Pharmacological profiles of medetomidine and its antagonist, atipamezole.

Abstract

Medetomidine, (+/-)-4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, is a very potent, selective and specific full agonist at both pre- and postsynaptic alpha 2-adrenoceptors as demonstrated in several models both in vitro and in vivo. In receptor binding experiments the alpha 2/alpha 1 selectivity ratio of medetomidine is 1620 compared to 260, 220 and 160 for detomidine, clonidine and xylazine, respectively. The alpha 2-adrenoceptor activity of medetomidine resides predominantly in its d-enantiomer (dexmedetomidine). Medetomidine induces a dose-dependent decrease in the release and turnover of noradrenaline, dopamine and serotonin in the CNS as measured by changes in metabolite concentrations or using pharmacological intervention techniques. Inhibition of sympathetic tone in the CNS by medetomidine leads for a characteristic pattern of pharmacodynamic responses including e.g. hypotension, bradycardia, sedation, relief of anxiety, analgesia and hypothermia. The potent, dose-dependent sedative effects of medetomidine have been demonstrated in several classical animal models (e.g. decrease in spontaneous motility in rats and mice, potentiation of barbiturate-induced anaesthesia in rats and mice, induction of sleep in young chicks). At high doses medetomidine has hypnotic of anaesthetic effects, a property which distinguishes it clearly from detomidine, clonidine and other alpha 2-agonists. The pharmacological, neurochemical and behavioral effects of medetomidine can be inhibited by prior, simultaneous of subsequent administration of a selective and specific alpha 2-antagonist, atipamezole. Besides verifying that the main pharmacodynamic effects of medetomidine are alpha 2-mediated, this finding forms a strong basis for the use of atipamezole as a reversing agent against medetomidine-induced effects in veterinary practice.