Clomethiazole (also calledchlormethiazole) is asedative andhypnotic originally developed byHoffmann-La Roche in the 1930s.[3] The drug is typically used in treating and preventing symptoms of acute alcohol withdrawal,anxiety and as a sedative-hypnotic.
It is structurally related tothiamine (vitamin B1), but acts like a sedative, hypnotic,anxiolytic,muscle relaxant andanticonvulsant, having the same mechanism of action as traditional barbiturates. It is also used for the management ofagitation, restlessness, andParkinson's disease. In theUK, it is sold under the brandHeminevrin (AstraZeneca Pharmaceuticals). Other brand names includeNevrin in Romania,Distraneurin inGermany andDistraneurine in Spain. The drug is marketed either as afree base in an oily solution containing 192 mg in capsule form, or as clomethiazoleedisylate syrup. Due to its high toxicity compared tobenzodiazepines it is not recommended as a first-line treatment for any indication and is particularly dangerous to patients with an elevated risk for drug abuse such as those with a personal or familial history of addiction.
Clomethiazole acts as apositive allosteric modulator at thebarbiturate/picrotoxin site of theGABAAreceptor. It works to enhance the action of theneurotransmitterGABA 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.[4] The oxazole homologue is also known[5] providing a littleQSAR 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.[citation needed]
Clomethiazole is a potentCYP2E1 enzyme inhibitor which slows down the metabolism of ethanol, hence its use in alcohol withdrawal. It is also an inhibitor ofCYP2B6 and possiblyCYP2A6 and thus can affect the plasma clearance of substrates of those enzymes.
When clomethiazole is administered via IV in addition tocarbamazepine, its clearance is increased by 30%, which results in a proportional reduction in plasma concentration. Therefore, when co-administered with carbamazepine or other potentCYP3A4 inducers via IV, it is necessary to increase the dose of clomethiazole.[6]
Long term and frequent use of clomethiazole can causetolerance andphysical dependence. Abrupt withdrawal may result in symptoms similar to those of sudden withdrawal of alcohol, short-actingbarbiturates or short-actingbenzodiazepines.[7]
Clomethiazole is particularly toxic and dangerous ifoverdosed and is potentially fatal.Alcohol multiplies the effect. As the drug can be fatal in high doses, prescribing clomethiazole for the management ofalcohol dependence outside of a controlled environment, for example a hospital, is not recommended, especially because there are much less toxic alternatives, such asdiazepam. 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.[8]
Due to clomethiazole's action at the barbiturate complex the benzodiazepine antidoteflumazenil 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 and/or excreted for the patient to breathe sufficiently without assistance.
DrummerKeith Moon of the rock bandThe Who died of a recreational clomethiazole overdose.[9] The autopsy found that the death was an accidental overdose, as Moon had a history of consuming extremely large quantities of barbiturates and alcohol and did not take all of the clomethiazole capsules or drink all of the alcohol.
^CH patent 200248, "Verfahren zur Darstellung von 4-Methyl-5-B-chloräthylthiazol", issued 1938-09-30, assigned to Hoffmann-La Roche
^Colado MI, O'Shea E, Esteban B, Granados R, Green AR (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.38 (2):307–314.doi:10.1016/S0028-3908(98)00174-9.PMID10218873.S2CID14772873.
^Reilly TM (April 1976). "Physiological dependence on, and symptoms of withdrawal from, chlormethiazole".The British Journal of Psychiatry.128 (4):375–8.doi:10.1192/bjp.128.4.375.PMID1260235.S2CID35647502.
^Reith DM, Fountain J, McDowell R, Tilyard M (2003). "Comparison of the fatal toxicity index of zopiclone with benzodiazepines".Journal of Toxicology. Clinical Toxicology.41 (7):975–80.doi:10.1081/CLT-120026520.PMID14705844.S2CID45870330.
^Springer M (2013-05-20)."Keith Moon's Last Interview, 1978". Retrieved2014-10-11.An autopsy showed that Moon had taken 32 capsules of clomethiazole and a large amount of alcohol. His doctor had told him not to exceed three per day.
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