DOCSLIB.ORG

Isoflurane Potentiation of GABAA Receptors Is Reduced But

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Isoflurane Potentiation of GABAA Receptors Is Reduced But International Journal of Molecular Sciences Article Isoflurane Potentiation of GABAA Receptors Is Reduced but Not Eliminated by the β3(N265M) Mutation Chong Lor, Misha Perouansky and Robert A. Pearce * Department of Anesthesiology, University of Wisconsin, Madison, WI 53705, USA; [email protected] (C.L.); [email protected] (M.P.) * Correspondence: [email protected]; Tel.: +1-608-279-3574 Received: 25 November 2020; Accepted: 11 December 2020; Published: 15 December 2020 Abstract: Background: Mice carrying the GABAA receptor β3(N265M) point mutation, which renders receptors incorporating β3-subunits insensitive to many general anesthetics, have been used experimentally to link modulation of different receptor subtypes to distinct behavioral endpoints. Remarkably, however, the effect of the mutation on the susceptibility to modulation by isoflurane (a standard reference agent for inhalational vapors) has never been tested directly. Therefore, we compared the modulation by isoflurane of expressed α5β3(N265M)γ2L receptors with their wild type counterparts. Methods: Using whole-cell electrophysiological recording and rapid solution exchange techniques, we tested the effects of isoflurane at concentrations ranging from 80 µM to 320 µM on currents activated by 1 µM GABA. We measured drug modulation of wild-type α5β3γ2L GABAA receptors and their counterparts harboring the β3(N265M) mutation. Results: Currents elicited by GABA were enhanced two- to four-fold by isoflurane, in a concentration-dependent manner. Under the same conditions, receptors incorporating the β3(N265M) mutation were enhanced by approximately 1.5- to two-fold; i.e., modulation by isoflurane was attenuated by approximately one-half. Direct activation by isoflurane was also present in mutant receptors but also attenuated. Conclusions: In contrast to the complete insensitivity of β3(N265M) mutant receptors to etomidate and propofol, the mutation has only a partial effect on receptor modulation by isoflurane. Therefore, the persistence of isoflurane effects in mutant mice does not exclude a possible contribution of β3-GABAA receptors. Keywords: anesthetic action; general anesthesia; unconsciousness; amnesia; GABA; intravenous anesthetics; volatile anesthetics 1. Introduction The ionotropic γ-aminobutyric acid receptor (GABAAR) remains a target of considerable interest in understanding the mechanism of action of general anesthetics [1–3]. To link modulation of specific subtypes of GABAARs to the various endpoints of anesthesia, a fruitful experimental strategy has utilized mice carrying point mutations of individual receptor subunits that alter or eliminate anesthetic sensitivity; by comparing drug effects in wild-type versus mutant animals, the role of the specific receptor subtypes can thereby be tested. For the injectable GABAergic anesthetics etomidate and propofol, this approach has linked GABAARs that incorporate β2 subunits to sedation and β3 subunits to loss of righting reflex, respiratory depression, and suppression of the hindlimb withdrawal reflex (“immobilization”) [4–6]. A similar strategy has been followed for the potent inhalational agents, including isoflurane. Mice carrying α1- or α2-subunit mutations weakly resisted isoflurane’s suppression of the righting Int. J. Mol. Sci. 2020, 21, 9534; doi:10.3390/ijms21249534 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 9534 2 of 8 reflex, but they did not differ from wild-type mice in tests of isoflurane-induced immobilization or memoryInt. J. Mol. [7,8 Sci.].Similarly, 2020, 21, x FOR mice PEER carrying REVIEW the β3(N265M) mutation partially resisted isoflurane-induced2 of 8 immobilization [9,10], but memory suppression did not differ from wild-type mice [10]. Taken together, memory [7,8]. Similarly, mice