased risk for tooth decay, patients should avoid sugary gum and hard candy. Blurred vision and photophobia. The blockade of muscarinic receptors on the ciliary muscle and the sphincter of the iris can paralyze these muscles. Paralysis of the ciliary muscle focuses the eye for far vision, causing nearby objects to appear blurred. Patients should be forewarned about this effect and advised to avoid hazardous activities if vision is impaired. In addition, paralysis of the iris sphincter prevents constriction of the pupil,

thereby rendering the eye unable to adapt to bright light. Patients should be advised to wear dark glasses if photophobia is a problem. Room lighting for hospitalized patients should be kept low. Elevation of intraocular pressure. Paralysis of the iris sphincter can raise IOP by a mechanism discussed in Chapter 87. Because they can increase IOP, anticholinergic drugs are contraindicated for patients with glaucoma, a disease characterized by abnormally high IOP. In addition, these drugs should be used with caution in patients who may not have glaucoma per se but for whom a predisposition to glaucoma may be present. Urinary retention. Blockade of muscarinic receptors in the urinary tract reduces pressure within the bladder and increases the tone of the urinary sphincter and trigone. These effects can produce urinary hesitancy or urinary retention. In the event of severe urinary retention, catheterization or treatment with a muscarinic agonist (e.g., bethanechol) may be required. Patients should be advised that urinary retention can be minimized by voiding just before taking their medication. Constipation. Muscarinic blockade decreases the tone and motility of intestinal smooth muscle. The resultant delay in transit through the intestine can produce constipation. Patients should be informed that constipation can be minimized by increasing dietary fiber, fluids, and physical activity. A laxative may be needed if constipation is severe. Because of their ability to decrease smooth muscle tone, muscarinic antagonists are contraindicated for patients with intestinal atony, a condition in which intestinal tone is already low. Anhidrosis. Blockade of muscarinic receptors on sweat glands can produce anhidrosis (a deficiency or absence of sweat). Because sweating is necessary for cooling, people who cannot sweat are at risk for hyperthermia. Patients should be warned of this possibility and advised to avoid activities that might lead to overheating (e.g., exercising on a hot day). Tachycardia. Blockade of cardiac muscarinic receptors eliminates parasympathetic influence

on the heart. By removing the “braking” influence of parasympathetic nerves, anticholinergic agents can cause tachycardia. Exercise caution in patients with preexisting tachycardia. Asthma. In patients with asthma, antimuscarinic drugs can cause thickening and drying of bronchial secretions and can thereby cause bronchial plugging. Consequently, although muscarinic antagonists can be used to treat asthma, they can also do harm.

Drug Interactions Several drugs that are not classified as muscarinic antagonists can nonetheless produce significant muscarinic blockade. Among these are antihistamines, phenothiazine antipsychotics, and tricyclic antidepressants. Because of their prominent anticholinergic actions, these drugs can greatly enhance the antimuscarinic effects of atropine and related agents. Accordingly, it is wise to avoid combined use of atropine with other drugs that can cause muscarinic blockade.

Summary of Key Prescribing Considerations Atropine Therapeutic Goal: Treatment of bradycardia or atrioventricular block, antidote to anticholinesterase poisoning, or as a preanesthetic medication. Baseline Data: Heart rate, blood pressure, ECG. Monitoring: Heart rate, blood pressure. Recheck ECG for patient reports of palpitations or chest pain. Identifying High-Risk Patients: Exercise caution with patients with non-bradycardic dysrhythmias, especially tachydysrhythmias, and in patients with myocardial ischemia. May precipitate acute glaucoma. May precipitate a myasthenic crisis in patients with MG. Can cause urinary retention, especially in patients with benign prostatic hyperplasia. Evaluating Therapeutic Effects: Depending on purpose of administration, restoration of normal sinus rhythm, prevention of

anesthetic or surgical associated complications,reversal of anticholinesterase poisoning. Minimizing Adverse Effects: Treat dry mouth with fluids, saliva stimulants (sour or tart candies, sugar-free chewing gum), and oral moisturizers. Manage photophobia with reduced lighting or sunglasses. Void prior to taking medication to decrease incidence of urinary retention. Be prepared for catheter insertion, if necessary.

