Theories of general anaesthetic action

A general anaesthetic (or anesthetic) is a drug that brings about a reversible loss of consciousness. These drugs are generally administered by an anaesthetist/anesthesiologist in order to induce or maintain general anaesthesia to facilitate surgery.

General anaesthetics have been widely used in surgery since 1842 when Crawford Long for the first time administered diethyl ether to a patient and performed a painless operation. It has long been believed that general anaesthetics exert their effects (analgesia, amnesia, immobility) by modulating the activity of membrane proteins in the neuronal membrane. However, the exact location and mechanism of this action are still largely unknown although much research has been done in this area. There are a number of theories, both outdated and modern, that attempt to explain anaesthetic action.

The concept of specific interactions between receptors and drugs first introduced by Paul Ehrlich states that drugs act only when they are bound to their targets (receptors). However, this concept does not seem to apply in the case of general anaesthetics because:

All these common features of general anaesthetics made it hard for early researchers to believe that general anaesthetics act in a specific manner and their action on neuronal membrane was thought to be global (through nonspecific perturbation of lipid membrane of CNS neurons) rather than through specific sites.

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.

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