Disulfiram

(BAN, rINN)
Disulfiram Chemical formula
Synonyms: Dissulfiramo; Disulfiraami; Disulfiramas; Disulfirame; Disulfiramum; Diszulfirám; Éthyldithiourame; TTD. Tetraethylthiuram disulphide; Bis(diethylthiocarbamoyl) disulfide.
Cyrillic synonym: Дисульфирам.

💊 Chemical information

Chemical formula: C10H20N2S4 = 296.5.
CAS — 97-77-8.
ATC — N07BB01; P03AA04.
ATC Vet — QN07BB01; QV03AA01.

Pharmacopoeias.

In Eur., Jpn, and US.

Ph. Eur. 6.2

(Disulfiram). A white or almost white, crystalline powder. M.p. 70° to 73°. Practically insoluble in water; sparingly soluble in alcohol; freely soluble in dichloromethane. Protect from light.

USP 31

(Disulfiram). A white to off-white, odourless crystalline powder. M.p. 69° to 72°. Very slightly soluble in water; soluble 1 in 30 of alcohol and 1 in 15 of ether; soluble in acetone, in carbon disulfide, and in chloroform. Store in airtight containers. Protect from light.

Stability.

Studies 1,2 on the stability of disulfiram preparations. 1. Gupta VD. Stability of aqueous suspensions of disulfiram. Am J Hosp Pharm 1981; 38: 363–4. 2. Philips M, et al. Stability of an injectable disulfiram formulation sterilized by gamma irradiation. Am J Hosp Pharm 1985; 42: 343–5.

💊 Adverse Effects and Treatment

Drowsiness and fatigue are common during initial treatment with disulfiram. Other adverse effects reported include a garliclike or metallic aftertaste, gastrointestinal upsets, body odour, bad breath, headache, impotence, and allergic dermatitis. Peripheral and optic neuropathies, psychotic reactions, and hepatotoxicity may occur. Disulfiram-alcohol reaction. The use of disulfiram in the management of alcoholism is based on the extremely unpleasant, but generally self-limiting, systemic effects which occur when a patient receiving the drug ingests alcohol. These effects begin with flushing of the face and, as vasodilatation spreads, throbbing in the head and neck and a pulsating headache may develop. Respiratory difficulties, nausea, copious vomiting, sweating, thirst, chest pain, tachycardia, palpitations, marked hypotension, giddiness, weakness, blurred vision, and confusion may follow. The intensity and duration of symptoms is very variable and even small quantities of alcohol may result in alarming reactions. In addition to the above effects, severe reactions have included respiratory depression, cardiovascular collapse, cardiac arrhythmias, myocardial infarction, acute heart failure, unconsciousness, convulsions, and sudden death. Severe reactions require intensive supportive therapy; oxygen and intravenous fluids may be necessary. Potassium concentrations should be monitored. Giving intravenous ascorbic acid, ephedrine sulfate, or antihistamines has been suggested.
1. Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Safety 1999; 20: 427–35.

Effects on the blood.

There were isolated reports of blood dyscrasias associated with disulfiram in the 1960s. US licensed product information recommends that blood counts should be performed during treatment.

Effects on the liver.

A review of 18 cases of hepatitis in patients receiving disulfiram.1 Symptoms have appeared between 10 days and 6 months after starting disulfiram, and clinical improvement has been seen within 2 weeks of stopping the drug, although liver enzyme values may not return to normal for several months. Fatal hepatic coma had been reported in 7 patients. The clinical picture of disulfiram-induced hepatitis is consistent with a hypersensitivity reaction. Another review2 evaluated 82 cases of liver injury thought to be due to disulfiram and reported to the Swedish Adverse Drug Reactions Advisory Committee between 1966 and 2002. All but one of the cases were of hepatocellular liver damage, and 4 patients died and 4 underwent liver transplantation. Although there was some evidence that hypersensitivity played a role, it might not be the only mechanism of disulfiram-induced liver disease.
1. Mason NA. Disulfiram-induced hepatitis: case report and review of the literature. DICP Ann Pharmacother 1989; 23: 872–4
2. Björnsson E, et al. Clinical characteristics and prognostic markers in disulfiram-induced liver injury. J Hepatol 2006; 44: 791–7.

Effects on the nervous system.

