Anesthesia Considerations for the Oral and Maxillofacial Surgeon

Library of Congress Cataloging-in-Publication Data

Names: Mizukawa, Matthew, editor. | McKenna, Samuel J., editor. | Vega, Luis G., editor.

Title: Anesthesia considerations for the oral and maxillofacial surgeon / edited by Matthew Mizukawa, Samuel McKenna, Luis Vega.

Description: Hanover Park, IL : Quintessence Publishing Co. Inc., [2017] | Includes bibliographical references and index.

Identifiers: LCCN 2017006580 (print) | LCCN 2017008471 (ebook) | eISBN 9780867158847

Subjects: | MESH: Oral Surgical Procedures | Anesthesia | Ambulatory Surgical Procedures | Intraoperative Complications--prevention & control | Postoperative Complications--prevention & control

Classification: LCC RK510 (print) | LCC RK510 (ebook) | NLM WU 600 | DDC 617.9/676--dc23

LC record available at https://lccn.loc.gov/2017006580

© 2017 Quintessence Publishing Co, Inc

Quintessence Publishing Co, Inc

4350 Chandler Drive

Hanover Park, IL 60133

www.quintpub.com

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All rights reserved. This book or any part thereof may not be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, or otherwise, without prior written permission of the publisher.

Editor: Bryn Grisham

Design: Erica Neumann

Production: Kaye Clemens

Printed in China

CONTENTS

Dedications

Preface

Contributors

SECTION I: PRINCIPLES OF ANESTHESIA ADMINISTRATION

1. Basic Principles of Anesthesia

Patrick J. Louis, Pamela J. Sims, and Matthew Mizukawa

2. Pharmacology and Utility of Intravenous Anesthesia

Matthew Mizukawa

3. Pharmacology and Utility of Inhalation Anesthesia

Charles H. Kates

4. Local Anesthesia Basics

James Bradford Lewallen, Paul G. Sims, and Matthew Mizukawa

5. Prophylactic and Perioperative Antibiotics

Rick Shamo and David Shafer

6. Analgesia Considerations in Anesthesia

Sean M. Young and H. Daniel Clark

7. Postoperative Nausea and Vomiting

Danielle L. Cruthirds, Pamela J. Sims, and Patrick J. Louis

8. Monitoring the Patient

Timothy M. Orr and Matthew Mizukawa

9. Electrocardiography

Andrew E. Wicke, Erik J. Nielsen, and Scott Hoffman

10. Pre-anesthetic Patient Evaluation

Charles H. Kates and Matthew Mizukawa

11. Management of Airway Urgencies and Emergencies

Luis G. Vega, Paul Hinchey, Matthew Mizukawa, and Samuel J. McKenna

12. Medical Emergencies

Samuel J. McKenna and Nicholas Piemontesi

13. Aftermath of an Adverse Outcome or Complication

Lewis Estabrooks

SECTION II: ANESTHESIA AND COMORBID DISEASE

14. The Central Nervous System

Casey R. Shepherd and Daniel L. Orr II

15. The Cardiovascular System

Prem B. Patel and Helen E. Giannakopoulos

16. The Pulmonary System

Ravi Agarwal and George Obeid

17. The Digestive System

Ben Bailey and Jasjit K. Dillon

18. The Renal System

Paul Hinchey and Luis G. Vega

19. The Hepatic System

Emily King and Stuart Lieblich

20. The Endocrine System

Erica L. Shook, A. Thomas Indresano, and Matthew Mizukawa

21. The Musculoskeletal System

Andrew Cheung, Matthew Mizukawa, Lindsey Nagy, Travis Witherington, and Joshua Campbell

22. The Immune System

Steven Zambrano and Leslie R. Halpern

SECTION III: ANESTHESIA IN SPECIAL PATIENT GROUPS

23. Hematopathology and Coagulopathy

Robbie J. Harris III, Matthew Mizukawa, and John Mizukawa

24. Malignancy

Matthew Myers, Gregory Romney, and Sudheer J. Surpure

25. Geriatrics

Wayne H. Dudley and Ryan M. Dudley

26. Special Needs Populations

Pamela J. Hughes and Mae Hyre

27. Pediatric Considerations

Brent DeLong, Adam S. Pitts, and Matthew Mizukawa

28. Pregnancy

Steven I. Kaltman and Trevor Johnson

29. Obesity and Obstructive Sleep Apnea

Salam O. Salman and Jeffrey Dembo

30. Considerations for the Substance Abuse Patient

Julie Ann Smith

APPENDICES

A. Comprehensive Drug Index

A1. Addiction Aids

A2. α-Adrenergics

A3. Analgesics

A4. Antihypertensives

A5. Antidiabetics

A6. Antiasthmatics

A7. Anorexigenics

A8. Antiarrhythmics

A9. Anticholinesterase Inhibitors

A10. Muscle Relaxants

A11. Herbals

A12. Parkinson Disease Drugs

A13. GERD Drugs

A14. Thyroid Drugs

A15. CNS Stimulants

A16. CNS Depressants

A17. Heme-Related Agents

A18. Antiepileptics

A19. Antidepressants

A20. Antihistamines

A21. Vasopressors

A22. Antiemetics

B. Commonly Used Drugs and Doses

C. Algorithms

C1. Algorithm for Adult Cardiac Arrest

C2. Algorithm for Pediatric Cardiac Arrest

C3. Algorithm for Adult Bradycardia With a Pulse

C4. Algorithm for Pediatric Bradycardia With a Pulse and Poor Perfusion

C5. Algorithm for Adult Tachycardia With a Pulse

C6. Algorithm for Pediatric Tachycardia With a Pulse and Poor Perfusion

Index

DEDICATIONS

My deepest gratitude and love to my wife, Julie, and my children for
supporting me in this project and sacrificing their time with me.

