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Disulfiram

Disulfiram and Anticonvulsants

Phenytoin serum levels are markedly and rapidly increased by the concurrent use of disulfiram. Phenytoin intoxication can develop. There is evidence that phenobarbitone and carbamazepine are not affected by disulfiram, and that calcium car-bimide does not interact with phenytoin.

Clinical evidence

The serum phenytoin levels of four patients on long-term treatment showed rises of 100-500% over a nine day period when concurrently treated with 400 mg disulfiram daily, with no signs of levelling off until the disulfiram was withdrawn. Two of them developed signs of mild intoxication. In a follow-up study on two patients, one of them showed ataxia and a serum phenytoin rise of 55% (from 18 to 28 /ig/ ml) within five days.

A study in 10 normal subjects showed that disulfiram increased the half-life of phenytoin from 11 to 19 h. There are case reports describing this interaction.

Mechanism

The disulfiram inhibits the liver enzymes concerned with the metabolism of the phenytoin thereby prolonging its stay in the body and resulting in a rise in its serum levels (to toxic concentrations in some instances). One study concluded that the inhibition was non-competitive.

Importance and management

An established, moderately well documented, clinically important and potentially serious interaction The evidence available indicates that it occurs in most patients and develops rapidly. Recovery may take 2-3 weeks when the disulfiram is withdrawn. Olesen offers the opinion that the dosage of phenytom could of course be reduced [to accommodate the interaction] but it would be difficult to maintain the precise balance required.

Alternative anticonvulsants include phenobarbitone which in one study (paralleling those cited above) showed only minor (10%) serum level fluctuations with disulfiram. Three of the patients were taking primidone and one phenobarbitone. Carbamazepine also appears not to interact. Signs of toxicity disappeared m a patient when phenytom was replaced by carbamazepine, and this observation was confirmed in a study on five non-alcoholic patients.

A different solution is to replace the disulfiram with calcium carbirrude. A study in four patients showed that 50 mg daily for a week followed by 100 mg for two weeks had no effect on serum phenytom levels.