AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Disulfiram (tetraethylthiuram disulfide [TETD]) has been used for more than 50 years as a deterrent to ethanol abuse in the management of alcoholism. Approximately 200,000 alcoholics take disulfiram, or Antabuse, regularly in the United States.

The first suggestion that disulfiram might be used in the treatment of alcoholism came in 1937 when an American physician noted that workers in the rubber industry who were exposed to TETD developed a reaction after drinking ethanol. A decade later, two Danish researchers at the Royal Danish School of Pharmacy in Copenhagen made the same discovery. Jens Hald and Eric Jacobsen were experimenting with disulfiram as a potential antihelminthic, and each took small doses to determine potential side effects in humans. Several days later, they attended a cocktail party and both became ill. They concluded that the facial flushing and tachycardia they experienced must be due to the disulfiram. Soon thereafter, physicians began prescribing disulfiram as a deterrent to ethanol abuse.

The disulfiram-ethanol reaction (DER) is due to increased acetaldehyde levels generated by metabolism of ethanol by alcohol dehydrogenase in the liver. This acetaldehyde normally does not accumulate because it is cleared rapidly by metabolism via aldehyde dehydrogenase. Disulfiram blocks this enzyme, irreversibly inhibiting the oxidation of acetaldehyde and causing a manifold increase in acetaldehyde levels after ethanol consumption. The discomfort associated with this acetaldehyde syndrome is intended to serve as a negative stimulus, but the reaction may be severe enough to cause hypotension and death.

In considering disulfiram toxicity, a distinction must be made between the clinical manifestations of the disulfiram-ethanol reaction and the toxic effects of disulfiram itself. Direct disulfiram toxicity may be further divided into acute poisoning versus chronic poisoning. The directly toxic effects of disulfiram include neurologic, cutaneous, and hepatotoxic sequelae in addition to the disulfiram-ethanol reaction.

Disulfiram received US Food and Drug Administration (FDA) approval for use in the treatment of alcoholism in 1951. At that time, it was commonly prescribed in very high doses, up to 3,000 mg a day in some cases. This resulted in a relatively high rate of extremely severe or fatal reactions. Today much lower doses are used, and the incidence of both adverse reactions and frank toxicity has waned.

Pathophysiology

Ethanol is mainly metabolized in the liver to acetaldehyde by alcohol dehydrogenase (ADH). Acetaldehyde is then oxidized to acetate by aldehyde dehydrogenase (ALDH). Disulfiram irreversibly inhibits the oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on ALDH (see Image 1). Ultimately, disulfiram reduces the rate of oxidation of acetaldehyde, causing a 5- to 10-fold increase in the concentration of acetaldehyde. The increased acetaldehyde levels are thought to produce the unpleasant side effects associated with acetaldehyde syndrome.

Alone, disulfiram is relatively nontoxic; however, it inhibits most of the hepatic microsomal enzymes (cytochrome P450), which leads to an interference with the metabolism of certain drugs (eg, Coumadin, some benzodiazepines, theophylline, phenytoin, caffeine, tricyclic antidepressants [TCAs]). Consequently, elevated serum levels ensue and corresponding toxicity may occur.

Disulfiram is highly lipid soluble (accumulates in adipose tissue) and has 80% bioavailability after an oral dose. Approximately 5-20% is not metabolized and is excreted unchanged in the feces; the remainder is metabolized to toxic and nontoxic metabolites. The elimination of disulfiram and its metabolites is a very slow process. Approximately 20% of the drug remains in the body for 1-2 weeks postingestion. Most of these metabolites are then eliminated through the gastrointestinal (GI), genitourinary (GU), and respiratory tracts.

Disulfiram metabolites cause clinically important effects in the body (see Image 2). Diethyldithiocarbamate (DDC), an active metabolite of disulfiram, chelates copper, thus impairing the activity of dopamine beta-hydroxylase, an enzyme that catalyzes the metabolism of dopamine to norepinephrine. DDC thus causes depletion of presynaptic norepinephrine and accumulation of dopamine. This dopamine agonism is thought to be the mechanism underlying both the hypotension and altered behavior associated with disulfiram toxicity.

Although no studies have examined the effects of low doses of disulfiram on psychotic symptoms, there have been many reports of hypomania and psychosis among alcoholics taking high-dose disulfiram (up to 2,000 mg a day). It may be the case that disulfiram, like L-dopa and amphetamine, unmasks or exacerbates preexisting psychotic symptoms in susceptible individuals by increasing central dopamine levels in this manner.

