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 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, unconsciousness, immobility) through a membrane mediated mechanism or by directly modulating the activity of membrane proteins in the neuronal membrane. In general, different anaesthetics exhibit different mechanisms of action such that there are numerous non-exclusionary molecular targets at all levels of integration within the central nervous system. However, for certain intravenous anaesthetics, such as propofol and etomidate, the main molecular target is believed to be GABAA receptor, with particular β subunits playing a crucial role. The concept of specific interactions between receptors and drugs first introduced by Paul Ehrlich in 1897 states that drugs act only when they are bound to their targets (receptors). The identification of concrete molecular targets for general anaesthetics was made possible only with the modern development of molecular biology techniques for single amino acid mutations in proteins of genetically engineered mice.

Lipid solubility-anaesthetic potency correlation (the Meyer-Overton correlation)

A nonspecific mechanism of general anaesthetic action was first proposed by Emil Harless and Ernst von Bibra 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. Two years later a similar theory was published independently by Charles Ernest 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 the lipid solubility of a compound in olive oil, the greater 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. 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 also noted 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.) The best characterized anesthetics site accounting for the Meyer-Overton correlation resides in ordered lipid domains. Anesthetics adhere non-specifically to the surface of a palmitate specific binding site within the lipid membrane, displacing the palmitate from ordered GM1 lipids. The process gives rise to a component of membrane-mediated anesthesia. A similar mechanism was shown for luciferase. The anesthetics bound non-specifically to a hydrophobic surface and out-competed the specific binding of luciferin. However luciferase is not physiologically relevant to vertebrates as it is not endogenously expressed in vertebrates.

Early lipid hypotheses of general anaesthetic action

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