carrying the β3(N265M) mutation partially resisted isoflurane-induced theseimmobilization findings have [9,10], been but taken memory to indicate suppression that GABA did notAR differ modulation from wild-type contributes mice modestly[10]. Taken to the abilitytogether, of isoflurane these findings to suppress have b movementeen taken tobut indicate not tothat its GABA abilityAR to modulation block memory. contributes modestly toOne the importantability of isoflurane caveat to suppress this last movement conclusion but isnot that to itsin ability vitro tostudies block memory. of β3(N265M) receptor modulationOne byimportant isoflurane caveat are to lacking. this last Inconclusion other studies is that ofin recombinantvitro studies of receptors, β3(N265M) the receptorβ3(N265M) mutationmodulation strongly by attenuatedisoflurane are modulation lacking. In ofotherα2 βstudies3γ2 receptors of recombinant by enflurane receptors, [11 ],the and β3(N265M) mutating the analogousmutation residue strongly of theattenuatedβ1 subunit modulation completely of α2β prevented3γ2 receptors isoflurane by enflurane from [11], modulating and mutatingα2β the1(S265I) receptorsanalogous [12]. residue However, of the manyβ1 subunit factors completely can influence prevented pharmacological isoflurane from modulating characteristics α2β1(S265I) of mutated receptors,receptors including [12]. However, the amino many acid fa usedctors tocan replace influence the nativepharmacological residue, the characteristics choice of the of other mutated subunits receptors, including the amino acid used to replace the native residue, the choice of the other subunits with which the mutant subunit is expressed, and the specific inhaled agent that is applied [11–13]. with which the mutant subunit is expressed, and the specific inhaled agent that is applied [11–13]. β GivenGiven the criticalthe critical nature nature of theof the assumption assumption that that the the β3(N265M)3(N265M) mutation also also eliminates eliminates sensitivity sensitivity to isoflurane,to isoflurane, the lack the of lack a direct of a direct test test of the of the eff ecteffect of of the the mutation mutation on on isofluraneisoflurane modulation modulation constitutes constitutes an importantan important knowledge knowledge gap. gap. To fillTo thisfill this gap, gap, we we tested tested the the sensitivity sensitivity ofof recombinant β3(N265M)-containingβ3(N265M)-containing receptors receptors to to isoflurane.isoflurane. We We chose chose to co-expressto co-expressβ β33 subunits subunits with αα55 and and γ2Lγ2L subunits subunits because because this thiscombination combination is is preferentiallypreferentially expressed expressed in the in hippocampus the hippocampus [14,15 [14,15]] and itand is a it plausible is a plausible target fortarget anesthetic for anesthetic interference withinterference memory formation with memory [16,17 ].formation We found [16,17]. that theWe mutation found that reduced, the mutation but did reduced, not eliminate, but did isoflurane not eliminate, isoflurane modulation. These results suggest that the conclusion that β3-GABAARs do not modulation. These results suggest that the conclusion that β3-GABAARs do not contribute to contribute to isoflurane-induced amnesia, and only contribute modestly to immobility, may be isoflurane-induced amnesia, and only contribute modestly to immobility, may be unwarranted. unwarranted. 