The ability of DDC to chelate copper may provide another mechanism for the neurotoxicity seen with both acute intoxication and chronic use of disulfiram. Lesions of the basal ganglia have been described in patients with extrapyramidal symptoms after therapy with disulfiram. It has been hypothesized that abnormal accumulation of metal in the CNS, leading to oxidative stress and neuronal cell death, is responsible for this. In addition, a recent study found that disulfiram and DDC increase the release of glutamate from striato-cortical synaptic vesicles, both in vitro and in rats. This may provide yet another mechanism for DDC-mediated neuronal damage.

DDC also chelates nickel, interferes with the sulfhydryl groups in cytochrome P-450 enzymes, and inhibits ADH and ALDH enzymes. Furthermore, DDC affects glutathione reductase in erythrocytes and inhibits superoxide dismutase, thereby impairing the ability to eliminate free radicals. DDC-induced methemoglobinemia also can occur secondary to impairment (consumption) of glutathione-dependent methemoglobin reduction.

Carbon disulfide (CS₂), another disulfiram metabolite from DDC metabolism, interacts with pyridoxal 5-phosphate to inhibit the monoamine oxidase (MAO) enzyme. This may cause seizures because it leads to a decrease in active pyridoxine (ie, vitamin B-6). CS₂ may deplete GABA levels in the brain because of an accumulation of amines caused by impaired metabolism. CS₂ inhibits dopamine beta hydroxylase. In addition to its neurotoxic effects (neurobehavioral toxin), CS₂ is hepatotoxic, inhibits cytochrome P-450, and is cardiotoxic.

Mortality/Morbidity

Disulfiram toxicity has a particular classification with significant overlap. The first classification is the classic disulfiram-ethanol reaction (DER), known as the acetaldehyde syndrome. Secondly, disulfiram has its own associated acute and chronic adverse drug reactions. Finally, disulfiramlike reactions are associated with many other substances that have an ethanol-like mechanism of toxicity with disulfiram.

• Disulfiram is usually prescribed with an initial dose of 500 mg/d for 1-2 weeks, followed by a maintenance dose of 125-500 mg/d. Close monitoring for adverse reactions is required.
• Disulfiram use is associated with adverse reactions at an intermediate rate of approximately 1 per 200-2000 each year. Frequently reported aversive reactions are mainly hepatic, neurologic, dermatologic, and psychiatric.
• Drowsiness is the most common side effect, and occurs in up to 5% of patients. It generally resolves after two weeks of treatment. Other side effects include dyspnea, sweating, alteration of taste, vasodilation, impotence, amblyopia, dizziness, headache, ataxia, polyneuritis, psychosis and hypertension.
• Acute disulfiram overdose is uncommon. In adults, clinical manifestations after acute overdose are rare with doses less than 3 g. Ingestion of 10-30 g may be lethal. Toxicity in children is reported with ingestion of 2.5 g of disulfiram. Symptoms of overdose in children are mostly neurologic.

CLINICAL

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History

The disulfiram-ethanol reaction (DER) is the classic manifestation of patients with disulfiram toxicity. This reaction occurs after the ingestion of even small amounts of ethanol with the concomitant use of disulfiram or disulfiramlike agents. Disulfiram toxicity may also occur in the absence of ethanol exposure. Directly toxic effects are seen with both chronic use and acute massive ingestion.

• Ethanol blood levels as low as 5-10 mg/dL can precipitate a DER; 120-150 mg/dL can lead to unconsciousness.
• • Patients may experience DER signs and symptoms through use of ethanol-containing foods, medications, and products (eg, over-the-counter cough medications, mouthwash, facial-cleaning products, liquid herbal extracts).
  • Some common medications that contain an ethanol concentration greater than 5% include Adult Tylenol liquid, Benadryl Elixir, Comtrex, Donnatal Elixir, Dramamine Liquid, Geritol Liquid, NyQuil Liquid, Formula 44 Cough Mixture, Tylenol & Codeine Elixir.
  • In general, severity and duration of the reaction depend on the amount of ethanol ingested, the dosage and duration of disulfiram therapy, and individual sensitivity.
  • DER symptoms usually occur within 15-30 minutes of ethanol ingestion and last for several hours; peak effects occur within 8-12 hours.
  • DER may occur within 3 hours of a disulfiram dose and up to 2 weeks following discontinuance of disulfiram.
  • Lethal DERs have been reported; however, most DER cases are mild and patients recover without serious sequelae.
• Obtain a detailed organ-specific history for proper diagnosis and management of disulfiram toxicity due to chronic use or acute massive ingestion.
• • Neurologic toxicity increases with dose and duration of therapy and includes the following:
    • Central and peripheral sensory motor neuropathy –
    • Diffuse toxic axonopathy
    • Psychosis - Limbic system stimulation by dopamine
    • Choreoathetosis - Basal ganglia stimulation by dopamine
    • Parkinsonism - Caused by basal ganglia low density lesions
    • Catatonia - Occurs more often with chronic toxicity than acute toxicity
    • Movement disorders - Excess dopamine enhanced excitotoxic effect of glutamate and calcium-mediated cell death
  • Dermatologic toxicity - Peaks at about 2 weeks of treatment; exfoliative dermatitis and allergic dermatitis (may be an unrecognized nickel allergy)
  • Gastrointestinal toxicity
    
