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Mechanisms of Action of General Anesthetics

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Title: Mechanisms of Action of General Anesthetics


1
Mechanisms of Action of General Anesthetics
  • BCP 401 - Principles of Pharmacology
  • JP Dilger
  • November 26, 2008

2
Outline
  • What is general anesthesia?
  • MAC - Minimum Alveolar Concentration
  • Chemical structures of general anesthetics
  • Meyer-Overton correlation exceptions
  • Possible anesthetic binding sites
  • Molecular approaches to understanding anesthesia
  • In vivo approaches to understanding anesthesia

3
What is general anesthesia?
Do you think I should give him 50 or 100?
4
Analgesia
5
Amnesia
6
Hypnosis/Sedation
7
Immobility
8
General Anesthesia
  • Analgesia
  • Amnesia
  • Hypnosis/sedation
  • Immobility

9
How is anesthesia measured?
  • Lack of purposeful response to painful stimulus
  • surgical incision (humans, other mammals)
  • tail clamp (rat, mouse)
  • heat (rat, mouse, fruit fly)
  • Loss of righting reflex (rat, mouse)
  • Loss of spontaneous movement
  • Swimming (goldfish, tadpole)
  • flying (fruit fly)
  • crawling (nematode)

10
MAC Minimum Alveolar Concentration
  • 1.0 MAC is the concentration of inhalational
    anesthetic required to blunt the muscular
    response to surgical skin incision of 50 of a
    population of unparalyzed patients.

11
MAC the population response to anesthetics
12
Halothane MAC in the Animal Kingdom
13
MAC is not the whole story
MAC for isoflurane in rats Control
1.300.25 Decerebrated 1.260.14
MAC for isoflurane in goats Control
1.20.3 CNS bypass 2.90.7 Recovery 1.30.1
14
Anesthetics - Halogenated ethers
MW
1
2
3
4
5
6
7
8
Diethyl ether
74
H
H
CH
H
H
H
H
H
3
Fluroxene
126
H
H
CH
H
F
F
F
2
Methoxyflurane
165
F
H
H
H
F
Cl
H
Cl
Desflurane
168
H
F
H
F
F
F
F
F
Isoflurane
184
H
F
H
F
Cl
F
F
F
Enflurane
184
F
F
H
F
F
Cl
H
F
Sevoflurane
200
H
H
F
H
CF
F
F
F
3
15
Other inhalational anesthetics
16
Intravenous anesthetics
  • Propofol
  • Etomidate
  • Alphaxalone

Thiopental Midazolam Ketamine
17
Anesthetic Properties
18
Partition Coefficients
19
Meyer Overton Correlation
HAL Halothane ISO Isoflurane ENF Enflurane SEV Sev
oflurane FLU Fluroxene DES Desflurane CYC Cyclopro
pane MOF Methoxyflurane DEE Diethylether CHL Chlor
oform DDM Dichlorodiflurormethane PFE Perfluoroeth
ane CTF Carbon tetrafluroide SHF Sulfur
hexafluoride CYC Cyclopropane ETH Ethylene NO2 Nit
rous oxide XEN Xenon NIT Nitrogen KRY Krypton ARG
Argon
20
Non-anesthetics (non-immobilizers)
Correlation of 22
anesthetics in mouse
10000
1000
100
10
1
0.1
Olive Oil Gas Partition Coefficient
21
Awake! Awareness during anesthesia
  • 25 incidents in 19,575 cases
  • 1-2 per 1000
  • 26,000 per year in US

Alba Christensen, 2007
22
Lipid-Based Theories of Anesthetic Action
  • Direct action on lipids leads to Indirect action
    on proteins
  • Thickness and/or Volume Fluidity
  • Curvature Dielectric properties
  • Phase Transitions Ionic Permeability

23
Status of Lipid Theories
  • Currently in disfavor
  • little physical evidence - effects on bilayer
    properties are small
  • anesthetic to lipid ratio is low
  • 50 mM anesthetic distributed uniformly through
    50Å thick membrane corresponds to
  • 1 anesthetic molecule per 60 lipids
  • 1.5 of the molecules
  • 1 of the volume
  • specificity problem - lipids are ubiquitous
  • what about nonimmobilizers?

24
Fireflies and Anesthetics
25
Protein-based theories of Anesthetic Action
  • Anesthetics bind to amphipathic sites on
    proteins.
  • induce/prevent conformational change
  • alter kinetics of conformational changes
  • compete with ligands

26
Status of Protein Theories
  • Currently favored by many investigators
  • anesthetic binding sites have been identified on
    several proteins
  • some of these sites are stereospecific
  • effects on some proteins seen at relevant
    concentrations of anesthetics
  • the binding of 1 anesthetic molecule to 1 protein
    could produce a significant effect if the binding
    occurred at a functionally important part of the
    protein

27
Status of Protein Theories
  • Problems
  • lack of a chemical anesthetic antagonist
  • specificity problem - proteins are ubiquitous
  • which protein(s)?

28
Where do anesthetics act in the CNS?
CNS
Neurons
Glia
Axons
Synapses
Channels
Receptors Pumps Second Messengers Intracellular
Enzymes ??
29
Synaptic Effects of Anesthetics
Without anesthetic
With anesthetic
30
Direct effects of anesthetics on ion channels
  • Channel blocking effects of general anesthetics
    on nicotinic AChR.

