Clomethiazole (also called chlormethiazole or Heminevrin) is a

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...

and

hypnotic Hypnotic (from Greek ''Hypnos'', sleep), or soporific drugs, commonly known as sleeping pills, are a class of (and umbrella term for) psychoactive drugs whose primary function is to induce sleep (or surgical anesthesiaWhen used in anesthesia ...

originally developed by

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

in the 1930s. The drug is used in treating and preventing symptoms of acute alcohol withdrawal. It is structurally related to

thiamine Thiamine, also known as thiamin and vitamin B1, is a vitamin, an essential micronutrient, that cannot be made in the body. It is found in food and commercially synthesized to be a dietary supplement or medication. Phosphorylated forms of thi ...

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

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 or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

, having the same mechanism of action as traditional barbiturates. It is also rarely used for the management of agitation, restlessness, short-term

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

and

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

in the elderly, when all other treatment options have failed. In the UK, it is sold under the brand Heminevrin (

AstraZeneca Pharmaceuticals AstraZeneca plc () is a British-Swedish multinational pharmaceutical and biotechnology company with its headquarters at the Cambridge Biomedical Campus in Cambridge, England. It has a portfolio of products for major diseases in areas includi ...

). Other brand names include Nevrin in Romania, Distraneurin in

Germany Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwe ...

and Distraneurine in Spain. The drug is marketed either as a

free base Free base (freebase, free-base) is the conjugate base (deprotonated) form of an amine, as opposed to its conjugate acid (protonated) form. The amine is often an alkaloid, such as nicotine, cocaine, morphine, and ephedrine, or derivatives thereo ...

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 In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds to ...

at the

barbiturate 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 we ...

picrotoxin Picrotoxin, also known as cocculin, is a poisonous crystalline plant compound. It was first isolated by the French pharmacist and chemist Pierre François Guillaume Boullay (1777–1869) in 1812. The name "picrotoxin" is a combination of the Gree ...

site of the GABA_A

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

. 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 synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

GABA at this receptor. GABA is the major inhibitory neurotransmitter in the brain and produces anxiolytic, anticonvulsant, sedative, and hypnotic effects. Chlomethiazole 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 also a CYP2A6 and CYP2E1 enzyme inhibitor, and thus can affect the plasma clearance of substrates of those enzymes. When clomethiazole is administered via IV in addition to

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other medi ...

, 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 chlomethiazole can cause

tolerance Tolerance or toleration is the state of tolerating, or putting up with, conditionally. Economics, business, and politics * Toleration Party, a historic political party active in Connecticut * Tolerant Systems, the former name of Veritas Software ...

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 certai ...

. Abrupt withdrawal may result in symptoms similar to those of sudden withdrawal of alcohol or

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...

Overdose

Clomethiazole is particularly toxic and dangerous if

overdosed A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended.

and can be 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, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...

. 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, code name Ro 15-1788) is a selective GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines ( ...

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 Keith John Moon (23 August 19467 September 1978) was an English drummer for the rock band the Who. He was noted for his unique style of playing and his eccentric, often self-destructive behaviour and addiction to drugs and alcohol. Moon grew ...

of the rock band

The Who The Who are an English rock band formed in London in 1964. Their classic lineup consisted of lead singer Roger Daltrey, guitarist and singer Pete Townshend, bass guitarist and singer John Entwistle, and drummer Keith Moon. They are considered ...

died of a clomethiazole overdose.

References

{{Glycinergics GABAA receptor positive allosteric modulators Glycine receptor agonists Hypnotics AstraZeneca brands Organochlorides Sedatives Thiazoles

Pharmacology

Adverse effects

Overdose

See also

References