Mechanism of anaesthesia-induced unconsciousness

[Ref: SH4:p37-39]

Bottomline

• A comprehesive explanation of the mechanism by which inhaled AA produce unconsciousness has NOT YET been developed.
• Loss of consciousness (hypnosis and amnesia) and loss of response to surgical stimuli (as reflected by MAC) are two separate phenomena.

Site of action

There are multiple possible targets of action by inhaled AA

In contrast,

Only GABAa receptors are likely to be responsible for mediating effects of IV anaesthetics (i.e. propofol and etomidate)

Almost certainly act by directly binding to proteins, rather than perturbing the lipid bilayers

Mechanism of unconsciousness

Inhaled AA can hyperpolarise cortical and spinal neurons

Inhaled AA enhance inhibitory synaptic transmission
* Especially in the reticular activating system
* Both GABA and glycine receptors are affected

Inhibition of neurosecretion, rather than inhibition of neurotransmitter synthesis or storage
* By inhibiting presynaptic sodium channel or voltage-gated calcium channel

NB:

• N2O and Xenon are devoid of effect on inhibitory GABAa receptors
  --> A different mechanism of action
• Peripheral nerves conduct normally during anaesthetics
• Inhaled AA do not appear to have significant effects on action potention
• All three types of glutamate receptors are insensitive to clinical concentration of inhaled AA
  * ??? In the context of unconsciousness, not immobility

Meyer-Overton Theory (critical volume hypothesis)

Old theory (Meyer-Overton)

Correlation between the lipid solubility of AA and the anaesthetic potency
--> Inhaled AA acts by disrupting the structure or dynamic properties of the lipid portions of the nerve membrane

Rebuttal

• Effects on lipid bilayers are very small and can be mimiced by temperature changes of 1%
• Stereoselectivity
  --> More likely to act by binding to proteins
• Not all lipid-soluble drugs are anaesthetics