ENCEPHALOPATHY. A 2% incidence of reversible toxic encephalopathy has been reported in patients receiving disulfiram.1 Onset varies from days to months following the start of therapy and early signs include impaired concentration, memory deficits, anxiety, depression, and somnolence. Confusion and disorientation follow, often accompanied by paranoid delusions and sometimes hallucinations. Other symptoms may include ataxia, loss of fine motor coordination, slurred speech, and intention tremor. The encephalopathy usually resolves within 3 days to 2 weeks of stopping disulfiram, although symptoms may persist for 6 weeks. There are conflicting opinions on whether this psychosis is a toxic reaction to disulfiram or a response to abstinence from alcohol, but the authors suspected that most cases represent a toxic encephalopathy. However, psychosis without any suggestion of encephalopathy has been reported.2
1. Hotson JR, Langston JW. Disulfiram-induced encephalopathy. Arch Neurol 1976; 33: 141–2
2. Rossiter SK. Psychosis with disulfiram prescribed under probation order. BMJ 1992; 305: 763.
PERIPHERAL NEUROPATHY. Reports of peripheral neuropathy associated with disulfiram and reference to previously reported cases.1,2 Onset of neuropathy varied from days to months after starting disulfiram treatment and could develop with doses of 250 or 500 mg daily. The most common symptom reported was pins and needles, but numbness, pain/burning, and weakness were frequently described; usually both muscle weakness and sensory loss were noted. Optic atrophy has also been described. Although there might be some improvement immediately after disulfiram withdrawal, the neurological deficit only improved slowly and symptoms might persist for as long as 2 years.1
1. Watson CP, et al. Disulfiram neuropathy. Can Med Assoc J 1980; 123: 123–6
2. Frisoni GB, Di Monda V. Disulfiram neuropathy: a review (1971-1988) and report of a case. Alcohol Alcohol 1989; 24: 429–37.

Effects on the respiratory tract.

Bronchospasm and hypertension were observed in an asthmatic patient taking disulfiram after an alcohol challenge test.1
1. Zapata E, Orwin A. Severe hypertension and bronchospasm during disulfiram-ethanol test reaction. BMJ 1992; 305: 870.

Effects on the skin.

Orange-coloured palms and soles, provoking an initial diagnosis of jaundice, developed in a 55-year-old man who had been taking disulfiram for about 2 months.1 It was postulated that the discoloration was due to accumulation of carotenes in the skin as a result of inhibition of vitamin A metabolism by disulfiram. The discoloration disappeared soon after disulfiram was stopped.
1. Santonastaso M, et al. Yellow palms with disulfiram. Lancet 1997; 350: 266.

Overdosage.

There has been a report of a 6-year-old boy who experienced disulfiram intoxication after receiving disulfiram 250 mg four times daily to a total of 13 doses but who later recovered.1 Of 6 previous reports one child died and 3 had moderate or severe brain damage. The syndrome of disulfiram intoxication in children is distinct from the disulfiram-alcohol interaction or acute disulfiram intoxication in adults. It is characterised by lethargy or somnolence, weakness, hypotonia, and vomiting, beginning about 12 hours after ingestion and progressing to stupor or coma. Dehydration, moderate tachycardia, and marked tachypnoea occur frequently, muscle tone is greatly decreased, and deep-tendon reflexes may be weak or absent. Severe neurological damage has also been reported2 in a 5-yearold girl after acute disulfiram intoxication which was initially diagnosed as diabetic ketoacidosis.
1. Benitz WE, Tatro DS. Disulfiram intoxication in a child. J Pediatr 1984; 105: 487–9
2. Mahajan P, et al. Basal ganglion infarction in a child with disulfiram poisoning. Pediatrics 1997; 99: 605–8.

💊 Precautions

Disulfiram is contra-indicated in the presence of cardiovascular disease or psychosis or severe personality disorders, and should not be given to patients known to be hypersensitive to it or to other thiuram compounds, such as those used in rubber vulcanisation or pesticides. It should be used with caution in the presence of diabetes mellitus, epilepsy, impaired hepatic or renal function, respiratory disorders, cerebral damage, or hypothyroidism. Caution is also advised when giving disulfiram to those who are addicted to other drugs in addition to alcohol. It is probably best avoided in pregnancy. Disulfiram should not be given until at least 24 hours after the last ingestion of alcohol. Patients beginning therapy should be fully aware of the disulfiram-alcohol reaction and should be warned to avoid alcohol in any form, including alcohol-containing medicines and alcohol-based topical preparations. Reactions to alcohol may occur as long as 2 weeks after the cessation of disulfiram. The US manufacturers have recommended that regular blood counts and liver function tests should be performed during longterm therapy.

Pregnancy.

A report of 2 infants with severe limb-reduction anomalies whose mothers had taken disulfiram during pregnancy.1 Only 2 similar cases had previously been reported.
1. Nora AH, et al. Limb-reduction anomalies in infants born to disulfiram-treated alcoholic mothers. Lancet 1977; ii: 664.

