Outdated theories of anaesthetic action
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See the general anaesthetic page for current theories.
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Lipid solubility
Von Bibra and Harless, in 1847, were the first to suggest that general anaesthetics may act by dissolving in the fatty fraction of brain cells. They proposed that anaesthetics dissolve and remove fatty constituents from brain cells, changing their activity and inducing anaesthesia. The first report of anaesthetic potency being related to lipid solubility was published by H. H. Meyer 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 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. 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 delivered, i.e., the gas or aqueous phase.
From the correlation between lipid solubility and anaesthetic potency, both Meyer and Overton had surmised that anaesthesia occurs when the anaesthetic reaches a critical concentration in some lipid phase within the body. However, 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. The necessity for general anaesthetics to cross the blood-brain barrier to have their effect is the main reason that more polar agents are less potent.
Protein binding sites
Two classes of proteins 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 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 their potency for general anaesthesia and also proportional to the anaesthetic molecule's lipid solubility.
The cutoff effect
There is a limitation to the Meyer-Overton correlation. As one ascends a homologous series of anaesthetics, such as the n-alcohols, one would expect from the Meyer-Overton correlation that the alcohols would become increasingly potent as the carbon chain length increases because the alcohols grow more hydrophobic. Instead of becoming increasingly potent without limit however, at certain chain lengths the addition of just one methylene group causes the molecule to lose its ability to anaesthetise. For the n-alcohols the cutoff occurs at a carbon chain length of about 13, and for the n-alkanes at a chain length of between 6 and 10, depending on the species.
If general anaesthetics disrupt ion channels by partitioning into and perturbing the lipid bilayer, then one would expect that their solubility in lipid bilayers would also display the cutoff effect. However, partitioning of alcohols into lipid bilayers does not display a cutoff for long-chain alcohols from n-decanol to n-pentadecanol. A plot of chain length vs. the logarithm of the lipid bilayer/buffer partition coefficient K is linear, with the addition of each methylene group causing a change in the Gibbs free energy of -3.63 kJ/mol.
The cutoff effect is easily interpreted if target sites for general anaesthetics are hydrophobic pockets of fixed dimensions in proteins. As the acyl chain grows, the anaesthetic fills more of the hydrophobic pocket and binds with greater affinity. When the molecule is too large to be entirely accommodated by the hydrophobic pocket, the binding affinity no longer increases with increasing chain length. When the aqueous solubility of the of the molecule exceeds that of the hydrophobic pocket, cutoff occurs.
Stereoisomers
A further blow for lipid theory is that some general anaesthetics (eg. isoflurane, thiopental, etomidate) exist in two mirror image forms, or optical isomers. The two forms have identical chemical properties, but can differ greatly in anaesthetic potencies. Where tested, optical isomers partition identically into lipid, but have differential effects on ion channels and synaptic transmission. This aacounts for the diffences in anaesthetic potency and happens because a protein binding site is a chiral environment, unlike the lipid.