Mechanism of General Anaesthetic Action

Question 1

What is the Meyer-Overton hypothesis?

Answer 1

Also known as the lipid-solubility hypothesis.

Proposes that once a set concentration of anaesthetic molecules had dissolved, general anaesthesia would be achieved.

That the target for hydrophobic anaesthetic agents was the hydrophobic lipid cell membrane, and that the drgs would dissolve at this target, particularly in the brain, to exert their effect.

Question 2

What is the critical volume hypothesis?

Answer 2

That it was the molecular volume of an anaesthetic drug that would occupy a critical volume within the lipid bilayer membrane, and this would disrupt the function of ion channels to provide anaesthesia.

So the molecular volume, not the chemical structure, was thought to be important. The larger the volume, the greater the anaesthetic effect.

Question 3

What is the lateral phase separation theory?

Answer 3

Suggests that anaesthetics act by fluidizing nerve membranes to the point where lipid regions no longer contain phase separations - so the proteins involved in ion gates, transmitter release and binding - are impaired

Question 4

What is the current working model for anaesthetic MOA?

Answer 4

That anaesthetic agents act at multiple specific target sites, likely a combo of membrane proteins, receptors and channels. The multisite hypothesis.

On a global level, these drugs impair neuronal activity in different parts of the brain, namely the front-parietal cortices and the thalamus.

Question 5

What is the likely prime target site of anaesthetic agents?

Answer 5

The superfamily of transmitter-gated ion channels, which include:

• GABA-A
• glycine (enhance inhibitory neurotransmission)
• nACh
• 5HT3
• glutamate (enhance excitatory neurotransmission)

These are located mostly on post-synaptic membranes.

Question 6

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