Thanks to my parents, John and Elaine, for raising me
to reach for the stars.

Sincere recognition of my complete dependence
on an Almighty God, who sustains me from day to day.

MM

To Elaine, Will, and Anna, who have supported my career and the
many nights and weekends in the hospital or at my desk.
Thank you for your unwavering love and support.

To the many Vanderbilt oral and maxillofacial surgery residents who
have been an inspiration and a part of my life
that I will always cherish.

SJM

I want to thank my wife, Marina. Without her
unconditional support, my world would stop.
To my daughters, Eva and Elena, thanks for filling my life
with love and laughter.

Drs Mizukawa and McKenna, your dedication and endless work
have been the true fuel that has carried this project to fruition.
Thank you for allowing me to work with you.

Finally to my past, present, and future residents, this book is for you.
Thanks for your companionship during so many “surgical battles,”
but more importantly, thank you for pushing me to be
the best teacher I could be.

LGV

PREFACE

Office-based anesthesia has been instrumental in the evolution of outpatient surgery. Oral and maxillofacial surgeons in particular have maximized the benefits of office-based anesthesia and have contributed greatly to its evolution. Surgical procedures can be performed in the office rather than in a hospital or surgical center, which reduces the financial and time demands on the patient. Likewise, the cost of anesthesia administered in the office is considerably lower than that of anesthesia administered in an operating room. Compliance with dental treatment in both the pediatric and adult populations can be substantially increased when intravenous anesthesia is utilized, which improves the overall dental health of the general population.

Oral and maxillofacial surgeons have been pioneers in office-based anesthesia administration. Their background in internal medicine and anesthesia acquired during residency training makes them uniquely qualified to administer anesthesia and perform surgical procedures simultaneously. Between the years 2000 and 2014, oral surgeons covered by the Oral and Maxillofacial Surgery National Insurance Company (OMSNIC) administered office-based anesthesia 42,792,419 times. On average, this number equates to 666 administrations per oral surgeon per year. Of those administrations, 415 anesthesia-related claims were reported to OMSNIC, including 121 deaths, which is equivalent to 1 death in every 353,657 administrations. The margin of safety established by oral surgeons in administering office-based anesthesia can largely be attributed to providers’ efforts to obtain and maintain deep knowledge in the fields of medicine and anesthesia, ensure prudent patient selection, and use safe and effective office-based anesthesia techniques.

The objective of this book is to assist providers in maintaining their knowledge base and properly selecting patients who can safely undergo anesthesia in the office setting. Every time a patient is encountered, the provider must be able to answer a sequence of questions:

These questions, when considered and observed, are critical in ensuring the safe, effective administration of office-based anesthesia and avoiding unforeseen adverse outcomes and complications.

This book is organized into three sections. Section I contains a review of the principles of anesthesia, including the pharmacology of commonly used office-based anesthetic agents, monitoring of the patient, preoperative evaluation, the airway, local anesthesia, analgesia, and effective use of antibiotics. Section II comprises the major organ systems of the body. For each system, a brief review of the normal anatomy and physiology is given. Some common comorbid conditions that affect these systems are reviewed, including pathophysiology, diagnosis, management, and anesthesia-related considerations. Each chapter, or organ system, has a tabbed cover page for quick reference. This cover page lists the contents of the chapter and includes the comorbid conditions discussed in the chapter, with page numbers. Section III reviews patient groups that warrant special consideration in the administration of office-based anesthesia.

The appendices cover frequently referenced material. Appendix A is a comprehensive drug index that outlines the drug classes commonly prescribed to treat the comorbid diseases discussed in the book. This index includes the drug classes, mechanisms of action, examples of commonly used drugs in the class, side effects, and anesthesia-related considerations. Appendix B lists commonly used office-based anesthesia drugs and their typical dosages. Finally, basic life support, advanced cardiovascular life support, and pediatric advanced life support algorithms are included in Appendix C for quick reference.

This book is not a primary textbook. The authors presume that the material found herein is a review. It is meant to serve as a quick reference when patients are encountered and these principles need review. Also, this book is not a comprehensive reference. It does not include every disease that affects the human body. Rather, it reviews conditions that are commonly encountered.

Because humans are living longer, with more comorbid diseases, office-based anesthesia administration has become more complex. The focus of this book is to guide practitioners along the decision tree as they encounter a wide spectrum of ages, diseases, and conditions and to strengthen the margin of safety of office-based anesthesia administration.

