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Disulfiram
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| Systematic (IUPAC) name | |
| 1-(diethylthiocarbamoyldisulfanyl)- N,N-diethyl-methanethioamide | |
| Identifiers | |
| CAS number | |
| ATC code | N07 P03AA04 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C10H20N2S4 |
| Mol. mass | 296.543 g/mol |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Metabolism | Hepatic to diethylthiocarbamate |
| Half life | 60-120 hours |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
C (US) |
| Legal status | |
| Routes | Oral |
Disulfiram is a drug 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.[1][2]
Contents |
Interaction with alcohol
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. 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 2 weeks after the initial intake; consequently, medical ethics dictate that patients must be fully informed about the disulfiram-alcohol reaction. Possible side effects while taking Disulfiram are numbness or tingling of the lower legs and shortness of breath.
Dosage
Disulfiram is supplied in 200 mg, 250 mg and 500 mg tablets. The usual initial dose is 500 mg 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.
History and Antiprotozoal use
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. The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.citation needed
A study reported that it may be potentially useful in the treatment of Giardia infection.[1] Another study found that it had activity against Trichomonas vaginalis which was resistant to the most common treatment, Metronidazole.[2]
Similarly acting substances
Coprine (N5-1-hydroxycyclopropyl-L-glutamine) which metabolises to 1-aminocyclopropanol, a closely-related chemical having the same metabolic effects, occurs naturally in several edible mushroom species, such as the Common Ink Cap.
Temposil, or citrated calcium carbamide, has the same function as disulfiram, but is weaker and safer.
Griseofulvin, an oral anti-fungal drug.
Dangerous drug interactions
Disulfiram should not be administered to patients who take certain stimulant drugs and antidepressants. Disulfiram has been found to inhibit the enzyme dopamine-beta-hydroxylase, blocking the metabolism of dopamine into norepinephrine. Combined with the dopamine agonist and/or reuptake effect of stimulants, this can cause a dramatic rise in synaptic dopamine levels, resulting in sleeplessness, paranoia, and, in extreme cases, stimulant psychosis.
Drugs that are known to interfere with the dopamine / norepinephrine system include, but are not limited to:
- Bupropion (Wellbutrin IR/SR/XL, Amfebutamone)citation needed
- Amphetamines (Adderall, Dexedrine, etc.)
- Methylphenidate (Ritalin, Concerta, Focalin, etc.)
- Cocaine (Occasionally used in dental procedures, and a known substance of abuse.)
The metabolism of other drugs may be inhibited by disulfiram, increasing their potential for toxic effects. Drugs known to have adverse effects when used concurrently with disulfiram include amitriptyline, isoniazid, and metronidazole (all with acute changes in mental state), phenytoin, some benzodiazepines, morphine, pethidine, and barbiturates.
Disulfiram vs. Cancer
A patient with metastatic ocular melanoma was successfully treated by disulfiram with zinc gluconate [1] This can be explained as disulfiram creating complexes with metals (dithiocarbamate complexes) is proteasome inhibitor [2] and can represent a new approach to proteasome inhibition [3] The clinical trials are recommended [4]
Organic chemistry
Disulfiram is an example of a thiuram disulfide, that is the oxidized derivative of diethyldithiocarbamate.
See also
References
- ^ a b Nash T, Rice WG (1998). "Efficacies of zinc-finger-active drugs against Giardia lamblia". Antimicrob. Agents Chemother. 42 (6): 1488–92. PMID 9624499.
- ^ a b Bouma MJ, Snowdon D, Fairlamb AH, Ackers JP (1998). "Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and -resistant Trichomonas vaginalis and Tritrichomonas foetus". J. Antimicrob. Chemother. 42 (6): 817–20. doi:. PMID 10052908.
External links
- Disulfiram (patient information)
- Toxicity, Mushroom - Disulfiramlike Toxins
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Wikipedia content modification information:
- This page was last modified on 29 August 2008, at 00:37.
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