Pharmacology

Antialcoholic

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 after 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 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.

Disulfiram plus even small amounts of alcohol produces flushing, throbbing in head and neck, throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions, there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death. The intensity of the reaction may vary with each individual but is generally proportional to the amount of disulfiram and alcohol ingested. In the sensitive individual, mild reactions may occur when the blood alcohol concentration is increased to as little as 5 to 10 mg/100 mL. At a concentration of 50 mg/100 mL symptoms are usually fully developed, and when the concentration reaches 125 to 150 mg/100 mL unconsciousness may occur.

The duration of the reaction is variable, from 30 to 60 minutes in mild cases, up to several hours in more severe cases or as long as there is alcohol remaining in the blood. In severe reactions, supportive measures to restore blood pressure and treat shock should be instituted. Other measures such as the administration of oxygen or carbogen (95% oxygen, 5% carbon dioxide), massive i.v. doses of vitamin C (1 g), ephedrine sulfate, or antihistamines i.v. might be indicated. Potassium levels should be monitored particularly in patients on digitalis since hypokalemia has been reported.

Disulfiram is slowly absorbed from the gastrointestinal tract and is slowly eliminated from the body. Ingestion of alcohol may produce unpleasant symptoms 1 or even 2 weeks after a patient has taken his last dose of disulfiram.

Prolonged administration of disulfiram does not produce tolerance. The longer a patient remains on therapy the more sensitive he becomes to alcohol.

Pharmacokinetic data are not clearly established; however, it has been shown that 80 to 95% of an ingested dose is absorbed from the gastrointestinal tract and rapidly distributed to tissues and organs: liver, spleen, adrenals, fatty tissues, and brain. It is then metabolized to diethyldithiocarbamate or mixed disulfides, one of the end products being carbon disulfide. The unabsorbed fraction is excreted in the feces, the intermediate and final metabolites are excreted in the urine, and the volatile metabolites in the breath.

Indications
As an aid in the management of selected chronic alcoholic patients who want to remain in a state of enforced sobriety so that supportive and psychotherapeutic treatment may be applied to best advantage.

Used alone, without proper motivation and without supportive therapy, disulfiram is not a cure for alcoholism, and it is unlikely that it will have more than a brief effect on the drinking pattern of the chronic alcoholic.

Contraindications
Patients who are receiving or have recently received metronidazole, paraldehyde, alcohol, or alcohol-containing preparations such as cough syrups, elixirs, should not be given disulfiram. Severe myocardial disease or coronary occlusion; diabetes mellitus; hepatic cirrhosis or insufficiency; hypothyroidism; epilepsy; cerebral damage; chronic and acute nephritis; psychoses; and hypersensitivity to disulfiram or other thiuram derivatives used in the manufacture of items such as pesticides or vulcanized rubber.

Warnings
Disulfiram should never be administered to a patient without his full knowledge or when he is in a state of alcohol intoxication. The attending physician should instruct those tending the patient accordingly.

Patients must be fully informed about the disulfiram-alcohol reaction. They must be strongly cautioned against surreptitious drinking while taking the drug and must be fully aware of possible consequences. They should be warned to avoid alcohol in disguised form, i.e., in sauces, vinegars, cough and cold mixtures, and even aftershave lotions or liniments. They should also be warned that reactions may occur with alcohol up to 14 days after ingestion of disulfiram.

For recommendations regarding management of the disulfiram reaction, see Pharmacology.

Precautions
Patients should be informed of the type of reaction which will be encountered if alcohol is taken overtly or as a component of food or other products (see Pharmacology).

Patients having a history of industrial contact dermatitis who currently work or have previously worked in the rubber industry should be evaluated for hypersensitivity to thiuram derivatives before receiving disulfiram (see Contraindications).

Patients exposed to organic solvents which may contain alcohol, acetaldehyde, paraldehyde or structural analogues are at risk of experiencing disulfiram alcohol reactions. Such exposure should be eliminated prior to treatment.

It is suggested that every patient under treatment carry an identification card stating that he is receiving disulfiram and describing the symptoms most likely to occur as a result of the disulfiram-alcohol reaction. In addition, this card should identify the attending physician or institution to be contacted in emergency. (Cards may be obtained from Ayerst upon request.)

Alcoholism may be associated or followed by dependence on narcotics or sedatives. Barbiturates have been administered concurrently with disulfiram without untoward effects, but the possibility of initiating a new dependence should be considered. Patients taking disulfiram should not be exposed to ethylene dibromide or its vapors. This precaution is based on animal studies which have suggested a possible toxic reaction between inhaled dibromide and ingested disulfiram. Rats exposed to this regimen have shown a higher incidence of tumors and mortality. Correlation of this finding in humans however has not been demonstrated.

Since disulfiram-alcohol reactions could aggravate some medical conditions such as diabetes mellitus, hypothyroidism, epilepsy, cerebral damage, chronic and acute nephritis, hepatic cirrhosis or hepatic insufficiency, disulfiram should be used with extreme care in patients having such a medical history. Baseline and follow-up transaminase tests (10 to 14 days) are suggested to detect any hepatic dysfunction that may be associated with disulfiram therapy. In addition, a complete blood count and a sequential multiple analysis-12 test (SMA-12) should be carried out every 6 months.

Disulfiram inhibits enzyme induction and may thus interfere with the metabolism of drugs taken concomitantly. It enhances the effects of the coumarin anticoagulants and phenytoin. Consequently, in patients on oral anticoagulants, such dosage should be adjusted. In patients on phenytoin therapy, a baseline phenytoin serum level should be obtained before initiation of disulfiram therapy. After initiation of therapy, serum levels should be reevaluated on different days for evidence of an increase or continuing rise in levels. Appropriate dosage adjustment should be made, if elevated levels are found. Disulfiram should be discontinued in patients taking isoniazid if an unsteady gait develops or there are marked changes in mental state.

Carcinogenicity and mutagenicity data are not clearly established. In rats, simultaneous ingestion in the diet of disulfiram and nitrite for 78 weeks has been reported to cause tumors. It has been suggested that conversion of nitrite to nitrosamines in the stomach could be responsible for the development of the tumors. Disulfiram alone did not lead to tumor development. The relevance of these findings to humans is not known at this time.

In one study, disulfiram had deleterious effects on the reproductive cycle and reproductive capabilities of female rats, and the growth of their pups. In another study, no adverse effect on fertility was noted. Studies in the hamster, rat, and mouse have not produced any teratogenic effect in the offspring.

Pregnancy and Lactation:
It is not known whether disulfiram can cause fetal harm when administered during pregnancy, but one report of limb reduction anomalies in infants born to disulfiram-treated mothers has been published. Because of these findings, extreme care should be exercised before administering disulfiram during pregnancy.

It is not known whether this drug is excreted in human milk. Since many drugs are, and because of the potential for serious adverse reactions in the nursing infants, before administering disulfiram to a nursing mother it would appear advisable to discontinue nursing.