Chlormethiazole‐mode of action
Authors: Ögren S. O. 
Published: August 2007

‐ Studies in mice demonstrated that the anticonvulsant profile of chlormethiazole differs from that of diazepam and the barbiturates. Chlormethiazole protects animals from convulsions induced by a wide variety of chemoconvulsants known to block the action of the inhibitory neurotransmitter γ‐aminobutyric acid (GABA), such as bicuculline, picrotoxin, isoniazid and pentetrazol, thus confirming and extending earlier studies on its broad anticonvulsant characteristics. Chlormethizole is particularly potent against isoniazid‐induced convulsions, which are probably induced by reductions of GABA levels in the brain.

Chlormethiazole was found to have a weak action on benzodiazepine receptor binding, GABA receptor binding and kainic acid receptor binding. Chlormethiazole inhibited picrotoxin binding at very high concentrations, but lowered the functional effects of picrotoxin at much lower concentrations than those affecting picrotoxin binding. Moreover, chlormethiazole failed to change GABA or glutamate levels in the brain and did not affect glutamic acid decarboxylase (GAD) activities in the rat brain. Muscimol (a GABAA agonist) enhanced the anticonvulsant activity of chlormethiazole against picrotoxin but not against bicuculline‐induced convulsions. Muscimol enhanced the anticonvulsant potency of diazepam against both chemoconvulsants. These data suggest that the anticonvulsant activity of chlormethiazole is not mediated directly through changes in GABA or glutamate levels or by a direct (agonist) action at the GABA or benzodiazepine receptor complex. These findings suggest that chlormethiazole may enhance GABA transmission beyond the GABA receptors, hypothetically at the level of the GABA receptor coupled ionophore (e.g. the chloride ion channel).

Applied micro‐iontophoretically, chlormethiazole was found to potentiate the inhibitory responses to GABA, muscimol and glycine, but not to acetylcholine. The potentiation of glycine‐mediated inhibition is unique for chlormethiazole and does not occur with any other known anticonvulsant (barbiturates, benzodiazepine, phenytoin or sodium valproate). Studies in primary cultures, derived from spinal cord neurones, showed that chlormethiazole produces hyperpolarization together with an increase in the threshold for action potential generation. Further in vitro studies indicated that chlormethiazole acts on some types of Ca2+‐dependent chloride ion channels.

In vivo studies indicated that the hypnotic effect of chlormethiazole involves primarily an action on the GABA system, as both the GABAA agonist, muscimol, and the inhibitor of GABA aminotransferase, aminooxyacetic acid, markedly enhanced chlormethiazole‐induced hypnosis in mice. Serotonergic (5‐HT‐ergic) or noradrenergic systems appear to play a minor role in the hypnotic action. Chlormethiazole also appears to cause an inhibition of dopaminergic transmission, probably secondary to an action mediated by GABA mechanisms. Thus, chlormethiazole markedly enhanced haloperidol‐induced catalepsy in a similar manner to the GABA agonists, such as muscimol. The inhibition of dopamine activity may play a role in the sedative and hypnotic action of the compound.

In conclusion, the available evidence suggests that chlormethiazole enhances GABA‐ergic transmission in the brain, by a mechanism which partly differs from that of the barbiturates and the benzodiazepines. Chlormethiazole appears to act on an allosteric site of the GABAA receptor complex, which is closely related to chloride‐channel functions (picrotoxin sensitive). Chlormethiazole also enhances glycine‐mediated inhibition. The action on the chloride‐channel function may be relevant for the anticonvulsant property of the drug. It is possible, that at higher doses, chlormethiazole also affects more general functions of GABA which underlie the hypnotic effects of the drug and its action on other transmitter systems.