Other Muscarinic Antagonists Scopolamine Scopolamine is an anticholinergic drug with actions much like those of atropine, but with two exceptions. First, whereas therapeutic doses of atropine produce mild CNS excitation, therapeutic doses of scopolamine produce sedation. And second, scopolamine suppresses emesis and motion sickness, whereas atropine does not. Principal uses for scopolamine are motion sickness (see Chapter 66), production of cycloplegia and mydriasis for ophthalmic procedures (see Chapter 87), and production of preanesthetic sedation and obstetric amnesia.

Ipratropium Bromide Ipratropium (Atrovent) is an anticholinergic drug used to treat asthma, COPD, and rhinitis caused by allergies or the common cold. The drug is administered by inhalation for asthma and COPD and by nasal spray for rhinitis. Systemic absorption is minimal for both formulations. As a result, therapy is not associated with typical antimuscarinic side effects (dry mouth, blurred vision, urinary hesitancy, constipation, and so forth). Ipratropium is discussed fully in Chapter 62.

Dicyclomine Dicyclomine (Bentyl, Bentylol) is indicated for irritable bowel syndrome (spastic colon, mucous colitis). It is also used for functional bowel disorders such as diarrhea and hypermotility.

Antisecretory Anticholinergics Muscarinic blockers can be used to suppress gastric acid secretion in patients

with peptic ulcer disease. However, because superior antiulcer drugs are available, and because anticholinergic agents produce significant side effects, most of these drugs have been withdrawn. Today, only four agents— glycopyrrolate (Robinul, Cuvposa), mepenzolate (Cantil), methscopolamine (Pamine), and propantheline (generic)—remain on the market. Glycopyrrolate oral solution (Cuvposa) is also approved for reducing severe drooling in children with chronic severe neurologic disorders. The drug is also approved for reducing salivation caused by anesthesia. Although it was originally approved as an adjunct in treatment of peptic ulcer disease, it is no longer indicated for this purpose.

Mydriatic Cycloplegics Five muscarinic antagonists—atropine, homatropine, scopolamine, cyclopentolate, and tropicamide—are employed to produce mydriasis and cycloplegia in ophthalmic procedures. These applications are discussed in Chapter 87.

Centrally Acting Anticholinergics Several anticholinergic drugs, including benztropine (Cogentin) and trihexyphenidyl, are used to treat Parkinson disease and drug-induced parkinsonism. Benefits derive from blockade of muscarinic receptors in the CNS. The centrally acting anticholinergics and their use in Parkinson disease are discussed in Chapter 19.

Use of Muscarinic Antagonists in Practice: Overactive Bladder Pathophysiology Overactive bladder (OAB)—also known as urgency incontinence—is a disorder with four major symptoms: urinary urgency (a sudden, compelling desire to urinate), urinary frequency (voiding 8 or more times in 24 hours), nocturia (waking 2 or more times to void), and urge incontinence (involuntary urine leakage associated with a strong urge to void). In most cases, urge incontinence results from involuntary contractions of the bladder detrusor (the smooth muscle component of the bladder wall). These contractions are often referred to as detrusor instability or detrusor overactivity. Urge incontinence should not be

confused with stress incontinence, defined as involuntary urine leakage caused by activities (e.g., exertion, sneezing, coughing, laughter) that increase pressure within the abdominal cavity, or overflow incontinence, which is the involuntary leakage of urine from an overly distended bladder. OAB is a common disorder, affecting up to one-third of Americans. The condition can develop at any age but is most prevalent in older populations. Among people ages 40 to 44 years, symptoms are reported by 3% of men and 9% of women. In comparison, among those 75 years and older, symptoms are reported by 42% of men and 31% of women. Because urine leakage, the most disturbing symptom, is both unpredictable and potentially embarrassing, many people with OAB curtail travel, social activities, and even work.

Treatment OAB has two primary modes of treatment: behavioral therapy and drug therapy (Fig. 14.1). Behavioral therapy, which is at least as effective as drug therapy and lacks side effects, should be tried first. Behavioral interventions include scheduled voiding, timing fluid intake, doing Kegel exercises (to strengthen pelvic floor muscles), and avoiding caffeine, a diuretic that may also increase detrusor activity. As a rule, drugs should be reserved for patients who don't respond adequately to behavioral measures. If behavioral therapy and drugs are inadequate, a provider may offer specialized treatments (e.g., sacral neuromodulation, peripheral tibial nerve stimulation).

Algorithm for Management of Overactive Bladder. OAB, Overactive bladder. (From the American Urologic Association. Available at: FIG. 14.1

https://www.auanet.org/Documents/education/clinical-guidance/OAB-Algorithm.pdf.)

