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DISULFIRAM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Disulfiram is a thiuram derivative that is an inhibitor of the enzyme acetaldehyde dehydrogenase. Acetaldehyde is a metabolite of ethanol, and disulfiram causes the accumulation of acetaldehyde.
    B) This management discusses only disulfiram overdose. Please refer to ETHANOL-DISULFIRAM REACTION or DISULFIRAM-LIKE REACTION documents for more information.

Specific Substances

    1) Disulfiramum
    2) Ethyldithiourame
    3) Molecular Formula: C10-H20-N2-S4
    4) TTD
    5) Tetraethylthiuram disulfide
    6) Bis(diethylthiocarbamoyl) disulfide
    7) CAS 97-77-8
    8) ANTIVITIUM
    9) ESPERAL
    10) REFUSAL
    11) THIURAM DILSULFIDE, TETRAETHYL-
    12) TUADS, ETHYL
    1.2.1) MOLECULAR FORMULA
    1) C10H20N2S4
    2) [(C2H5)2NCS]2S2
    3) C10-H2O-N2-S4

Available Forms Sources

    A) FORMS
    1) Disulfiram is available as 250 mg and 500 mg tablets (Prod Info disulfiram oral tablets, 2014).
    2) Disulfiram has been described as a white, off-white, yellowish, or light gray crystalline powder with no or slight odor and a slightly bitter taste (Ashford, 1994; HSDB , 1999; Lewis, 1996; Lewis, 1998; NIOSH , 1999).
    3) Sittig (1991) describes disulfiram as a dark brown crystalline solid (Sittig, 1991).
    B) SOURCES
    1) Disulfiram separates out from an alcohol solution mixture of diethylamine, caron disulfide, and iodine; to quicken the separation, ice water may be added (HSDB , 2000).
    C) USES
    1) MEDICINAL
    a) Disulfiram is used to maintain sobriety in patients with chronic ethanol abuse. (Prod Info disulfiram oral tablets, 2014).
    2) AGRICULTURAL
    a) Disulfiram is used as a seed disinfectant and a fungicide. It may have been used as a pesticide without the approval for such use by EPA (Ashford, 1994; S Budavari , 2001; HSDB , 1999; Lewis, 1998; Sittig, 1991).
    3) INDUSTRIAL
    a) It is used as a rubber accelerator (in compounding natural, styrene-butadiene, isobutylene-isoprene and neoprene with rubbers), a primary or secondary accelerator with aldehyde amines and guanidinesan, an activator of thiazole accelerators, a plasticizer in neoprene production, a cure retarder in chloroprene and neoprene G rubbers, and a vulcanizer (Ashford, 1994; S Budavari , 2001; Hathaway et al, 1996; HSDB , 1999; Lewis, 1998; Sittig, 1991).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Disulfiram also known as antabuse or tetraethylthiuram disulfide (TETD) is used as an industrial antioxidant, fungicide, disinfectant, and most commonly to maintain sobriety in patients with chronic ethanol abuse. This document discusses toxicity related to disulfiram overdose. Please refer to ETHANOL-DISULFIRAM REACTION or DISULFIRAM-LIKE REACTION documents for more information regarding adverse events from interactions with ethanol.
    B) PHARMACOLOGY: Disulfiram inhibits aldehyde dehydrogenase and dopamine betahydroxylase which leads to inhibition of alcohol oxidation at the acetylation stage and results in high levels of acetaldehyde and produces a disulfiram-alcohol reaction.
    C) TOXICOLOGY: Disulfiram-induced inhibition of dopamine betahydroxylase results in norepinephrine depletion at presynaptic sympathetic nerve endings. The carbon disulfide metabolite (industrial solvent & pesticide) of acetaldehyde may cause the CNS and peripheral nerve toxicity associated with disulfiram.
    D) EPIDEMIOLOGY: Disulfiram overdose alone is uncommon and severe manifestations of toxicity are rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Metallic taste, garlic/sulfur/acetone odor, nausea, vomiting, headache, drowsiness, and ataxia.
    2) RARE: Dermatitis, liver injury (may progress to fulminant hepatic failure), seizure, neuropathy, encephalopathy, and optic neuritis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, diarrhea, odor of sulfur, acetone, or garlic, headache, lethargy, weakness, tachypnea, ketosis, ataxia, hypotension, and tachycardia may develop.
    2) SEVERE TOXICITY: Psychosis, hallucinations, ataxia, metabolic acidosis, seizures, extrapyramidal movement disorders, paralysis, encephalopathy, coma, cardiovascular collapse, hypotension, cardiogenic shock, and sensorimotor neuropathy have been reported.
    3) CHRONIC DISULFIRAM TOXICITY: Headache, drowsiness, seizures, neuropathy, and dermatitis. Occasionally implicated in producing psychosis, optic neuritis, and encephalopathy. Hematologic, neuromuscular, and gastrointestinal toxicity and hepatotoxicity may occur 10 days to 12 months after therapy has begun. Toxic or hypersensitivity hepatitis, including death, has been reported. Fatal hepatic necrosis following six weeks of disulfiram therapy (250 mg/day) has also been reported. Effects appear at highly variable time intervals ranging from weeks to years of treatment.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Increased respirations, hypertension, tachycardia and fever may occur. Hypotension may occur with severe overdose.
    0.2.20) REPRODUCTIVE
    A) A medical literature search of disulfiram during human pregnancy has revealed that 4 of 14 fetuses developed congenital anomalies, including 2 cases of clubfoot, 1 case of multiple anomalies with VACTERL syndrome, 1 case of microcephaly/mental retardation, 1 case of Pierre Robin syndrome, and 1 case of phocomelia involving the lower extremities. Another case report revealed possible fetal alcohol syndrome exacerbated by disulfiram, with acetaldehyde as the teratogen. Animal data have shown embryotoxicity and resorption of fetus in rats.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, renal function, hepatic enzymes, and serum glucose.
    C) Obtain a serum lactate and venous blood gases in patients with acidosis.
    D) A serum ethanol concentration may be useful if an ethanol-disulfiram interaction is suspected.
    E) Disulfiram concentrations are not readily available or useful to guide therapy.
    F) Obtain an ECG and institute continuous cardiac monitoring in patients with severe symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) IV fluids, antiemetics and supportive care are usually sufficient for the treatment of mild to moderate toxicity.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is generally supportive with aggressive use of IV fluids and antiemetics. In severe cases, patients develop seizures, profound obtundation, and hypotension. Meticulous supportive care with attention directed to oxygenation, ventilation, and circulation generally are sufficient. Treat seizures with IV benzodiazepines. Treat hypotension refractory to IV fluids with a direct acting vasopressor such as norepinephrine. Endotracheal intubation will be necessary in patients with significantly depressed mental status, coma or recurrent seizures.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal are generally not recommended as patients often have nausea and vomiting from the exposure.
    2) HOSPITAL: Charcoal is not indicated for patients who present with severe nausea and vomiting, but may be considered in a patient who presents early after a large overdose who is not vomiting. Lavage and whole bowel irrigation are generally not recommended.
    D) AIRWAY MANAGEMENT
    1) Administer 100% oxygen as needed for respiratory support. Intubate and provide assisted ventilation in patients who cannot protect their airway due to seizures or decreased mental status.
    E) ANTIDOTE
    1) None.
    F) SEIZURE
    1) Use IV benzodiazepines, barbiturates.
    G) HYPOTENSIVE EPISODE
    1) Keep patient supine, IV 0.9% NS, norepinephrine.
    H) ENHANCED ELIMINATION
    1) Hemodialysis, hemoperfusion, or forced diuresis have not been shown to be effective in enhancing elimination.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic children with inadvertent ingestions of one or two doses can probably be managed at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions, children who ingest more than two doses inadvertently, and any patient with more than minimal symptoms should be referred to a healthcare facility for evaluation and 8 to 12 hours of observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged.
    3) ADMISSION CRITERIA: Patients with severe or persistent symptoms should be admitted, patients with significant alteration in mental status, recurrent seizures, or hypotension should be admitted to intensive care.
    4) CONSULT CRITERIA: Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is unclear.
    J) PITFALLS
    1) Pitfalls include failure to recognize a disulfiram-ethanol reaction, underestimation of clinical severity of symptoms or utilization of pharmaceutical agents containing ethanol during treatment of the patient. Also, failure to recognize acute alcohol withdrawal as an etiology of altered mentation is also a pitfall. Consider folate, thiamine and pyridoxine replacement in all patients with recent ethanol abuse.
    K) PHARMACOKINETICS
    1) Following oral dosing, about 80% of disulfiram is absorbed within 1 hour from the small intestine. Peak effects, occur 8-12 hours post-dose and effects persist for 7-14 days after the last dose. It is highly lipid soluble and 50% protein bound. Peak plasma concentration occurs 8-10 hours after dosing. It is slowly eliminated from the body by oxidation and glucuronidation in the liver and reduction by erythrocytes.
    L) TOXICOKINETICS
    1) Symptoms can often be delayed up to 12 hours post ingestion. Maximal symptoms are often not present until 24 hours post ingestion.
    M) DIFFERENTIAL DIAGNOSIS
    1) Gastritis, hypoglycemia, trauma, allergic reaction, other CNS depressant ingestions, acute alcohol or benzodiazepine withdrawal and sepsis.