2. Results 2. Results 2.1. Isoflurane Modulation of GABA—Elicited Currents 2.1. Isoflurane Modulation of GABA—Elicited Currents µ ApplicationApplication of 1of 1M μM GABA GABA to to recombinant recombinant GABA AARsRs induced induced currents currents through through both bothwild-type wild-type (α5β(3αγ52L)β3γ2L) and and mutant mutant (α 5(αβ53(N265M)β3(N265M)γγ2L)2L) receptors (Figure (Figure 1A).1A). Peak Peak currents currents ranged ranged from from −61 to 61 to − 1205−1205 pA andpA and from from65 − to65 to693 −693 pA pA for for wild-type wild-type and and mutant mutant receptors, receptors, respectively, respectively, reflecting reflecting thethe lesser − − − potencylesser of potency GABA atof mutantGABA at receptors. mutant receptors. [18] Co-application [18] Co-application of isoflurane of isoflurane resulted resulted in a dose-dependent, in a dose- reversibledependent, potentiation reversible of potentiation the currents of inthe both currents wild-type in both andwild-typeβ3(N265M) and β3(N265M) receptors receptors (Figure (Figure1B). At the highest1B). concentration At the highest ofconcentratio isofluranen of tested isoflurane (320 µ testedM), responses (320 μM), toresponses GABA rangedto GABA from ranged263 from to −2633612 for − − wild-typeto −3612 and for wild-type129 to 1491 and − pA129 for to −β14913(N265M) pA for mutantβ3(N265M) receptors. mutant receptors. A summary A summary of the modulatory of the modulatory− effect of− isoflurane on GABA-elicited currents in wild-type and mutant receptors is effect of isoflurane on GABA-elicited currents in wild-type and mutant receptors is shown in Figure2. shown in Figure 2. A α5β3γ2L GABA 1 µM Isoflurane 80 µM 160 µM 320 µM B α5β3(N256M)γ2L 400 pA 400 500 ms GABA 1 µM Isoflurane 80 µM 160 µM 320 µM FigureFigure 1. Activation 1. Activation and and modulation modulation of of GABA-elicitedGABA-elicited currents currents by by isoflurane isoflurane in wild-type in wild-type and mutant and mutant GABAARs. Traces show whole-cell currents elicited by 500 ms applications of isoflurane alone GABA Rs. Traces show whole-cell currents elicited by 500 ms applications of isoflurane alone followed followedA by isoflurane plus 1 μM GABA, for (A) α5β3γ2L and (B) α5β3(N265M)γ2L recombinant by isoflurane plus 1 µM GABA, for (A) α5β3γ2L and (B) α5β3(N265M)γ2L recombinant receptors receptors expressed in HEK293 cells.
Load more

Recommended publications
  • Analgesia and Sedation in Hospitalized Children
    Analgesia and Sedation in Hospitalized Children By Elizabeth J. Beckman, Pharm.D., BCPS, BCCCP, BCPPS Reviewed by Julie Pingel, Pharm.D., BCPPS; and Brent A. Hall, Pharm.D., BCPPS LEARNING OBJECTIVES 1. Evaluate analgesics and sedative agents on the basis of drug mechanism of action, pharmacokinetic principles, adverse drug reactions, and administration considerations. 2. Design an evidence-based analgesic and/or sedative treatment and monitoring plan for the hospitalized child who is postoperative, acutely ill, or in need of prolonged sedation. 3. Design an analgesic and sedation treatment and monitoring plan to minimize hyperalgesia and delirium and optimize neurodevelopmental outcomes in children. INTRODUCTION ABBREVIATIONS IN THIS CHAPTER Pain, anxiety, fear, distress, and agitation are often experienced by GABA γ-Aminobutyric acid children undergoing medical treatment. Contributory factors may ICP Intracranial pressure include separation from parents, unfamiliar surroundings, sleep dis- PAD Pain, agitation, and delirium turbance, and invasive procedures. Children receive analgesia and PCA Patient-controlled analgesia sedatives to promote comfort, create a safe environment for patient PICU Pediatric ICU and caregiver, and increase patient tolerance to medical interven- PRIS Propofol-related infusion tions such as intravenous access placement or synchrony with syndrome mechanical ventilation. However, using these agents is not without Table of other common abbreviations. risk. Many of the agents used for analgesia and sedation are con- sidered high alert by the Institute for Safe Medication Practices because of their potential to cause significant patient harm, given their adverse effects and the development of tolerance, dependence, and withdrawal symptoms. Added layers of complexity include the ontogeny of the pediatric patient, ongoing disease processes, and presence of organ failure, which may alter the pharmacokinetics and pharmacodynamics of these medications.