When drug therapy is indicated, anticholinergic agents (e.g., oxybutynin, tolterodine) are indicated. These drugs block muscarinic receptors on the bladder detrusor and thereby inhibit bladder contractions and the urge to void. Unfortunately, drugs that block muscarinic receptors in the bladder can also block muscarinic receptors elsewhere and cause the typical anticholinergic side effects previously described. Anticholinergic side effects can be reduced in at least three ways: (1) using long-acting formulations, (2) using drugs that don't cross the blood–brain barrier, and (3) using drugs that are selective for muscarinic receptors in the bladder. Long-acting formulations (e.g., extendedrelease [ER] capsules, transdermal patches) reduce side effects by providing a steady but relatively low level of drug, thereby avoiding the high peak levels that can cause intense side effects. Drugs that can't cross the blood–brain barrier are unable to cause CNS effects. What about drugs that are selective for muscarinic receptors in the bladder?

To answer this question, we must first discuss muscarinic receptor subtypes. As noted in Chapter 12, there are five known muscarinic receptor subtypes. However, only three—designated M1, M2, and M3—have clearly identified functions. Locations of these receptor subtypes, and responses to their activation and blockade, are shown in Table 14.3. As indicated, M3 receptors are the most widely distributed, being found in salivary glands, the bladder detrusor, GI smooth muscle, and the eyes. M2 receptors are found only in the heart and M1 receptors are found in salivary glands and the CNS. At each location, responses to receptor activation are the same as we discussed in Chapter 12—although, in that chapter, we didn't identify the receptors by subtype; rather, we called all of them muscarinic. TABLE 14.3

CNS, Central nervous system; GI, gastrointestinal.

With this background, we can consider how receptor selectivity might decrease anticholinergic side effects of drugs for OAB. To be beneficial, an anticholinergic agent must block muscarinic receptors in the bladder detrusor. That is, it must block the M3 receptor subtype. Because M3 receptors are also found in GI smooth muscle, the eyes, and salivary glands, an M3-selective blocker will still have some unwanted anticholinergic effects—namely, constipation (from reducing bowel motility), blurred vision and photophobia (from preventing contraction of the ciliary muscle and iris sphincter), dry eyes (from blocking tear production), and some degree of dry mouth (from blocking salivary gland M3 receptors, while sparing salivary M1 receptors). What an M3-

selective blocker will not do is cause tachycardia (because muscarinic receptors in the heart are the M2 type) or impairment of CNS function (because muscarinic receptors in the brain are primarily the M1 type).

Specific Anticholinergic Drugs for Overactive Bladder In the United States, six anticholinergic drugs are approved specifically for OAB (Table 14.4). All six work by M3-muscarinic receptor blockade, although most block M1 and M2 receptors as well. With all of these drugs, we want sufficient M3 blockade to reduce symptoms of OAB, but not so much as to cause urinary retention. You should be aware that responses to these agents are relatively modest and, for many patients, only slightly better than a placebo. None of the anticholinergics used for OAB are clearly superior to the others. However, if one anticholinergic fails to reduce symptoms, success may occur with a different anticholinergic approved for OAB. TABLE 14.4

aTitrate dose upward as needed and tolerated. bFor patients with severe renal impairment, decrease dosage to 20 mg once daily at bedtime.

ER, Extended release; IR, immediate release.

Of note, in 2012, the FDA approved mirabegron (Myrbetriq), a β3 agonist, for management of OAB. It has not demonstrated increased efficacy compared to anticholinergics, and it may be cost-prohibitive for many patients; however, it remains an alternative for patients who should not take anticholinergics or for whom anticholinergic side effects are intolerable. It may also be added to an anticholinergic regimen as an OAB management option (β agonists are discussed in Chapter 15). Oxybutynin.

Oxybutynin (Ditropan XL, Gelnique, Oxytrol) is an anticholinergic agent that acts primarily at M3 muscarinic receptors. The drug is approved only for OAB. Benefits derive from blocking M3 receptors on the bladder detrusor. Oxybutynin is available in five formulations. Two are short acting (syrup and immediate-release [IR] tablets), and three are long acting (transdermal patch, topical gel, and ER tablets). The short-acting formulations have a short half-life (2 to 3 hours), and hence multiple daily doses are required. Another disadvantage of the IR formulation is that side effects are more intense. For these reasons, most patients prefer long-acting formulations of the drug. Dosing of oxybutynin and other drugs for OAB is provided in Table 14.4. Pharmacokinetics of anticholinergic drugs for OAB are provided in Table 14.5. TABLE 14.5

aLonger half-life characteristic of poor metabolizers.

