indication

For the treatment and management of chronic alcoholism

pharmacology

Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body. Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol.

mechanism of action

Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake causing an accumulation of acetaldehyde in the blood producing highly unpleasant symptoms. Disulfiram blocks the oxidation of alcohol through its irreversible inactivation of aldehyde dehydrogenase, which acts in the second step of ethanol utilization. In addition, disulfiram competitively binds and inhibits the peripheral benzodiazepine receptor, which may indicate some value in the treatment of the symptoms of alcohol withdrawal, however this activity has not been extensively studied.

toxicity

LD₅₀=8.6g/kg (orally in rats). Symptoms of overdose include irritation, slight drowsiness, unpleasant taste, mild GI disturbances, and orthostatic hypotension.

biotransformation

Hepatic.

absorption

Disulfiram is absorbed slowly from the gastrointestinal tract (80 to 90% of oral dose).

drug interactions

Acenocoumarol: Disulfiram may increase the anticoagulant effect of acenocoumarol.

Aminophylline: Disulfiram may increase the effect and toxicity of aminophylline.

Amprenavir: Increased irsk of side effects (oral solution)

Anisindione: Disulfiram may increase the anticoagulant effect of anisindione.

Chlorzoxazone: Disulfiram may increase the serum level of chlorzoxazone by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of chlorzoxazone if diltiazem is initiated, discontinued or dose changed.

Cocaine: Increases the cardiac toxicity of cocaine

Dicumarol: Disulfiram may increase the anticoagulant effect of dicumarol.

Dyphylline: Increases the effect and toxicity of theophylline

Ethotoin: Increases the effect of phenytoin

Fosphenytoin: Disulfiram may increase the effect of fosphenytoin.

Isoniazid: Increased risk of CNS adverse effects

Mephenytoin: Increases the effect of phenytoin

Metronidazole: Possible acute psychosis and confusion

Oxtriphylline: Disulfiram may increase the effect and toxicity of oxtriphylline.

Phenytoin: Disulfiram may increase the therapeutic and adverse effects of phenytoin.

Theophylline: Disulfiram may increase the effect and toxicity of theophylline.

Tipranavir: Disulfiram may cause Tipranavir (Aptivus brand) toxicity by inhibiting alcohol metabolism. Aptivus capsules contain alcohol.

Trimethadione: Disulfiram, a strong CYP2E1 inhibitor, may decrease the metabolism and clearance of Trimethadione, a CYP2E1 substrate. Consider alternate therapy or monitor for changes in Trimethadione therapeutic and adverse effects if Disulfiram is initiated, discontinued or dose changed.

Warfarin: Disulfiram may increase the anticoagulant effect of warfarin.