Disulfiram
 |
|
 |
|
| Clinical data | |
|---|---|
| Trade names | Antabuse |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682602 |
| Pregnancy category |
|
| Routes of administration |
Oral, subdermal implant |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Metabolism | Hepatic to diethylthiocarbamate |
| Biological half-life | 60–120 hours |
| Identifiers | |
|
|
| Synonyms | 1-(diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide |
| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| NIAID ChemDB | |
| ECHA InfoCard | 100.002.371 |
| Chemical and physical data | |
| Formula | C10H20N2S4 |
| Molar mass | 296.539 g/mol |
| 3D model (Jmol) | |
|
|
|
|
  (what is this?) (verify) |
|
Disulfiram (sold under the trade names Antabuse and Antabus) is a drug discovered in the 1920s[1] used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, which means many of the effects of a "hangover" are felt immediately after alcohol is consumed. "Disulfiram plus alcohol, even small amounts, produce flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death" [2]
In the body, alcohol is converted to acetaldehyde, which is then broken down by aldehyde dehydrogenase. If the dehydrogenase enzyme is inhibited, acetaldehyde builds up and causes unpleasant effects. Disulfiram should be used in conjunction with counseling and support.
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, elevated blood pressure, restlessness, and other unpleasant symptoms.[citation needed] Several studies have reported that it has antiprotozoal activity, as well.[3][4] Disulfiram is the subject of research for treatment of cancer and HIV (to activate the reservoir of HIV-infected resting CD4 cells).[5]
Contents
Uses[edit]
Alcoholism[edit]
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 a harmless acetic acid derivative (acetyl coenzyme A). Disulfiram blocks this reaction at the intermediate stage by blocking acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be five 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 five to 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 syncope, and circulatory collapse.
Disulfiram should not be taken if alcohol has been consumed in the last 12 hours.[6] There is no tolerance to disulfiram: the longer it is taken, the stronger its effects.[7] 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.[8]
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%.[9]
Disulfiram does not reduce alcohol cravings, so a major problem associated with this drug is extremely poor compliance. A classic study by Fuller (1986) that followed chronic alcoholics for a period of one year found no statistically significant differences in abstinence rates between the group that received 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.[10] 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.
Cancer[edit]
When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor[11] and can represent a new approach to proteasome inhibition.[12] Clinical trials are recommended.[13] A clinical trial of disulfiram with copper gluconate against liver cancer is being conducted in Utah (ClinicalTrials.gov Identifier: NCT00742911) and a clinical trial of disulfiram as adjuvant against lung cancer is happening in Israel (ClinicalTrials.gov Identifier: NCT00312819).
Side effects in absence of alcohol[edit]
The most common side effects in the absence of alcohol are headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur.[14] Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment.[15]
Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms.[16]
Disulfiram disrupts metabolism of several other compounds, including paracetamol (acetaminophen),[17] theophylline[18] and caffeine.[19] However, in most cases, this disruption is mild and presents itself as a 20–40% increase in the half-life of the compound at typical dosages of disulfiram.
Similarly acting substances[edit]
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:
- Antibiotics (nitroimidazoles), e.g. metronidazole
- First-generation sulfonylureas, e.g. tolbutamide and chlorpropamide
- Several cephalosporin drugs, including cefoperazone, cefamandole and cefotetan, that have a N-methylthio-tetrazole moiety
- Griseofulvin, an oral antifungal drug
- Procarbazine
- Temposil, or citrated calcium carbimide, has the same function as disulfiram, but is weaker and safer.[citation needed]
- Coprine, which metabolizes to 1-aminocyclopropanol, a chemical having the same metabolic effects as disulfiram. It occurs naturally in the otherwise edible common ink cap mushroom (Coprinopsis atramentaria), hence its colloquial name "tippler's bane". Similar reactions have been recorded with Clitocybe clavipes and Suillellus luridus, although the agent in those species is unknown.
History[edit]
This chemical and similar compounds were used in the vulcanization of rubber for tires, and it had been noted that workers in those industries often had adverse reactions to alcohol; the connection between the reaction and exposure to these chemicals, though, had not been deduced. However in 1948 researchers Erik Jacobsen, Jens Hald, and Keneth Ferguson at the Danish drug company Medicinalco uncovered the connection when they self-dosed with the chemical in the course of testing it as a possible anti-parasitic, and found themselves reacting violently to alcohol consumption.[20][21]
Disulfiram is currently sold under the trade names Antabuse and Antabus, manufactured by Odyssey Pharmaceuticals.
Safety[edit]
Though the Occupational Safety and Health Administration (OSHA) in the US has not set a permissible exposure limit (PEL) for disulfiram in the workplace, the National Institute for Occupational Safety and Health has set a recommended exposure limit (REL) of 2 mg/m3 and recommended that workers avoid concurrent exposure to ethylene dibromide.[22]
See also[edit]
References[edit]
- ^ US Patent 1782111 - Method of Manufacturing Tetra-alkylated Thiuramdisulphides
- ^ NIH (May 23, 2016). "ANTABUSE- disulifram tablet". DailyMed. NIH. Retrieved 4 July 2016.