IR, Immediate release; ER, extended release; h, hour(s).

Anticholinergic side effects are common. The incidence of dry mouth is very high, in part because of muscarinic blockade by oxybutynin itself, and in part because of blockade by N-desethyloxybutynin. Other common side effects include constipation, tachycardia, urinary hesitancy, urinary retention, mydriasis, blurred vision, and dry eyes. In the CNS, cholinergic blockade can result in confusion, hallucinations, insomnia, and nervousness. In postmarketing reports of CNS effects, hallucinations and agitation were prominent among reports involving pediatric patients, whereas hallucinations, confusion, and sedation were prominent among reports involving older-adult patients. The combined use of oxybutynin with other anticholinergic agents (e.g., antihistamines, tricyclic

antidepressants, phenothiazine antipsychotics) can intensify all anticholinergic side effects. Drugs that inhibit or induce CYP3A4 may alter oxybutynin blood levels and may thereby either increase toxicity (inhibitors of CYP3A4) or reduce effectiveness (inducers of CYP3A4). Darifenacin. Of the anticholinergic agents used for OAB, darifenacin (Enablex) displays the greatest degree of M3 selectivity. As a result, the drug can reduce OAB symptoms while having no effect on M1 receptors in the brain or M2 receptors in the heart. However, darifenacin does block M3 receptors outside the bladder, so it can still cause dry mouth, constipation, and other M3-related effects. Clinical benefits are similar to those of oxybutynin and tolterodine. On average, treatment reduces episodes of urge incontinence from 15/week down to 7/week (using 7.5 mg/day) and from 17/week down to 6/week (using 15 mg/day). Darifenacin is relatively well tolerated. The most common side effect is dry mouth. Constipation is also common. Other adverse effects include dyspepsia, gastritis, and headache. Darifenacin has little or no effect on memory, reaction time, word recognition, or cognition. The drug does not increase heart rate. Levels of darifenacin can be raised significantly by strong inhibitors of CYP3A4. Among these are azole antifungal drugs (e.g., ketoconazole, itraconazole), certain protease inhibitors used for HIV/AIDS (e.g., ritonavir, nelfinavir), and clarithromycin (a macrolide antibiotic). If darifenacin is combined with any of these, its dosage must be kept low. In patients with moderate liver impairment and in those taking powerful inhibitors of CYP3A4, doses should be kept low. In patients with severe liver impairment, darifenacin should be avoided. Solifenacin. Solifenacin (VESIcare) is very similar to darifenacin, although it's not quite as M3 selective. In clinical trials, the drug reduced episodes of urge incontinence from 18/week down to 8/week (using 5 mg/day) and from 20/week down to 8/week (using 10 mg/day). The most common adverse effects are dry mouth, constipation, and blurred vision. Dyspepsia, urinary retention, headache, and nasal dryness occur

infrequently. Rarely, solifenacin has caused potentially fatal angioedema of the face, lips, tongue, and larynx. At high doses (10 to 30 mg/day), solifenacin can prolong the QT interval, thereby posing a risk for a fatal dysrhythmia. Accordingly, caution is needed in patients with a history of QT prolongation and in those taking other QT-prolonging drugs. As with darifenacin, levels of solifenacin can be increased by strong inhibitors of CYP3A4 (e.g., ketoconazole, ritonavir, clarithromycin). Solifenacin should be swallowed intact with liquid. Dosing may be done with or without food. For patients with moderate hepatic impairment or severe renal impairment, and for those taking a powerful CYP3A4 inhibitor, dosage should not exceed 5 mg/day. For patients with severe hepatic impairment, solifenacin should be not be used. Tolterodine. Tolterodine (Detrol, Detrol LA) is a nonselective muscarinic antagonist approved only for OAB. Like oxybutynin, tolterodine is available in short- and long-acting formulations. Anticholinergic side effects are less intense with the long-acting form. Anticholinergic side effects with tolterodine affect fewer patients compared with other anticholinergics prescribed for OAB. For example, dry mouth occurs in 35% of patients taking IR tolterodine versus 70% with IR oxybutynin. At a dose of 2 mg twice daily, the most common side effects are dry mouth, constipation, and dry eyes. Effects on the CNS—somnolence, vertigo, dizziness —occur infrequently. The incidence of both tachycardia and urinary retention is less than 1%. Anticholinergic effects can be intensified by concurrent use of other drugs with anticholinergic actions (e.g., antihistamines, tricyclic antidepressants, phenothiazine antipsychotics). Drugs that inhibit CYP3A4 (e.g., erythromycin, ketoconazole) can raise levels of tolterodine and can thereby intensify beneficial and adverse effects. In addition to its anticholinergic effects, tolterodine can prolong the QT interval and can thereby promote serious cardiac dysrhythmias. Because of this risk, dosage should not exceed 4 mg/day. Fesoterodine. Fesoterodine (Toviaz) is a nonselective muscarinic antagonist very similar to tolterodine. Both fesoterodine and tolterodine are used only for OAB, and at a dosage of 4 mg/day, both are equally effective. Furthermore, both agents undergo

