Clomethiazole (also called chlormethiazole) is a

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

and

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

originally developed by

Hoffmann-La Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...

in the 1930s. The drug is typically used in treating and preventing symptoms of acute alcohol withdrawal,

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

and as a sedative-hypnotic. It is structurally related to

thiamine Thiamine, also known as thiamin and vitamin B1, is a vitamin – an Nutrient#Micronutrients, essential micronutrient for humans and animals. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosp ...

(vitamin B₁), but acts like a sedative, hypnotic,

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

and

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

, having the same mechanism of action as traditional barbiturates. It is also used for the management of agitation, restlessness, and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. In the UK, it is sold under the brand Heminevrin ( AstraZeneca Pharmaceuticals). Other brand names include Nevrin in Romania, Distraneurin in

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

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

benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...

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 Barbiturates are a class of depressant, depressant drugs that are chemically derived from barbituric acid. They are effective when used medication, medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological a ...

/ picrotoxin site of the GABA_A

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

. It works to enhance the action of the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

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 Cytochrome P450 2E1 (abbreviated CYP2E1, ) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, inclu ...

enzyme inhibitor which slows down the metabolism of ethanol, hence its use in alcohol withdrawal. It is also an inhibitor of

CYP2B6 Cytochrome P450 2B6 is an enzyme that in humans is encoded by the ''CYP2B6'' gene. CYP2B6 is a member of the cytochrome P450 group of enzymes. Along with CYP2A6, it is involved with metabolizing nicotine, along with many other substances. Func ...

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 Carbamazepine, sold under the brand name Tegretol among others, is an anticonvulsant medication used in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medications and as ...

, 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 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...

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 Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certa ...

. Abrupt withdrawal may result in symptoms similar to those of sudden withdrawal of alcohol, short-acting

barbiturates Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...

or short-acting

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

Overdose

Clomethiazole is particularly toxic and dangerous if overdosed and is potentially fatal.

Alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

multiplies the effect. As the drug can be fatal in high doses, prescribing clomethiazole for the management of

alcohol dependence Alcohol dependence is a previous (DSM-IV and ICD-10) psychiatric diagnosis in which an individual is physically or psychologically dependent upon alcohol (also chemically known as ethanol). In 2013, it was reclassified as alcohol use disorder ...

outside of a controlled environment, for example a hospital, is not recommended, especially because there are much less toxic alternatives, such as

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

. 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 action at the barbiturate complex the benzodiazepine antidote

flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...

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 Keith John Moon (23 August 1946 – 7 September 1978) was an English musician who was the drummer for the rock band the Who. Regarded as one of the greatest drummers in the history of rock music, he was noted for his unique style of playing and ...

of the rock band

The Who The Who are an English Rock music, rock band formed in London in 1964. Their classic lineup (1964–1978) consisted of lead vocalist Roger Daltrey, guitarist Pete Townshend, bassist John Entwistle and drummer Keith Moon. Considered one of th ...

died of a recreational clomethiazole overdose. 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.

References

{{Glycinergics GABAA receptor positive allosteric modulators Glycine receptor agonists Hypnotics Drugs developed by AstraZeneca Chloroethyl compounds Sedatives Thiazoles

Pharmacology

Adverse effects

Overdose

See also

References