CONTRIBUTORS

Ravi Agarwal, DDS

Residency Program Director

Department of Oral and Maxillofacial Surgery

MedStar Washington Hospital Center

Washington, District of Columbia

Ben Bailey, DMD

Chief Resident

Department of Oral and Maxillofacial Surgery

School of Dentistry

University of Washington

Seattle, Washington

Joshua Campbell, DDS

Assistant Professor

Department of Oral and Maxillofacial Surgery

University of Tennessee Medical Center

Knoxville, Tennessee

Andrew Cheung, DDS

Gratis Clinical Assistant Professor

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Nashville, Tennessee

Guest Lecturer

Department of Oral and Maxillofacial Surgery

Department of Hospital and General Dentistry

University of Tennessee Medical Center

Knoxville, Tennessee

Private Practice Limited to Oral and Maxillofacial Surgery

Oak Ridge and Crossville, Tennessee

H. Daniel Clark, DDS, MD

Private Practice Limited to Oral and Maxillofacial Surgery

Franklin, Tennessee

Danielle L. Cruthirds, PhD

Associate Professor of Pharmaceutical Sciences

Department of Pharmaceutical, Social and Administrative Sciences

McWhorter School of Pharmacy

Samford University

Birmingham, Alabama

Brent DeLong, DDS

Clinical Professor

Department of Oral and Maxillofacial Surgery

San Antonio Military Medical Center

Wilford Hall Ambulatory Surgery Center

Lackland Air Force Base

San Antonio, Texas

Jeffrey Dembo, DDS, MS

Professor Emeritus

Department of Oral and Maxillofacial Surgery

College of Dentistry

University of Kentucky

Lexington, Kentucky

Jasjit K. Dillon, DDS, MD, BDS, FDSRCS

Clinical Associate Professor

Department of Oral and Maxillofacial Surgery

School of Dentistry

University of Washington

Acting Chief of Service and Program Director

Oral and Maxillofacial Surgery

Clinic Harborview Medical Center

Seattle, Washington

Ryan M. Dudley, MD

Resident, Internal Medicine

School of Medicine

University of Nevada, Las Vegas

Las Vegas, Nevada

Wayne H. Dudley, DDS

Private Practice Limited to Oral and Maxillofacial Surgery

St George, Utah

Lewis Estabrooks, DMD, MS

Associate Clinical Professor

Department of Oral and Maxillofacial Surgery

School of Dental Medicine

Tufts University

Boston, Massachusetts

Helen E. Giannakopoulos, DDS, MD

Associate Professor of Oral and Maxillofacial Surgery/Pharmacology

Director, Postdoctoral Oral and Maxillofacial Surgery Residency Program

Penn Dental Medicine

University of Pennsylvania

Philadelphia, Pennsylvania

Leslie R. Halpern, MD, DDS, PhD, MPH

Associate Professor, Program Director

Department of Oral and Maxillofacial Surgery

School of Dentistry

Meharry Medical College

Nashville, Tennessee

Robbie J. Harris III, DDS

Private Practice Limited to Oral and Maxillofacial Surgery

Paducah, Kentucky

Paul Hinchey, DMD, MD

Resident

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Nashville, Tennessee

Scott Hoffman, MD

Retired Professor of Clinical Anesthesiology

Department of Anesthesiology

Vanderbilt University School of Medicine

Vanderbilt University Hospital

Nashville, Tennessee

Pamela J. Hughes, DDS

Associate Professor and Chair

Department of Oral and Maxillofacial Surgery

School of Dentistry

Oregon Health & Science University

Portland, Oregon

Mae Hyre, DMD, MD

Oral and Maxillofacial Surgeon

Facial Surgery

Center Charleston Area Medical Center

Private Practice Limited to Oral and Maxillofacial Surgery

Charleston, West Virginia

A. Thomas Indresano, DMD

Dr T. Galt and Lee Dehaven Atwood Professor and Chair

Department of Oral and Maxillofacial Surgery

University of the Pacific Arthur A. Dugoni School of Dentistry

San Francisco, California

Trevor Johnson, DMD

Chief Resident

Department of Surgery

Department of Oral and Maxillofacial Surgery

College of Dental Medicine

Nova Southeastern University

Broward Health Medical Center

Fort Lauderdale, Florida

Steven I. Kaltman, DMD, MD

Professor and Chairman

Department of Oral and Maxillofacial Surgery

Dean of Hospital and Extramural Affairs

College of Dental Medicine

Nova Southeastern University

Fort Lauderdale, Florida

Charles H. Kates, DDS, PA

Clinical Associate Professor of Clinical Anesthesiology

Clinical Associate Professor of Surgery

Miller School of Medicine

University of Miami

Director of Anesthesia and Pain Management

Division of Oral and Maxillofacial Surgery and Dentistry

Department of Surgery

University of Miami at Jackson Memorial Hospital

Miami, Florida

Private Practice Limited to Oral and Maxillofacial Surgery and Anesthesiology

Aventura, Florida

Emily King, DMD

Resident

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Nashville, Tennessee

James Bradford Lewallen, DDS, MD, MSC

Private Practice Limited to Oral and Maxillofacial Surgery

Franklin, Tennessee

Stuart Lieblich, DMD

Clinical Professor

Division of Oral and Maxillofacial Surgery

School of Dental Medicine

University of Connecticut

Farmington, Connecticut

Private Practice Limited to Oral and Maxillofacial Surgery

Avon, Connecticut

Patrick J. Louis, DDS, MD

Professor and Residency Training Program Director