conversion to the same active metabolite—5-hydroxymethyl tolterodine—which is later inactivated by CYP3A4 and CYP2D6. In patients taking a strong inhibitor of CYP3A4 (e.g., ketoconazole, clarithromycin), beneficial and adverse effects are increased. Conversely, in patients taking a strong inducer of CYP3A4 (e.g., rifampin, carbamazepine), beneficial and adverse effects are reduced. As with tolterodine, the most common side effect is dry mouth. Another common side effect is constipation. Less common side effects include dizziness, fatigue, and blurred vision. Unlike tolterodine, fesoterodine has not been associated with QT prolongation and hence probably does not pose a risk for dysrhythmia. Trospium. Trospium (Sanctura XR, Trosec ) is a nonselective muscarinic blocker indicated only for OAB. Compared with other drugs for OAB, trospium is notable for its low bioavailability, lack of CNS effects, and lack of metabolismrelated interactions with other drugs. Trospium IR tablets (Trosec) reduce episodes of urge incontinence from 27/week down to 12/week (compared with 30/week down to 16/week with placebo). Reductions in urinary frequency are minimal. Trospium is generally well tolerated. The most common side effects are dry mouth and constipation. Rarely, the drug causes dry eyes and urinary retention. Trospium is a quaternary ammonium compound. Owing to its positive charge, trospium cannot cross the blood–brain barrier and hence is devoid of CNS effects. Few studies of drug interactions have been done. However, because trospium is eliminated by the kidneys, we can assume it may compete with other drugs that undergo renal tubular excretion. Among these are vancomycin (an antibiotic), metformin (used for diabetes), and digoxin and procainamide (both used for cardiac disorders). Because trospium is not metabolized by CYP enzymes, the drug is unlikely to influence the hepatic metabolism of other agents.

Patient Education Muscarinic Antagonists • Teach patients that dry mouth can be relieved by sipping fluids, chewing sugar-free gum, treating the mouth with a saliva substitute, and using an

alcohol-free mouthwash. Owing to increased risk for tooth decay, advise patients to avoid sugared gum, hard candy, and cough drops. • Because these drugs can cause blurred vision, advise patients to avoid hazardous activities if vision is impaired. Recommend wearing sunglasses to decrease discomfort due to glare and excessive light related to pupil dilation. Indoors, lights may need to be turned down. • Advise patients that urinary retention can be minimized by voiding just before taking anticholinergic medication. • Counsel patients that constipation can be reduced by increasing dietary fiber and fluids and can be treated with a laxative if severe. Reinforce the need for adequate fluids if fiber supplements are taken to avoid worsening constipation. • Caution patients to avoid vigorous exercise in warm environments to prevent hyperthermia. Heat-related illness is a particular concern in older patients taking anticholinergic drugs.

Toxicology of Muscarinic Antagonists Sources of Antimuscarinic Poisoning Sources of poisoning include natural products (e.g., A. belladonna, D. stramonium) and selective antimuscarinic drugs (e.g., atropine, scopolamine). Drugs with pronounced antimuscarinic properties (e.g., antihistamines, phenothiazines, tricyclic antidepressants) can also cause toxicity.