Range Of Toxicity

    A) TOXICITY: PEDIATRICS: Ingestion of 2.5 g to 3 g in children produced symptoms such as lethargy, ataxia, and seizure. ADULTS: Ingestions of 6 g have been reported without adverse symptoms; however, ingestion of 3 g may result in symptoms. An adult male patient with a history of alcohol abuse ingested 7.5 g of disulfiram and developed psychosis followed by delirium, somnolence, and catatonic-like behavior for 48-hour period. Ingestion of 10 to 30 g in an adult has resulted in death.
    B) THERAPEUTIC DOSE: For alcohol dependence, 125 mg to 500 mg given orally in the morning or evening is recommended with the patient abstinent from alcohol for at least 12 hours prior to dosing. There is no pediatric dosing available for disulfiram.
    C) Please refer to ETHANOL-DISULFIRAM REACTION or DISULFIRAM-LIKE REACTION documents for more information.

Clinical Effects

Summary Of Exposure

    A) USES: Disulfiram also known as antabuse or tetraethylthiuram disulfide (TETD) is used as an industrial antioxidant, fungicide, disinfectant, and most commonly to maintain sobriety in patients with chronic ethanol abuse. This document discusses toxicity related to disulfiram overdose. Please refer to ETHANOL-DISULFIRAM REACTION or DISULFIRAM-LIKE REACTION documents for more information regarding adverse events from interactions with ethanol.
    B) PHARMACOLOGY: Disulfiram inhibits aldehyde dehydrogenase and dopamine betahydroxylase which leads to inhibition of alcohol oxidation at the acetylation stage and results in high levels of acetaldehyde and produces a disulfiram-alcohol reaction.
    C) TOXICOLOGY: Disulfiram-induced inhibition of dopamine betahydroxylase results in norepinephrine depletion at presynaptic sympathetic nerve endings. The carbon disulfide metabolite (industrial solvent & pesticide) of acetaldehyde may cause the CNS and peripheral nerve toxicity associated with disulfiram.
    D) EPIDEMIOLOGY: Disulfiram overdose alone is uncommon and severe manifestations of toxicity are rare.
    E) WITH THERAPEUTIC USE
    1) COMMON: Metallic taste, garlic/sulfur/acetone odor, nausea, vomiting, headache, drowsiness, and ataxia.
    2) RARE: Dermatitis, liver injury (may progress to fulminant hepatic failure), seizure, neuropathy, encephalopathy, and optic neuritis.
    F) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Nausea, vomiting, abdominal pain, diarrhea, odor of sulfur, acetone, or garlic, headache, lethargy, weakness, tachypnea, ketosis, ataxia, hypotension, and tachycardia may develop.
    2) SEVERE TOXICITY: Psychosis, hallucinations, ataxia, metabolic acidosis, seizures, extrapyramidal movement disorders, paralysis, encephalopathy, coma, cardiovascular collapse, hypotension, cardiogenic shock, and sensorimotor neuropathy have been reported.
    3) CHRONIC DISULFIRAM TOXICITY: Headache, drowsiness, seizures, neuropathy, and dermatitis. Occasionally implicated in producing psychosis, optic neuritis, and encephalopathy. Hematologic, neuromuscular, and gastrointestinal toxicity and hepatotoxicity may occur 10 days to 12 months after therapy has begun. Toxic or hypersensitivity hepatitis, including death, has been reported. Fatal hepatic necrosis following six weeks of disulfiram therapy (250 mg/day) has also been reported. Effects appear at highly variable time intervals ranging from weeks to years of treatment.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Increased respirations, hypertension, tachycardia and fever may occur. Hypotension may occur with severe overdose.
    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) TACHYPNEA: Increased respirations have been reported (Reichelderfer, 1969).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTHERMIA: Fever has been reported (Reichelderfer, 1969; Kirubakaran et al, 1983).
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) HYPERTENSION has occurred (Kirubakaran et al, 1983).
    2) HYPOTENSION may develop after overdose (Linden et al, 1984).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) TACHYCARDIA: Increased pulse rate has been reported (Reichelderfer, 1969; Kirubakaran et al, 1983).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) OPTIC NEUROPATHY: CASE REPORT: Progressive bilateral visual loss, with flash evoked potentials showing significant delay and reduced amplitude, was reported in a 54-year-old man receiving disulfiram 200 mg 5 days/week for 3 years and 3 days/week for 6 months.
    a) Disulfiram was discontinued; visual acuity had improved 2 months later, and visual evoked potentials were normal 8 months later (Acheson & Howard, 1988).
    2) BLEPHAROSPASM has been reported (Laplane et al, 1992).
    3) OPTIC NEURITIS
    a) Optic neuritis may occur following administration of disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Lemoyne et al, 2009).
    b) Bilateral optic neuritis has been reported after several months of regular dosage of disulfiram (with alcohol intake stopped but tobacco use continuing). Color vision was abnormal with hyperemia of the optic nervehead. Visual acuity was reported to decrease due to central or cecocentral scotoma (Grant & Schuman, 1993).
    c) CASE REPORT: A 52-year-old man presented with severe bilateral loss of visual acuity (1/10) with central scotomas, indicative of optic neuritis, approximately 3 years after beginning disulfiram 500 mg daily (Boukriche et al, 2000).
    4) RETROBULBAR NEURITIS: Retrobulbar neuritis can also result from disulfiram. It generally improves when disulfiram is discontinued, and vision may return to normal within a few weeks of stopping disulfiram. Retrobulbar neuritis may recur if disulfiram is given again. Exceptional cases of persisting vision impairment associated with pallor of the nervehead have been reported (Grant & Schuman, 1993).
    B) WITH POISONING/EXPOSURE
    1) MIOSIS may occur (Kirubakaran et al, 1983).
    3.4.5) NOSE
    A) WITH THERAPEUTIC USE
    1) Therapeutic use may cause an odor of acetone, garlic, or sulfur (Kirubakaran et al, 1983).
    3.4.6) THROAT
    A) Acute vocal cord palsy has been reported after disulfiram intoxication.
    B) WITH POISONING/EXPOSURE
    1) Vocal Cord Palsy
    a) CASE REPORT: A 49-year-old woman presented with severe hoarseness, quadriparesis and sensory changes one month after ingesting 32.5 grams of disulfiram in a suicide attempt. Direct laryngoscopy revealed decreased vocal cord movement on the left side during phonation. The patient was managed with supportive care and hoarseness improved after 60 days of incident (Bae, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported in children following a disulfiram-only overdose (S Sweetman , 2001).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension may occur as a result of a severe overdose (Kuffner, 2006).
    b) CASE REPORT/CHILD: A 2-year-old boy developed lethargy, drowsiness, unresponsiveness, seizures, persistent encephalopathy, and dystonia after a suspected ingestion of 8 to 10 disulfiram tablets (strength not reported). Examination of the patient revealed acidotic breathing with hypotension (60/40 mmHg) and a Glasgow coma scale score of 6. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.02, PCO2 12, HCO3 6) and an MRI of the brain showed swollen and symmetrical hyperintense signal changes involving the globus pallidus and substantia nigra. The patient was treated with megavitamins but he continued to have persistent extrapyramidal symptoms with minimal improvement 1 month post-ingestion (Vykuntaraju & Ramalingaiah, 2013).
    C) CARDIOGENIC SHOCK
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Cardiogenic shock was reported in a 49-year-old woman who ingested 15 grams of disulfiram, 8 mg of clonazepam, 450 mg of maprotiline, and ethanol in an attempted suicide. An initial ECG revealed sinus tachycardia, with no changes consistent with acute ischemia. An echocardiography showed moderate impairment of the left ventricular systolic function, with a 36% ejection fraction and global hypokinesia, with no other abnormalities. Chest radiography revealed bilateral alveolar opacities, suggesting cardiogenic pulmonary edema. Following supportive care, he recovered completely (Jeronimo et al, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) Alterations in mental status reported have included delirium, somnolence and catatonic-like behavior (Laplane et al, 1992; Kirubakaran et al, 1983).
    b) CASE REPORT: Schmuecker et al (1992) reported a case of a 56-year-old man, with a history of schizophrenia and alcohol abuse, who developed shortness of breath, confusion, memory loss, and disorientation 3 weeks after initiating disulfiram therapy, 250 mg daily.
