Mechanism of anaesthesia-induced unconsciousness

[Ref: SH4:p37-39]

Overview

• 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