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Unformatted text preview: See discussions, stats, and author profiles for this publication at: Anesthetics Drug Pharmacodynamics Article in Handbook of experimental pharmacology · February 2008 DOI: 10.1007/978-3-540-74806-9_18 · Source: PubMed CITATIONS READS 2 10,966 3 authors: P. Bischoff 108 PUBLICATIONS 1,134 CITATIONS SEE PROFILE Gerhard Schneider Technische Universität München 273 PUBLICATIONS 2,940 CITATIONS SEE PROFILE Eberhard F Kochs Technische Universität München 688 PUBLICATIONS 8,686 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: Antibiotic Stewardship View project Adverse drug interactions in suspected brain death View project All content following this page was uploaded by Eberhard F Kochs on 16 May 2014. The user has requested enhancement of the downloaded file. Handbook of Experimental Pharmacology Volume 182 Editor-in-Chief K. Starke, Freiburg i. Br. Editorial Board S. Duckles, Irvine, CA M. Eichelbaum, Stuttgart D. Ganten, Berlin F. Hofmann, München C. Page, London W. Rosenthal, Berlin G. Rubanyi, San Diego, CA Jürgen Schüttler • Helmut Schwilden Editors Modern Anesthetics Contributors J. Ahonen, G. Akk, B. Antkowiak, M. Arras, V. Billard, P. Bischoff, T.W. Bouillon, J.G. Bovill, D. Brian, F. Camu, A. De Wolf, B. Drexler, J. Fechner, B.M. Graf, C. Grashoff, J.F.A. Hendrickx, T.K. Henthorn, R. Jurd, E. Kochs, K. Kück, G. Kullik, S. Lambert, J. Manigel, M. Maze, S. Mennerick, J.-U. Meyer, C. Nau, K.T. Olkkola, M. Perouansky, U. Rudolph, R.D. Sanders, W. Schlack, G. Schneider, J. Schüttler, H. Schwilden, F. Servin, S.L. Shafer, B. Sinner, D.R. Stanski, J.H. Steinbach, B.W. Urban, C. Vanlersberghe, N.C. Weber, N. Wruck, A. Zeller Prof. Dr. h.c. Jürgen Schüttler Klinik fu¯r Anästhesiologie Friedrich-Alexander-Universität Erlangen-Nürnberg Krankenhausstr. 12 D-91054 Erlangen Germany [email protected] ISBN: 978-3-540-72813-9 Prof. Dr. Dr. Helmut Schwilden Klinik fu¯r Anästhesiologie Friedrich-Alexander-Universität Erlangen-Nürnberg Krankenhausstr. 12 D-91054 Erlangen Germany [email protected] e-ISBN: 978-3-540-74806-9 Handbook of Experimental Pharmacology ISSN 0171-2004 Library of Congress Control Number: 2007936361 © 2008 Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover Design: WMXDesign GmbH, Heidelberg Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com Preface Some important constraints of anesthesia must be taken into consideration when the pharmacological properties of modern anesthetics are discussed. The most important of these could be that the target effect be achieved preferably within seconds, at most within a few minutes. Similarly, offset of drug action should be achieved within minutes rather hours. The target effects, such as unconsciousness, are potentially life-threatening, as are the side effects of modern anesthetics, such as respiratory and cardiovascular depression. Finally, the patient’s purposeful responses are not available to guide drug dosage, because, either the patient is unconscious, or more problematically, the patient is aware but unable to communicate pain because of neuromuscular blockade. These constraints were already recognised 35 years ago, when in 1972 Volume XXX entitled “Modern Inhalation Anesthetics” appeared in this Handbook Series. The present volume is meant as a follow up and extension of that volume. At the beginning of the 1970’s anesthesia was commonly delivered by inhalation, with only very few exceptions. The clinical understanding of that time considered anesthesia as a unique state achieved by any of the inhalation anesthetics, independent of their specific molecular structure. “The very mechanism of anesthetic action at the biophase” was discussed within the theoretical framework of the “unitary theory of narcosis”. This theoretical understanding was based on the MeyerOverton correlation and the apparent additivity of MAC when several inhalational anesthetics were given simultaneously, MAC being the measure of anesthetic potency and anesthetic depth developed in the mid-1960’s. Since the 1980’s this understanding has changed completely. Today “general anesthesia” is commonly considered a collection of neurophysiologically very different states, achieved by a multitude of very different drugs (delivered not only by inhalation) acting on a plethora of subcellular structures. Unconsciousness and absence of pain are always