Disulfiram


OVERVIEW


Disulfiram (Antabuse) may cause severe cardiovascular and CNS toxicity. In pure disulfiram overdose the toxicity is often delayed for up to 12 hours. In contrast, the ethanol-disulfiram reaction leads to the very rapid onset of symptoms. The treatment is primarily supportive, however, fomepizole should theoretically be of use in the alcohol-disulfiram reaction if there is still unmetabolised alcohol, and vitamin C has also been
recommended.

MECHANISM OF TOXIC EFFECTS


At therapeutic doses, disulfiram inhibits the enzyme aldehyde dehydrogenase. The alcohol-disulfiram reaction occurs due to the inhibition by disulfiram of an intermediary step in the metabolism of ethanol which leads to the accumulation of the metabolite acetaldehyde. Acetaldehyde accumulates rapidly and causes marked vasodilatation and other less well understood adverse effects.

The inhibition of aldehyde dehydrogenase occurs rapidly and is irreversible. For enzyme activity to be restored, new enzymes must be synthesised. Thus, the reaction to ethanol may occur for up to 14 days after the last dose of disulfiram.

Many other substances (i.e. sulphonylureas, metronidazole, some cephalosporins, cyanamide, Coprinus atramentarius) may also inhibit aldehyde dehydrogenase and cause disulfiram-like reactions with subsequent ingestion of alcohol.

Disulfiram, and it's metabolite diethyldithiocarbamate, may also inhibit many other enzymes. The delayed onset of toxicity with acute disulfiram overdose is in keeping with toxicity due to accumulation of some endogenous substance or a metabolite (rather than direct toxicity, c.f. MAO Inhibitors) but it is not known which enzymes or substances are involved. Disulfiram does inhibit dopamine beta-hydroxylase, which may lead to
depletion of noradrenaline in nerve terminals and metabolites may inhibit monoamine oxidase. Either of these may partially explain the hypotension and CNS effects that are commonly observed.

KINETICS IN OVERDOSE


In therapeutic use, disulfiram is rapidly absorbed, and converted within minutes to the active metabolite diethyldithiocarbamate . This is metabolised by conjugation with glutathione. As these compounds bind irreversibly to enzymes it is likely that the kinetics are largely irrelevant to management.

CLINICAL EFFECTS


The onset of symptoms may be delayed up to 12 hours. Milder symptoms include flushing and vomiting. Cardiovascular and CNS toxicity may be severe and fatalities have been recorded.

Cardiac effects

Tachycardia, hypertension, hypotension, shock, ECG changes.

Death from cardiovascular collapse may be preceded by
  • Vomiting
  • Lethargy
  • Dehydration
  • Tachypnea

Central nervous system effects

The CNS toxicity has many and varied manifestations. Vomiting, headache, agitation, lethargy, coma, ataxia, extrapyramidal reactions, paralysis, hallucinations, psychosis, and seizures may all be seen.

Symptoms become maximal 12 to 24 hours after ingestion and may take many days to resolve.

Other effects

Vomiting, diarrhoea and abdominal pain are common, nonspecific symptoms. A distinctive garlic odour has also been reported, attributed to a metabolite of disulfiram. This would not differentiate acute overdose from regular use.

ETHANOL-DISULFIRAM REACTION


The clinical effects are not dissimilar, except that the onset is extremely rapid.

Common symptoms include flushing, headache, thirst, sweating, dyspnoea, anxiety, vertigo, nausea, vomiting, confusion, blurred vision, hypotension, syncope, seizures and arrhythmias.

The severity does not correlate well with the amount of ethanol ingested and reactions have been observed even after topical administration (e.g. after-shave lotion). The symptoms usually resolve over a few hours.

INVESTIGATIONS


Blood concentrations

Blood concentrations of acetaldehyde are raised in the ethanol-disulfiram reaction but these are not helpful in management.

ECG

All patients with symptoms should have an ECG. Changes are most common in those with underlying ischaemic heart disease.

DETERMINATION OF SEVERITY


The severity of the ethanol-disulfiram reaction correlates poorly with the dose of ethanol ingested.

The severity of disulfiram overdose correlates roughly with dose ingested. Ingestion of 2.5 to 3 g in children has resulted in lethargy, ataxia, and seizures.

TREATMENT


Supportive

All patients with disulfiram overdose need to be observed for at least 12 hours for the delayed onset of symptoms. Admission to intensive care is indicated for unconscious patients and those with seizures or marked hypotension. Great care should be taken to avoid interactions from alcohol containing medication, food and beverages. Such precautions will be necessary for the following two weeks.

Give intravenous fluids and correct electrolytes. Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is particularly important in overdose with drugs that lead to hypotension.

GI Decontamination

Patients should be given activated charcoal if they present within 1 hour of exposure.

Elimination enhancement

Due to the short half life of these drugs, there is unlikely to be significant benefit from repeated doses of activated charcoal.

As disulfiram binds irreversibly to enzymes there is no rationale for enhancing elimination in disulfiram overdose. A very large ingestion of alcohol, leading to the alcohol-disulfiram reaction would theoretically benefit from haemodialysis to remove ethanol but evidence of clinical benefit has not been shown.

Treatment of specific complications


Ethanol-disulfiram reaction
No specific treatment has been tested, although fomepizole (an alcohol dehydrogenase inhibitor) would be expected to be useful.

Seizures
Seizures should be treated with diazepam 5-20 mg IV followed, if necessary, by phenobarbitone 15 mg/kg.

Hypotension
Treatment should be initially with fluids and a central venous pressure line should be inserted.

Intractable hypotension is a poor prognostic sign. Direct acting sympathomimetics (e.g. noradrenaline) should be preferred to indirect-acting sympathomimetics (e.g. dopamine), if pressor agents are required.

LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP


Long term neurological sequelae have been reported, including neuropsychiatric, basal ganglia and peripheral nerve damage. It is possible that some of these may have predated the overdoses as disulfiram has caused similar effects with long term use. Follow up should be routinely arranged for all patients with significant toxicity.

All patients should be warned about further food and drug interaction occurring over the next two weeks.

REFERENCES


Brewer C. Recent developments in disulfiram treatment. Alcohol & Alcoholism 1993;28(4):383-395.
Ryan TV, Sciara AD, Barth JT. Chronic Neuropsychological impairment resulting from disulfiram overdose. J Stud Alcohol 1993; 54(4): 389-92.