    [Show full text]
  • Euthanasia of Experimental Animals
    EUTHANASIA OF EXPERIMENTAL ANIMALS • *• • • • • • • *•* EUROPEAN 1COMMISSIO N This document has been prepared for use within the Commission. It does not necessarily represent the Commission's official position. A great deal of additional information on the European Union is available on the Internet. It can be accessed through the Europa server (http://europa.eu.int) Cataloguing data can be found at the end of this publication Luxembourg: Office for Official Publications of the European Communities, 1997 ISBN 92-827-9694-9 © European Communities, 1997 Reproduction is authorized, except for commercial purposes, provided the source is acknowledged Printed in Belgium European Commission EUTHANASIA OF EXPERIMENTAL ANIMALS Document EUTHANASIA OF EXPERIMENTAL ANIMALS Report prepared for the European Commission by Mrs Bryony Close Dr Keith Banister Dr Vera Baumans Dr Eva-Maria Bernoth Dr Niall Bromage Dr John Bunyan Professor Dr Wolff Erhardt Professor Paul Flecknell Dr Neville Gregory Professor Dr Hansjoachim Hackbarth Professor David Morton Mr Clifford Warwick EUTHANASIA OF EXPERIMENTAL ANIMALS CONTENTS Page Preface 1 Acknowledgements 2 1. Introduction 3 1.1 Objectives of euthanasia 3 1.2 Definition of terms 3 1.3 Signs of pain and distress 4 1.4 Recognition and confirmation of death 5 1.5 Personnel and training 5 1.6 Handling and restraint 6 1.7 Equipment 6 1.8 Carcass and waste disposal 6 2. General comments on methods of euthanasia 7 2.1 Acceptable methods of euthanasia 7 2.2 Methods acceptable for unconscious animals 15 2.3 Methods that are not acceptable for euthanasia 16 3. Methods of euthanasia for each species group 21 3.1 Fish 21 3.2 Amphibians 27 3.3 Reptiles 31 3.4 Birds 35 3.5 Rodents 41 3.6 Rabbits 47 3.7 Carnivores - dogs, cats, ferrets 53 3.8 Large mammals - pigs, sheep, goats, cattle, horses 57 3.9 Non-human primates 61 3.10 Other animals not commonly used for experiments 62 4.
    [Show full text]
  • The Cardiorespiratory and Anesthetic Effects of Clinical and Supraclinical
    THE CARDIORESPIRATORY AND ANESTHETIC EFFECTS OF CLINICAL AND SUPRA CLINICAL DOSES OF ALF AXALONE IN CYCLODEXTRAN IN CATS AND DOGS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Master of Science in the Graduate School of The Ohio State University By Laura L. Nelson, B.S., D.V.M. * * * * * The Ohio State University 2007 Dissertation Committee: Professor Jonathan Dyce, Adviser Professor William W. Muir III Professor Shane Bateman If I have seen further, it is by standing on the shoulders of giants. lmac Ne1vton (1642-1727) Copyright by Laura L. Nelson 2007 11 ABSTRACT The anesthetic properties of steroid hormones were first identified in 1941, leading to the development of neurosteroids as clinical anesthetics. CT-1341 was developed in the early 1970’s, featuring a combination of two neurosteroids (alfaxalone and alphadolone) solubilized in Cremophor EL®, a polyethylated castor oil derivative that allows hydrophobic compounds to be carried in aqueous solution as micelles. Though also possessing anesthetic properties, alphadolone was included principally to improve the solubility of alfaxalone. CT-1341, marketed as Althesin® and Saffan®, was characterized by smooth anesthetic induction and recovery in many species, a wide therapeutic range, and no cumulative effects with repeated administration. Its cardiorespiratory effects in humans and cats were generally mild. However, it induced severe hypersensitivity reactions in dogs, with similar reactions occasionally occurring in cats and humans. The hypersensitivity reactions associated with this formulation were linked to Cremophor EL®, leading to the discontinuation of Althesin® and some other Cremophor®-containing anesthetics. More recently, alternate vehicles for hydrophobic drugs have been developed, including cyclodextrins.