    1) A diagnosis of delirium with underlying schizophrenia was made. Catatonia developed upon initial withdrawal of all medications, including disulfiram. The patient gradually improved until time of hospital discharge 12 days later (Schmuecker et al, 1992).
    B) COMA
    1) WITH POISONING/EXPOSURE
    a) Lethargy, encephalopathy, agitation, weakness, ataxia, and coma may occur after acute ingestion of 3 grams or more (Lemoyne et al, 2009; Rainey, 1977; Woolley & Devenyi, 1980; Rothrock et al, 1984; Ryan et al, 1993).
    b) CASE REPORT: Coma was seen after 8 grams orally in an adult (Kirubakaran et al, 1983).
    c) CASE REPORT: Severe toxic encephalopathy, seizures, and coma developed in a 35-year-old man who ingested 20 grams of disulfiram along with an unknown amount of carbamazepine in a suicide attempt. Following supportive therapy, he recovered gradually (Lemoyne et al, 2009).
    d) PEDIATRIC: Coma also occurred in a child who ingested an unknown amount (Reichelderfer, 1969).
    e) CASE REPORT/CHILD: A 2-year-old boy developed lethargy, drowsiness, unresponsiveness, seizures, persistent encephalopathy, and dystonia after a suspected ingestion of 8 to 10 disulfiram tablets (strength not reported). Examination of the patient revealed acidotic breathing with hypotension (60/40 mmHg) and a Glasgow coma scale score of 6. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.02, PCO2 12, HCO3 6) and an MRI of the brain showed swollen and symmetrical hyperintense signal changes involving the globus pallidus and substantia nigra. The patient was treated with megavitamins but he continued to have persistent extrapyramidal symptoms with minimal improvement 1 month post-ingestion (Vykuntaraju & Ramalingaiah, 2013).
    C) SEIZURE
    1) WITH THERAPEUTIC USE
    a) Seizures associated with disulfiram may be due to carbon disulfide, a potent neurotoxic metabolite; lowering of the seizure threshold; drug induced pyridoxine deficiency; or altered catecholamine levels in the brain.
    b) CASE REPORT: EEG abnormalities, Capgras syndrome (delusion that important people have been replaced by imposters), and seizures were reported in a 28-year-old woman following disulfiram 500 mg/day for 2 weeks (Daniel et al, 1987).
    c) CASE REPORT: McConchie et al (1983) reviewed the literature on disulfiram associated seizures and found 22 case reports, with only one subject having a documented history of a prior seizure.
    1) Fifty percent of the cases (11) were not associated with the disulfiram-ethanol reaction. Of these 11 cases, 2 were attributed to acute disulfiram intoxication, 2 were provoked by photostimulation, and the remaining 7 cases were linked with chronic disulfiram intoxication (500 mg/day or more for at least 2 weeks in association with other major side effects such as psychosis, coma, hemiparesis, amnesia, and severe abdominal pains) (McConchie et al, 1983).
    2) WITH POISONING/EXPOSURE
    a) Grand mal seizures have occurred after ingestion of 3 grams or more (McConchie et al, 1983; Rainey, 1977; Woolley & Devenyi, 1980).
    b) CASE REPORT: A 35-year-old man ingested 20 grams of disulfiram along with an unknown amount of carbamazepine in a suicide attempt. Severe toxic encephalopathy with coma and rapid succession myoclonia persisted for approximately 50 hours after ingestion (Lemoyne et al, 2009).
    c) CASE REPORT/CHILD: A 2-year-old boy developed lethargy, drowsiness, unresponsiveness, seizures, persistent encephalopathy, and dystonia after a suspected ingestion of 8 to 10 disulfiram tablets (strength not reported). Examination of the patient revealed acidotic breathing with hypotension (60/40 mmHg) and a Glasgow coma scale score of 6. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.02, PCO2 12, HCO3 6) and an MRI of the brain showed swollen and symmetrical hyperintense signal changes involving the globus pallidus and substantia nigra. The patient was treated with megavitamins but he continued to have persistent extrapyramidal symptoms with minimal improvement 1 month post-ingestion (Vykuntaraju & Ramalingaiah, 2013).
    D) ELECTROENCEPHALOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) EEG abnormalities have been reported (Kirubakaran et al, 1983)(Daniel et al, 1987; (Laplane et al, 1992).
    E) NEUROPATHY
    1) WITH THERAPEUTIC USE
    a) Axonal degeneration and myelinated fiber loss have been demonstrated in patients with peripheral sensorimotor polyneuropathy secondary to therapeutic disulfiram therapy (Bergouignan et al, 1988).
    b) ONSET may occur as early as 10 days after beginning therapy. The usual time interval is 5 to 6 months (Gardner-Thorpe & Benjamin, 1971; Moddel et al, 1978; Hayman & Wilkins, 1956).
    1) CASE REPORT: Late onset of disulfiram-induced peripheral neuropathy after 30 years of taking the drug has been reported. A disulfiram-alcohol interaction was not required for the neuropathy to develop (Borrett, 1985).
    2) Gradual onset and steady progression usually occurred, but acute onset, in 48 hours, has been reported (Watson, 1980).
    3) CASE REPORT: A 31-year-old woman presented with weakness in distal segments of the lower limbs associated with burning dysesthesias, numbness and pain in the soles of the feet and legs below the knees after two months therapy of disulfiram 250 mg daily. Two weeks after symptoms developed, she developed gait difficulties with foot drop and disequilibrium and was diagnosed with bilateral walking steppage. Painful paraesthesias improved but patient's strength and sensation deficits remained unchanged seven months after discontinuing medication (Filosto et al, 2008).
    4) CASE REPORT: A 27-year-old man presented with seizure, unsteady gait with bilateral steppage and foot drop, and overall sensation impairment below the knees two weeks after starting therapy with disulfiram 1600 mg/day. Nine months after disulfiram was discontinued, the patient's neurological exam showed complete recovery (Filosto et al, 2008).
    c) Frequent symptoms: The legs and arms have numbness, "pin and needle" sensations, pain/burning, and weakness. Hands, facial muscles, and ocular muscles may also be affected (Mokri, 1981).
    1) Sensory loss (perception of light touch, pinprick, temperature, joint position and vibration) is common (Watson, 1980; Olney & Miller, 1980; Mokri, 1981). This may progress to severe incapacitation.
    d) Upon withdrawal of disulfiram some immediate improvements may be noted, but usually, partial or complete recovery of sensory and motor function is slow. In some case reports, symptoms have persisted after 2 years (Olney & Miller, 1980; Mokri, 1981).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 49-year-old woman presented with severe hoarseness, quadriparesis and sensory changes one month after ingesting 32.5 grams of disulfiram in a suicide attempt. Sensory examination revealed decreased sense of touch, pain, temperature, vibration and proprioception in a glove and stocking distribution of limbs. Severe sensorimotor axonal polyneuropathy measured by nerve conduction study was noted 35 days after incident. Following supportive care, the patient's symptoms improved 60 days after incident (Bae, 2009).
    b) Tetraparesis was reported in a 54-year-old chronic alcoholic following a suicidal ingestion of 25 grams of disulfiram. Concurrent ethanol intake was excluded. Upper extremity and some lower extremity strength had returned by one year follow-up (Hirschberg et al, 1987).
    F) TOXIC ENCEPHALOPATHY
    1) WITH POISONING/EXPOSURE
    a) Catatonia and encephalopathy (Wilson, 1984) and acute psychosis (Kirubakaran et al, 1983) have been described.
    b) Chronic neuropsychological impairment may result from disulfiram overdose (Ryan et al, 1993).
    c) CASE REPORT: Subacute flaccid tetraparesis with associated encephalopathy was seen in a chronic alcoholic who ingested 25 grams of disulfiram (Hirschberg et al, 1987).
    d) Encephalopathy, hallucinations, and acute psychosis have been seen after disulfiram overdose (Manoguerra & Kearney, 1982; Wilson, 1984; Kirubakaran et al, 1983; Laplane et al, 1992).
    e) CASE REPORT/CHILD: A 2-year-old boy developed lethargy, drowsiness, unresponsiveness, seizures, persistent encephalopathy, and dystonia after a suspected ingestion of 8 to 10 disulfiram tablets (strength not reported). Examination of the patient revealed acidotic breathing with hypotension (60/40 mmHg) and a Glasgow coma scale score of 6. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.02, PCO2 12, HCO3 6) and an MRI of the brain showed swollen and symmetrical hyperintense signal changes involving the globus pallidus and substantia nigra. The patient was treated with megavitamins but he continued to have persistent extrapyramidal symptoms with minimal improvement 1 month post-ingestion (Vykuntaraju & Ramalingaiah, 2013).