Symptoms Symptoms of antimuscarinic poisoning, which are the direct result of excessive muscarinic blockade, include dry mouth, blurred vision, photophobia secondary to mydriasis, hyperthermia, CNS effects (hallucinations, delirium), and skin that is hot, dry, and flushed. Death results from respiratory depression secondary to blockade of cholinergic receptors in the brain. (See Box 14.2 for a mnemonic to help you remember antimuscarinic poisoning.) Box 14.2

Antimuscarinic (Anticholinergic) Toxicity A mnemonic is commonly used to remember the signs and symptoms of antimuscarinic (anticholinergic) toxicity. Hot as a hare (hyperthermia) Dry as a bone (dry eyes, dry mouth, dry skin) Red as a beet (flushed face) Blind as a bat (mydriasis) Mad as a hatter (delirium)

Treatment Treatment consists of (1) minimizing intestinal absorption of the antimuscarinic agent and (2) administering an antidote. Minimizing absorption is accomplished by administering activated charcoal, which will adsorb the poison within the intestine, thereby preventing its absorption into the blood. The most effective antidote to antimuscarinic poisoning is physostigmine, an inhibitor of acetylcholinesterase. By inhibiting cholinesterase, physostigmine causes acetylcholine to accumulate at all cholinergic junctions. As acetylcholine builds up, it competes with the antimuscarinic agent for receptor binding, thereby reversing excessive muscarinic blockade.

Warning It is important to differentiate between antimuscarinic poisoning, which often resembles psychosis (hallucinations, delirium), and an actual psychotic episode. We need to make the differential diagnosis because some antipsychotic drugs have antimuscarinic properties of their own and hence will intensify symptoms if given to a victim of antimuscarinic poisoning. Fortunately, because a true psychotic episode is not ordinarily associated with signs of excessive muscarinic blockade (dry mouth, hyperthermia, dry skin, and so forth), differentiation is not usually difficult.

Summary of Key Prescribing Considerations Atropine and Other Muscarinic Antagonists

Assessment Therapeutic Goal Atropine has many applications, including treatment of bradycardia, biliary colic, intestinal hypertonicity and hypermotility, and muscarinic agonist poisoning.

Identifying High-Risk Patients Atropine and other muscarinic antagonists are contraindicated for patients with glaucoma, intestinal atony, urinary tract obstruction, and tachycardia. Use with caution in patients with asthma.

Administration Considerations Dry mouth from muscarinic blockade may interfere with swallowing. Advise patients to moisten the mouth by sipping water before oral administration.

Ongoing Monitoring and Interventions Minimizing Adverse Effects Xerostomia Decreased salivation can dry the mouth. Common interventions such as sipping fluids frequently, chewing gum, and sucking on hard candies will usually alleviate symptoms. Saliva substitutes are available for severe cases. Blurred Vision Paralysis of the ciliary muscle may reduce visual acuity. Patients should not participate in activities such as driving where good vision is necessary. Photophobia Muscarinic blockade prevents the pupil from constricting in response to bright light. Keep room lighting low to reduce visual discomfort. Sunglasses are often required. Urinary Retention Muscarinic blockade in the urinary tract can cause urinary hesitancy or retention. If urinary retention is severe, catheterization or treatment with bethanechol (a muscarinic agonist) may be required. Keep in mind, however, that a muscarinic agonist will also counteract positive effects of anticholinergics. Constipation Reduced tone and motility of the gut may cause constipation. Increasing

fluids, fiber, and activity will be helpful. Hyperthermia Suppression of sweating may result in hyperthermia. Tachycardia Blockade of cardiac muscarinic receptors can accelerate heart rate. Monitor pulse and report significant increases. Minimizing Adverse Interactions Antihistamines, tricyclic antidepressants, and phenothiazines have prominent antimuscarinic actions. Combining these agents with atropine and other anticholinergic drugs can cause excessive muscarinic blockade.

Management of Acute Toxicity Symptoms Overdose produces dry mouth, blurred vision, photophobia, hyperthermia, hallucinations, and delirium; the skin becomes hot, dry, and flushed. Differentiate muscarinic antagonist poisoning from psychosis! Treatment Treatment centers on limiting absorption of ingested poison (e.g., by giving activated charcoal to adsorb the drug) and administering physostigmine, an inhibitor of acetylcholinesterase.

15

Adrenergic Agonists Abstract Adrenergic agonists are some of our most important drugs. They have a wide range of uses from management of common annoyances such as nasal congestion to life-threatening conditions such as shock. Because they activate the same adrenergic receptors as endogenous neurotransmitters, their therapeutic and adverse effects can be easily predicted. Thus, a sound knowledge of the physiological effects of sympathetic nervous system stimulation provides a strong foundation for safe practice when prescribing and managing conditions using these drugs.