    [Show full text]
  • Pharmacology/Therapeutics II Block III Lectures 2013-14
    Pharmacology/Therapeutics II Block III Lectures 2013‐14 66. Hypothalamic/pituitary Hormones ‐ Rana 67. Estrogens and Progesterone I ‐ Rana 68. Estrogens and Progesterone II ‐ Rana 69. Androgens ‐ Rana 70. Thyroid/Anti‐Thyroid Drugs – Patel 71. Calcium Metabolism – Patel 72. Adrenocorticosterioids and Antagonists – Clipstone 73. Diabetes Drugs I – Clipstone 74. Diabetes Drugs II ‐ Clipstone Pharmacology & Therapeutics Neuroendocrine Pharmacology: Hypothalamic and Pituitary Hormones, March 20, 2014 Lecture Ajay Rana, Ph.D. Neuroendocrine Pharmacology: Hypothalamic and Pituitary Hormones Date: Thursday, March 20, 2014-8:30 AM Reading Assignment: Katzung, Chapter 37 Key Concepts and Learning Objectives To review the physiology of neuroendocrine regulation To discuss the use neuroendocrine agents for the treatment of representative neuroendocrine disorders: growth hormone deficiency/excess, infertility, hyperprolactinemia Drugs discussed Growth Hormone Deficiency: . Recombinant hGH . Synthetic GHRH, Recombinant IGF-1 Growth Hormone Excess: . Somatostatin analogue . GH receptor antagonist . Dopamine receptor agonist Infertility and other endocrine related disorders: . Human menopausal and recombinant gonadotropins . GnRH agonists as activators . GnRH agonists as inhibitors . GnRH receptor antagonists Hyperprolactinemia: . Dopamine receptor agonists 1 Pharmacology & Therapeutics Neuroendocrine Pharmacology: Hypothalamic and Pituitary Hormones, March 20, 2014 Lecture Ajay Rana, Ph.D. 1. Overview of Neuroendocrine Systems The neuroendocrine
    [Show full text]
  • IV Induction Agents
    Intravenous drugs used for the induction of anaesthesia Dr Tom Lupton, Specialist Registrar in Anaesthesia Dr Oliver Pratt, Consultant Anaesthetist Salford Royal Hospitals NHS Foundation Trust, Salford, UK Key questions This tutorial reviews the basic pharmacology of common intravenous (IV) anaesthetic drugs. By the end of the tutorial, you should be able to decide on the most appropriate drug to use in the situations below and for what reason: 1. A patient with intestinal obstruction requires an emergency laparotomy. 2. A patient with a history of throat cancer, showing marked stridor and signs of respiratory distress, requires a tracheostomy. 3. A patient requiring a burn dressing change. 4. A patient with a history of heart failure requires a general anaesthetic. 5. A dehydrated hypovolaemic patient requires an emergency general anaesthetic. 6. A patient with porphyria comes for an inguinal hernia repair and is requesting a general anaesthetic. 7. A patient requires sedation on the intensive care unit. 8. Anaesthesia in the prehospital environment. What are IV induction drugs? These are drugs that, when given intravenously in an appropriate dose, cause a rapid loss of consciousness. This is often described as occurring within “one arm-brain circulation time” that is simply the time taken for the drug to travel from the site of injection (usually the arm) to the brain, where they have their effect. They are used: • To induce anaesthesia prior to other drugs being given to maintain anaesthesia. • As the sole drug for short procedures. • To maintain anaesthesia for longer procedures by intravenous infusion. • To provide sedation. The concept of intravenous anaesthesia was born in 1932, when Wesse and Schrapff published their report into the use of hexobarbitone, the first rapidly acting intravenous drug.
    [Show full text]
  • Safety and Efficacy of Etomidate And
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2016 Safety and efficacy of etomidate and propofol anesthesia in elderly patients undergoing gastroscopy: A double-blind randomized clinical study Qing-Tao Meng Wuhan University Chen Cao The Third Hospital of Wuhan Hui-Min Liu Wuhan University Zhong-Yuan Xia Wuhan University Wei Li Wuhan University See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Meng, Qing-Tao; Cao, Chen; Liu, Hui-Min; Xia, Zhong-Yuan; Li, Wei; Tang, Ling-Hua; Chen, Rong; Jiang, Meng; Wu, Yang; Leng, Yan; and Lee, Chris C., ,"Safety and efficacy of etomidate and propofol anesthesia in elderly patients undergoing gastroscopy: A double-blind randomized clinical study." Experimental and Therapeutic Medicine.12,3. 1515-1524. (2016). https://digitalcommons.wustl.edu/open_access_pubs/5193 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Qing-Tao Meng, Chen Cao, Hui-Min Liu, Zhong-Yuan Xia, Wei Li, Ling-Hua Tang, Rong Chen, Meng Jiang, Yang Wu, Yan Leng, and Chris C. Lee This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/5193 EXPERIMENTAL AND THERAPEUTIC MEDICINE 12: 1515-1524, 2016 Safety and efficacy of etomidate and propofol anesthesia in elderly patients undergoing gastroscopy: A double‑blind randomized clinical study QING-TAO MENG1*, CHEN CAO2*, HUI-MIN LIU1*, ZHONG-YUAN XIA1, WEI LI1, LING-HUA TANG1, RONG CHEN1, MENG JIANG1, YANG WU1, YAN LENG1 and CHRIS C.