    G) ATAXIA
    1) WITH POISONING/EXPOSURE
    a) Hallucinations, ataxia, irritability, speech difficulty, and uncontrollable arm movements have been described in a 2-year-old boy who ingested 2.5 grams of disulfiram (Manoguerra & Kearney, 1982). The patient had been asymptomatic for 12 hours.
    H) EXTRAPYRAMIDAL DISEASE
    1) WITH THERAPEUTIC USE
    a) BASAL GANGLIA LESIONS: Confined to the lentiform nuclei, disulfiram-induced PARKINSONISM, and PSEUDOBULBAR-like syndrome have been reported after disulfiram treatment (Laplane et al, 1992; Boukriche et al, 2000).
    b) CASE REPORT: A 52-year-old man presented with severe hypophonia, dysphagia, and bradykinesis with hypertonia and facial hypomobility approximately 3 years after beginning disulfiram therapy, 500 mg daily. CT scan of the brain revealed bilateral and symmetrical hypodensities in the pallidal nuclei. MRI with administration of IV gadolinium showed enhancement of the pallidal nuclei, indicative of disruption of the blood-brain barrier. Although the patient's extrapyramidal signs spontaneously improved following discontinuation of disulfiram therapy, he continued to experience hypophonia and dysphagia two months after onset (Boukriche et al, 2000).
    2) WITH POISONING/EXPOSURE
    a) Severe extrapyramidal signs have been described in adults who ingested overdoses of disulfiram with or without alcohol. These signs have been associated with CT or MRI-confirmed lesions in the pallidal nuclei and the putamen. Bilateral signs have been associated with unilateral lesions; dystonic symptoms may worsen or improve over time as lesions progress. Extrapyramidal signs will rarely persist and worsen over a period of many years (Krauss et al, 1991; De Mari et al, 1993).
    b) CASE REPORT/CHILD: A 2-year-old boy developed lethargy, drowsiness, unresponsiveness, seizures, persistent encephalopathy, and dystonia after a suspected ingestion of 8 to 10 disulfiram tablets (strength not reported). Examination of the patient revealed acidotic breathing with hypotension (60/40 mmHg) and a Glasgow coma scale score of 6. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.02, PCO2 12, HCO3 6) and an MRI of the brain showed swollen and symmetrical hyperintense signal changes involving the globus pallidus and substantia nigra. The patient was treated with megavitamins but he continued to have persistent extrapyramidal symptoms with minimal improvement 1 month post-ingestion (Vykuntaraju & Ramalingaiah, 2013).
    I) DISTURBANCE IN THINKING
    1) WITH POISONING/EXPOSURE
    a) In some cases, ataxia and intellectual impairment have persisted following recovery from acute overdose, possibly due to neurotoxic effects of carbon disulfide (Rainey, 1977).
    J) PSYCHOTIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 32-year-old man developed a paranoid psychosis following disulfiram therapy. The paranoid symptoms disappeared after discontinuation of disulfiram and initiation of chlorpromazine therapy. The patient's paranoid delusions recurred within 10 days of reintroduction of disulfiram, and the symptoms again disappeared upon stopping the medication (Rossiter, 1992).
    K) CHRONIC POISONING
    1) WITH THERAPEUTIC USE
    a) Psychosis, optic neuritis, encephalopathy, extrapyramidal signs, ataxia, and peripheral neuropathy have been described following chronic therapeutic use (Liddon, 1967; Hotson, 1976; Knee & Razani, 1974; Weddington, 1980; Mokri, 1981; Watson, 1980; Gardner-Thorpe, 1971; Linden et al, 1984).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH POISONING/EXPOSURE
    a) Gastrointestinal disturbances have occurred after ingestion of 3 grams or more (Rainey, 1977; Woolley & Devenyi, 1980). Nausea, vomiting, abdominal pain, and diarrhea may occur as initial symptoms (Reichelderfer, 1969) but may be delayed in presentation for up to 12 hours (Manoguerra & Kearney, 1982; Linden et al, 1984).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) TOXIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) Disulfiram-induced hepatitis has been reported during therapeutic use. Symptomatology and biochemical abnormalities occurred 2 weeks to 2 months after initiation of therapy (Ranek, 1977; Eisen & Ginsberg, 1975; Kristensen, 1981; Keeffe & Smith, 1974).
    b) CASE REPORT: Hepatitis complicated by fatal liver failure was reported after ingestion of 500 mg/day over a 3-week period (Wright, 1988; Cereda, 1989).
    c) CASE SERIES: One study reviewed 82 cases of suspected disulfiram-induced liver damage. The average duration of disulfiram therapy prior to onset of abnormal liver enzymes was 2 months (range 7 to 270 days), and no concurrent alcohol consumption was confirmed in 74 cases (90%). Eight patients either expired (n=4) or received a liver transplant (n=4), and these patients had significantly higher serum bilirubin, AST, AST/ALT ratio and INR values compared to the remainder of the study population. However, serum bilirubin was the only marker found to independently predict poor outcome.
    1) The authors speculate a possibility of 2 different mechanisms for disulfiram-induced liver disease. Liver biopsy results were available in 17 cases, and the majority showed eosinophilic leukocyte infiltrates, suggesting a hypersensitivity reaction. There were a few cases that demonstrated hepatocyte "drop-out" and bridging necrosis, and these were associated with a poorer outcome (Bjornsson et al, 2006).
    B) HEPATIC NECROSIS
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Fatal hepatic necrosis following 6 weeks of disulfiram therapy (250 mg/day) has also been reported (Schade et al, 1983).
    C) HEPATIC FAILURE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 36-year-old man, with a 10-year history of excessive alcohol consumption, presented to the emergency department with pain, fatigue, vomiting, and altered mental status approximately 2 weeks after discontinuing disulfiram therapy, 250 mg three times per week for eight weeks. The patient's laboratory analysis showed an ALT of 3270 Units/L, an AST of 1870 Units/L, and a total bilirubin of 7.9 mg/dL.
    1) Despite discontinuation of the disulfiram, the patient continued to deteriorate with the development of significant jaundice and worsening liver function tests, requiring liver transplantation. The transplantation was uneventful and histologic examination of the explanted liver showed signs of massive necrosis (Rabkin et al, 1998).
    b) CASE REPORT: A 66-year-old man, with a history of hypertension, type 2 diabetes mellitus, atrial fibrillation, and heavy alcohol use (24 ounces of whiskey daily for 20 years), presented with hypoglycemia and a several day history of not feeling well. Approximately 21 days prior to presentation, the patient had stopped alcohol consumption and had started taking disulfiram. Approximately 10 days after initiating disulfiram therapy, the patient began to feel unwell and discontinued therapy at the advice of his physician. Following presentation, the patient was transferred to another facility. Initial laboratory data at that facility (hospital day 1) revealed elevated liver enzymes (AST 2774 international units/liter, ALT 3156 international units/liter, lactate dehydrogenase 950 international units/liter, GGT 217 international units/liter, alkaline phosphatase 189 international units/liter), a total bilirubin of 13 international units/liter, and an INR of greater than 10. A liver ultrasound with doppler showed increased echo texture of the liver parenchyma indicative of hepatic parenchymal disease and a CT scan revealed a non-cirrhotic liver. Viral hepatitis serologies were negative and hepatitis A, B, C, and HIV testing were negative. The patient's INR decreased to 3.8 following administration of oral vitamin K; however, by hospital day 8, his bilirubin and INR increased to 36 mg/dL and 7. Encephalopathy and fulminant hepatic failure developed, believed to be temporally associated with his disulfiram use, as all other causes were ruled out. The patient was not a candidate for liver transplantation due to his alcohol dependence. His hepatic encephalopathy and coagulopathy progressively worsened and he was discharged to an inpatient hospice facility (Watts et al, 2014).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH POISONING/EXPOSURE
    a) Hematuria and ketonuria have been described (Kirubakaran et al, 1983).
    B) ABNORMAL URINE
    1) WITH POISONING/EXPOSURE
    a) ACETONEMIA and acetonuria have been reported (Stowell et al, 1983; Kirubakaran et al, 1983).

