Lipid vs Protein
Davis MDCH 5210 - General Anesthetics 2006
Inhalation Anesthetic Structures
Davis MDCH 5210 - General Anesthetics 2006
Analgesic Anesthetics - Fentanyls
Davis MDCH 5210 - General Anesthetics 2006
Fentanyl - Actiq (fentanyl on a stick), Duragesic transdermal
patches (12, 25, 50, 100 g/h) Therapeutic index=400, morphine = 70
Alfentanil - Ultra-short acting, 5-10 minutes analgesic
durationRemifentanil - Shortest acting opioid - 1/2 time is 4-6
minutes. Used in MAC anesthesia. TI=30,000Sufentanil - 5-10x
Fentanyl, used for heart surgery.Carfentanil - (100x Fentanyl)
Thought that it was used in the 2002 Moscow theater crisis to
subdue Chechen hostage takers. Didnt turn out so well. 42
terrorists and 130 hostages died. Works well on bears.Fentanyls
Davis MDCH 5210 - General Anesthetics 2006
Barbiturates (thiopental, methohexital),
benzodiazepines (diazepam, lorazepam, midazolam);
Etimodate;
neuroleptic butyrophenones (droperidol);
muscle relaxers neuromuscular blocking agents, i.e. nicotinic
antagonists could be either depolarizing or non-depolarizing
(succinylcholine or tubocurarine);
ketamine, propofol.
Other Important anesthetic and pre-anesthetic compounds.How do
analgesics potentiate anesthetic action?
I.e. lower the MAC value of volatile anesthetics.
Davis MDCH 5210 - General Anesthetics 2006
Ketamine (Ketalar) Causes dissociative anesthesia. Patients feel
dissociated from the environment. Similar to neuroleptic
anesthesia, but caused by a single agent. Phencyclidine (PCP) has
similar effects. Ketamine is injectable.Mechanism Blocks NMDA
glutamate receptors
Etimodate (Amidate) is a ultrashort acting hypnotic without
analgesic properties. Used only for induction because of the very
short, 5 minute, duration.Mechanism GABA receptor. Similar to
barbiturates
Propofol (Diprivan) Another IV anesthetic. Similar to thiopental
in anesthetic effects and application, but has little renal or
hepatic interaction and/or toxicity. Low incidence of side effects,
little post-operative confusion.Mechanism Probably similar to the
volatile anesthetics and ethanol. GABA, nACh Injectable anesthetics
- Mechanisms
Davis MDCH 5210 - General Anesthetics 2006
Molecular and Neuronal Substrates for General AnestheticsNature
Reviews Neuroscience (2004) 5, 709-720. Rudolph, U. and Antkowiak,
B.
Anesthetics and Ion Channels: Molecular Models and Sites of
Action. Annu. Rev. Pharmacol. Toxicol. (2001) 41, 23-51. Yamakura,
T., Bertaccini, E., Trudell, J.R., Harris, R.A.
Ethanol enhances 43 and 63 gamma-aminobutyric acid type A
receptors at low concentrations known to affect humans. Proc. Natl.
Acad. Sci. (2003) 100, 15218-15223. Wallner M, Hanchar HJ, Olsen
RW.What is the Evidence that They Work This Way?How Do General
Anesthetics Work
Davis MDCH 5210 - General Anesthetics 2006
Figure 1 Mihic et al.5 have found that single amino-acid
substitutions at two positions remove the potentiating effects of
volatile anaesthetics and ethanol on GABAA (-aminobutyric acid) and
glycine receptors. a, GABAA and glycine receptors bind the
neurotransmitters that are released at inhibitory chemical
synapses, and open to allow chloride ions to diffuse across the
postsynaptic membrane. b, The main effect of volatile anaesthetics
is to prolong channel opening and, hence, to increase postsynaptic
inhibition. c, The receptor channels consist of pentamers of
closely related subunits, and the structure of a single subunit is
shown in d. The authors suggest that the two critical amino acids
may form a binding site for general anesthetics and ethanol.
Comment by Franks and Lieb on Mihic et al. (1997) Nature, 385-389
(1997)
Davis MDCH 5210 - General Anesthetics 2006
The GABAA Cl- channel is structurally related to Na+, 5HT and
nACh channels
Anesthetics inhibit nACh, but potentiate the others.A specific
anesthetic binding site was mapped using mutational genetics.
Mutational experiments didnt necessarily prove that these were
the binding sites, one would need to do pharmacological experiments
for that.
Ion channel mutations in vivo would prove that these were the
channels involved in anesthesia. An experiment similar to the
opioid receptor that we learned about. Could also be good for
looking at anticonvulsants.Summary of 1997 Nature Article on
Anesthetics.
Davis MDCH 5210 - General Anesthetics 2006
gamma-Aminobutyric acid type A receptors (GABARs) have long been
implicated in mediating ethanol (EtOH) actions, but so far most of
the reported recombinant GABAR combinations have shown EtOH
responses only at fairly high concentrations (> or = 60 mM).
We show that GABARs containing the delta-subunit, which are
highly sensitive to gamma-aminobutyric acid, slowly inactivating,
and thought to be located outside of synapses, are enhanced by EtOH
at concentrations that are reached with moderate, social EtOH
consumption.Ethanol enhances 43 and 63 gamma-aminobutyric acid type
A receptors at low concentrations known to affect humans. Proc.
Natl. Acad. Sci. (2003) 100, 15218-15223. Wallner M, Hanchar HJ,
Olsen RW.Ethanol Binding ot GABA-A Receptors
Copyright 2003 by the National Academy of SciencesWallner, M. et
al. (2003) Proc. Natl. Acad. Sci. USA 100, 15218-15223Synaptic
versus extrasynaptic receptors
Davis MDCH 5210 - General Anesthetics 2006
Membrane fluidity seems to be unsupported except in
non-physiological model systems.
Temperature dependence: Increasing temperature decreases
anesthetic potency, but increases fluidity.
Age correlations of anesthetic potency are the reverse of
fluidity.
Differential sensitivity of different types of neurons argues
against a generic fluid model. You would think the membranes would
be similar.
Mutational experiments show specific amino acids are involved in
the receptors.
Many general anesthetics have a stereochemical preference, even
though physical properties are the same.
Some lipid soluble, halogenated compounds do not have anesthetic
activity.Summary of Anesthetic mechanisms.
Davis MDCH 5210 - General Anesthetics 2006
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