Molecular Bases of Anesthesia (Handbooks in Pharmacology and Toxicology)

346 Pages·2000·20.37 MB·English

by  Eric Moody

Molecular Bases of
Anesthesia
Pharmacology and Toxicology: Basic and Clinical Aspects
Mannfred A. Hollinger, Series Editor
University of California, Davis
Published Titles
Biomedical Applications of Computer Modeling, 2001, Arthur Christopoulos
Molecular Bases of Anesthesia, 2001, Eric Moody and Phil Skolnick
Manual of Immunological Methods, 1999, Pauline Brousseau, Yves Payette,
Helen Tryphonas, Barry Blakley, Herman Boermans, Denis Flipo, Michel Fournier
CNS Injuries: Cellular Responses and Pharmacological Strategies, 1999, Martin Berry
and Ann Logan
Infectious Diseases in Immunocompromised Hosts,1998, Vassil St. Georgiev
Pharmacology of Antimuscarinic Agents, 1998, Laszlo Gyermek
Basis of Toxicity Testing, Second Edition, 1997, Donald J. Ecobichon
Anabolic Treatments for Osteoporosis, 1997, James F. Whitfield and Paul Morley
Antibody Therapeutics, 1997, William J. Harris and John R. Adair
Muscarinic Receptor Subtypes in Smooth Muscle, 1997, Richard M. Eglen
Antisense Oligodeonucleotides as Novel Pharmacological Therapeutic Agents, 1997,
Benjamin Weiss
Airway Wall Remodelling in Asthma, 1996, A.G. Stewart
Drug Delivery Systems, 1996, Vasant V. Ranade and Mannfred A. Hollinger
Brain Mechanisms and Psychotropic Drugs, 1996, Andrius Baskys and Gary Remington
Receptor Dynamics in Neural Development, 1996, Christopher A. Shaw
Ryanodine Receptors, 1996, Vincenzo Sorrentino
Therapeutic Modulation of Cytokines, 1996, M.W. Bodmer and Brian Henderson
Pharmacology in Exercise and Sport, 1996, Satu M. Somani
Placental Pharmacology, 1996, B. V. Rama Sastry
Pharmacological Effects of Ethanol on the Nervous System, 1996, Richard A. Deitrich
Immunopharmaceuticals, 1996, Edward S. Kimball
Chemoattractant Ligands and Their Receptors, 1996, Richard Horuk
Pharmacological Regulation of Gene Expression in the CNS, 1996, Kalpana Merchant
Experimental Models of Mucosal Inflammation, 1995, Timothy S. Gaginella
Human Growth Hormone Pharmacology: Basic and Clinical Aspects, 1995,
Kathleen T. Shiverick and Arlan Rosenbloom
Placental Toxicology, 1995, B. V. Rama Sastry
Stealth Liposomes, 1995, Danilo Lasic and Frank Martin
TAXOL®: Science and Applications, 1995, Matthew Suffness
Endothelin Receptors: From the Gene to the Human, 1995, Robert R. Ruffolo, Jr.
Alternative Methodologies for the Safety Evaluation of Chemicals in the
Cosmetic Industry,1995, Nicola Loprieno
Phospholipase A in Clinical Inflammation: Molecular Approaches to Pathophysiology,
2
1995, Keith B. Glaser and Peter Vadas
Serotonin and Gastrointestinal Function, 1995, Timothy S. Gaginella and
James J. Galligan
Chemical and Structural Approaches to Rational Drug Design, 1994, David B. Weiner
and William V. Williams
Biological Approaches to Rational Drug Design, 1994, David B. Weiner and
William V. Williams
Pharmacology and Toxicology: Basic and Clinical Aspects
Published Titles (Continued)
Direct and Allosteric Control of Glutamate Receptors, 1994, M. Palfreyman,
I. Reynolds, and P. Skolnick
Genomic and Non-Genomic Effects of Aldosterone, 1994, Martin Wehling
Peroxisome Proliferators: Unique Inducers of Drug-Metabolizing Enzymes, 1994,
David E. Moody
Angiotensin II Receptors, Volume I: Molecular Biology, Biochemistry, Pharmacology,
and Clinical Perspectives, 1994, Robert R. Ruffolo, Jr.
Angiotensin II Receptors, Volume II: Medicinal Chemistry, 1994,
Robert R. Ruffolo, Jr.
Beneficial and Toxic Effects of Aspirin, 1993, Susan E. Feinman
Preclinical and Clinical Modulation of Anticancer Drugs, 1993, Kenneth D. Tew,
Peter Houghton, and Janet Houghton
In Vitro Methods of Toxicology, 1992, Ronald R. Watson
Human Drug Metabolism from Molecular Biology to Man, 1992, Elizabeth Jeffreys
Platelet Activating Factor Receptor: Signal Mechanisms and Molecular Biology,
1992, Shivendra D. Shukla
Biopharmaceutics of Ocular Drug Delivery, 1992, Peter Edman
Pharmacology of the Skin, 1991, Hasan Mukhtar
Inflammatory Cells and Mediators in Bronchial Asthma, 1990, Devendra K. Agrawal
and Robert G. Townley
Molecular Bases of
Anesthesia
Edited by
Eric Moody
and Phil Skolnick
CRC Press
Boca Raton London New York Washington, D.C.
8555_frame_FM Page 6 Tuesday, November 7, 2000 12:58 PM
Library of Congress Cataloging-in-Publication Data
Molecular bases of anesthesia / edited by Eric Moody and Phil Skolnick.
p. cm.-- (Pharmacology and toxicology)
Includes bibliographical references and index.
ISBN 0-8493-8555-5 (alk. paper)
1. Anesthetics. 2. Molecular pharmacology. I. Moody, Eric. II. Skolnick, Phil. III.
Pharmacology & toxicology (Boca Raton, Fla.)
RD82 .M633 2000
617.9′6—dc21 00-064136