    [Show full text]
  • Anaesthetic Modulation of Ion Channel Kinetics in Bovine Chromaffin Cells
    280740062X ANAESTHETIC MODULATION OF ION CHANNEL KINETICS IN BOVINE CHROMAFFIN CELLS BY PAUL CHARLESWORTH Thesis submitted for the degree of Doctor of Philosophy to the Faculty of Science of the University of London Department of Physiology Royal Free Hospital School of Medicine Rowland Hill Street Hampstead London NW3 2PF ProQuest Number: U063786 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a com plete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest U063786 Published by ProQuest LLC(2017). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States C ode Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 ABSTRACT The thesis describes a patch clamp study of the action of anaesthetics on the ion channels primarily responsible for initiating secretion in bovine chromaffin cells. The adrenal chromaffin cell is homologous with sympathetic post-ganglionic neurones and was chosen as a model for studying excitatory neuronal synapses. Pre- and post- synaptic events are modelled by effects on the voltage-gated calcium channels and nicotinic acetylcholine receptor channel respectively. The overall aim has been to describe anaesthetic depression of excitatory synaptic transmission at the ion channel level. Results of experiments with a representative range of anaesthetic agents are shown.
    [Show full text]
  • Etomidate Injection, USP Approximately Double That Seen in Healthy Subjects
    2585 suggest that the volume of distribution and elimination half-life of etomidate are Etomidate Injection, USP approximately double that seen in healthy subjects. 2 mg/mL (Reference: H. Van Beem, et. al., Anaesthesia 38 (Supp 38:61-62, July 1983). Rx only In clinical studies, elderly patients demonstrated decreased initial distribution DESCRIPTION volumes and total clearance of etomidate. Protein binding of etomidate to serum Etomidate Injection, USP is a sterile, nonpyrogenic solution. Each milliliter contains albumin was also significantly decreased in these individuals. etomidate, 2 mg, propylene glycol 35% v/v. The pH is 6.0 (4.0 to 7.0). Reduced plasma cortisol and aldosterone levels have been reported following It is intended for the induction of general anesthesia by intravenous injection. induction doses of etomidate. These results persist for approximately 6 to 8 hours The drug etomidate is chemically identified as (R)-(+)-ethyl-1-(1-phenylethyl)-1H- and appear to be unresponsive to ACTH stimulation. This probably represents imidazole -5-carboxylate and has the following structural formula: blockage of 11 beta-hydroxylation within the adrenal cortex. O N (References: 1. R.J. Fragen, et. al., Anesthesiology 61:652-656, 1984. 2. R.L. Wagner & P.F. White, Anesthesiology 61:647-651, 1984. 3. F.H. DeJong, et. al., CH3 CH2 O C N Clin. Endocrinology and Metabolism 59:(6):1143-1147, 1984, and three additional drafts of Metabolic Studies, all submitted to NDA 18-228 on April 1, 1985). H C CH INDICATIONS AND USAGE 3 Etomidate injection, USP is indicated by intravenous injection for the induction of general anesthesia.
