Disulfiram-alcohol reaction

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Disulfiram-alcohol reaction (DAR)
Other namesDisulfiram ethanol reaction (DER), Antabuse effect, acetaldehyde syndrome
The Alcohol Flushing Response.png
Alcohol flush reaction is a visible effect of DAR.
Specialty Toxicology
Symptoms Flush, nausea, lightheadedness, headache, sweating, vomiting, vertigo, etc
CausesIngestion of disulfiram with alcohol

Disulfiram-alcohol reaction (DAR) is the effect of the interaction in the human body of alcohol drunk with disulfiram or some mushrooms. [1] [2] The DAR is key to disulfiram therapy that is widely used for alcohol-aversive treatment and management of other addictions (e.g. cocaine [3] [4] use). [5] [6] Once disulfiram-treated patients take alcohol, even in small doses, they experience strong unpleasant sensations (flush, nausea, lightheadedness, headache, sweating, vomiting, and vertigo). [7]

Contents

Disulfiram has been used to treat alcoholism since 1948 after its accidental discovery in Denmark. [8] [9] [10]

Pharmacology

DAR symptoms usually begin within 5–15 minutes of the ingestion of alcohol by a patient who has taken disulfiram 3–12 hours before. [8]

Increased acetaldehyde content in blood is considered to be the cause of the toxic effect. [11] [12] Disulfiram inhibits several human aldehyde dehydrogenases (ALDH), [13] most importantly the version coded for by gene ALDH2 which metabolizes acetaldehyde. [14] The reaction is found to depend on a disulfiram-induced predisposition reflected by alkalosis, the blood acetaldehyde level, and an individual predisposition reflected by dopamine β-hydroxylase activity. [15]

The intensity of a patient's experience of DAR varies with race of the subject. [16]

It has long been known that disulfiram can cause hepatitis and can be fatal (1 case per 30,000 patients), although due to dosage reductions in recent decades, such cases are extremely rare. [17] Death, however, from the reaction itself without significant liver damage is also possible as an atypical case. [18] [19]

Unintended initiations

DAR can occur from skin contact of a disulfiram-treated patient with alcohol-containing skin care products such as colognes, sunscreen lotions, aftershave lotions, and alcohol-based tar gels, [20] but a significant toxic effect does not appear to be achieved in this way. [21] During the COVID-19 pandemic, there were also cases of DAR initiation due to the use of alcohol-based hand sanitizers. [22]

Some mushrooms contain substances that, when combined with alcohol, cause DAR. [23] They include lurid bolete (Boletus luridus), [24] inky cap (Coprinopsis atramentaria), [25] [26] and club-foot (Clitocybe clavipes). [27] Because of the similarities to disulfiram (tetraethylthiuram disulfide) poisoning, it was long speculated that disulfiram was the active ingredient in common inkcap. In 1975, coprine was identified as the compound in the common inkcap, with the mechanism identified in 1979. [28] [29] [30]

See also

Related Research Articles

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Acetaldehyde is an organic chemical compound with the formula CH3 CHO, sometimes abbreviated as MeCHO. It is a colorless liquid or gas, boiling near room temperature. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale in industry. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants. It is also produced by the partial oxidation of ethanol by the liver enzyme alcohol dehydrogenase and is a contributing cause of hangover after alcohol consumption. Pathways of exposure include air, water, land, or groundwater, as well as drink and smoke. Consumption of disulfiram inhibits acetaldehyde dehydrogenase, the enzyme responsible for the metabolism of acetaldehyde, thereby causing it to build up in the body.

<span class="mw-page-title-main">Alcohol dehydrogenase</span> Group of dehydrogenase enzymes

Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. In humans and many other animals, they serve to break down alcohols that are otherwise toxic, and they also participate in the generation of useful aldehyde, ketone, or alcohol groups during the biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.

<span class="mw-page-title-main">Disulfiram</span> Chemical compound

Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.

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<span class="mw-page-title-main">Acetaldehyde dehydrogenase</span> Class of enzymes

Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:

<span class="mw-page-title-main">Alcohol flush reaction</span> Effect of alcohol consumption on the human body

Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, ears, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.

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<span class="mw-page-title-main">Aldehyde dehydrogenase</span> Group of enzymes

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<i>Coprinopsis atramentaria</i> Species of fungus

Coprinopsis atramentaria, commonly known as the common ink cap, tippler's bane, or inky cap, is an edible mushroom found in Europe and North America. Previously known as Coprinus atramentarius, it is the second best known ink cap and previous member of the genus Coprinus after C. comatus. It is a widespread and common fungus found throughout the northern hemisphere. Clumps of mushrooms arise after rain from spring to autumn, commonly in urban and disturbed habitats such as vacant lots and lawns, as well as grassy areas. The grey-brown cap is initially bell-shaped before opening, after which it flattens and disintegrates. The flesh is thin and the taste mild. It can be eaten, but due to the presence of coprine within the mushroom, it is poisonous when consumed with alcohol, as it heightens the body's sensitivity to ethanol in a similar manner to the anti-alcoholism drug disulfiram.

