Clomethiazole (also called chlormethiazole) is a
sedative and
hypnotic originally developed by
Hoffmann-La Roche in the 1930s.[3] The drug is used in treating and preventing symptoms of acute alcohol withdrawal.
It is structurally related to
thiamine (vitamin B1), but acts like a sedative, hypnotic,
muscle relaxant and
anticonvulsant, having the same mechanism of action as traditional barbiturates. It is also rarely used for the management of
agitation, restlessness, short-term
insomnia and
Parkinson's disease in the elderly, when all other treatment options have failed. In the
UK, it is sold under the brand Heminevrin (
AstraZeneca Pharmaceuticals). Other brand names include Nevrin in Romania, Distraneurin in
Germany and Distraneurine in Spain. The drug is marketed either as a
free base in an oily solution containing 192 mg in capsule form, or as clomethiazole
edisylate syrup. Due to its high toxicity compared to similar drugs 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.
Pharmacology
Clomethiazole acts as a
positive allosteric modulator at the
barbiturate/
picrotoxin site of the
GABAAreceptor. It works to enhance the action of the
neurotransmitterGABA 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 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.[citation needed]
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.[6]
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 or
benzodiazepines.[7]
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 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.[8]
Due to clomethiazole's action at the barbiturate complex 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 and/or excreted for the patient to breathe sufficiently without assistance.
Drummer
Keith Moon of the rock band
The Who died of a clomethiazole overdose.[9]
^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". Retrieved 2014-10-11. An autopsy showed that Moon had taken 32 tablets of clomethiazole. His doctor had told him not to exceed three per day.