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Preface
The concept of this monograph began with the search for a comprehensive, focused
source of information on anesthetic mechanisms. Here, we have gathered a number
of contributions from researchers with diverse points of view, and have sought to
cover the most important areas of current interest concerning anesthetic mechanisms.
The focus of this monograph is squarely on neuroreceptors, with deliberate emphasis
on ion channels. This reflects the area of greatest current interest. Lipid interactions
with general anesthetics have not been covered separately, but information relevant
to this topic is covered in the introductory chapter. This bias is fully consistent with
a rapidly accumulating body of evidence, including the recent identification of targets
for anesthetics on protein ion channels.
The field of anesthetic mechanisms is far different from what it was a decade
or two ago. The unique pharmacology and low potencies of general anesthetics
complicated the search for appropriate targets, and our meager understanding of the
basic foundations of consciousness led to myriad anesthetic theories. Likewise, basic
conceptual issues, such as whether lipids or proteins were the primary targets of
anesthetics, resulted in little common ground between these two groups of research-
ers. The seminal observation that the effects of anesthetics on lipids were very modest
and mimicked by other conditions (such as small changes in temperature) caused
many researchers to focus on proteins as targets of anesthetic action. At the same
time, the basic physiology and structure of receptors and ion channels were eluci-
dated. For example, insight into benzodiazepine actions at the GABA receptors led
A
to studies with barbiturates, alcohols, and volatile anesthetics at this family of ligand-
gated ion channels. Simultaneously, studies were being conducted with anesthetics
at other potential loci of action.
The use of molecular biological techniques has also been applied to this study
of anesthetic mechanisms. As can be seen from many of the contributions to this
monograph, recombinant receptors have been very useful in elucidating anesthetic
actions. Several researchers have used mutagenesis techniques to identify crucial
segments of receptors involved in anesthetic action. Putative loci for volatile anes-
thetics and alcohols, as well as intravenous anesthetics have been described. These
are exciting findings providing a framework to evaluate theories of anesthesia and
allowing a better understanding of anesthetic actions at the molecular level. Substi-
tution of various amino acids at crucial loci on a receptor provide an opportunity to
determine the size of potential binding sites. Moreover, the use of transgenic animals
may provide the opportunity to determine if the in vitro effects of anesthetics cause
in vivo changes in anesthetic effects. Such experiments, if successful, may provide
a method for determining the pharmacological relevance of experimental observa-
tions and resolving discrepancies between opposing theories of anesthesia. Many of
the opposing concepts relating to anesthetic mechanisms are not fully resolved. It
is our hope that this volume will provide the information and framework for readers
to review and evaluate these issues. In addition, we trust that this book will be a
useful reference for those with an interest in anesthesiology, and will stimulate
further study.
Dedication
This work is dedicated to the postdoctoral fellows whose hard work and commitment
resulted in much of the data contained in this book, and to the Intramural Program
at the National Institutes of Health for creating an exciting research environment
which encouraged risk taking.