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INTRODUCTION

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 in the United States since 1951 as a drug in the treatment of alcoholism. Ingestion of ethanol while taking disulfiram causes a well-defined unpleasant reaction, the fear of which provides a negative incentive to drink alcohol. Clinical toxicity is caused by overdose or occurs as a result of a disulfiram–ethanol drug interaction. Disulfiram is being investigated for the treatment of cocaine addiction, drug-resistant fungal infections, and malignancies. The toxicities resulting from disulfiram overdose differ from those of disulfiram–ethanol interaction.

MECHANISM OF TOXICITY

  1. Disulfiram causes inhibition of two critical enzymes. It binds irreversibly to aldehyde dehydrogenase, leading to accumulation of toxic acetaldehyde after ethanol ingestion. Inhibition 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.

  2. Disulfiram is metabolized via cytochrome P450-mediated phase I oxidation, and by phase II methylation and glucuronidation. A metabolite is carbon disulfide (see also Carbon Disulfide), which may play a role in central and peripheral nervous system toxicity.

  3. 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 or distal sensory-motor and optic neuropathy may also occur with chronic use.

  4. Pharmacokinetics. Disulfiram is absorbed rapidly and completely, but because enzyme inhibition is the mechanism of action, peak effects may be delayed for 8–12 hours. Although the elimination half-life is 7–8 hours, clinical effects may persist for days because of high lipid solubility and slow enzyme resynthesis. Disulfiram is metabolized in the liver. It inhibits multiple cytochrome P450 enzymes, thus inhibiting the metabolism of many other drugs, including isoniazid, phenytoin, theophylline, warfarin, and many benzodiazepines.

TOXIC DOSE

  1. Disulfiram overdose. A typical therapeutic dose of disulfiram is 250 mg/day. Ingestion of 2.5 g or more has caused toxicity in children after a delay of 3–12 hours.

  2. 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.

CLINICAL PRESENTATION

  1. 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 ...

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