💊 Interactions

Disulfiram inhibits hepatic enzymes and may interfere with the metabolism of other drugs taken at the same time. It enhances the effects of phenytoin and coumarin anticoagulants and their dosage may need to be reduced. It also inhibits the metabolism and excretion of rifampicin. Toxic reactions have occurred when disulfiram was given with isoniazid or metronidazole. Disulfiram may inhibit the metabolism of paraldehyde leading to an accumulation of acetaldehyde and these drugs should not be used together.
1. Frye RF, Branch RA. Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N-acetyltransferase in healthy human subjects. Br J Clin Pharmacol 2002; 53: 155–62.

Analgesics.

The potential of disulfiram to impair drug metabolism was shown1 when it was found to prolong the plasma halflife of phenazone, probably by inhibiting the hepatic microsomal mixed function oxidases. It was also suggested1 that disulfiram alters catecholamine metabolism since urinary excretion of vanilmandelic acid was significantly reduced and that of homovanillic acid was increased.
1. Vesell ES, et al. Impairment of drug metabolism by disulfiram in man. Clin Pharmacol Ther 1971; 12: 785–92.

Antidepressants.

It has been reported1 that amitriptyline appeared to enhance the disulfiram-alcohol reaction. There is the potential for serious interactions during the disulfiram-alcohol reaction with drugs having CNS actions mediated by noradrenaline or dopamine, such as tricyclic antidepressants or those inhibiting the same enzymes as disulfiram, such as MAOIs.2
1. MacCallum WAG. Drug interactions in alcoholism treatment. Lancet 1969; i: 313
2. Sellers EM, et al. Drugs to decrease alcohol consumption. N Engl J Med 1981; 305: 1255–62.

Antiprotozoals.

For reference to toxicity associated with metronidazole given to alcoholic patients who were also receiving disulfiram, see Alcohol, under Interactions of Metronidazole.

Antipsychotics.

It has been suggested1 that phenothiazine antiemetics such as chlorpromazine might increase hypotension because of their α-adrenoceptor blocking activity and should therefore be contra-indicated in patients taking disulfiram. There is the potential for serious interactions during the disulfiramalcohol reaction with drugs having CNS actions mediated by noradrenaline or dopamine, such as phenothiazines.2
1. Kwentus J, Major LF. Disulfiram in the treatment of alcoholism: a review. J Stud Alcohol 1979; 40: 428–46
2. Sellers EM, et al. Drugs to decrease alcohol consumption. N Engl J Med 1981; 305: 1255–62.

Benzodiazepines.

Diazepam was reported1 to reduce the intensity of the disulfiram-alcohol reaction.
1. MacCallum WAG. Drug interactions in alcoholism treatment. Lancet 1969; i: 313.

Cannabis.

For a suggestion that a combination of disulfiram and cannabis may produce a hypomanic state.

Cardiovascular drugs.

Clinically serious pharmacodynamic interactions might be anticipated during the disulfiram-alcohol reaction in patients taking other drugs that impair blood pressure regulation, such as alpha blockers, beta blockers, or vasodilators.1
1. Sellers EM, et al. Drugs to decrease alcohol consumption. N Engl J Med 1981; 305: 1255–62.

Macrolides.

Fatal toxic epidermal necrolysis and fulminant hepatitis have been reported1 after starting clarithromycin treatment in a patient who was receiving disulfiram.
1. Masiá M, et al. Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy. Arch Intern Med 2002; 162: 474–6.

💊 Pharmacokinetics

Disulfiram is absorbed variably from the gastrointestinal tract and is rapidly reduced to diethyldithiocarbamate, principally by the glutathione reductase system in the erythrocytes; reduction may also occur in the liver. Diethyldithiocarbamate is metabolised in the liver to its glucuronide and methyl ester and to diethylamine, carbon disulfide, and sulfate ions. Metabolites are excreted primarily in the urine; carbon disulfide is exhaled in the breath. Variability might result from the marked lipid solubility of disulfiram, differences in plasma protein binding, or enterohepatic cycling. Average times to reach peak plasma concentrations after single or repeated doses were 8 to 10 hours for disulfiram, diethyldithiocarbamate, diethyldithiocarbamate-methyl ester, and diethylamine, and for carbon disulfide in breath; peak plasma concentrations of carbon disulfide occurred after 5 to 6 hours. Plasma concentrations of disulfiram were negligible within 48 hours of a dose, although concentrations of some metabolites were still raised. In urine, 1.7 and 8.3% of a disulfiram dose was eliminated as diethyldithiocarbamate-glucuronide in the 24 hours after a single and repeated dose respectively, while diethylamine accounted for 1.6 and 5.7%, respectively. In the 24 hours after a single and repeated dose 22.4 and 31.3%, respectively, was eliminated as carbon disulfide in the breath.
1. Faiman MD, et al. Elimination kinetics of disulfiram in alcoholics after single and repeated doses. Clin Pharmacol Ther 1984; 36: 520–6.