Department of Oral and Maxillofacial Surgery

School of Dentistry

University of Alabama at Birmingham

Birmingham, Alabama

Samuel J. McKenna, DDS, MD

Professor and Chair

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Nashville, Tennessee

John Mizukawa, DDS

Chief Resident

Department of Oral and Maxillofacial Surgery and Dentistry

Vanderbilt University School of Medicine

Nashville, Tennessee

Matthew Mizukawa, DMD

Assistant Clinical Professor

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Nashville, Tennessee

Private Practice Limited to Oral and Maxillofacial Surgery

St George, Utah

Matthew Myers, DMD

Chief Resident

Department of Oral and Maxillofacial Surgery

Banner University Medical Center

University of Arizona College of Medicine

Phoenix, Arizona

Lindsey Nagy, DDS

Private Practice Limited to Oral and Maxillofacial Surgery

Oak Ridge, Tennessee

Erik J. Nielsen, DDS

Resident

Department of Oral and Maxillofacial Surgery and Dentistry

Vanderbilt University School of Medicine

Nashville, Tennessee

George Obeid, DDS

Chairman

Department of Oral and Maxillofacial Surgery

MedStar Washington Hospital Center

Washington, District of Columbia

Daniel L. Orr II, DDS, MS (Anesthesiology), PhD, JD, MD

Professor and Director of Oral and Maxillofacial Surgery and Anesthesiology

School of Dental Medicine

University of Nevada, Las Vegas

Las Vegas, Nevada

Clinical Professor of Surgery and Anesthesiology

School of Medicine

University of Nevada, Reno

Reno, Nevada

Timothy M. Orr, DMD

Anesthesiologist

Austin, Texas

Prem B. Patel, DMD, MD

Private Practice Limited to Oral and Maxillofacial Surgery

Chicago, Illinois

Nicholas Piemontesi, DMD, MD

Resident

Department of Oral and Maxillofacial Surgery and Dentistry

Vanderbilt University School of Medicine

Nashville, Tennessee

Adam S. Pitts, DDS, MD

Chairman, Department of Oral and Maxillofacial Surgery

Tristar Centennial Medical Center

Clinical Instructor

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Private Practice Limited to Oral and Maxillofacial Surgery

Nashville, Tennessee

Gregory Romney, DMD

Private Practice Limited to Oral and Maxillofacial Surgery

Mesa, Arizona

Salam O. Salman, MD, DDS

Associate Program Director and Assistant Professor

Department of Oral and Maxillofacial Surgery

College of Medicine

University of Florida, Jacksonville

Jacksonville, Florida

David Shafer, DMD

Associate Professor, Chair, and Residency Program Director

Department of Oral and Maxillofacial Surgery

University of Connecticut School of Dental Medicine

Farmington, Connecticut

Rick Shamo, DDS, MD

Director of Oral and Maxillofacial Surgery

Memorial Hospital of Sweetwater County

Rock Springs, Wyoming

Casey R. Shepherd, DMD, MD

Private Practice Limited to Oral and Maxillofacial Surgery

Kalispell, Montana

Erica L. Shook, DDS

Maxillofacial Surgeon

Kaiser Permanente Hospital

Oakland Medical Center

Oakland, California

Pamela J. Sims, PharmD, PhD

Professor of Pharmaceutical Sciences

Department of Pharmaceutical, Social and Administrative Sciences

McWhorter School of Pharmacy

Samford University

Birmingham, Alabama

Paul G. Sims, DDS

Private Practice Limited to Oral and Maxillofacial Surgery

Butte, Montana

Julie Ann Smith, DDS, MD, MCR

Private Practice Limited to Oral and Maxillofacial Surgery

Portland, Oregon

Sudheer J. Surpure, MD, DDS

Chief, Division of Oral and Maxillofacial Surgery

Director, Oral and Maxillofacial Surgery Residency Program

Oral and Maxillofacial Surgery Center

Banner—University Medical Center Phoenix

Clinical Assistant Professor

Division of Oral and Maxillofacial Surgery

Department of Surgery

College of Medicine—Phoenix

University of Arizona

Phoenix, Arizona

Luis G. Vega, DDS

Associate Professor and Residency Program Director

Department of Oral and Maxillofacial Surgery

Vanderbilt University Medical Center

Nashville, Tennessee

Andrew E. Wicke, DMD

Chief Resident

Department of Oral and Maxillofacial Surgery and Dentistry

Vanderbilt University School of Medicine

Nashville, Tennessee

Travis Witherington, DDS

Private Practice Limited to Oral and Maxillofacial Surgery

Oak Ridge, Tennessee

Sean M. Young, DDS, MD

Private Practice Limited to Oral and Maxillofacial Surgery

Franklin, Tennessee

Steven Zambrano, DDS

Private Practice Limited to Oral and Maxillofacial Surgery

Cordova, Tennessee

The pharmacologic effects of drugs are determined by pharmacokinetic and pharmacodynamic principles. Pharmacokinetics describes the absorption, distribution, metabolism, and excretion of the drug. Pharmacodynamics describes the interaction of the drug with the target receptor and the subsequent effect on an organ, tissue, or system. Understanding the pharmacokinetic and pharmacodynamic properties of each anesthetic agent is essential to predict the patient’s response.

Pharmacokinetics

When a drug is administered to a patient to produce a systemic effect, the drug undergoes four pharmacokinetic processes: absorption, distribution, metabolism, and excretion.

