general anaesthesia 2015

Lipid vs Protein

Davis MDCH 5210 - General Anesthetics 2006

Inhalation Anesthetic Structures


Analgesic Anesthetics - Fentanyls


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


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.


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


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


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)


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.


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


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.


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