- ^ Nash, T; Rice, WG (1998). "Efficacies of zinc-finger-active drugs against Giardia lamblia". Antimicrobial Agents and Chemotherapy. 42 (6): 1488–92. PMC 105627
. PMID 9624499. - ^ Bouma, M. J.; Snowdon, D.; Fairlamb, A. H.; Ackers, J. P. (1998). "Activity of disulfiram (bis(diethylthiocarbamoyl)disulphide) and ditiocarb (diethyldithiocarbamate) against metronidazole-sensitive and - resistant Trichomonas vaginalis and Tritrichomonas foetus". Journal of Antimicrobial Chemotherapy. 42 (6): 817–20. doi:10.1093/jac/42.6.817. PMID 10052908.
- ^ Doyon, Geneviève; Zerbato, Jennifer; Mellors, John W.; Sluis-Cremer, Nicolas (2013). "Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog". AIDS. 27 (2): F7–F11. doi:10.1097/QAD.0b013e3283570620. PMID 22739395.
- ^ "Disulfiram Official FDA information, side effects and uses.". Retrieved 2011-04-11.
- ^ NIH (May 23, 2016). "ANTABUSE- disulifram tablet". Dailymed. NIH. Retrieved 4 July 2016.
- ^ Wright, Curtis; Moore, Richard D. (1990). "Disulfiram treatment of alcoholism". The American Journal of Medicine. 88 (6): 647–55. doi:10.1016/0002-9343(90)90534-K. PMID 2189310.
- ^ Krampe, Henning; Stawicki, Sabina; Wagner, Thilo; Bartels, Claudia; Aust, Carlotta; Ruther, Eckart; Poser, Wolfgang; Ehrenreich, Hannelore (2006). "Follow-up of 180 Alcoholic Patients for up to 7 Years After Outpatient Treatment: Impact of Alcohol Deterrents on Outcome". Alcoholism: Clinical and Experimental Research. 30 (1): 86–95. doi:10.1111/j.1530-0277.2006.00013.x. PMID 16433735.
- ^ Fuller, Richard K.; Branchey, L; Brightwell, DR; Derman, RM; Emrick, CD; Iber, FL; James, KE; Lacoursiere, RB; et al. (1986). "Disulfiram Treatment of Alcoholism: A Veterans Administration Cooperative Study". JAMA. 256 (11): 1449–55. doi:10.1001/jama.1986.03380110055026. PMID 3528541.
- ^ Cvek, B.; Dvorak, Z. (2007). "Targeting of Nuclear Factor-κB and Proteasome by Dithiocarbamate Complexes with Metals". Current Pharmaceutical Design. 13 (30): 3155–67. doi:10.2174/138161207782110390. PMID 17979756.
- ^ Cvek, Boris; Dvorak, Zdenek (2008). "The value of proteasome inhibition in cancer". Drug Discovery Today. 13 (15–16): 716–22. doi:10.1016/j.drudis.2008.05.003. PMID 18579431.
- ^ Wickström, Malin; Danielsson, Katarina; Rickardson, Linda; Gullbo, Joachim; Nygren, Peter; Isaksson, Anders; Larsson, Rolf; Lövborg, Henrik (2007). "Pharmacological profiling of disulfiram using human tumor cell lines and human tumor cells from patients". Biochemical Pharmacology. 73 (1): 25–33. doi:10.1016/j.bcp.2006.08.016. PMID 17026967.
- ^ "Disulfiram Side Effects". Drugs.com. Retrieved 6 November 2010.
- ^ Cornford, E M; Bocash, W D; Braun, L D; Crane, P D; Oldendorf, W H; MacInnis, A J (1979). "Rapid distribution of tryptophol (3-indole ethanol) to the brain and other tissues". Journal of Clinical Investigation. 63 (6): 1241–8. doi:10.1172/JCI109419. PMC 372073. PMID 447842.
- ^ Boukriche, Yassine; Weisser, Isabelle; Aubert, Pascale; Masson, Catherine (2000). "MRI findings in case of late onset disulfiram-induced neurotoxicity". Journal of Neurology. 247 (9): 714–5. doi:10.1007/s004150070119. PMID 11081815.
- ^ Poulsen, H. E.; Ranek, L.; Jørgensen, L. (1991). "The influence of disulfiram on acetaminophen metabolism in man". Xenobiotica. 21 (2): 243–9. doi:10.3109/00498259109039466. PMID 2058179.
- ^ Loi, Cho-Ming; Day, John D; Jue, Sandra G; Bush, Ernie D; Costello, Patrick; Dewey, Larry V; Vestal, Robert E (1989). "Dose-dependent inhibition of theophylline metabolism by disulfiram in recovering alcoholics". Clinical Pharmacology and Therapeutics. 45 (5): 476–86. doi:10.1038/clpt.1989.61. PMID 2721103.
- ^ Beach, Cynthia A; Mays, Dennis C; Guiler, Robert C; Jacober, Cynthia H; Gerber, Nicholas (1986). "Inhibition of elimination of caffeine by disulfiram in normal subjects and recovering alcoholics". Clinical Pharmacology and Therapeutics. 39 (3): 265–70. doi:10.1038/clpt.1986.37. PMID 3948467.
- ^ Hvad er antabus, a Danish site describing the discovery of the drug’s effects.
- ^ Larimer, Robert C. (September 13, 1952). "Treatment of Alcoholism with Antabuse". Journal of the American Medical Association. 150 (2): 79. doi:10.1001/jama.1952.03680020013004. Retrieved 2016-03-11.
- ^ "NIOSH Pocket Guide to Chemical Hazards #0244". National Institute for Occupational Safety and Health (NIOSH).
External links[edit]
- Toxicity, Mushroom - Disulfiramlike Toxins at eMedicine
- CDC - NIOSH Pocket Guide to Chemical Hazards
