Contents

Clomethiazole

Clomethiazole

Clinical data
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral
ATC code	N05CM02 (WHO)
Legal status
Legal status	BR: Class C1 (Other controlled substances)[1] UK: POM (Prescription only)[2] US: ℞-only In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life	3.6–5 hours
Identifiers
IUPAC name 5-(2-Chloroethyl)-4-methyl-1,3-thiazole
CAS Number	533-45-9 N
PubChem CID	10783
ChemSpider	10327 Y
UNII	0C5DBZ19HV
KEGG	D07330 Y
ChEMBL	ChEMBL315795 Y
CompTox Dashboard (EPA)	DTXSID6022842
ECHA InfoCard	100.007.788
Chemical and physical data
Formula	C6H8ClNS
Molar mass	161.65 g·mol−1
3D model (JSmol)	Interactive image
SMILES ClCCC1=C(C)N=CS1
InChI InChI=1S/C6H8ClNS/c1-5-6(2-3-7)9-4-8-5/h4H,2-3H2,1H3 Y Key:PCLITLDOTJTVDJ-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

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, DistraneurininGermany 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[edit]

Clomethiazole acts as a positive allosteric modulator at the barbiturate/picrotoxin site of the GABA_A 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.^[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[edit]

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[edit]

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]

See also[edit]

• Drug of last resort
• Therapeutic index

References[edit]