General anaesthetic

An anaesthetic which brings about a reversible loss of consciousness. The sites of action of general anaesthetics have proved difficult to find because they have many different structures ranging from complex steroids to the inert monatomic gas xenon. It is clear, however, that general anaesthetics must act upon the central nervous system by modifying the electrical activity of neurons. A change in electrical activity must be brought about at the molecular level by modifying the function of ion channels. This could occur by anaesthetic molecules binding directly to ion channels or by disrupting the function of molecules that maintain ion channels.

Many forms of ion channel have been cloned in the past decade, adding greatly to our knowledge of proteins involved in neuronal excitability. These range from voltage-gated ion channels, such as sodium, potassium and calcium channels to the ligand-gated ionotropic ion channel superfamily and G protein-coupled ion channel superfamily. Although it is generally agreed that ion channels are the ultimate site of action of general anaesthetics, there is considerable disagreement about the molecular mechanisms involved. Some hold that anaesthetics disrupt the actions of ion channels by modifying physical properties of the lipid bilayer, indirectly modifying the function of ion channels. Others believe that anaesthetics act by directly binding to specific sites on ion channel proteins.

Lipid Solubility

Von Bibra and Harless, in 1847, were the first to suggest that anaesthetics may act by dissolving in the fatty moiety in brain cells. They proposed that anaesthetics dissolved and removed fatty constituents from brain cells, chainging their activity, and inducing anaesthesia. The first report of anaesthetic potency being related to lipid solubility was published by H. H. Meyer fifty years later in a paper published in 1899 entitled "Zur theorie der Alkoholnarkose". Two years later a similar theory was published independently by Overton.

Meyer and Overton had discovered the most striking correlation observed between the physical properties of general anaesthetic molecules and their potency. Meyer compared the potency of many agents, defined as the reciprocal of the molar concentration required to induce anaesthesia in tadpoles, with the olive oil/water partition coefficient. He found a nearly linear relationship beween potency and the partition coefficient for many different types of anaesthetic molecule such as alcohols, aldehydes, ketones, ethers and esters. Meyer and Overton also found that 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 applied i.e. the gas or aqueous phases.

Protein Binding Sites

Two classes of proteins have been found that are inactivated by clinical doses of anaesthetic in the total absence of lipid. These are luciferases, which are used by bioluminescent animals and bacteria to produce light, and cytochrome P450, which is a group of heme proteins that hydroxylate a very diverse group of compounds, including fatty acids, steroids and xenobiotics such as phenobarbital. These proteins bind general anaesthetics and are inhibited with a potency that is approximately equal to potency for general anaesthesia and also proportional to the anaesthetic molecule's lipid solubility. From the correlation between lipid solubility and anaesthetic potency both Meyer and Overton surmised that anaesthesia occurs the anaesthetic reaches a critical concentration in some lipid phase within the body. These results on lipid-free proteins show that the correlation between lipid solubility and potency of general anaesthetics is a necessary but not sufficient condition for inferring a lipid target site; general anaesthetics could equally well be binding to hydrophobic target sites on proteins in the brain.