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT/CHILD: A 2-year-old boy developed lethargy, drowsiness, unresponsiveness, seizures, persistent encephalopathy, and dystonia after a suspected ingestion of 8 to 10 disulfiram tablets (strength not reported). Examination of the patient revealed acidotic breathing with hypotension (60/40 mmHg) and a Glasgow coma scale score of 6. Arterial blood gas analysis revealed severe metabolic acidosis (pH 7.02, PCO2 12, HCO3 6) and an MRI of the brain showed swollen and symmetrical hyperintense signal changes involving the globus pallidus and substantia nigra. The patient was treated with megavitamins but he continued to have persistent extrapyramidal symptoms with minimal improvement 1 month post-ingestion (Vykuntaraju & Ramalingaiah, 2013).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) In a double-blind randomized placebo-controlled clinical trial to evaluate the safety and efficacy of Diethyldithiocarbamate, a metabolite of disulfiram, it was shown that Diethyldithiocarbamate was associated with a decrease in neutrophils, monocytes, and platelets when administered to HIV-infected children and young adults (Shenep et al, 1994).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTACT DERMATITIS
    1) WITH THERAPEUTIC USE
    a) A few cases of contact dermatitis have been reported occupationally (nurses) or in patients with disulfiram implants (Mathelier-Fusade & Leynadier, 1994).
    b) Patients with histories of nickel contact dermatitis may experience an episode of dermatitis after initiating disulfiram therapy. This "recall dermatitis" may occur with removal of protein-bound nickel (disulfiram is a potent chelator) (Gamboa et al, 1993).
    2) WITH POISONING/EXPOSURE
    a) A few cases of contact dermatitis have been reported occupationally (nurses) or in patients with disulfiram implants (Mathelier-Fusade & Leynadier, 1994).
    B) DISCOLORATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 55-year-old man developed orange-colored palms and soles approximately 2 months after beginning disulfiram therapy. The patient's serum bilirubin was normal and abdominal ultrasound did not show any hepatic abnormalities. The discoloration disappeared after discontinuing the disulfiram.
    1) It is speculated that the disulfiram may have caused the subcutaneous accumulation of carotene deposits, due to disulfiram's inhibition of vitamin A metabolism, thus causing the skin discoloration which simulated the appearance of jaundice (Santonastaso et al, 1997).

