Disulfiram (tetraethylthiuram disulfide [CASRN 97-77-8], or Antabuse) is an antioxidant industrial chemical produced since 1881 for the vulcanization of rubber. Introduced in the 1930s into clinical medicine as a vermicide and scabicide, it has been used since 1951 as a drug in the treatment of alcoholism. Ingestion of ethanol by someone taking disulfiram causes a well-defined unpleasant reaction, the fear of which provides a negative incentive to drink. Clinical toxicity is caused by overdose or occurs as a result of a disulfiram-alcohol drug interaction. The epidemiology of disulfiram toxicity may soon change, as alternative drugs have been approved for treatment of alcoholism (naltrexone and acamprosate) and disulfiram is being investigated for treatment of cocaine addiction, drug-resistant fungal infections, and malignancies. The clinical pictures resulting from disulfiram overdose differ from those of disulfiram-ethanol interaction.
Mechanism of toxicity
Disulfiram causes toxicity by inhibiting two enzymes. Blockage of aldehyde dehydrogenase leads to accumulation of toxic acetaldehyde after ethanol ingestion. Blockage of dopamine beta-hydroxylase (necessary for norepinephrine synthesis from dopamine) results in norepinephrine depletion at presynaptic sympathetic nerve endings, leading to vasodilation and orthostatic hypotension. The resulting surplus of dopamine may potentiate psychosis and provides a theoretic basis for the use of disulfiram in treating cocaine dependence.
Disulfiram is metabolized to small amounts of carbon disulfide (see also Carbon Disulfide), which may play a role in central and peripheral nervous system toxicity.
Disulfiram and its metabolites contain either sulfhydryl (S–H) or thiocarbonyl (C=S) moieties common to chelating agents. Chronic use may cause depletion of certain essential metals (copper, zinc). This may in part be the cause of the enzyme-inhibiting effects of disulfiram, as both of these enzymes require copper as a cofactor. Idiosyncratic fulminant hepatic failure may also occur.
Pharmacokinetics. Disulfiram is absorbed rapidly and completely, but peak effects involve enzyme inhibition and may require 8–12 hours. Although the elimination half-life is 7–8 hours, clinical actions may persist for several days, in part because of high lipid solubility. Disulfiram is metabolized in the liver. It inhibits the metabolism of many other drugs, including isoniazid, phenytoin, theophylline, warfarin, and many benzodiazepines (see also Table II–61.)
Disulfiram overdose. Ingestion of 2.5 g or more has caused toxicity in children after a delay of 3–12 hours.
Disulfiram-ethanol interaction. Ingestion of as little as 7 mL of ethanol can cause a severe reaction in patients taking as little as 200 mg of disulfiram per day. Mild reactions have been reported after use of cough syrup, aftershave lotions, and other alcohol-containing products.
Acute disulfiram overdose (without ethanol) is uncommon and exhibits primarily neurologic symptoms, with headache, ataxia, confusion, lethargy, seizures, and prolonged coma. Multiple authors report neuropathy and basal ganglia lesions. Neuropsychological impairment may be chronic. A garlic-like breath odor, vomiting, and hypotension have been reported with acute disulfiram overdose.
Disulfiram-ethanol interaction. The severity of the reaction usually depends on the dose of disulfiram and ethanol. Mild reactions (mild headache, facial flushing) may occur almost immediately after ...