included in this collection of different states. Three main factors contributed to this changed understanding: 1) the increasing use of intravenous anesthesia, facilitated by the development of new intravenous anesthetics, not only for the induction but also for the maintenance of anesthesia 2) the discovery of non-additive types of anesthetic interactions, v vi Preface 3) the development of molecular techniques (biological, pharmacological and physiological) to study the interaction of anesthetic drug molecules with receptive cell structures. For these reasons, when the outline of this Handbook was discussed at a brainstorming meeting in Erlangen in February 2005, it became clear that it should be entitled “Modern Anesthetics” and contain in addition to a section on “Inhalation Anesthetics” one on “Intravenous Anesthetics”, preceded by another on “Molecular Mechanisms of Anesthetic Action”. Emphasis was put on the term “molecular” to draw attention to the discovery in the past decades of a great many findings on the interaction of anesthetic compounds with subcellular entities. On the other hand, this emphasis was to underline the lack of our understanding concerning the summation of all the different interactions from the molecular level through the progressive stages of integration within the CNS, which needs to be studied in the future. While these considerations may be considered mainstream of current research in experimental anesthetic pharmacology, it was strongly felt that the particularities of anesthetic drug therapy discussed above require not only specific drugs, but also very particular modes of their delivery and administration. It is not only the properties of the compounds but the combination of compounds plus drug delivery system which turns the compounds into a clinically effective and safe drug. It was therefore thought necessary to integrate a fourth section on “Pharmacokinetics-Pharmacodynamics based Administration of Anesthetics”. This final section illustrates a strategy, still at an experimental stage, in which the integration of drug, medical technology and computational medicine leads to optimized anesthetic therapeutic systems. We wish to thank all colleagues and authors for their endurance and willingness to contribute all their efforts and a considerable amount of time, to share freely their outstanding expertise and knowledge for this Handbook. Special thanks go to those who took responsibilities for each of the four sections: to Bernd Urban for “Molecular Mechanisms of Anesthetic Action”, to Jim Bovill for “Modern Inhalation Anesthetics”, to Frederic Camu for “Modern Intravenous Anesthetics”, and to Don Stanski for “Phamacokinetics-Pharmacodynamics based Administration of Anesthetics”. Erlangen, Germany Jürgen Schüttler Helmut Schwilden Contents Part I Molecular Mechanisms of Anesthetic Action Section Editor: B.W. Urban The Site of Anesthetic Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B.W. Urban Inhibitory Ligand-Gated Ion Channels as Substrates for General Anesthetic Actions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Zeller, R. Jurd, S. Lambert, M. Arras, B. Drexler, C. Grashoff, B. Antkowiak, and U. Rudolph Actions of Anesthetics on Excitatory Transmitter-Gated Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Akk, S. Mennerick, and J.H. Steinbach 3 31 53 Voltage-Gated Ion Channels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Nau 85 G-Protein-Coupled Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . R.D. Sanders, D. Brian, and M. Maze 93 Part II Modern Inhalation Anesthetics Section Editor: J.G. Bovill Inhalation Anaesthesia: From Diethyl Ether to Xenon . . . . . . . . . . . . . . . . 121 J.G. Bovill General Anesthetics and Long-Term Neurotoxicity . . . . . . . . . . . . . . . . . . . 143 vii viii Contents M. Perouansky Special Aspects of Pharmacokinetics of Inhalation Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 J.F.A. Hendrickx and A. De Wolf Inhalational Anaesthetics and Cardioprotection . . . . . . . . . . . . . . . . . . . . . 187 N.C. Weber and W. Schlack Non-Immobilizing Inhalational Anesthetic-Like Compounds. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 M. Perouansky Part III Modern Intravenous Anesthetics Section Editor: F. Camu Propofol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 C. Vanlersberghe and F. Camu Pharmacokinetics and Pharmacodynamics of GPI 15715 or Fospropofol (Aquavan Injection) – A Water-Soluble Propofol Prodrug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253 J. Fechner, H. Schwilden, and J. Schüttler Etomidate and Other Non-Barbiturates . . . . . . . . . . . . . . . . . . . . . . . . . . . . 