WHAT IS THE MECHANISM OF DISULFIRAM ACTION?

What is the Mechanism of Disulfiram action?

Disulfiram acts by binding irreversibly to the enzyme acetaldehyde dehydrogenase, (ALDH) leading to inactivation of the enzyme. When alcohol is consumed subsequent to disulfiram intake, there is an accumulation of acetaldehyde due to inhibition of the enzyme that metabolizes it. Elevated levels of acetaldehyde are responsible for the unpleasant effects experienced. This is termed as the Disulfiram- Ethanol Reaction (DER).

Pharmacokinetics

Absorption of disulfiram from the gastrointestinal tract is rapid but incomplete and approximately 20% is excreted in the feces. Because of its high lipid solubility, disulfiram is widely distributed and accumulated in various fat depots. Disulfiram is rapidly metabolized to diethyldithiocarbamate (DDC), which is partly excreted as carbon disulfide in the expired air and is partly metabolized in the liver to Me-DDC. Me-DDC is metabolized further to the active metabolite Me-DTC (diethylthiocarbaminic acid methyl ester). The concentration of Me-DTC reaches its maximum after about four hours, but the maximum enzyme inhibiting effect (aldehyde dehydrogenase [ALDH]) is first reached after three daily doses. The plasma half-life for Me-DTC is about ten hours, but the enzyme inhibiting effect of ALDH lasts considerably longer. The effect can thus persist for 7 to 14 days after discontinuation. In patients receiving disulfiram maintenance treatment, the ingestion of alcohol brings about a typical disulfiram-alcohol reaction within the course of five to ten minutes.

Metabolism is not appreciably affected by a mild to moderate decrease in hepatic function. The metabolites are chiefly excreted with the urine. A part is recovered in the expired air as carbon disulfide.

Toxicity.

Drowsiness followed by coma, persistent nausea, vomiting, aggressive and psychotic behavior, and ascending flaccid paralysis are manifestations of toxicity.

Drug Interactions.

Disulfiram inhibits enzyme induction and thus may interfere with the metabolism of drugs taken concomitantly. An increase in the levels of oral anticoagulants, phenytoin, and oral hypoglycaemic may occur.

Indication.

Disulfiram is recommended to persons suffering from alcohol dependence syndrome who are at risk of relapse.

Preparations of Disulfiram.

200/250 mg oral tablet in a package of 10 tablets.

Trade name : ESPERAL; DISULFIRAM; DIZONE.

Cost : Rs. 11 - 16 for 10 tablets depending on the brand.