[Mechanisms of action of ketamine]

Abstract

Racemic ketamine is a mixture of equal amounts of the two enantiomers (S)-ketamine and (R)-ketamine. The analgesic and anaesthetic potency of (S)-ketamine is about threefold superior to (R)-ketamine. Along with faster elimination, improved control of the anaesthetic state with reduced drug load is achieved. Pharmacokinetic properties of (S)-ketamine are generally comparable with the racemic mixture. The pharmacological profile of ketamine is characterized by the so-called "dissociative anaesthesic state" with profound analgesic and moderate hypnotic properties and by marked sympathomimetic reactions. Important adverse effects are hallucinations and hypersalivation. This pharmacological profile cannot be explained by a single mechanism. Analgesic, anaesthetic and sympathomimetic effects are mediated by different sites of action. N-methyl-D-aspartate (NMDA)-receptor antagonism is the most important neuropharmacological mechanism for the analgesic effects of ketamine. The same mechanism may be involved in the supposed neuroprotective potency of the substance. Effects on opiate receptors may contribute to the analgesic state as well as to dysphoric reactions. Sympathomimetic properties are mediated by enhanced central peripheral monoaminergic transmission. Inhibition of central and peripheral cholinergic transmission may contribute to the induction of anaesthetic state and hallucinations. Effects on neuromuscular transmission are unimportant. Local anaesthetic qualities are obvious as well, but are not responsible for systemic effects. At the different sites of action, qualitatively comparable effects of (S)- and (R)-ketamine were found, but significant quantitative differences are obvious as well.