3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.2. Inhalational anaesthetic agents
                      3.1.3.2.2. Pharmacodynamics of inhalational anaesthetics
 3.1.3.2.2.3. Mechanism of anaesthesia-induced unconsciousness 

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