Absorption is the process of movement of the drug from the site of administration into the bloodstream. Although many routes of administration are available, common routes utilized in office-based anesthesia include intravenous, oral, intramuscular, intraosseous, transmucosal, transcutaneous, inhaled, and intranasal. If the drug is administered intravenously (directly into the bloodstream), the process of absorption and its potential variability is avoided. Drugs administered by other routes of administration must be absorbed from the site of administration into the bloodstream. Most drug absorption occurs by passive diffusion based on Fick’s law of diffusion:

where K is the partition coefficient; A, the surface area (diffusional area); D, the diffusion coefficient; C₁, the extracellular concentration; C₂, the intracellular concentration; and h, the thickness of the membrane (diffusional distance).

Lipophilic drugs in their un-ionized form generally have higher partition and diffusion coefficients, which favors absorption. Blood flow away from the absorption site maintains the concentration gradient and promotes drug absorption. Thinner, well-perfused membranes (eg, vascular mucosa) favor absorption. Additionally, the greater the surface area to which the drug is administered or exposed, the more absorption will occur. The bioavailability of a drug, or the fraction of the dose administered that reaches systemic circulation, can vary among the nonintravenous routes of administration. For example, when a drug is administered orally, only a fraction of the initial dose may survive the acid and digestive enzymes of the stomach and/or the first-pass metabolism across the gastric mucosa and the portal circulation from the duodenum through the liver. Consequently, only a portion of the initial dose administered may reach the central nervous system to elicit an effect. An advantage of oral dosing, however, is the ease of administration compared with more invasive routes, such as intramuscular, intraosseous, and intravenous.

Intramuscular administration and intraosseous administration are efficient because exposure of a drug to well-perfused muscle and bone tissue results in rapid absorption into the venous circulation. These routes also avoid initial metabolism of the drug in the digestive system, so smaller doses are often required to achieve the same effect than would be required with oral administration.

Bronchial inhaled administration is rapid. When drug is inhaled, it is absorbed into the pulmonary venous circulation and then transported to the left heart and subsequently to the systemic circulation, including the central nervous system. Three main factors affect absorption of gases into the blood: relative solubility of the drug in blood and gas, cardiac output, and the gradient of alveolar partial pressure to venous partial pressure.

Solubility of the anesthetic agent is determined by the blood/gas partition coefficient. This coefficient indicates the relative capacity of blood and gas to hold the drug. For example, isoflurane has a blood/gas coefficient of 1.4, which means that, at equilibrium, blood holds 1.4 times the amount of isoflurane that gas does. Desflurane has a blood/gas coefficient of 0.45, which means that, at equilibrium, more of the drug stays in the alveoli in the gas phase than enters the blood.

Cardiac output, defined as the product of heart rate and stroke volume, describes the movement of blood through the circulation. Cardiac output is required to push blood through the pulmonary circulation to maintain the gradient of partial pressure required for absorption. The more blood that passes through the pulmonary circulation, the more drug can be absorbed and carried back to the heart. If stasis of blood occurs in the pulmonary circulation, the blood will become saturated and unable to absorb any more of the drug.

The gradient of alveolar and venous partial pressures of the drug also affects absorption. This gradient is driven by delivery and unloading of the drug in brain, muscle, fat, and other tissues, creating a pressure difference. Tissue uptake of the anesthetic agent is essential in creating this gradient.

Distribution describes the movement of a drug to and from the bloodstream and extravascular sites. For most drugs, the site of action is outside the bloodstream. For the drug to reach the site of action and elicit a pharmacologic response, it must distribute from the bloodstream through the capillary and other phospholipid bilayer membranes to the target tissue or organ. Factors that influence distribution and extravascular migration of the drug include the size of the drug molecule, the degree of protein binding, the lipophilicity of the drug, and the pK_a of the drug.

Drug molecules with small molecular weight generally diffuse passively across most biologic membranes. Because general anesthetics, sedatives, and opioid analgesics elicit their pharmacologic effect in the central nervous system, they must penetrate the tight junctions of the highly lipophilic blood-brain barrier. Small drug molecules that can squeeze between the tight junctions of blood vessels and the blood-brain barrier diffuse more readily into the central nervous system than larger drug molecules do.

The binding of drugs to plasma proteins, such as albumin or α1-acid glycoprotein, limits drug distribution because of the size of the protein-drug complex. In the case of drugs with lower protein binding, or as the protein binding of a drug decreases because of lower protein concentrations or displacement by other protein-bound drugs, a higher concentration of free drug is available to distribute extravascularly to peripheral sites. Because the concentration of plasma proteins influences distribution, many elderly patients who have decreased serum protein concentrations can have increased free drug concentrations; therefore, for a drug to achieve the same effect in these patients as it would have in younger adult patients, a markedly lower dose may be required.

Lipophilicity, described by the octanol/water partition coefficient, promotes the movement of a drug across membranes, particularly lipophilic barriers, such as the blood-brain barrier. Lipophilic drugs have a high affinity for fatty tissue, into which they distribute more slowly than they do into highly perfused organs and tissues. This high affinity for and slower distribution into fat creates a drug reservoir that results in redistribution of the drug into and out of the blood and central nervous system over time, which can prolong the drug’s action.

As determined by the Henderson-Hasselbalch equation, drugs in the un-ionized form favor movement across membranes. Because many general anesthetic agents are basic, a pK_a below or approaching 7.4 means that more of the drug will be un-ionized at physiologic pH. For the barbiturate anesthetics and propofol, which are acidic, a pK_a above or approaching 7.4 means that more of the drug will be un-ionized at physiologic pH.

