Theories of anaesthesia



Theories of anaesthesia

·         The mode of action of general anaesthetics has been studied for many decades but still there is no clear explanation regarding the mechanism of action.
·         Anaesthetics appear to act principally on the cell membrane; therefore, theories of anaesthesia focus primarily on the interaction of anaesthetics with two main membrane components namely lipids and proteins.

Lipid theory / Meyer and Overton theory
·         Meyer (1899) and Overton (1901) in separate studies identically postulated that anaesthetic potency varies with the lipid solubility of the drug.
·         The more lipid soluble a drug is, the greater its anaesthetic potency.
·         But it is now known that all highly lipid soluble substances are not anaesthetics and some potent anaesthetics are not lipid soluble.

Pauling and Miller theory / Hydrate theory
·         Pauling and Miller in 1961 postulated that when anaesthetic agents are administered, simple molecules like water may be linked together by hydrogen bonding to form ice- like cages / structures which are occupied by anaesthetic agents and form anaesthetic hydrate crystals (ice burgs) or calthrates.
·         These calthrates disturbs function of membrane proteins and also interfere with ionic movements.
·         It gives poorer correlation of anaesthetic potency with hydrate formation.

Membrane expansion theory
·         This theory postulates that anaesthetic molecules penetrate into hydrophobic region of the cell membrane and causes its expansion
·         Here, the mechanism of expansion has not been fully explained

Membrane fluidization theory
·         This theory postulates that anaesthetic agents by dissolving in the membrane lipids cause loosing or fluidization of lipid bilayer region of the membrane.
·         The increase in fluidity or disordering restricts the mobility of protein molecules surrounding the ionic channels, thereby impeding opening up of the ion channels
·         But this theory also fails to explain the mechanism of fluidization.

Biochemical theory
·         A number of biochemical theories have also been postulated and reviewed.
·         These include inhibition of glucose metabolism in brain cells, interference in ATP production, cellular respiration etc.,
·         But there are no conclusive evidence for such mechanisms occurs in the intact brain when general anaesthetics are administered.

Protein theory
·         There is increasing evidence that anaesthetics exert their effect probably by direct interactions with proteins at molecular levels, rather than by disturbing the matrix of lipid bilayer as postulated earlier.
·         Structural changes in protein conformation are induced by anaesthetic compounds results in altering receptor or channel function.
·         Eg: Many inhalation anaesthetics, barbiturates, benzodiazepines and Propofol potentiate action of the inhibitory neurotransmitter GABA at GABAA and GABAB receptor.

In summary, recent evidence tends to argue more in favour of a protein site.

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