(Dilger et al 1994)
31
Nicotine Reversal of Sedation?
  • Implant cannula for microinjection of nicotine
    into rat thalamus (?4?2 AChR)
  • After 1 week, induce loss of righting reflex with
    sevoflurane
  • Inject nicotine look for signs of arousal
  • Partial eye or other purposeful movements
  • Complete turning over ambulation

(Alkire et al 2007)
32
Effects of Nicotine
(Alkire et al 2007)
33
What about nicotine antagonists?
  • They do NOT induce LORR themselves
  • Consider nicotinic activity in thalamus as
    regulating an on switch but not an off switch

34
An Anesthetic Binding Site on the GABAA Receptor?
Krasowski et al 1998
35
Model of Binding Site
Mascia et al 2000
36
Genetics
  • Jurd et al 2003
  • Knock-in mice b3(N265M) GABAA receptors
  • Molecular biology
  • Electrophysiology
  • Behavioral
  • Anesthetics etomidate, propofol, enflurane,
    alphaxolone

37
Jurd et al. - etomidate
38
Jurd et al. enflurane
39
Working Hypothesis for Anesthesia
Eger et al, 1997 Solt Forman, 2007
40
Milestones in Anesthetic Mechanisms
  • Meyer-Overton Correlation
  • Anesthetics may interact directly with proteins
  • Brain vs. spinal cord
  • Role of GABAA receptor for propofol and etomidate
    effects on awareness

41
Summary?
  • Progress in anesthesia research is severely
    hindered by
  • our inadequate understanding of the brain
  • the low affinity of anesthetics for their site of
    action
  • the lack of a graded measure of depth of
    anesthesia
  • the lack of an agent that reverses anesthesia
  • many nonspecific effects

42
Summary!
  • Progress in anesthesia research is attainable
    because of
  • the powerful tools of molecular biology,
    electrophysiology and genetics
  • many people are studying many possible targets
    for anesthetics

43
Bibliography
  • Alkire MT, McReynolds JR, Hahn EL, Trivedi AN.
    Thalamic microinjection of nicotine reverses
    sevoflurane-induced loss of righting reflex in
    the rat. Anesthesiology 107 264-672, 2007
  • Antognini JF, Schwartz K. Exaggerated anesthetic
    requirements in the preferentially anesthetized
    brain. Anesthesiology 79 1244-1249 , 1993
  • Dilger JP, Vidal AM, Mody HI, Liu Y Evidence for
    direct actions of general anesthetics on an ion
    channel protein - a new look at a unified
    mechanism of action. Anesthesiology 81
    431-442, 1994
  • Eger EI, Koblin DD, Harris RA, Kendig JJ,
    Pohorille A, Halsey MJ, Trudell JR Hypothesis -
    inhaled anesthetics produce immobility and
    amnesia by different mechanisms at different
    sites. Anesthesia Analgesia. 84915-918, 1997
  • Franks NP, Lieb WR Molecular and cellular
    mechanisms of general anaesthesia. Nature 367
    607-614 , 1994
  • Franks NP, Lieb WR Do general anaesthetics act by
    competitive binding to specific receptors? Nature
    310 599, 1984
  • Jurd R, Arras M, Lambert S, Drexler B, Siegwart
    R, Crestani F, Zaugg M, Vogt KE, Ledermann B,
    Antkowiak B, Rudolph U. General anesthetic
    actions in vivo strongly attenuated by a point
    mutation in the GABAA receptor b3 subunit. FASEB
    J 17, 250, 2003
  • Koblin DD, Chortkoff BS, Laster MJ, Eger EI,
    Halsey MJ, Ionescu P Polyhalogenated and
    perfluorinated compounds that disobey the
    Meyer-Overton hypothesis. Anesthesia and
    Analgesia 79 1043-1048, 1994
  • Krasowski MD, Koltchine VV, Rick CE, Ye Q, Finn
    SE, Harrison NL. Propofol and other intravenous
    anesthetics have sites of action on the
    g-aminobutyric acid type A receptor distinct from
    that for isoflurane. Molecular Pharmacology 53
    530-538,1998
  • Mascia MP, Trudell JR, Harris RA. Specific
    binding sites for alcohols and anesthetics on
    ligand-gated ion channels. Proc Natl Acad Sci U S
    A. 979305-10, 2000
  • Rampil IJ, Mason P, Singh H Anesthetic potency
    (MAC) is independent of forebrain structures in
    the rat. Anesthesiology 78 707-712 , 1993
  • Sebel PS, et al. The incidence of awareness
    during anesthesia A multicenter United States
    study. Anesth Analg 99833-9, 2004
  • Solt K, Forman SA. Correlating the clinical
    actions and molecular mechanisms of general
    anesthetics. Curr Opin Anaesth 20300-6, 2007
  • Sonner JM, Antognini JF, Dutton RC, Flood P, Gray
    AT, Harris RA, Homanics GE, Kendig J, Orser B,
    Raines DE, Rampil IJ, Trudell J, Vissel B, Eger
    EI. Inhaled anesthetics and immobility
    mechanisms, mysteries, and minimum alveolar
    anesthetic concentration. Anesth Analg.
    97718-40, 2003
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