267 C. Vanlersberghe and F. Camu Remifentanil and Other Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 283 F.S. Servin and V. Billard Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 B. Sinner and B.M. Graf Midazolam and Other Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 K.T. Olkkola and J. Ahonen Part IV Pharmacokinetics-Pharmacodynamics Based Administration of Anesthetics Section Editor: D.R. Stanski The Effect of Altered Physiological States on Intravenous Anesthetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363 T.K. Henthorn Contents ix Anesthetics Drug Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 379 P. Bischoff, G. Schneider, and E. Kochs Defining Depth of Anesthesia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409 S.L. Shafer and D.R. Stanski Target Controlled Anaesthetic Drug Dosing . . . . . . . . . . . . . . . . . . . . . . . . . 425 H. Schwilden and J. Schüttler Advanced Technologies and Devices for Inhalational Anesthetic Drug Dosing. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 451 J.-U. Meyer, G. Kullik, N. Wruck, K. Kück, and J. Manigel Hypnotic and Opioid Anesthetic Drug Interactions on the CNS, Focus on Response Surface Modeling. . . . . . . . . . . . . . . . . . . . 471 T.W. Bouillon Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489 Contributors J. Ahonen Helsinki University Central Hospital, Department of Anesthesia and Intensive Care Medicine, Women’s Hospital, P.O. Box 140 (Haartmaninkatu 2), FIN-00029 Hus, Finland, [email protected] G. Akk Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, USA B. Antkowiak Section of Experimental Anesthesiology, University of Tübingen, Tübingen, Baden-Württemberg, Germany M. Arras Institute of Laboratory Animal Sciences, University of Zurich, Zurich, Switzerland V. Billard Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif Cedex, France, [email protected] P. Bischoff Klinik und Poliklinik für Anästhesiologie, Universitätsklinikum HamburgEppendorf, Gebäude O50, Martinistraße 52, 20246 Hamburg, Germany, [email protected] T.W. Bouillon Novartis Pharma AG, PH346, Modeling & Simulation, CHBS, WSJ-027.4.048, Lichtstraße 35, CH-4056 Basel, Switzerland, [email protected] J.G. Bovill Department of Anaesthesiology, Leiden University Medical Centre, P.O. Box 9600, NL-2300 RC Leiden, The Netherlands, [email protected] xi xii Contributors D. Brian Academic Anaesthetics, Imperial College, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK F. Camu Department of Anesthesiology, V.U.B. Medical Center, University of Brussels, Laarbeeklaan 101, B-1090 Brussels, Belgium, [email protected] A. De Wolf Department of Anesthesiology, Feinberg School of Medicine, Northwestern University, 251 E. Huron St, F5-704, Chicago, IL 60611, USA, [email protected] B. Drexler Section of Experimental Anesthesiology, University of Tübingen, Tübingen, Baden-Württemberg, Germany J. Fechner Klinik fu¯r Anästhesiologie, Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany, [email protected] B.M. Graf Zentrum Anästhesiologie, Abt. Anästhesiologie I, Universitätsklinikum Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany, [email protected] C. Grashoff Section of Experimental Anesthesiology, University of Tübingen, Tübingen, Baden-Württemberg, Germany J.F.A. Hendrickx Department of Anesthesiology and Intensive Care, OLV Hospital, Moorselbaan 164, 9300 Aalst, Belgium, [email protected] T.K. Henthorn Department of Anesthesiology, University of Colorado HSC, 4200 E. 9th Avenue, Denver, CO 80262, USA, [email protected] R. Jurd Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland E. Kochs Klinik für Anästhesiologie, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany, [email protected] Contributors xiii K. Kück Drägerwerk Aktiengesellschaft, Moislinger Allee 53-55, 23542 Lübeck, Germany G. Kullik Drägerwerk Aktiengesellschaft, Moislinger Allee 53-55, 23542 Lübeck, Germany S. Lambert Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland J. Manigel Drägerwerk Aktiengesellschaft, Moislinger Allee 53-55, 23542 Lübeck, Germany M. Maze Head of Department of Anaesthetics, Imperial College London, Chelsea and Westminster Hospital, 369, Fulham Road, London SW10 9NH, UK, [email protected] S. Mennerick Departments of Psychiatry and Anatomy & Neurobiology and the Neurosciences Program, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, MO 63110, USA J.