    • Rotten-egg odor on breath (sulfide metabolites), garliclike or metallic aftertaste in mouth
    • Hypersensitive or toxic hepatitis - Peaks at about 2 months of therapy and has a fatality rate of approximately 1 in 25,000 cases
    • A recent retrospective review of the use of disulfiram among alcoholic patients being treated for active tuberculosis with isoniazid-containing regimens found no increased hepatotoxicity in patients taking both disulfiram and INH. However, conclusions from this study are limited due to the retrospective nature and the very small sample size (13 patients) of the study.
    • Cholestatic jaundice
  • Ophthalmologic toxicity - Optic neuritis (atrophy)
  • Hematologic toxicity - Agranulocytosis, eosinophilia, thrombocytopenia, and methemoglobinemia

Physical

• Acetaldehyde syndrome
• • Head, neck, and chest flushing - Histamine-induced vasodilation
  • Throbbing headaches
  • Nausea, vomiting (may be refractory), diarrhea, and abdominal pain
  • Weakness, dizziness, confusion, and anxiety
  • Vertigo and ataxia
  • Orthostatic hypotension - Hypotensive flushing reaction with warm extremities
  • Diaphoresis
  • Palpitations and dysrhythmias
  • Pruritus
  • Refractory cyanosis (eg, methemoglobinemia)
• Signs and symptoms of acute disulfiram overdose in adults and children include the following:
• • Hypotension, tachycardia, and dyspnea
  • Abdominal pain, nausea, vomiting, and sulfur or garlic odor on breath
  • Agitation, dysarthria, chorea, hallucinations, and lethargy
  • Coma and seizures
  • Parkinsonlike syndrome (eg, dystonia, spastic tetraparesis)
  • Polyneuropathy
  • Hypersensitive hepatitis and hepatic failure
  • Loss of developmental milestones

Causes

• Agents that produce disulfiramlike reactions with ethanol include the following:
• • Industrial solvents ("degreasers' flush")
  • Mushrooms (eg, Coprinus atramentarius [inky cap], Clitocybe claviceps)
  • Antibiotics (eg, metronidazole, sulfonamides, some cephalosporins, nitrofurantoin, chloramphenicol)
  • Oral hypoglycemic agents
  • Pesticides (eg, carbamates, monosulfiram [Tetmosol])
  • Chloralhydrate
  • Antifungals (griseofulvin)

DIFFERENTIALS

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Other Problems to be Considered

Metaldehyde toxicity

WORKUP

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Lab Studies

• Glucose level
• Electrolyte levels
• Renal function tests
• Liver function tests
• Ethanol level
• Acetaminophen level
• Serum osmolality
• Arterial blood gas analysis
• Methemoglobin level (%)

Imaging Studies

• CT of the head and/or MRI studies are valuable in demonstrating CNS involvement (eg, basal ganglia ischemia, infarction) as well as in excluding other causes of altered mental status.

Other Tests

• Specific laboratory studies generally have little value in the treatment of acute toxicity. In addition, results are not usually available in a timely fashion.
• Other specific laboratory studies to consider are as follows:
• • Acetaldehyde level test (toxic level >5.0 mg/L)
  • DDC level test
  • CS₂ level test
  • Tetraethylthiuram level (disulfiram level) test

TREATMENT

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Prehospital Care

• Provide supplemental oxygen, obtain intravenous access, and place all patients on a monitor. Administer thiamine, glucose, and naloxone to patients with altered mental status, as needed.
• Intravenous fluids should be instituted if hypotension, tachycardia, or severe vomiting is present.
• Patients with coma or severely altered mental status should be intubated for airway protection. The frequent occurrence of vomiting secondary to DER puts these patients at high risk for aspiration.