    [Show full text]
  • Anesthetic Agents: General and Local Anesthetics T IMOTHY J
    Chapter 16 Anesthetic Agents: General and Local Anesthetics T IMOTHY J. MAHER Drugs Covered in This Chapter Inhaled general anesthetics • Propofol • Levobupivacaine • Ether • Fospropofol • Lidocaine • Halothane • Thiopental • Prilocaine • Desflurane Local anesthetics • Procaine • Ropivacaine • Enflurane • Articaine • Tetracaine • Isoflurane • Benzocaine • Methoxyflurane • Bupivacaine • Sevoflurane • Chloroprocaine • Nitrous oxide • Cocaine Intravenous general anesthetics • Dibucaine • Etomidate • Dyclonine • Ketamine • Mepivacaine Abbreviations BTX, batrachotoxin GABA, g-aminobutyric acid NO, nitric oxide CNS, central nervous system HBr, hydrobromic acid NMDA, N-methyl-D-aspartate COCl2, phosgene HCl, hydrochloric acid PABA, p-aminobenzoic acid EEG, electroencephalograph MAC, minimum alveolar concentration PCP, phencyclidine EMLA, Eutectic Mixture of a Local Na/K-ATPase, sodium-potassium STX, saxitoxin Anesthetic adenosine triphosphatase TTX, tetrodotoxin 508 LLemke_Chap16.inddemke_Chap16.indd 550808 112/9/20112/9/2011 44:14:08:14:08 AAMM CHAPTER 16 / ANESTHETIC AGENTS: GENERAL AND LOCAL ANESTHETICS 509 SCENARIO Paul Arpino, R.Ph. CDL is a 70-year-old obese man scheduled for carpal tunnel sur- During the preoperative assessment before the scheduled day of gery. A review of his medical file indicates a history of obstruc- surgery, the team discovers that CDL has an undefined allergy tive sleep apnea and benign prostatic hypertrophy (BPH). CDL to procaine (Novocain) and that he experienced severe blistering sleeps with a continuous positive pressure airway device and his after a dental procedure many years ago and was told he cannot BPH is treated with tamsulosin, 0.4 mg daily. Given that patients receive “drugs like Novocain again.” with sleep apnea are at high risk for respiratory depression, the clinical team decides that a peripheral nerve block would be a (The reader is directed to the clinical solution and chemical analy- better alternative to both neuraxial and general anesthesia.
    [Show full text]
  • Dexmedetomidine Combined with Etomidate Or Emulsified Isoflurane for Induction Reduced Cardiopulmonary Response in Dogs
    RESEARCH ARTICLE Dexmedetomidine combined with etomidate or emulsified isoflurane for induction reduced cardiopulmonary response in dogs Chao LiuID, Tingting LinID, Zhenlei Zhou* College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China * [email protected] a1111111111 Abstract a1111111111 To investigate the effects of etomidate, emulsified isoflurane, and their combination with a1111111111 a1111111111 dexmedetomidine on physiological parameters, electrocardiogram (ECG) results, and the a1111111111 quality of induction and recovery during isoflurane maintenance anaesthesia. 5 mixed- breed dogs received each of four treatments: etomidate (E group); emulsified isoflurane (EI group); both dexmedetomidine and etomidate (DE group); or both dexmedetomidine and emulsified isoflurane (DEI group). All drugs were IV injection administered for induction, fol- OPEN ACCESS lowed by 1.5 MAC (minimal alveolar concentration) of isoflurane to maintain anaesthesia. Rectal temperature (RT), respiratory rate (RR), heart rate (HR), mean arterial pressure Citation: Liu C, Lin T, Zhou Z (2018) Dexmedetomidine combined with etomidate or (MAP), and ECG were measured at baseline, 0, 5, 10, 20, 40, and 60 minutes after intuba- emulsified isoflurane for induction reduced tion. The quality of induction and recovery was evaluated for all dogs. All the anaesthetic cardiopulmonary response in dogs. PLoS ONE 13 procedures provided good conditions for induction of anaesthesia. The quality of induction (12): e0208625. https://doi.org/10.1371/journal. pone.0208625 and recovery in the E group was worse than other groups. The decrease of RR in the E and DE groups was stronger than that in the EI and DEI groups. The dogs in the E group had the Editor: Francesco Staffieri, University of Bari, ITALY most significant prolongation of the Q-T interval and changes in the S-T segment.
