DESCRIPTION

Disulfiram is an oral medication used in the treatment of alcoholism.

FORMS AND USES

• Disulfiram is used for the adjunctive treatment of alcoholism in adults.
• Disulfiram (Antabuse) is available in 250- or 500-mg tablet form, or as a suspension 25 mg/ml.
• The dose is 500 mg orally once a day for 1 to 2 weeks, then 250 mg/day.

TOXIC DOSE

• A disulfiram reaction may result when ethanol is ingested while patient is on a therapeutic dose.
• In the absence of alcohol, ingestion of several grams may produce toxicity in a child, but adults tolerate a much larger dose.

PATHOPHYSIOLOGY

• Disulfiram inhibits the hepatic enzyme acetaldehyde dehydrogenase. Accumulation of acetaldehyde during metabolism of ethanol causes the disulfiram reaction.
• Disulfiram also inhibits dopamine-beta-hydroxylase, which leads to inhibition of norepinephrine synthesis and decreased reuptake of norepinephrine into adrenergic nerve terminals. This may explain the hypotension associated with disulfiram-ethanol reactions.
• The metabolites of disulfiram also have been demonstrated to inhibit acetaldehyde dehydrogenase and dopamine-beta-hydroxylase.

EPIDEMIOLOGY

• Isolated disulfiram toxicity is uncommon.
• Disulfiram-ethanol reactions are common.
• Toxic effects following either isolated disulfiram ingestion or disulfiram-ethanol reactions are typically mild, with death occurring rarely.

CAUSES

• The cause of primary disulfiram poisoning is usually suicidal ingestion.
• Disulfiram-ethanol reactions may be unintentional but commonly occur in alcoholics who ingest ethanol while under treatment with disulfiram.
• The possibility of child neglect or abuse should be considered in patients less than 1 year of age; suicide attempt should be considered in patients more than 6 years of age.

DRUG AND DISEASE INTERACTIONS

Ingestion of ethanol-containing products (e.g., cologne, Listerine) may precipitate a disulfiram-ethanol reaction.

PREGNANCY AND LACTATION

US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• TOXIC DOSE
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

A reaction resembling the ethanol-disulfiram reaction may occasionally occur following the ingestion of ethanol and another medication: antimicrobials, oral sulfonylurea agents (chlorpropamide, glipizide, others), several industrial agents (carbon disulfide, trichloroethylene, ethylene dibromide, thiuram, others), chloral hydrate, monoamine oxidase inhibitors (tranylcypromine, procarbazine), or Coprinus mushrooms (inky-caps).

SIGNS AND SYMPTOMS

• After acute ingestion of disulfiram alone, symptoms may require up to 12 hours to develop.
• The disulfiram-ethanol reaction usually peaks within an hour following ethanol ingestion and resolves over 2 to 4 hours.

Vital Signs

Tachycardia, hypotension, and tachypnea may follow either disulfiram overdose or the disulfiram-ethanol reaction.

HEENT

• Ketotic, garlic, or sulfur odor on breath may occur either with disulfiram overdose or during chronic therapy.
• Reversible optic neuritis may occur rarely during chronic therapy.
• Conjunctival injection is common.

Dermatologic

Flushing, erythema, skin warmth, and diaphoresis are common during the disulfiram-ethanol reaction.

Cardiovascular

• Palpitations, tachycardia, chest pain, and ECG changes of ischemia may develop during the disulfiram-ethanol reaction.
• Chronic disulfiram therapy may cause coronary atherosclerosis secondary to the carbon disulfide metabolite.

Gastrointestinal

Nausea, vomiting, and abdominal pain are common with either disulfiram overdose or the disulfiram-ethanol reaction.

Hepatic

• Chronic therapy may produce hepatic transaminase elevations that may be falsely attributed to underlying hepatic damage from alcohol.
• Idiosyncratic hepatitis is rare but has resulted in death during chronic therapy.

Hematologic

Idiosyncratic thrombocytopenia occurs rarely.

Fluids and Electrolytes

Hypokalemia may occur during the disulfiram-ethanol reaction.

Musculoskeletal

Arthritic syndromes have been reported with chronic therapy.

Neurologic

• Headache is common during the disulfiram-ethanol reaction.
• Parkinsonian syndrome, choreoathetosis, and thalamic syndrome have occurred following large ingestion.
• Peripheral neuropathy similar to Guillain-Barré syndrome has been reported after weeks to months of chronic therapy, but has also occurred following acute overdose.
• The peripheral neuropathy may progress for weeks following the discontinuation of disulfiram but eventually resolves.
• Psychosis, depression, hallucinations, encephalopathy, extrapyramidal symptoms, and seizures occur rarely either with therapeutic dosing or following overdose.
• Neurologic effects during therapeutic use or following overdose may be related to the metabolite carbon disulfide: tremor, lethargy, restlessness, headache, lightheadedness, ataxia, incoordination, dysarthria, drowsiness, confusion, memory impairment, and encephalopathy.

Reproductive

Loss of libido and sexual dysfunction may develop.

Endocrine

Elevated serum cholesterol may occur during chronic therapy.

PROCEDURES AND LABORATORY TESTS

Essential Tests

No tests are needed for minimal effects following acute overdose.