-U. Meyer Drägerwerk Aktiengesellschaft, Moislinger Allee 53-55, 23542 Lübeck, Germany, [email protected] C. Nau Klinik fu¯r Anästhesiologie, Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany, [email protected] K.T. Olkkola Department of Anaesthesiology, Intensive Care, Emergency Care and Pain Medicine, Turku University Hospital, PO Box 52 (Kiinamyllynkatu 4-8), FI-20521 Turku, Finland, [email protected] M. Perouansky Department of Anesthesiology, Room 43, Bardeen Labs, 1300 University Ave., Madison, WI 53792-3272, USA, [email protected] U. Rudolph Laboratory of Genetic Neuropharmacology, McLean Hospital, Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA, [email protected] xiv Contributors R.D. Sanders Academic Anaesthetics, Imperial College, Chelsea & Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK W. Schlack Department of Anaesthesiology, University of Amsterdam (AMC), Meibergdreef 9, NL-1100 DD Amsterdam, The Netherlands, [email protected] G. Schneider Klinik für Anästhesiologie, Klinikum Rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany J. Schüttler Klinik fu¯r Anästhesiologie, Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany, [email protected] H. Schwilden Klinik fu¯r Anästhesiologie, Universität Erlangen-Nürnberg, Krankenhausstr. 12, 91054 Erlangen, Germany, [email protected] F.S. Servin Service d’Anesthésie-Réanimation chirurgicale, Hôpital Bichat, 46, rue Henri-Huchard, 75877 Paris Cedex 18, France, [email protected], [email protected] S.L. Shafer Department of Anesthesiology, Stanford University School of Medicine, 300 Pasteur Dr., Stanford, CA 94305A, USA, [email protected] B. Sinner Zentrum für Anaesthesie, Rettungs- und Intensivmedizin, Georg August Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany D.R. Stanski 3903 Albemerle N.W., Washington, DC 20016, USA, [email protected] J.H. Steinbach Department of Anesthesiology, Washington University School of Medicine, 660 South Euclid Ave, Saint Louis, MO 63110, USA, [email protected] B.W. Urban Klinik für Anästhesiologie, Universität Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany, [email protected] Contributors xv C. Vanlersberghe Department of Anesthesiology, V.U.B. Medical Center, University of Brussels, Laarbeeklaan 101, B-1090 Brussels, Belgium, [email protected] N.C. Weber Department of Anaesthesiology, University of Amsterdam (AMC), Meibergdreef 15, M0-128, NL-Amsterdam 1105 AZ, The Netherlands, [email protected] N. Wruck Drägerwerk Aktiengesellschaft, Moislinger Allee 53-55, 23542 Lübeck, Germany A. Zeller Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland The Site of Anesthetic Action B.W. Urban 1 2 Introduction.......................................................................................................................... Anesthetics and Their Targets .............................................................................................. 2.1 General Anesthetics in Clinical Use ........................................................................... 2.2 General Anesthetics in Experimental Use .................................................................. 2.3 Anesthetic Potency...................................................................................................... 2.4 Identifying Molecular Targets..................................................................................... 3 Physical and Chemical Nature of Anesthetic Interactions................................................... 3.1 Thermodynamic Approaches ...................................................................................... 3.2 Weak Forces Stabilizing Structures of Biological Macromolecules........................... 3.3 Ion–Ion Interactions .................................................................................................... 3.4 Ion–Dipole Interactions .............................................................................................. 3.5 Van der Waals Interactions (Dipole–Dipole) .............................................................. 3.6 Hydrogen Bonding .....................................................
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