Mechanism of General Anaesthesia

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Chapter: Essential pharmacology : General Anaesthetics

The mechanism of action of GAs is not precisely known. A wide variety of chemical agents produce general anaesthesia. Therefore, GA action had been related to some common physicochemical property of the drugs.


MECHANISM OF GENERAL ANAESTHESIA

 

The mechanism of action of GAs is not precisely known. A wide variety of chemical agents produce general anaesthesia. Therefore, GA action had been related to some common physicochemical property of the drugs. Mayer and Overton (1901) pointed out a direct parallelism between lipid/water partition coefficient of the GAs and their anaesthetic potency.

 

Minimal Alveolar Concentration (MAC) is the lowest concentration of the anaesthetic in pulmonary alveoli needed to produce immobility in response to a painful stimulus (surgical incision) in 50% individuals. It is accepted as a valid measure of potency of inhalational GAs because it remains fairly constant for a given species even under varying conditions.

 

The MAC of a number of GAs shows excellent correlation with their oil/gas partition coefficient. However, this only reflects capacity of the anaesthetic to enter into CNS and attain sufficient concentration in the neuronal membrane, but not the mechanism by which anaesthesia is produced.

 

Recent evidence favours a direct interaction of the GA molecules with hydrophobic domains of membrane proteins or the lipidprotein interface.

 

It has now been realised that different anaesthetics may be acting through different molecular mechanisms, and various components of the anaesthetic state involve action at discrete loci in the cerebrospinal axis. The principal locus of causation of unconsciousness appears to be in the thalamus or reticular activating system, amnesia may result from action in hippocampus, while spinal cord is the likely seat of immobility on surgical stimulation.

 

Recent findings show that ligand gated ion channels (but not voltage sensitive ion channels) are the major targets of anaesthetic action. The GABAA receptor gated Cl¯ channel is the most important of these. Many inhalational anaesthetics, barbiturates, benzodiazepines and propofol potentiate the action of inhibitory transmitter GABA to open Cl¯ channels. Each of the above anaesthetics appears to interact with its own specific binding site on the GABAA receptor Cl¯ channel complex, but none binds to the GABA binding site as such; though some inhaled anaesthetics and barbiturates (but not benzodiazepines) can directly activate Cl– channels. Action of glycine (another inhibitory transmitter which also activates Cl¯ channels) in the spinal cord and medulla is augmented by barbiturates, propofol and many inhalational anaesthetics. This action may block responsiveness to painful stimuli resulting in immobility of the anaesthetic state. Certain fluorinated anaesthetics and barbiturates, in addition, inhibit the neuronal cation channel gated by nicotinic cholinergic receptor which may mediate analgesia and amnesia.

 

On the other hand, N2O and ketamine do not affect GABA or glycine gated Cl¯ channels. Rather they selectively inhibit the excitatory NMDA type of glutamate receptor. This receptor gates mainly Ca2+ selective cation channels in the neurones, inhibition of which appears to be the primary mechanism of anaesthetic action of ketamine as well as N2O. The volatile anaesthetics have little action on this receptor.

 

Neuronal hyperpolarization caused by GAs has been ascribed to activation of a specific type of K+ channels, while inhibition of transmitter release from presynaptic neurones has been related to interaction with certain critical synaptic proteins. Thus, different facets of anaesthetic action may have distinct neuronal basis, as opposed to the earlier belief of a global neuronal depression.

 

Unlike local anaesthetics which act primarily by blocking axonal conduction, the GAs appear to act by depressing synaptic transmission.

 

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