Reproductive

    3.20.1) SUMMARY
    A) A medical literature search of disulfiram during human pregnancy has revealed that 4 of 14 fetuses developed congenital anomalies, including 2 cases of clubfoot, 1 case of multiple anomalies with VACTERL syndrome, 1 case of microcephaly/mental retardation, 1 case of Pierre Robin syndrome, and 1 case of phocomelia involving the lower extremities. Another case report revealed possible fetal alcohol syndrome exacerbated by disulfiram, with acetaldehyde as the teratogen. Animal data have shown embryotoxicity and resorption of fetus in rats.
    3.20.2) TERATOGENICITY
    A) CONGENITAL ANOMALY
    1) Limited data regarding the use of disulfiram during human pregnancy exists.
    a) A search of the medical literature has revealed only 13 women that had ingested disulfiram during pregnancy (Helmbrecht & Hoskins, 1993; RMDCC, 1987; Briggs et al, 1998). The patients in many studies have ingested multiple substances, and are compromised socioeconomically.
    b) Four of 14 fetuses (1 set of twins) developed congenital anomalies, 5 pregnancies were terminated electively, and 1 spontaneous abortion occurred (Nora, 1977; Favre-Tissot & Delatour, 1965; Briggs et al, 1998; Helmbrecht & Hoskins, 1993).
    c) Malformations included:
    1) Clubfoot - 2 cases
    2) Multiple anomalies with VACTERL syndrome - 1 case
    a) (radial aplasia, vertebral fusion, tracheoesophageal fistula)
    3) Microcephaly/mental retardation - 1 case
    a) (possibly fetal alcohol syndrome)
    4) Pierre Robin syndrome - 1 case
    5) Phocomelia involving lower extremities - 1 case
    d) One case report reveals a malformed child born to a previously alcoholic mother who denied alcohol ingestion during pregnancy; however, she may have taken disulfiram postconception in addition to short, low-dose courses of phenobarbital. The child had symptoms consistent with fetal alcohol syndrome. Based on the complicated history, it was not possible to conclude why malformations occurred. It could have been fetal alcohol syndrome exacerbated by disulfiram, with acetaldehyde as the teratogen (Gardner & Clarkson, 1981).
    B) ANIMAL STUDIES
    1) Some data exist in rats and hamsters in which no teratogenic effects with disulfiram were found (Fastner, 1984). Other data have reported embryotoxicity in rats (resorption of fetus) (Nora, 1977; Shepherd, 1976).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to this agent during lactation in humans (Prod Info Antabuse(R) oral tablets, 2010).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS97-77-8 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) IARC Classification
    a) Listed as: Disulfiram
    b) Carcinogen Rating: 3
    1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) LACK OF EFFECT
    a) In a lifetime carcinogenicity bioassay, disulfiram was fed to rats and mice. The highest dose administered to rats was 600 ppm, and the highest dose administered to mice was 2000 ppm. Disulfiram was found not to be carcinogenic in neither rats nor mice (Hathaway, 1996).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, renal function, hepatic enzymes, and serum glucose.
    C) Obtain a serum lactate and venous blood gases in patients with acidosis.
    D) A serum ethanol concentration may be useful if an ethanol-disulfiram interaction is suspected.
    E) Disulfiram concentrations are not readily available or useful to guide therapy.
    F) Obtain an ECG and institute continuous cardiac monitoring in patients with severe symptoms.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) DISULFIRAM: Blood levels of disulfiram and its 4 major metabolites are highly variable between subjects following therapeutic administration. Assays for disulfiram are available from a few specialized laboratories, but correlations of blood disulfiram concentrations to toxic effects have not been established. Disulfiram concentrations may be useful to document exposure in rare circumstances.
    2) The following table compares the plasma levels of disulfiram and its metabolites in a patient who had ingested thirty 250 mg disulfiram tablets (Kirubakaran et al, 1983) with 15 sober alcoholic volunteers (without liver or renal disease) on a therapeutic dose (given 250 mg/day of disulfiram for 11 days) of disulfiram (Faiman et al, 1984a):
    Peak Plasma Concentration (mcg/mL)
     PatientVolunteers
     Day 4Day 7MeanSE
    Disulfiram1.80.70.410.03
    Diethyldithio-carbamate1.04.91.140.07
    Diethyldithio-carbamate-methylester3.71.41.220.13
    Carbon disulfide117.5132.024.01.16
    Diethylamine103.522.43.80.28