Recommended Tests

• Serum liver function tests should be performed prior to initiation of disulfiram therapy and periodically during therapy.
• Ethanol level should be measured to assess presence of ethanol and likelihood of disulfiram-ethanol reaction.
• ECG should be ordered; ischemic changes may occur with either chronic disulfiram therapy or disulfiram-ethanol reaction.
• Serum acetaminophen and aspirin levels should be measured in an overdose setting to detect occult ingestion.

Not Recommended Tests

Disulfiram, diethyldithiocarbamate, carbon disulfide, or diethylamine in plasma or urine can be measured to confirm exposure, but are not usually available.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Vital Signs
  • HEENT
  • Dermatologic
  • Cardiovascular
  • Gastrointestinal
  • Hepatic
  • Hematologic
  • Fluids and Electrolytes
  • Musculoskeletal
  • Neurologic
  • Reproductive
  • Endocrine
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests
  • Not Recommended Tests

• Treatment should focus on gastrointestinal decontamination and cardiovascular support.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care provider should call the poison control center when:

• Hypotension, peripheral neuropathy, encephalopathy, movement disorder, hepatitis, or other serious effects are present.
• Toxic effects are not consistent with disulfiram poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Any toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient treatment is warranted when the patient has altered mental status, persistent symptoms, cardiac ischemia, or severe hypotension.

DECONTAMINATION

Out of Hospital

• Emesis should be induced with ipecac within 1 hour of a large ingestion for alert pediatric or adult patients if health-care evaluation will be delayed.
• Ipecac should not be administered to patients who have concurrent ingestion of ethanol because of the risk of CNS depression.

In Hospital

• Gastric lavage should be performed in pediatric (tube size 24-32 French) or adult patients (tube size 36-42 French) presenting within 1 hour of a large ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

There is no antidote for acute or chronic disulfiram toxicity.

ADJUNCTIVE TREATMENT

Persistent Vomiting

• Suggested antiemetic adult regimens include metoclopramide 0.5 to 1 mg/kg plus diphenhydramine 25 to 50 mg combined with prochlorperazine 10 mg or droperidol 2.5 mg intravenously.
• Ondansetron 8 mg intravenously infused over 15 minutes is an alternative.

Control of Agitation

• A benzodiazepine with which the provider has experience should be administered.
  • Diazepam
    • Adult dose is 5 to 10 mg intravenously.
    • Pediatric dose is 0.2 to 0.5 mg/kg intravenously.
    • Doses are repeated at 10-minute intervals, titrating to effect.
  • Lorazepam
    • Adult dose is 1 to 2 mg intravenously.
    • Pediatric dose is 0.05 mg/kg intravenously.
    • Doses are repeated at 10-minute intervals titrating to effect.
  • The airway should be monitored closely.

Hypokalemia

Potassium chloride should be administered. Adult dose is 10 to 40 mEq/h intravenously. Pediatric dose is 0.3 mEq/kg/h intravenously.

Hypotension

• The patient should be administered 10 to 20 ml/kg 0.9% saline intravenously and placed in the Trendelenburg position.
• Further fluid therapy should be guided by central pressure monitoring to avoid volume overload.
• A vasopressor should be added if needed.

Fomepizole

Anecdotal reports suggest that 4-methylpyrazole can inhibit the production of acetaldehyde, thereby decreasing acetaldehyde accumulation (see SECTION III, Fomepizole chapter, for details of administration).

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Persistent Vomiting
  • Control of Agitation
  • Hypokalemia
  • Hypotension
  • Fomepizole

PATIENT MONITORING

• Respiratory and cardiac monitoring should be performed continuously in symptomatic patients.
• Liver function tests and ECG should be performed as clinically indicated by toxic manifestations.

EXPECTED COURSE AND PROGNOSIS

• Most exposures result in only mild toxicity.
• Toxicity should occur within 12 hours of an isolated disulfiram ingestion and within 4 hours of ethanol ingestion in a patient treated with disulfiram therapeutically.
• There are typically no complications, except for idiosyncratic and potentially fatal hepatitis.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Following gastrointestinal decontamination, asymptomatic patients may be discharged 8 to 12 hours after an isolated disulfiram ingestion or 4 to 6 hours after a disulfiram-ethanol reaction.
  • Psychiatric clearance should be obtained as appropriate.
• From the hospital. Patients may be discharged after signs of disulfiram intoxication have resolved following psychiatric clearance, if needed.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

DIAGNOSIS

• Patients presenting with signs or symptoms of a disulfiram-ethanol reaction may have been exposed to another drug instead of disulfiram.
• Disulfiram-ethanol reactions can occur following exposure to many drugs and chemicals containing ethanol.
• Unexpected sources of ethanol include cold and cough preparations, skin care products, mouthwash, and many intravenous medications.

FOLLOW-UP

Following termination of disulfiram therapy, the disulfiram-ethanol reaction may occur if ethanol is ingested within the subsequent 1 to 2 weeks.

Section Outline:

• DIAGNOSIS
• FOLLOW-UP

Poisoning by other and unspecified drugs and medicinal substances: alcohol deterrents.

See Also: SECTION II, Hypotension chapter; and SECTION III, Fomepizol (Antizol) chapter.

RECOMMENDED READING

Mokri B. Disulfiram neuropathy. Neurology 1981;31:730-735.

Ryan TV, Sciara AD, Barth JT. Chronic neuropsychological impairment resulting from disulfiram overdose. J Stud Alcohol 1993;54:389-392.

Author: Edwin K. Kuffner

Reviewer: Luke Yip