| Systematic (IUPAC) name | |
|---|---|
| 1,1',1'',1'''-[disulfanediylbis(carbonothioylnitrilo)]tetraethane | |
| Clinical data | |
| Trade names | Antabuse |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a682602 |
| Pregnancy cat. | C (US) |
| Legal status | ? |
| Routes | Oral, subdermal implant |
| Pharmacokinetic data | |
| Metabolism | Hepatic to diethylthiocarbamate |
| Half-life | 60–120 hours |
| Identifiers | |
| CAS number | 97-77-8 |
| ATC code | N07BB01 P03AA04 |
| PubChem | CID 3117 |
| DrugBank | DB00822 |
| ChemSpider | 3005 |
| UNII | TR3MLJ1UAI |
| KEGG | D00131 |
| ChEBI | CHEBI:4659 |
| ChEMBL | CHEMBL964 |
| Synonyms | 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide |
| Chemical data | |
| Formula | C10H20N2S4 |
| Mol. mass | 296.539 g/mol |
| SMILES | eMolecules & PubChem |
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Disulfiram is a drug discovered in the 1920s[1] and used to support the treatment of chronic alcoholism by producing an acute sensitivity to alcohol. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals. Disulfiram is also being studied as a treatment for cocaine dependence, as it prevents the breakdown of dopamine (a neurotransmitter whose release is stimulated by cocaine); the excess dopamine results in increased anxiety, higher blood pressure, restlessness and other unpleasant symptoms. Several studies have reported that it has anti-protozoal activity as well.[2][3] Research for possible disulfiram use in cancer therapy has been announced.
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The drug's action was discovered by accident in 1948 by the researchers Erik Jacobsen, Jens Hald, and Keneth Ferguson at the Danish drug company Medicinalco.[4] The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.
Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to the harmless acetic acid. Disulfiram blocks this reaction at the intermediate stage by blocking the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a "hangover" this produces immediate and severe negative reaction to alcohol intake. Some 5–10 minutes after alcohol intake, the patient may experience the effects of a severe hangover for a period of 30 minutes up to several hours. Symptoms include flushing of the skin, accelerated heart rate, shortness of breath, nausea, vomiting, throbbing headache, visual disturbance, mental confusion, postural fainting, and circulatory collapse.
Disulfiram should not be taken if alcohol has been consumed in the last 12 hours.[5] There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body the effects may last for up to two weeks after the initial intake; consequently, medical ethics dictate that patients must be fully informed about the disulfiram-alcohol reaction.[6]
A nine-year study published in 2006 found that incorporation of supervised disulfiram and a related compound calcium carbimide into a comprehensive treatment program resulted in an abstinence rate of over 50%.[7]
Disulfiram does not reduce alcohol cravings, and therefore a major problem associated with this drug is extremely poor compliance. A classic study by Fuller et al (1986) that followed chronic alcoholics for a period of 1 year found no statistically significant differences in abstinence rates between the group that received 250 mg/day of disulfiram and the group that only received counseling. The reason for this finding was that only 20% of subjects in disulfiram group were estimated to be in good compliance with the drug regimen.[8] Methods to improve compliance include subdermal implants, which release the drug continuously over a period of up to 12 weeks, and supervised administration practices, for example, having the drug regularly administered by one's spouse.
Although disulfiram remained the most common pharmaceutical treatment of alcohol abuse till the end of the 20th century, today it is often replaced or accompanied with newer drugs, primarily the combination of naltrexone and acamprosate, which directly attempt to address physiological processes in the brain associated with alcohol abuse.
A study reported that it may be potentially useful in the treatment of Giardia infection.[2] Another study found that it had activity against Trichomonas vaginalis which was resistant to the most common treatment, metronidazole.[3]
It is also useful in the treatment of scabies as a combination drug of Benzyl benzoate/disulfiram.[9]
A patient with metastatic ocular melanoma was successfully treated by disulfiram with zinc gluconate.[10] This can be explained as disulfiram creating complexes with metals (dithiocarbamate complexes) is proteasome inhibitor[11] and can represent a new approach to proteasome inhibition.[12] Clinical trials are recommended.[13] There is ongoing clinical trial of disulfiram with copper gluconate against liver cancer in Utah (ClinicalTrials.gov Identifier: NCT00742911) and clinical trial of disulfiram as adjuvant against lung cancer in Israel (ClinicalTrials.gov Identifier: NCT00312819).
The most common side effects (in the absence of alcohol) are drowsiness, headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur.[14] Tryptophol is a chemical compound that induces sleep in humans. It is formed in the liver after disulfiram treatment.[15]
Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.[16]
Disulfiram is supplied in 200 mg, 250 mg, and 500 mg tablets. The usual initial dose is 500 mg a day for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg–500 mg) per day. The total daily dosage should not exceed 500 mg.[17]
Disulfiram is given 1 g on 1st day, 0.75 g on 2nd day, 0.5 g on 3rd day and 0.25 g subsequently. Sensitization to alcohol develops after 2-3 hours of first dose, reaches its peak at ~12 hours and lasts for 7-14 days after stopping it, because inhibition of aldehyde dehydrogenase with disulfiram is irreversible: synthesis of fresh enzyme is required for return of activity.
Disulfiram may be prepared from oxidation of sodium diethyldithiocarbamate with iodine:
In medicine, the term "disulfiram effect" refers to an adverse effect of a particular medication in causing an unpleasant hypersensitivity to alcohol, similar to the effect caused by disulfiram administration.
Examples:
Coprine (N5-1-hydroxycyclopropyl-L-glutamine), which metabolises to 1-aminocyclopropanol, a closely related chemical having the same metabolic effects, occurs naturally in the common ink cap (Coprinopsis atramentaria), an otherwise edible mushroom. Similar reactions have been recorded with Clitocybe clavipes and Boletus luridus, although the agent in those species is unknown.
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