    3) Carbon disulfide, which has been implicated as the cause of the neurotoxicity of disulfiram (Rainey, 1977), has the highest plasma concentrations.
    4) LIVER FUNCTION TESTS: Hepatotoxicity is idiosyncratic and not dose related.
    a) In a review of 17 cases, the latency from initiation of therapy to development of symptoms ranged from 10 days to 6 months; the majority occurred between 2 weeks and 2 months. It is suggested that patients receiving disulfiram therapeutically have liver function studies prior to treatment, every 2 weeks for 2 months after starting treatment, and every 3 to 6 months thereafter (Wright, 1988).
    4.1.4) OTHER
    A) OTHER
    1) ECG
    a) Obtain an ECG in substantial overdose or ethanol-reaction.
    2) ELECTROPHYSIOLOGICAL TESTING
    a) Patients with peripheral neuropathy should be evaluated by a neurologist with consideration for nerve conduction velocity studies, EMG, and nerve biopsy.

Radiographic Studies

    A) RADIOGRAPHIC-OTHER
    1) Patients with central nervous system involvement should be scanned, using CT or MRI, for lesions (most commonly reported in the pallidal and putamenal areas). Scans may be repeated periodically to track the patient's progress. Some authors believe that magnetic resonance imaging is more sensitive for detection of small lesions; others disagree (Krauss et al, 1991; Riley, 1992; De Mari et al, 1993).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with severe or persistent symptoms should be admitted, patients with significant alteration in mental status, recurrent seizures, or hypotension should be admitted to intensive care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic children with inadvertent ingestions of one or two doses can probably be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions, children who ingest more than two doses inadvertently, and any patient with more than minimal symptoms should be referred to a healthcare facility for evaluation and 8 to 12 hours of observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged.

Monitoring

    A) Monitor vital signs and mental status.
    B) Monitor serum electrolytes, renal function, hepatic enzymes, and serum glucose.
    C) Obtain a serum lactate and venous blood gases in patients with acidosis.
    D) A serum ethanol concentration may be useful if an ethanol-disulfiram interaction is suspected.
    E) Disulfiram concentrations are not readily available or useful to guide therapy.
    F) Obtain an ECG and institute continuous cardiac monitoring in patients with severe symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Activated charcoal are generally not recommended as patients often have nausea and vomiting from the exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) SUMMARY: Charcoal is not indicated for patients who present with severe nausea and vomiting, but may be considered in a patient who presents early after a large overdose who is not vomiting. Lavage and whole bowel irrigation are generally not recommended.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Monitor serum electrolytes, renal function, hepatic enzymes, and serum glucose.
    3) Obtain a serum lactate and venous blood gases in patients with acidosis.
    4) A serum ethanol concentration may be useful if an ethanol-disulfiram interaction is suspected.
    5) Disulfiram concentrations are not readily available or useful to guide therapy.
    6) Obtain an ECG and institute continuous cardiac monitoring in patients with severe symptoms.
    B) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    C) HYPOTENSIVE EPISODE
    1) POSTURAL REPOSITIONING with patient supine.
    2) Severe hypotension was resistant to dopamine in one patient but responded dramatically to high-dose norepinephrine infusion (2 micrograms/kilogram/minute). Since dopamine acts partially by releasing endogenous norepinephrine stores, which may be depleted by disulfiram, norepinephrine may be the preferred agent (Motte et al, 1986).
    3) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    4) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    D) DRUG-INDUCED DYSTONIA
    1) ADULT
    a) BENZTROPINE: 1 to 4 mg once or twice daily intravenously or intramuscularly; maximum dose: 6 mg/day; 1 to 2 mg of the injection will usually provide quick relief in emergency situations (Prod Info benztropine mesylate IV, IM injection, 2009).
    b) DIPHENHYDRAMINE: 10 to 50 mg intravenously at a rate not exceeding 25 mg/minute or deep intramuscularly; maximum dose: 100 mg/dose; 400 mg/day (Prod Info diphenhydramine hcl injection, 2006).
    2) CHILDREN
    a) DIPHENHYDRAMINE: 5 mg/kg/day or 150 mg/m(2)/day intravenously divided into 4 doses at a rate not to exceed 25 mg/min, or deep intramuscularly; maximum dose: 300 mg/day. Not recommended in premature infants and neonates (Prod Info diphenhydramine hcl injection, 2006).
    E) EXPERIMENTAL THERAPY
    1) PYRIDOXINE: One gram intravenously may be administered to patients exhibiting neurological toxicity from disulfiram (Linden et al, 1984). The efficacy is not yet proven.

Enhanced Elimination

    A) SUMMARY
    1) Hemodialysis, hemoperfusion, or forced diuresis have not been shown to be effective in enhancing elimination of disulfiram.

Abstracts

Case Reports

    A) ADULT
    1) OVERDOSE: Intentional overdose of approximately 30 disulfiram tablets (250 mg/tablet) resulted in initial manifestations of psychosis, followed by delirium, somnolence, and catatonic-like behavior which fluctuated markedly during the first 2 days following admission in a 31-year-old man with a 7 year history of alcoholism.
    a) The patient had no prior history of psychosis. Treatment with haloperidol resulted in improvement on day 4 following ingestion. Four days following ingestion, disulfiram serum concentrations were 1.8 mcg/mL, declining to 0.7 mcg/mL on day 7.
    b) Carbon disulfide levels on day 4 and 7 were 117 and 132 mcg/mL, respectively (5 times higher than alcoholic volunteers). Corresponding disulfiram plasma levels in sober alcoholic volunteers were 0.41 mcg/mL with doses of 250 mg/day (Kirubakaran et al, 1983).

Range Of Toxicity

Summary

    A) TOXICITY: PEDIATRICS: Ingestion of 2.5 g to 3 g in children produced symptoms such as lethargy, ataxia, and seizure. ADULTS: Ingestions of 6 g have been reported without adverse symptoms; however, ingestion of 3 g may result in symptoms. An adult male patient with a history of alcohol abuse ingested 7.5 g of disulfiram and developed psychosis followed by delirium, somnolence, and catatonic-like behavior for 48-hour period. Ingestion of 10 to 30 g in an adult has resulted in death.
    B) THERAPEUTIC DOSE: For alcohol dependence, 125 mg to 500 mg given orally in the morning or evening is recommended with the patient abstinent from alcohol for at least 12 hours prior to dosing. There is no pediatric dosing available for disulfiram.
    C) Please refer to ETHANOL-DISULFIRAM REACTION or DISULFIRAM-LIKE REACTION documents for more information.