<span class="mw-page-title-main">ALDH2</span> Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.

<span class="mw-page-title-main">Cyclopropanone</span> Chemical compound

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<span class="mw-page-title-main">Hangover</span> Discomfort following alcohol consumption

A hangover is the experience of various unpleasant physiological and psychological effects usually following the consumption of alcohol, such as wine, beer, and liquor. Hangovers can last for several hours or for more than 24 hours. Typical symptoms of a hangover may include headache, drowsiness, concentration problems, dry mouth, dizziness, fatigue, gastrointestinal distress, absence of hunger, light sensitivity, depression, sweating, hyper-excitability, irritability, and anxiety.

<span class="mw-page-title-main">ADH1B</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Short-term effects of alcohol consumption</span> Overview of the short-term effects of the consumption of alcoholic beverages

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<span class="mw-page-title-main">Coprine</span> Chemical compound

Coprine is a mycotoxin. It was first isolated from common inkcap. It occurs in mushrooms in the genera Coprinopsis. When combined with alcohol, it causes "Coprinus syndrome". It inhibits the enzyme aldehyde dehydrogenase, which is involved in the metabolism of alcohol. This inhibition leads to a buildup of acetaldehyde, causing an alcohol flush reaction. Because of this, the mushroom is commonly referred to as Tippler's Bane.

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<span class="mw-page-title-main">Alcohol intolerance</span> Medical condition

Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde. This polymorphism is most often reported in patients of East Asian descent. Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. Severe pain after drinking alcohol may indicate a more serious underlying condition.

<span class="mw-page-title-main">Disulfiram-like drug</span> Drug that causes an adverse reaction to alcohol

A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects are caused by accumulation of acetaldehyde, a major but toxic metabolite of alcohol formed by the enzyme alcohol dehydrogenase. The reaction has been variously termed a disulfiram-like reaction, alcohol intolerance, and acetaldehyde syndrome.