Pharmacokinetic models view the body as compartments in relationship to the bloodstream. The bloodstream and the organs and tissues that are immediately perfused are considered the central compartment. The tissues and organs into which drugs distribute more slowly are considered peripheral compartments (Fig 1-1). In the two-compartment model, the distribution of drug to and from the blood and perfused tissues and organs results in a rapid decline in concentration in the bloodstream in the distribution phase, followed by a slower decline in drug concentration in the bloodstream caused by metabolism and excretion of the drug (the elimination phase). In the two-compartment model, the half-life of the drug in the distribution phase, α, is always much shorter than the half-life in the elimination phase, β, and is generally more predictive of the duration of the drug’s effects in the perfused organs, such as the central nervous system. For drugs that subsequently distribute into less well-perfused tissues or organs, such as muscle or fat, the deeper peripheral compartment may be considered a third compartment. Distribution of the drug into and out of this deeper peripheral compartment frequently creates a drug reservoir that can result in prolonged redistribution and effect of the drug. The extent of distribution of the drug from the bloodstream to extravascular sites is described by the apparent volume of distribution, V_d. Therefore, lipophilic drugs with a higher V_d are more extensively distributed outside the bloodstream than hydrophilic drugs with a smaller V_d are. Because V_d is directly related to half-life, drugs with a larger V_d have a longer half-life, described in the equation t_½ = 0.693V_d / C_l.

Fig 1-1 Diagram depicting the pharmacokinetic journey of drugs from their site of administration to their ultimate clearance from the body.

Metabolism describes the conversion of active drug to inactive metabolites that can be excreted from the body. Although some drugs are metabolized outside the liver, drug clearance is generally accomplished primarily by means of biotransformation or metabolism in the liver and excretion by the kidneys and to a lesser degree in bile. The primary purpose of hepatic biotransformation is to produce polar metabolites that can be excreted by the kidneys. Because general anesthetic agents, sedatives, and opioid analgesics are lipophilic molecules, they must be metabolized by the liver and undergo biotransformation into water-soluble metabolites that can be excreted by the kidneys or in bile. Hepatic metabolic processes are classified as phase I or phase II. Phase I consists of oxidative/reductive metabolic processes that generally produce polar metabolites that are excreted by the kidneys. Cytochrome P450 enzymes, the largest group of phase I enzymes, are susceptible to induction and inhibition drug interactions, and their function decreases with aging. Phase II consists of conjugative metabolic processes that are generally employed when phase I metabolism does not produce sufficiently polar metabolites. Of the phase II processes, glucuronidation is of greatest relevance to the metabolism of general anesthetic agents, sedatives, and opioid analgesics because glucuronide metabolites often undergo biliary excretion and subsequently are enterohepatically recirculated from the gastrointestinal tract into the bloodstream. Enterohepatic recirculation of glucuronide metabolites occurs when gastrointestinal flora cleave the glucuronide conjugate from the drug or drug metabolite molecule and the active drug or drug metabolite is reabsorbed from the gastrointestinal tract through the hepatic portal vein into systemic circulation. The processes of enterohepatic recirculation of glucuronide metabolites and the redistribution of lipophilic drugs into and out of the central nervous system contribute to the variable and prolonged effects of several general anesthetic agents, sedatives, and opioid analgesics.

Renal excretion of polar metabolites of general anesthetic agents, sedatives, and opioid analgesics generally has little impact on their effect in patients. If a renally excreted metabolite has pharmacologic activity, alterations in renal function can result in adverse effects.

Considerations of inhaled anesthetics

For inhaled anesthetics, potency is described in terms of minimum alveolar concentration (MAC). The concentration of an inhaled anesthetic that prevents movement in response to surgical stimulation in 50% of patients is defined as the MAC of that anesthetic agent. MAC_awake is a fraction of the MAC that indicates the alveolar concentration of anesthetic agent at which suppression of verbal response and memory formation is achieved. Inhaled anesthetic agents behave as gases do, not as liquids do. As they distribute between tissues, or between blood and gas, equilibrium is reached when the partial pressure of anesthetic gas is equal in the two tissues or between the blood and gas. At equilibrium, the concentrations differ because of differences in solubility in those tissues or physiologic environments, resulting in unique blood/gas, brain/blood, and fat/blood partition coefficients. These ratios demonstrate that inhaled anesthetic agents are more soluble in some tissues, such as fat, than in others, such as blood, and that the different agents have a range of solubility within each tissue or physiologic environment (Table 1-1). For inhaled anesthetics that are not very soluble in blood or fat, such as nitrous oxide, equilibrium is achieved quickly. For an agent that is more soluble in fat, such as halothane, equilibrium is achieved more slowly because fat represents a large anesthetic reservoir that is poorly perfused and therefore fills slowly.

Table 1-1 Properties of common inhaled anesthetic agents

An important consideration is the speed of anesthetic induction. Anesthesia occurs when the partial pressure of the anesthetic agent in the brain is equal to or greater than the MAC of that anesthetic. Because the brain is highly perfused, the partial pressure of the anesthetic in the brain becomes equal to the partial pressure in alveolar gas and blood within several minutes. Therefore, anesthesia is achieved shortly after alveolar partial pressure reaches the MAC. For anesthetic agents that are highly soluble in blood and other tissues, the partial pressure will rise more slowly. This limitation on the speed of induction can be overcome by delivering higher inspired partial pressure of the anesthetic agent.