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) Initial dose: After patient has abstained from ethanol for at least 12 hours, up to a maximum of 500 mg/day given as a single dose for 1 to 2 weeks (Prod Info disulfiram oral tablets, 2014).
    2) Maintenance dose: 250 mg/day with a range of 125 to 500 milligrams/day; MAX: 500 mg/day (Prod Info disulfiram oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) Safety and efficacy in the pediatric or adolescent population have not been established (Prod Info disulfiram oral tablets, 2014).

Minimum Lethal Exposure

    A) ACUTE
    1) Adults may have clinical signs after acute ingestion of about 3 g of disulfiram; death may occur with ingestion of 10 to 30 g (Krauss et al, 1991).

Maximum Tolerated Exposure

    A) ACUTE
    1) OVERDOSE
    a) PEDIATRICS: Lethargy, ataxia, seizures, and coma have occurred after ingestion of 2.5 to 3 g in children (Woolley & Devenyi, 1980; Manoguerra & Kearney, 1982).
    b) ADULTS: CASE REPORT: A 49-year-old woman survived ingestion of 32.5 g of disulfiram in a suicide attempt. Morbidity after ingestion included sensory changes and vocal cord palsy(Bae, 2009).
    c) Single doses of up to 6 g/day have been reported in adults without adverse effect (Talbot & Gander, 1973).
    B) CHRONIC
    1) CASE REPORT: A 27-year-old man presented with seizure, unsteady gait with bilateral steppage and foot drop, and overall sensation impairment below the knees, two weeks after starting therapy with disulfiram 1600 mg/day. Nine months after disulfiram was discontinued, the patient's neurological exam showed complete recovery (Filosto et al, 2008).
    2) Brewer (1993) reported a case of an adult who ingested 600 mg daily for over six years and experienced no significant side effects other than slight drowsiness (Brewer, 1993).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) ADULT
    a) Blood disulfiram levels in patients taking the drug therapeutically are generally 2 to 10 mcg/mL (Reichelderfer, 1969).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) PEDIATRIC
    1) In a 2-year-old who was severely ill from a disulfiram overdose, a blood disulfiram level 9 days after admission was 17.4 mcg/mL.
    b) ADULT
    1) An adult male died following ingestion of an unknown amount of alcohol while taking disulfiram therapeutically. A post-mortem blood sample yielded the following levels: ethanol, 115 mg/100 mL; acetaldehyde, 41 mg/L; and the metabolites of disulfiram: diethyldithiocarbamate, 31 mg/L; and diethylamine 8 mg/L (Heath et al, 1992).

Workplace Standards

    A) ACGIH TLV Values for CAS97-77-8 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Disulfiram
    a) TLV:
    1) TLV-TWA: 2 mg/m(3)
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A4
    2) Codes: Not Listed
    3) Definitions:
    a) A4: Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    c) TLV Basis - Critical Effect(s): Vasodilation; nausea
    d) Molecular Weight: 296.54
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS97-77-8 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Disulfiram
    2) REL:
    a) TWA: 2 mg/m(3)
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s): [Precautions should be taken to avoid concurrent exposure to ethylene dibromide.]
    3) IDLH: Not Listed

    C) Carcinogenicity Ratings for CAS97-77-8 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A4 ; Listed as: Disulfiram
    a) A4 :Not Classifiable as a Human Carcinogen: Agents which cause concern that they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other categories.
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Disulfiram
    a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Disulfiram
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS97-77-8 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Budavari, 2001 ACGIH, 1991; Lewis, 1996 RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 75 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 1980 mg/kg
    3) LD50- (SUBCUTANEOUS)MOUSE:
    a) 2600 mg/kg
    4) LD50- (INTRAPERITONEAL)RAT:
    a) 248 mg/kg
    5) LD50- (ORAL)RAT:
    a) 500 mg/kg
    b) 8.6 g/kg

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Disulfiram (tetraethylthiuram disulfide - TETD) is an anti-oxidant drug used in the treatment of alcoholism. It inhibits enzymatic oxidation of acetaldehyde to acetate which occurs in the liver during normal liver catabolism (Eneanya DI, 1981).
    B) Both disulfiram and its metabolites are strong chelating agents for zinc of the ethanol dehydrogenase enzyme and for molybedenum and iron of the aldehyde dehydrogenase enzyme. Disulfiram activity is related to the inactivation of these enzymes.

Toxicologic Mechanism

    A) Buildup of acetaldehyde occurs following administration of ethanol. The carbon disulfide metabolite may also contribute to the toxic effects (Eneanya DI, 1981).
    B) CARBON DISULFIDE - Carbon disulfide is a pesticide and industrial solvent. It is a major metabolite of disulfiram and may cause the central nervous system and peripheral nerve toxicity seen with disulfiram (Rainey, 1977; Kane, 1970).
    C) Decreased sensitivity to circulating catecholamines caused by disulfiram-induced inhibition of dopamine-beta-hydroxylase with depletion of tissue levels of the neurotransmitter norepinephrine (Musacchio et al, 1964) may be responsible for the well known disulfiram-ethanol (DE) reaction.
    1) It seems likely that mechanisms aside from acetaldehyde accumulation are at least partially responsible for DE reactions, since injection of acetaldehyde in animals produces increases in blood pressure and cardiac output secondary to release of catecholamines from sympathetic nerve endings and the adrenal medulla.
    2) In disulfiram-treated animals, acetaldehyde decreased blood pressure, heart rate, myocardial contractility and increases pulmonary arterial pressure (Nakano et al, 1974).
    D) Disulfiram is a potent heavy metal chelator. Patients carrying a body burden of metals such as lead may experience redistribution with the possibility of increased brain heavy metal levels (Miller, 1993). Patients with known dermatologic sensitivity to specific metals have been reported to experience dermatitis upon initiation of disulfiram therapy (Gamboa et al, 1993). Research is needed to elucidate the details of this proposed mechanism.

Physicochemical

Physical Characteristics

    A) Disulfiram has been described as a white, off-white, yellowish, or light gray crystalline powder with no or slight odor and a slightly bitter taste (ACGIH, 1991; (Ashford, 1994; HSDB , 1999) Hathaway, 1996; Lewis, 1993; (Lewis, 1996; Lewis, 1998; NIOSH , 1999).
    B) Sittig (1991) describes disulfiram as a dark brown crystalline solid.

Molecular Weight

    A) 296.52

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