Keywords adrenergic agonists; adrenergic receptors; catecholamines; alpha1; alpha2; beta1; beta2; receptor specificity Adrenergic agonists produce their effects by activating adrenergic receptors. Because the sympathetic nervous system acts through these same receptors, responses to adrenergic agonists and responses to stimulation of the sympathetic nervous system are very similar. Because of this similarity, adrenergic agonists are often referred to as sympathomimetics. They have a broad spectrum of indications, ranging from heart failure to asthma to preterm labor. Learning about adrenergic agonists can be a challenge. To facilitate the process, our approach to these drugs has four stages. We begin with the general mechanisms by which drugs can activate adrenergic receptors. Next, we establish an overview of the major adrenergic agonists, focusing on their receptor specificity and chemical classification. Then we address the adrenergic receptors themselves; for each receptor type—α1, α2, β1, β2, and dopamine—we discuss the beneficial and harmful effects that can result from receptor activation. Finally, we integrate all of this information by discussing the

characteristic properties of representative sympathomimetic drugs. This chapter is intended only as an introduction to the adrenergic agonists. Our objective is to discuss the basic properties of the sympathomimetic drugs and to establish an overview of their applications and adverse effects. In later chapters, we will discuss the clinical applications of these agents in greater depth.

Mechanisms of Adrenergic Receptor Activation Drugs can activate adrenergic receptors by four basic mechanisms: (1) direct receptor binding, (2) promotion of norepinephrine (NE) release, (3) blockade of NE reuptake, and (4) inhibition of NE inactivation. Note that only the first mechanism is direct. With the other three mechanisms, receptor activation occurs by an indirect process. Examples of drugs that act by these four mechanisms are presented in Table 15.1. TABLE 15.1

aEphedrine is a mixed-acting drug that activates receptors directly and by promoting release of

norepinephrine. MAO, Monoamine oxidase; NE, norepinephrine.

Direct Receptor Binding

Direct interaction with receptors is the most common mechanism by which drugs activate peripheral adrenergic receptors. The direct-acting receptor stimulants produce their effects by binding to adrenergic receptors and mimicking the actions of natural transmitters (NE, epinephrine, dopamine). All of the drugs discussed in this chapter activate receptors directly.

Promotion of Norepinephrine Release By acting on terminals of sympathetic nerves to cause NE release, drugs can bring about indirect activation of adrenergic receptors. Agents that act by this mechanism include amphetamines and ephedrine. (Ephedrine can also activate adrenergic receptors directly.)

Inhibition of Norepinephrine Reuptake Recall that reuptake of NE into terminals of sympathetic nerves is the major mechanism for terminating adrenergic transmission. By blocking NE reuptake, drugs can cause NE to accumulate within the synaptic gap and can thereby increase receptor activation. Agents that act by this mechanism include cocaine and the tricyclic antidepressants.

Inhibition of Norepinephrine Inactivation As discussed in Chapter 12, some of the NE in terminals of adrenergic neurons is subject to inactivation by monoamine oxidase (MAO). Hence drugs that inhibit MAO can increase the amount of NE available for release and enhance receptor activation. (In addition to being present in sympathetic nerves, MAO is present in the liver and the intestinal wall. The significance of MAO at these other sites is considered later.) In this chapter, which focuses on peripherally acting sympathomimetics, nearly all of the drugs discussed act exclusively by direct receptor activation. The only exception is ephedrine, a drug that works by a combination of direct receptor activation and the promotion of NE release. Most of the indirect-acting adrenergic agonists are used for their ability to activate adrenergic receptors in the central nervous system (CNS)—not for their effects in the periphery. The indirect-acting sympathomimetics (e.g., amphetamine, cocaine) are mentioned here to emphasize that, although these

agents are employed for effects on the brain, they can and will cause activation of adrenergic receptors in the periphery. Peripheral activation is responsible for certain toxicities of these drugs (e.g., cardiac dysrhythmias, hypertension).

Overview of the Adrenergic Agonists Chemical Classification: Catecholamines Versus Noncatecholamines The adrenergic agonists fall into two major chemical classes: catecholamines and noncatecholamines, which differ in three important respects: (1) availability for oral use, (2) duration of action, and (3) ability to act in the CNS. Accordingly, if we know to which category a particular adrenergic agonist belongs, we will know three of its prominent features.

Catecholamines The catecholamines are so named because they contain a catechol group and an amine group. A catechol group is simply a benzene ring that has hydroxyl groups on two adjacent carbons. The amine component of the catecholamines is ethylamine. Structural formulas for each of the major catecholamines— epinephrine, NE, isoproterenol, dopamine, and dobutamine—are shown in Fig. 15.1. Because of their chemistry, all catecholamines have three properties in common: (1) they cannot be used orally, (2) they have a brief duration of action, and (3) they cannot cross the blood–brain barrier.

