Theories of General Anaesthetic Action - Lipid Solubility-anaesthetic Potency Correlation (the Meyer-Overton Correlation)

Lipid Solubility-anaesthetic Potency Correlation (the Meyer-Overton Correlation)

The nonspecific mechanism of general anaesthetic action was first proposed by Von Bibra and Harless in 1847. They suggested that general anaesthetics may act by dissolving in the fatty fraction of brain cells and removing fatty constituents from them, thus changing activity of brain cells and inducing anaesthesia. In 1899 Hans Horst Meyer published the first experimental evidence of the fact that anaesthetic potency is related to lipid solubility in his article entitled "Zur Theorie der Alkoholnarkose". Two years later a similar theory was published independently by Overton.

Meyer compared the potency of many agents, defined as the reciprocal of the molar concentration required to induce anaesthesia in tadpoles, with their olive oil/water partition coefficient. He found a nearly linear relationship between potency and the partition coefficient for many types of anaesthetic molecules such as alcohols, aldehydes, ketones, ethers, and esters. The anaesthetic concentration required to induce anaesthesia in 50% of a population of animals (the EC₅₀) was independent of the means by which the anaesthetic was delivered, i.e., the gas or aqueous phase.

Meyer and Overton had discovered the striking correlation between the physical properties of general anaesthetic molecules and their potency: the greater is the lipid solubility of the compound in olive oil the greater is its anaesthetic potency. This correlation is true for a wide range of anaesthetics with lipid solubilities ranging over 4-5 orders of magnitude if olive oil is used as the oil phase. However, this correlation can be improved considerably in terms of both the quality of the correlation and the increased range of anaesthetics if bulk octanol or a fully hydrated fluid lipid bilayer is used as the “oil” phase. It was noted also that volatile anaesthetics are additive in their effects (a mixture of a half dose of two different volatile anaesthetics gave the same anaesthetic effect as a full dose of either drug alone).

Nb: The y-axis in the accompanying graph is incorrectly labelled and should read "log of Minimum Alveolar Concentration or MAC" - The lesser the MAC the greater the potency (Halothane has a MAC of slightly less than 1 while Nitrous oxide has a MAC of around 105, halothane is much more potent and it is because the log of the MAC is plotted on the y axis that halothane has a value of 0.01 and nitrous oxide has a value of 1. The drug potency increases and the dose required to produce anaesthesia reduces as the oil:gas solubility increases.