References

  1. ↑ Elenbaas, R. M. (August 1977). "Drug therapy reviews: management of the disulfiram-alcohol reaction". American Journal of Hospital Pharmacy. 34 (8): 827–831. PMID   331944.
  2. ↑ Johansson, Benny; Angelo, Helle R.; Christensen, Jens Knud; Møller, Ib Walther; Rønsted, Per (March 1991). "Dose-Effect Relationship of Disulfiram in Human Volunteers. II: A Study of the Relation between the Disulfiram-Alcohol Reaction and Plasma Concentrations of Acetaldehyde, Diethyldithiocarbamic Acid Methyl Ester, and Erythrocyte Aldehyde Dehydrogenase Activity". Pharmacology & Toxicology. 68 (3): 166–170. doi:10.1111/j.1600-0773.1991.tb01216.x. PMID   1647526.
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  4. ↑ O'Shea, Brian (December 2000). "Disulfiram revisited". Hospital Medicine. 61 (12): 849–851. doi:10.12968/hosp.2000.61.12.1483. PMID   11211585.
  5. ↑ Beyeter, Christine; Fisch, Hans-Ulrich; Preisig, Rudotf (March 1985). "The Disulfiram-Alcohol Reaction: Factors Determining and Potential Tests Predicting Severity". Alcoholism: Clinical and Experimental Research. 9 (2): 118–124. doi:10.1111/j.1530-0277.1985.tb05531.x. PMID   3890590.
  6. ↑ Tayyareci, Yelda; Acarel, Esra (January 2009). "Acute myocardial infarction associated with disulfiram-alcohol interaction in a young man with normal coronary arteries". Turk Kardiyoloji Dernegi Arsivi. 37 (1): 48–50. PMID   19225254.
  7. ↑ Amuchastegui, Tomas; Amuchastegui, Marcos; Donohue, Thomas (February 2014). "Disulfiram--alcohol reaction mimicking an acute coronary syndrome". Connecticut Medicine. 78 (2): 81–84. PMID   24741856.
  8. 1 2 Murthy, K. Krishna; Praveenlal, K. (July 1988). "An Experience with Disulfiram in the management of Alcohol Dependence Syndrome". Indian Journal of Psychological Medicine. 11 (2): 145–148. doi: 10.1177/0975156419880213 . S2CID   220676012.
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  13. ↑ Agarwal, Rakesh (2022). "Diffuse subendocardial ischemia secondary to disulfiram-alcohol ingestion". Indian Journal of Pharmacology. 54 (2): 146–147. doi: 10.4103/ijp.ijp_930_21 . PMC   9249151 . PMID   35546467.
  14. ↑ Omran, Z (15 May 2021). "Development of new disulfiram analogues as ALDH1a1-selective inhibitors". Bioorganic & Medicinal Chemistry Letters. 40: 127958. doi:10.1016/j.bmcl.2021.127958. PMID   33744437. S2CID   232311209.
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  16. ↑ Zeiner, Arthur R. (1981). "Are Differences in the Disulfiram-Alcohol Reaction the Basis of Racial Differences in Biological Sensitivity to Ethanol?". Drug Dependence and Alcoholism. pp. 573–581. doi:10.1007/978-1-4684-3614-3_69. ISBN   978-1-4684-3616-7.
  17. ↑ Chick, Jonathan (1999). "Safety Issues Concerning the Use of Disulfiram in Treating Alcohol Dependence". Drug Safety. 20 (5): 427–435. doi:10.2165/00002018-199920050-00003. PMID   10348093. S2CID   19476907.
  18. ↑ Amador, Elias; Gazdar, Adi (December 1967). "Sudden Death during Disulfiram—Alcohol Reaction". Quarterly Journal of Studies on Alcohol. 28 (4): 649–654. doi:10.15288/qjsa.1967.28.649. PMID   6082192.
  19. ↑ Heath, M.J.; Pachar, J.V.; Perez Martinez, A.L.; Toseland, P.A. (September 1992). "An exceptional case of lethal disulfiram-alcohol reaction". Forensic Science International. 56 (1): 45–50. doi:10.1016/0379-0738(92)90145-M. PMID   1398376.
  20. ↑ Stoll, David (7 November 1980). "Disulfiram-Alcohol Skin Reaction to Beer-Containing Shampoo". JAMA: The Journal of the American Medical Association. 244 (18): 2045. doi:10.1001/jama.1980.03310180015010. PMID   6448928.
  21. ↑ Haddock, Neil F. (March 1982). "Cutaneous Reactions to Lower Aliphatic Alcohols Before and During Disulfiram Therapy". Archives of Dermatology. 118 (3): 157–159. doi:10.1001/archderm.1982.01650150019013. PMID   7065662.
  22. ↑ Ghosh, Abhishek; Mahintamani, Tathagata; Balhara, Y P S; Roub, Fazl E; Basu, Debashish; Bn, Subodh; Mattoo, S K; Mishra, Eepsita; Sharma, Babita (4 January 2021). "Disulfiram Ethanol Reaction with Alcohol-Based Hand Sanitizer: An Exploratory Study". Alcohol and Alcoholism. 56 (1): 42–46. doi:10.1093/alcalc/agaa096. PMC   7665335 . PMID   33150930.
  23. ↑ Johansson, B. (November 1992). "A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites". Acta Psychiatrica Scandinavica. 86 (S369): 15–26. doi:10.1111/j.1600-0447.1992.tb03310.x. PMID   1471547. S2CID   23832065.
  24. ↑ Budmiger, H.; Kocher, F. (21 August 1982). "Hexen-Röhrling (Boletus luridus) mit Alkohol. Schweiz. Medizinische Wochenschrift" [Boletus luridus and alcohol. Case report]. Schweizerische Medizinische Wochenschrift (in German). 112 (34): 1179–1181. PMID   7134946.
  25. ↑ Lash, Erica; Hack, Jason B. (August 2019). "Disulfiram and Hypotension in a 53-year-old Woman". Rhode Island Medical Journal. 102 (6): 44–46. PMID   31398969.
  26. ↑ Lash, Erica; Hack, Jason B (2019). "Disulfiram and Hypotension in a 53-year-old Woman". Rhode Island Medical Journal (2013). 102 (6): 44–46. PMID   31398969.
  27. ↑ Cochran, Kenneth W.; Cochran, Martha W. (September 1978). "Clitocybe Clavipes : Antabuse-Like Reaction to Alcohol". Mycologia. 70 (5): 1124–1126. doi:10.1080/00275514.1978.12020326. PMID   569766.
  28. ↑ Lindberg, Per; Bergman, Rolf; Wickberg, Börje (1975). "Isolation and structure of coprine, a novel physiologically active cyclopropanone derivative from Coprinus atramentarius and its synthesis via 1-aminocyclopropanol". Journal of the Chemical Society, Chemical Communications (23): 946–947. doi:10.1039/C39750000946.
  29. ↑ Lindberg, Per; Bergman, Rolf; Wickberg, Börje (1977). "Isolation and structure of coprine, the in vivo aldehyde dehydrogenase inhibitor in Coprinus atramentarius; syntheses of coprine and related cyclopropanone derivatives". Journal of the Chemical Society, Perkin Transactions 1 (6): 684–691. doi:10.1039/P19770000684.
  30. ↑ Wiseman, Jeffrey S.; Abeles, Robert H. (May 2002). "Mechanism of inhibition of aldehyde dehydrogenase by cyclopropanone hydrate and the mushroom toxin coprine". Biochemistry. 18 (3): 427–435. doi:10.1021/bi00570a006. PMID   369602.
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