Structures of Representative Catecholamines and Noncatecholamines. Catecholamines: All of the catecholamines share the same basic chemical formula. Because of their biochemical properties, the catecholamines cannot be used orally, cannot cross the blood–brain barrier, and have short half-lives (owing to rapid inactivation by monoamine oxidase [MAO] and catechol-Omethyltransferase [COMT]). Noncatecholamines: Although structurally similar to catecholamines, noncatecholamines differ from catecholamines in three important ways: they can be used orally; they can cross the blood–brain barrier; and, because they are not rapidly metabolized by MAO or COMT, they have much longer half-lives. FIG. 15.1

The actions of two enzymes—monoamine oxidase and catechol-Omethyltransferase (COMT)—explain why the catecholamines have short halflives and cannot be used orally. MAO and COMT are located in the liver and intestinal wall. Both enzymes are very active and quickly destroy catecholamines administered by any route. Because these enzymes are located in

the liver and intestinal wall, catecholamines that are administered orally become inactivated before they can reach the systemic circulation. Hence catecholamines are ineffective if given by mouth. Because of rapid inactivation by MAO and COMT, three catecholamines—NE, dopamine, and dobutamine—are effective only if administered by continuous infusion. Administration by other parenteral routes (e.g., subcutaneously, intramuscularly) will not yield adequate blood levels, owing to rapid hepatic inactivation. Catecholamines are polar molecules, so they cannot cross the blood–brain barrier. (Recall from Chapter 4 that polar compounds penetrate membranes poorly.) The polar nature of the catecholamines is due to the hydroxyl groups on the catechol portion of the molecule. Because they cannot cross the blood-brain barrier, catecholamines have minimal effects on the CNS. Be aware that catecholamine-containing solutions, which are colorless when first prepared, turn pink or brown over time. This pigmentation is caused by oxidation of the catecholamine molecule. Catecholamine solutions should be discarded as soon as discoloration develops. The only exception is dobutamine, which can be used up to 24 hours after the solution was made, even if discoloration appears.

Noncatecholamines The noncatecholamines have ethylamine in their structure (see Fig. 15.1), but do not contain the catechol moiety that characterizes the catecholamines. Here we discuss three noncatecholamines: ephedrine, albuterol, and phenylephrine. The noncatecholamines differ from the catecholamines in three important respects. First, because they lack a catechol group, noncatecholamines are not substrates for COMT and are metabolized slowly by MAO. As a result, the halflives of noncatecholamines are much longer than those of catecholamines. Second, because they do not undergo rapid degradation by MAO and COMT, noncatecholamines can be given orally, whereas catecholamines cannot. Third, noncatecholamines are considerably less polar than catecholamines and hence are more able to cross the blood–brain barrier.

Receptor Specificity To understand the actions of individual adrenergic agonists, we need to know their receptor specificity. Variability in receptor specificity among the adrenergic agonists can be illustrated with three drugs: albuterol, isoproterenol, and

epinephrine. Albuterol is highly selective, acting at β2 receptors only. Isoproterenol is less selective, acting at β1 receptors and β2 receptors. Epinephrine is even less selective, acting at all four adrenergic receptor subtypes: α1, α2, β1, and β2. The receptor specificities of the major adrenergic agonists are shown in Table 15.2. In the upper part of the table, receptor specificity is presented in tabular form. In the lower part, the same information is presented schematically. By learning this content, you will be well on your way to understanding the pharmacology of the sympathomimetic drugs. TABLE 15.2 Receptor Specificity of Representative Adrenergic Agonists

a

Ephedrine is a mixed-acting agent that causes NE release and activates α and β receptors directly. b Receptor activation by dopamine is dose dependent. c This chart presents in graphic form the same information on receptor specificity given above. Arrows indicate the range of receptors that the drugs can activate (at usual therapeutic doses). α, Alpha; β, beta; NE, norepinephrine. Note that the concept of receptor specificity is relative, not absolute. The ability of a drug to selectively activate certain receptors to the exclusion of others depends on the dose: at low doses, selectivity is maximal; as the dose increases, selectivity declines. For example, when albuterol is administered in low to moderate doses, the drug is highly selective for β2-adrenergic receptors.