Emergency Department Care

ED treatment of the DER is primarily supportive. No specific antidote is available for the treatment of DER or acute disulfiram overdose.

• In acute disulfiram overdose, administer activated charcoal (AC), if available. Use of multiple dose activated charcoal (MDAC) may be beneficial.
  • MDAC can increase the rate of elimination of disulfiram and its metabolites that undergo enterohepatic recirculation. AC is not indicated for disulfiramlike syndromes, and it is not indicated for the treatment of DER.
  • The risk-benefit of administering charcoal to a patient with altered mental status and a high likelihood of vomiting and potential aspirationmust be carefully weighed.
• In severe DER, hemodialysis may be indicated to enhance the elimination of ethanol and acetaldehyde. Neither hemodialysis nor hemoperfusion has been beneficial for treatment of acute disulfiram overdose.
• Induced emesis with ipecac syrup is not recommended. Ipecac syrup contains ethanol and could precipitate DER. Emesis may delay administration of AC, worsen nausea and vomiting associated with toxicity, and increase incidence of pulmonary aspiration caused by an unprotected airway if seizures and coma suddenly
  supersede.
• Decontamination procedures are not likely to be beneficial once the reaction begins. Consider gastric lavage in the hospital setting in cases of massive ethanol ingestion; maintain a patent and protected airway.
• Mild sedation with benzodiazepines may be useful in the agitated patient. Benzodiazepines may also be used to treat seizures.
• Patients with severely altered mental status or coma should be intubated for airway protection. The risk of aspiration in patients with DER is high.
• In cases of intractable vomiting, phenothiazine use must be considered cautiously because their alpha-blockade effect may worsen or induce hypotension. Metoclopramide, ondansetron, or granisetron are considered antiemetics of choice in these cases.
• Intravenous fluids should be given to patients experiencing a DER to replete volume losses from emesis and third spacing of intravascular fluid.
• Intravenous fluids and vasopressors are indicated to support blood pressure and treat patients in shock.
• Some authors have suggested that fomepizole (Antizol) may be beneficial in cases of severe DER. Fomepizole is a potent inhibitor of alcohol dehydrogenase that may limit the metabolism of ethanol by this enzyme and thereby prevent further accumulation of acetaldehyde. No studies have examined the utility of fomepizole in this context; however, a theoretical benefit exists in patients taking disulfiram who present with DER after a large ethanol ingestion.

Consultations

• Consult with the local poison control center or a medical toxicologist.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: GI decontaminant

Empirically used to minimize systemic absorption of the toxin.

Drug Category: Cardiovascular agents

Treat hypotensive patients with IV crystalloid (eg, 0.9 NS or LR). If pressors are indicated, norepinephrine (Levophed) is DOC (over dopamine) because of catecholamine depletion.

Drug Category: Antihistamines

Improves the flushing response in DER. Diphenhydramine (H1 blocker) and cimetidine or ranitidine (H2 blockers) may be beneficial. NSAIDs (eg, Toradol) may ameliorate flushing response by blocking the synthesis of prostaglandins.

Drug Category: Pharmacologic antidotes

NSAIDs may benefit by reducing the severity of the flushing response. Pyridoxine (vitamin B-6) may be useful in patients who demonstrate evidence of neurological toxicity or intractable seizures.

Drug Category: Antiemetics

These agents are useful in cases of vomiting to mitigate symptoms and to avoid volume depletion.

FOLLOW-UP

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Further Inpatient Care

• Monitor all patients with DER or acute disulfiram overdose for a minimum of 8-12 h, even if they lack significant signs or symptoms of toxicity.
• Admit patients to the ICU if they demonstrate signs and symptoms of significant toxicity.

Further Outpatient Care

• Prompt follow-up care with the primary care physician responsible for treating the patient's alcoholism should be arranged for all patients presenting with DER or disulfiram toxicity prior to discharge.
• Patients with alcoholism who are treated with disulfiram must wear a medic alert bracelet indicating its usage.
• Refer patients with alcoholism to an alcoholic detoxification center and advise them not to drink alcohol or consume any medication or food product containing alcohol for at least 2 weeks after the last dose of disulfiram.
• All overdose patients should be evaluated by a psychiatrist before discharge.