    [Show full text]
  • Clinical and Molecular Pharmacology of Etomidate
    REVIEW ARTICLE David S. Warner, M.D., Editor Clinical and Molecular Pharmacology of Etomidate Stuart A. Forman, M.D., Ph.D.* ABSTRACT TOMIDATE [R-1-(1-ethylphenyl)imidazole-5-ethyl E ester] (fig. 1) is a unique drug used for induction of general anesthesia and sedation. The first report on etomi- This review focuses on the unique clinical and molecular date was published in 1965 as one of several dozen aryl alkyl pharmacologic features of etomidate. Among general anes- imidazole-5-carboxylate esters1 synthesized by Janssen Phar- thesia induction drugs, etomidate is the only imidazole, and maceuticals (a division of Ortho-McNeil-Jannsen Pharma- it has the most favorable therapeutic index for single-bolus ceuticals, Titusville, NJ). Initially developed as antifungal administration. It also produces a unique toxicity among agents, the potent hypnotic activity of several compounds anesthetic drugs: inhibition of adrenal steroid synthesis that was observed during animal testing; and several com- far outlasts its hypnotic action and that may reduce survival pounds, including etomidate, appeared significantly safer of critically ill patients. The major molecular targets mediat- than barbiturates. ing anesthetic effects of etomidate in the central nervous Etomidate contains a chiral carbon (fig. 1). Initial studies ␥ system are specific -aminobutyric acid type A receptor sub- of racemic etomidate in rats demonstrated lethality at ap- types. Amino acids forming etomidate binding sites have proximately 12 times its effective hypnotic dose (median been identified in transmembrane domains of these proteins. lethal dose/ED50, approximately 12) compared with barbi- Etomidate binding site structure models for the main en- turates with median lethal dose/ED50 ratios (therapeutic in- zyme mediating etomidate adrenotoxicity have also been de- dexes) of 3–5.1 Subsequent studies2,3 found that the isolated veloped.
    [Show full text]
  • Rapid Sequence Intubation: Medications, Dosages, and Recommendations
    Rapid Sequence Intubation: Medications, dosages, and recommendations Timeline of Rapid Sequence Intubation S Zero Minus Zero Minus Zero Minus Zero Zero plus 20- Zero plus 10 Minutes 5 Minutes 3 Minutes 30 seconds 45 seconds 7. Post- intubation management 1. Preparation 2. Preoxygenation 3. 4. Paralysis/ 5. Positioning 6. Placement Pretreatment Induction with proof 1. Preparation – Assemble all necessary equipment, drug, etc. 2. Preoxygenation – Replace the nitrogen in the patient’s functional reserve with oxygen – “nitrogen wash out – oxygen wash in” 3. Pretreatment – Ancillary medications are administered to mitigate the adverse physiologic consequences of intubation 4. Paralysis with induction – Administer sedative induction agent via IV push, followed immediately by administration of paralytic via IV push 5. Positioning – Position patient for optimal laryngoscopy; Sellick’s maneuver, if desired, is applied now 6. Placement with proof – Assess mandible for flaccidity; perform intubation, confirm placement 7. Post-intubation management – Long-term sedation/analgesia/paralysis as indicated Pre-treatment – agents should be given 3 minutes prior to intubation (can be given in any order) Drug Dose Indication Other notes Lidocaine 100 mg Head injury, traumatic Lidocaine will help brain injury, unknown protect the patient mechanism of injury, from increases in elevated ICP intracranial pressure caused by intubation Fentanyl 2-3 mcg/kg Elevated ICP, Fentanyl helps decrease cardiovascular disease catecholamine (ischemic coronary discharge secondary to disease, aneurismal intubation, thus disease, great vessel decreasing the risks rupture or dissection, associated from BP intracranial increases in pts with CV hemorrhage) disease, aortic dissections, etc. Be careful if the patient is already hypotensive Rocuronium 0.1 mg/kg Head injury, traumatic Defasciculation no (defasciculation) (e.g., 7 mg in a 70 kg pt) brain injury, unknown longer routinely mechanism of injury, recommended.
    [Show full text]