Clomethiazole

Pharmacology

Clomethiazole acts as a positive allosteric modulator at the barbiturate/picrotoxin site of the GABAA receptor. It works to enhance the action of the neurotransmitter GABA at this receptor. GABA is the major inhibitory neurotransmitter in the brain and produces anxiolytic, anticonvulsant, sedative, and hypnotic effects. Clomethiazole appears to also have another mechanism of action mediating some of its hypothermic and neuroprotective effects. The oxazole homologue is also known providing a little QSAR information.

As opposed to barbiturates, clomethiazole doesn't affect the electrophysiological responses to excitatory aminoacids, and additionally, it also directly acts on chloride ion channels.

Clomethiazole is a potent CYP2E1 enzyme inhibitor which slows down the metabolism of ethanol, hence its use in alcohol withdrawal. It is also an inhibitor of CYP2B6 and possibly CYP2A6 and thus can affect the plasma clearance of substrates of those enzymes.

When clomethiazole is administered via IV in addition to carbamazepine, its clearance is increased by 30%, which results in a proportional reduction in plasma concentration. Therefore, when co-administered with carbamazepine or other potent CYP3A4 inducers via IV, it is necessary to increase the dose of clomethiazole.

Adverse effects

Long term and frequent use of clomethiazole can cause tolerance and physical dependence. Abrupt withdrawal may result in symptoms similar to those of sudden withdrawal of alcohol, short-acting barbiturates or short-acting benzodiazepines.

Overdose

Clomethiazole is particularly toxic and dangerous if overdosed and is potentially fatal. Alcohol multiplies the effect. As the drug can be fatal in high doses, prescribing clomethiazole for the management of alcohol dependence outside of a controlled environment, for example a hospital, is not recommended, especially because there are much less toxic alternatives, such as diazepam. Diazepam is one of many drugs belonging to the benzodiazepine class, with a long half-life (50–100 hours) and a very low risk of a fatal overdose, so long as the patient does not also consume alcohol or certain other types of medication.

Due to clomethiazole's unique chemical structure the benzodiazepine antidote flumazenil cannot reverse the effects of overdose; overdose treatment is restricted to the application of a mechanical ventilation apparatus until enough of the drug has been metabolized or excreted for the patient to breathe sufficiently without assistance.

Drummer Keith Moon of the rock band The Who died of a clomethiazole overdose.

References

References

1. Anvisa. (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
2. "Heminevrin / Clomethiazole 192 mg Capsules".
3. (February 1999). "In vivo evidence against clomethiazole being neuroprotective against MDMA ('ecstasy')-induced degeneration of rat brain 5-HT nerve terminals by a free radical scavenging mechanism". Neuropharmacology.
4. US Patent 3401172 4-methyl-5-(beta-chloroethyl)oxazole
5. [http://www.halmed.hr/upl/lijekovi/SPC/SPC_UP-I-530-09-17-02-642.pdf Distraneurin 192mg: Summary of effects (In Croatian)]
6. (April 1976). "Physiological dependence on, and symptoms of withdrawal from, chlormethiazole". The British Journal of Psychiatry.
7. (2003). "Comparison of the fatal toxicity index of zopiclone with benzodiazepines". Journal of Toxicology. Clinical Toxicology.
8. (2013-05-20). "Keith Moon's Last Interview, 1978".