The elimination of an inhaled anesthetic mimics in reverse the process of uptake. For anesthetic agents with low solubility in blood and tissue, recovery is independent of the duration of anesthetic administration and should mirror the speed of induction. For anesthetic agents with high blood and tissue solubility, accumulation in the fat prevents blood and alveolar partial pressures from rapidly declining, and recovery depends on the duration of anesthetic administration. Patients will be arousable when alveolar partial pressures reach MAC_awake.

Considerations of parenteral anesthetics

Parenteral anesthetics are small lipophilic compounds that quickly partition into the highly perfused and lipophilic tissues of the central nervous system, where they rapidly produce anesthesia. After a single intravenous bolus, anesthetic concentrations in the bloodstream decline rapidly as the anesthetic distributes into the central nervous system. Anesthetic concentrations in the central nervous system then fall rapidly as the anesthetic redistributes from the central nervous system back into the blood, where it either is transported to and metabolized by the liver or diffuses into viscera and muscle and subsequently into poorly perfused adipose tissue. The termination of the anesthetic effect primarily results from redistribution of the anesthetic agent from the central nervous system, not metabolism. Therefore, the duration of the anesthetic effect after a single dose often depends more on the distribution half-life (α) than on the elimination half-life (β) of the anesthetic agent. After administration of multiple doses or prolonged infusion of a parenteral anesthetic agent, its lipophilic properties (resulting in its accumulation in fatty tissue) and elimination half-life (reflecting the metabolic clearance) are more predictive of the duration of effect. The physicochemical and pharmacokinetic properties of common parenterally administered general anesthetic agents are provided in Table 1-2.

Table 1-2 Properties of common parenterally administered general anesthetic agents

NM, not measurable.

Clinical drug efficacy and safety

The efficacy of a drug refers to its ability to elicit a specific physiologic effect. Efficacy is generally expressed in terms of the maximum effect of a drug, compared with the maximum effect of another. For example, if drug A elicits a greater effect than drug B does, despite the dose given, then drug A is said to have greater efficacy.¹ The potency of intravenous anesthetic agents is more difficult to measure and is defined as the amount of a drug required to elicit a certain effect. In comparing two anesthetic agents, if one agent produces the desired effect with 10 mg and the other agent requires 100 mg to produce the same effect, the first agent is more potent. Potency can be easily illustrated in a typical dose-response curve (Fig 1-2).

Fig 1-2 Dose-response curves demonstrating potency of two drugs. Drug A is more potent than drug B because it achieves the desired response at a smaller dose. Although the efficacy (maximum effect) of the two drugs is the same, the leftward shift of the dose-response curve of drug A indicates greater potency.

The safety of drugs is expressed in terms of effective doses and lethal doses. The median effective dose (ED₅₀) is the free plasma concentration at equilibrium that produces a specific response in 50% of patients. In anesthesia, the desired response is lack of response to surgical stimulation. The median lethal dose (LD₅₀) is the dose that results in death in 50% of patients. The therapeutic index of a drug is equal to the ratio LD₅₀:ED₅₀; the greater the ratio, the safer the drug. In other words, the greater the difference between ED₅₀ and LD₅₀, the less likely it is that administration of the drug at effective doses will result in death.

Pharmacodynamics

Pharmacodynamics is defined as the study of the biochemical and physiologic effects of drugs and the mechanism of their actions, including the correlation of their action and effect with their chemical structure. For a substance to produce an effect, it must bind to a receptor within the body. Several types of receptors have naturally occurring ligands, or molecules that bind to them. Drugs may be agonists or antagonists for these receptors, thereby producing effects within the body that influence the potency and efficacy of the drug.

Ligands

A ligand is any molecule that binds to a receptor. Ligands can be endogenous, such as antibodies, hormones, and neurotransmitters, or they can be exogenous, such as the vast spectrum of drugs available for therapeutic use. Drugs can be classified as agonists, which have excitatory or inhibitory effects, or antagonists. Agonistic drugs are designed to elicit effects similar to those of endogenous agonists, whereas antagonists are molecules that prevent an agonist from binding to a receptor, thus blocking its effect. Antagonists can be further characterized as competitive or noncompetitive. A competitive antagonist competes with an agonist and reversibly binds to a receptor. A noncompetitive antagonist irreversibly binds to a receptor and permanently blocks the agonist action until new receptors can be generated. At the neuromuscular junction, acetylcholine mediates muscle contraction by reversibly binding to the postsynaptic nicotinic acetylcholine receptor. Atracurium (a non-depolarizing neuromuscular blocking drug) is an example of a competitive antagonist. Botulinum toxin is an example of a noncompetitive antagonist. Some drugs, classified as inverse agonist or superantagonist, decrease receptor response to less than that which occurs in the absence of the agonist. This scenario can occur because some receptors are in an activated state in the absence of an agonist, creating a baseline effect.²

Receptors

Receptors are present in the cell membrane and intracellularly. Receptors in the cell membrane include membrane receptors, voltage-gated ion channels, and ligand-gated ion channels. These receptors interact with water-soluble ligands that do not readily cross the hydrophobic lipid bilayer.