Patient Education

• For excellent patient education resources, visit eMedicine's Poisoning - First Aid and Emergency Center, Substance Abuse Center, and Mental Health and Behavior Center. Also, see eMedicine's patient education articles Poisoning, Activated Charcoal, Alcoholism, and Substance Abuse.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to remember that medicines, foods, and other consumer products may contain alcohol and precipitate DER
• Disulfiram should only be prescribed to alcoholic persons in a monitored detoxification or therapy setting and not by emergency physicians, who cannot provide adequate follow-up care to these patients.

MULTIMEDIA

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Media file 1:  The pathway of ethanol metabolism. Disulfiram reduces the rate of oxidation of acetaldehyde by competing with the cofactor nicotinamide adenine dinucleotide (NAD) for binding sites on aldehyde dehydrogenase (ALDH).
	View Full Size Image
Media type:  Graph

Media file 2:  Disulfiram, prodrug for active metabolites.
	View Full Size Image
Media type:  Graph

REFERENCES

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• Burman WJ, Terra M, Breese P. Lack of toxicity from concomitant directly observed disulfiram and isoniazid-containing therapy for active tuberculosis. Int J Tuberc Lung Dis. 2002;6(9):839-842.
• Ellenhorn MJ. Disulfiram. In: Ellenhorn's Medical Toxicology. Vol 2. Lippincott Williams & Wilkins;1997:1356-62.
• Enghusen Poulsen H, Loft S, Andersen JR, et al. Disulfiram therapy--adverse drug reactions and interactions. Acta Psychiatr Scand Suppl. 1992;369:59-65; discussion 65-6. [Medline].
• Forns X, Caballeria J, Bruguera M, et al. Disulfiram-induced hepatitis. Report of four cases and review of the literature. J Hepatol. Nov 1994;21(5):853-7. [Medline].
• Goldfrank LR. Disulfiram and disulfiram-like reactions. In: Goldfrank's Toxicology Emergencies. Vol 5. Appleton & Lange;1994:899-903.
• Heath MJ, Pachar JV, Perez Martinez AL, et al. An exceptional case of lethal disulfiram-alcohol reaction. Forensic Sci Int. Sep 1992;56(1):45-50. [Medline].
• Hirschberg M, Ludolph A, Grotemeyer KH, Gullotta F. Development of a subacute tetraparesis after disulfiram intoxication. Case report. Eur Neurol. 1987;26(4):222-8. [Medline].
• Kirubakaran V, Faiman MD, Liskow B, Mayfield D. Plasma measurements of disulfiram and its metabolites in a case of severe disulfiram-ethanol reaction. Psychiatr J Univ Ott. Sep 1986;11(3):166-8. [Medline].
• Krauss JK, Mohadjer M, Wakhloo AK, Mundinger F. Dystonia and akinesia due to pallidoputaminal lesions after disulfiram intoxication. Mov Disord. 1991;6(2):166-70. [Medline].
• Laplane D, Attal N, Sauron B, et al. Lesions of basal ganglia due to disulfiram neurotoxicity. J Neurol Neurosurg Psychiatry. Oct 1992;55(10):925-9. [Medline].
• Mahajan P, Lieh-Lai MW, Sarnaik A, Kottamasu SR. Basal ganglia infarction in a child with disulfiram poisoning. Pediatrics. Apr 1997;99(4):605-8. [Medline].
• Nasrallah HA. Vulnerability to Disulfiram Psychosis. The Western Journal of Medicine. 1979;130:575-577.
• Stransky G, Lambing MK, Simmons GT, Robinson A. Methemoglobinemia in a fatal case of disulfiram-ethanol reaction [letter]. J Anal Toxicol. Mar-Apr 1997;21(2):178-9. [Medline].
• Vaccari A, Ferraro L, Saba P. Differential Mechanisms in the Effects of Disulfiram and Diethyldithiocarbamate Intoxication on Striatal Release and Vesicular Transport of Glutamate. J Pharmacol Exper Ther. 1998;285(3):961-967.
• Zorzon M, Mase G, Biasutti E, et al. Acute encephalopathy and polyneuropathy after disulfiram intoxication. Alcohol Alcohol. Sep 1995;30(5):629-31. [Medline].
• de Mari M, De Blasi R, Lamberti P, et al. Unilateral pallidal lesion after acute disulfiram intoxication: a clinical and magnetic resonance study. Mov Disord. Apr 1993;8(2):247-9. [Medline].

Article Last Updated: Jan 8, 2007