💊 Uses and Administration

Disulfiram is used as an adjunct in the treatment of chronic alcoholism. Disulfiram is not a cure and the treatment is likely to be of little value unless it is undertaken with the willing cooperation of the patient and is used with supportive psychotherapy. Disulfiram inhibits aldehyde dehydrogenase, the enzyme responsible for the oxidation of acetaldehyde, a metabolite of alcohol. The resulting accumulation of acetaldehyde in the blood is widely believed to be responsible for many of the unpleasant symptoms of the disulfiram-alcohol reaction which occur when alcohol is taken, even in small quantities, after disulfiram (see Adverse Effects and Treatment, above). Symptoms can arise within 10 minutes of the ingestion of alcohol and last from half an hour in mild cases to several hours in severe cases. It is advisable to carry out the initial treatment in hospital or in a specialised unit where the patient can be kept under close supervision. Disulfiram is given by mouth. In the UK, the dose is 800 mg, taken as a single dose, on the first day of treatment, reduced by 200 mg daily to a maintenance dose which is usually 100 to 200 mg daily. In the USA, where doses above 500 mg daily are not recommended, an initial dose of 500 mg daily for 1 to 2 weeks is given, followed by a maintenance dose of 250 mg daily or within the range of 125 to 500 mg daily. Treatment should be reviewed after no longer than 6 months. Maintenance therapy with disulfiram may need to be continued for months or years, until the patient is fully recovered socially and a basis for permanent self-control has been established. A test dose of alcohol has been given under close supervision when the patient is receiving maintenance doses of disulfiram, in order to demonstrate the nature of the disulfiram-alcohol reaction. However, these challenge tests are not routinely recommended, and should not in any case be used in patients over 50 years of age. Many authorities consider that an explicit description of the reaction is sufficient. Disulfiram implants have been used in an attempt to overcome problems of patient compliance but have been largely abandoned due to lack of clinical efficacy.

Alcoholism.

References.
1. Wright C, Moore RD. Disulfiram treatment of alcoholism. Am J Med 1990; 88: 647–55
2. Hughes JC, Cook CCH. The efficacy of disulfiram: a review of outcome studies. Addiction 1997; 92: 381–95
3. O’Shea B. Disulfiram revisited. Hosp Med 2000; 61: 849–51
4. Brewer C, et al. Does disulfiram help to prevent relapse in alcohol abuse? CNS Drugs 2000; 14: 329–341
5. Suh JJ, et al. The status of disulfiram: a half of a century later. J Clin Psychopharmacol 2006; 26: 290–302.

Cocaine dependence.

Cocaine use may affect the dopaminergic modulation of CNS function; disulfiram is one of several drugs that interact with dopaminergic systems and have been tried in treatment of cocaine abuse and dependence.
1. Carroll KM, et al. Efficacy of disulfiram and cognitive behavior therapy in cocaine-dependent outpatients: a randomized placebo-controlled trial. Arch Gen Psychiatry 2004; 61: 264–72.

💊 Preparations

BP 2008: Disulfiram Tablets; USP 31: Disulfiram Tablets.

Proprietary Preparations

Arg.: Abstensyl; Vandisul†; Austral.: Antabuse; Austria: Antabus; Belg.: Antabuse; Braz.: Antietanol; Sarcoton; Chile: Antabus; Tolerane; Cz.: Antabus; Denm.: Antabus; Fin.: Antabus; Fr.: Esperal; Ger.: Antabus; Hung.: Antaethyl; India: Esperal; Irl.: Antabuse; Israel: Antabuse†; Ital.: Antabuse; Etiltox; Mex.: Etabus; Neth.: Antabus; Refusal; Norw.: Antabus; NZ: Antabuse; Pol.: Anticol; Port.: Tetradin; Rus.: Esperal (Эспераль); S.Afr.: Antabuse; Spain: Antabus; Swed.: Antabus; Switz.: Antabus; Thai.: Antabuse†; Difiram; Turk.: Antabus; UK: Antabuse; USA: Antabuse. Multi-ingredient: Fr.: TTD-B -B ; Rus.: Lidevine (Лидевин); Swed.: Te nutex.
Published May 08, 2019.