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 B
1), 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
GABAA 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, ...
s.
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.
See also
*
Drug of last resort
A drug of last resort (DoLR), also known as a heroic dose, is a pharmaceutical drug which is tried after all other drug options have failed to produce an adequate response in the patient. Drug resistance, such as antimicrobial resistance or antine ...
*
Therapeutic index
The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug. It is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes ...
References
{{Glycinergics
GABAA receptor positive allosteric modulators
Glycine receptor agonists
Hypnotics
AstraZeneca brands
Organochlorides
Sedatives
Thiazoles