Guanine nucleotide–binding proteins (G proteins) are membrane-associated, heterotrimeric proteins composed of α, β, and γ subunits.^3,4 The G protein–coupled receptor (GPCR) superfamily of proteins provide the primary mechanism by which cells detect changes in the external environment and present this information intracellularly.⁵ Binding of an extracellular agonist to a GPCR induces a change in conformation of the receptor. The activated receptor promotes the exchange of bound guanosine diphosphate (GDP) for guanosine triphosphate (GTP) on the G protein α subunit. GTP binding changes the conformation of switch regions within the α subunit, allowing the bound inactive trimeric G protein to be released from the receptor and to dissociate into an active α subunit (GTP-bound) and a β/γ dimer.⁶ The α subunit and the β/γ dimer then activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors regulate the intracellular concentrations of secondary messengers, including cyclic adenosine monophosphate (cAMP), diacylglycerol, and sodium and calcium cations.⁷ The result is a physiologic response caused by downstream regulation of gene transcription. Hydrolysis of α subunit–bound GTP to GDP allows the α and β/γ subunits to reassociate and bind to the receptor, terminating the signal.⁶ Stimuli to which GPCRs are known to respond include neurotransmitters, neuropeptides, light, gustatory compounds, odors, hormones, and glycoproteins. Examples of GPCRs include (1) presynaptic α₂-adrenergic receptors, which cause inhibition of voltage-dependent calcium channels and decrease the release of norepinephrine,⁸ and (2) opioid receptors, which prevent calcium influx into presynaptic terminals and reduce glutaminergic excitatory transmission.⁹

Voltage-gated ion channels are charged water-filled pores composed of several proteins that span the membrane. Ion pairs between positive and negative charges help stabilize these channels. Changes in membrane potential cause a conformational change in the central pore, with rearrangement of ion pairs that results in increased permeability of the ion specific to that channel. Examples of voltage-gated channels include (1) voltage-gated sodium channels, which are responsible for depolarization and for creation and propagation of action potential; (2) voltage-gated potassium channels, which are responsible for repolarization; (3) voltage-gated calcium channels, which link muscle excitation with contraction and neuronal excitation with release of neurotransmitters; (4) hyperpolarization-activated cyclic nucleotide-gated channels, which are permeable to potassium and sodium and function as pacemaking channels in the heart; and (5) voltage-gated proton channels, which open with depolarization and are strongly pH sensitive, allowing protons to leave the cell.¹⁰

A ligand-gated ion channel is a combination of a receptor protein and an ion channel. Binding of certain molecules to this ionotropic receptor directly alters the membrane potential by causing a conformational change in the channel protein. This change results in the opening of the channel and flux of ions across the cell membrane. Examples of ligand-gated ion channels include (1) anion-permeable γ-aminobutyric acid (GABA_A) receptor, which causes intracellular flux of chloride ions, resulting in hyperpolarization of the membrane potential; (2) anion-permeable glycine receptor (GlyR), the activity of which is similar to that of GABA_A receptor; (3) cation-permeable nicotinic acetylcholine receptor, which causes sodium and potassium influx, resulting in depolarization; (4) cation-permeable ionotropic glutamate-gated receptors, which cause sodium, potassium, and calcium flux, resulting in depolarization; and (5) two-pore-domain potassium channels, which cause potassium influx, resulting in hyperpolarization at the presynaptic and postsynaptic levels.¹⁰

Central Nervous System Regulation

General anesthetics work by causing a decrease in central nervous system activity, reportedly as a result of stimulation of inhibitory neurotransmitters and inhibition of excitatory neurotransmitters. This section gives a pertinent overview of this complex topic and presents the major modulators of the central nervous system, including inhibitory neurotransmitters, excitatory neurotransmitters, and intracellular signaling.

Inhibitory neurotransmitters

γ-aminobutyric acid receptor

GABA receptor is an inhibitory receptor found within the central nervous system. The most abundant inhibitory neurotransmitter receptor in the brain, it is found in high concentrations in the thalamus and cerebral cortex. It is a heteromeric transmembrane protein.¹¹ The subtype that has been widely studied is the GABA_A receptor. The receptor is composed of five subunits. Stimulation of the GABA_A receptor allows for the flux of chloride ion through the ionophore, causing hyperpolarization and a decrease in excitatory neurotransmission.¹¹ Binding sites for benzodiazepines, barbiturates, and neurosteroids have been identified.^12,13 Volatile anesthetics and ethanol appear to bind at the neurosteroid site.

Transient inhibitory postsynaptic currents (IPSCs) are generated by the stimulation of GABAergic receptors located in high concentration at the postsynaptic terminals of excitatory neurons. GABAergic drugs, including general anesthetics, sedatives, and anxiolytics, enhance the blockade of fast excitatory impulses by the generation of IPSCs.¹⁴ GABAergic drugs also have other mechanisms of action, including potentiation of GABA, direct stimulation of the GABA receptor, and desensitization of non-postsynaptic receptors for GABA. GABAergic drugs potentiate the binding of GABA to the GABA receptor by means of allosteric modulation of the GABA receptor that can increase the receptor’s affinity for GABA.¹⁵ Desensitization allows for prolonged binding.

Glycine

¹⁶¹⁷N¹⁸¹⁹