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DISULFIRAM-ETHANOL REACTION

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) This management discusses disulfiram-ethanol reaction. Please refer to DISULFIRAM management for information on disulfiram overdose. Refer to DISULFIRAM-LIKE REACTION management for information on ethanol use with other agents.

Specific Substances

    1) DER
    2) Disulfiram-alcohol reaction
    3) Disulfiram-alcohol interaction
    4) Disulfiram-ethanol interaction
    5) Disulfiram-ethanol-like reaction

Available Forms Sources

    A) SOURCES
    1) Disulfiram-ethanol reactions have been reported following exposure to oral or subcutaneous disulfiram, and to ethanol by any route (Kuffner, 2006).
    2) Unwitting ingestion, dermal exposure, or inhalation of patent medicines or toiletries containing ethanol (such as cough syrups, shampoo or cologne) may also precipitate a reaction (Stoll, 1980; Koff, 1971).
    3) Ethanol is often a hidden component of products and pharmaceuticals; some pharmaceuticals for intravenous administration are solubilized in up to 10 percent ethanol bases (Edwards et al, 1986).
    4) The following common household products may contain ethanol: adhesives; alcohols (denatured alcohol, rubbing alcohol); detergents; foods (liquor-containing desserts, fermented vinegar, some sauces); nonprescription medications (analgesics, antacids, antidiarrheal, cough and cold preparations, topical anesthetics, vitamins); personal hygiene products (after-shave lotions, colognes, deodorants, liquid soaps, mouthwashes, perfumes, skin liniments, lotions), solvents (Kuffner, 2006).
    5) DERMAL ABSORPTION - Reactions are unusual, but may occur due to dermal absorption. A woman taking 200 mg disulfiram daily reported that she and her husband both experienced mucosal soreness and stinging after intercourse. The reaction happened only after the husband had consumed large amounts of alcohol, and lessened in severity when the wife's disulfiram dose was decreased to 100 mg daily (Chick, 1988).

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 is used to treat alcoholism by causing adverse effects when ethanol is ingested.
    B) PHARMACOLOGY: Disulfiram blocks hepatic aldehyde dehydrogenase. Acetaldehyde, the major metabolite of ethanol by liver alcohol dehydrogenase, reaches high levels, causing many adverse effects. Disulfiram also impairs norepinephrine synthesis as its metabolite, diethyldithiocarbamate, inhibits dopamine beta-hydroxylase, the rate-limiting step in norepinephrine synthesis. Disulfiram also inhibits the liver cytochrome P450, CYP2E1.
    C) TOXICOLOGY: The disulfiram-ethanol reaction can be precipitated after exposure to ethanol by any route.
    D) EPIDEMIOLOGY: Disulfiram-ethanol reactions are common; most reactions are self-limiting, lasting several hours. Rarely, reactions are severe or life threatening.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Diaphoresis, cutaneous warmth, flushing, pruritus, nausea and vomiting, blurred vision, conjunctival injection, tachycardia, hypotension including orthostasis, hypertension, palpitations, chest pain, altered mentation, confusion, anxiety, somnolence, headache, anxiety, vertigo, tremor, bronchospasm, dyspnea, hyperventilation, respiratory depression.
    2) SEVERE TOXICITY: Severe vomiting, esophageal rupture, hypotension, tachydysrhythmias, myocardial infarction, sudden cardiac death, fulminant polyneuropathy, visual hallucinations, seizures, delirium, coma, respiratory depression.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, hypotension, and hypertension have been reported following concomitant use of ethanol and disulfiram.

Laboratory Monitoring

    A) Monitor vital signs and mental status.
    B) Disulfiram and/or acetaldehyde concentrations are of little clinical value and are not readily available. Serum ethanol concentrations may help to confirm exposure, but very low ethanol levels are occasionally associated with severe reactions.
    C) No specific lab work is needed in most patients. If diagnosis is unclear, or patient has significant vomiting or cardiac ectopy, check general labs including serum electrolytes and ECG.
    D) Obtain a CT scan of the chest with water soluble oral contrast to exclude esophageal perforation in patients with severe chest pain after vomiting.
    E) In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography) and ECG.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Most disulfiram-ethanol reactions may be safely managed with supportive care that includes monitoring airway, breathing and circulation. Intravenous fluids may be needed for mild hypotension, sedation for agitation, antiemetics to control gastrointestinal irritation. Decontamination is typically unnecessary due to the quick absorption of alcohol and vomiting caused by the reaction itself.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Orotracheal intubation for airway protection should be performed if increasing somnolence, coma, respiratory depression or distress. Insertion of a nasogastric tube to suction ethanol from the stomach may be considered if there is recent large ethanol ingestion and the patient's airway is protected, but it is rarely indicated. For seizures, treat with benzodiazepines; add barbiturates or propofol if seizures persist. For hypotension not responding to intravenous fluids, administer H1 (ie, diphenhydramine) and H2 (ie, ranitidine) antagonists to counteract any histamine-induced hypotension. If vasopressors needed, norepinephrine (0.5 to mcg/min, titrated) may be more effective than dopamine due to disulfiram's inhibition of dopamine beta-hydroxylase, the rate-limiting step in norepinephrine synthesis. Fomepizole (15 mg/kg IV) should be considered in severe reactions refractory to standard treatments. Fomepizole blocks the conversion of ethanol to acetaldehyde.
    C) DECONTAMINATION
    1) PREHOSPITAL: Activated charcoal is not recommended because of potential for agitation, somnolence and vomiting.
    2) HOSPITAL: Activated charcoal may be considered if there is a recent, large disulfiram ingestion and the patient is alert or airway is protected. Insertion of a nasogastric tube to suction ethanol from the stomach may be considered if there is a recent large ethanol ingestion and the patient's airway is protected, but it is rarely indicated.
    D) AIRWAY MANAGEMENT
    1) Intubate if patient is unable to protect airway due to worsening agitation, somnolence or coma.
    E) ANTIDOTE
    1) In rare life-threatening cases, fomepizole (15 mg/kg IV) should be administered. Fomepizole, an alcohol dehydrogenase enzyme blocker, has been used to treat disulfiram-ethanol reactions. It prevents the metabolism of alcohol to acetaldehyde by blocking alcohol dehydrogenase and should be considered in patients with severe reactions not responding to supportive care.
    F) SEIZURES
    1) Administer intravenous benzodiazepines; barbiturates or propofol if seizures recur or persist.
    G) HYPOTENSIVE EPISODE
    1) Keep patient supine; administer IV 0.9% normal saline or norepinephrine.
    H) DRUG-INDUCED DYSTONIA
    1) Adult - Benztropine 1 to 2 mg IV or diphenhydramine 1 mg/kg/dose IV over 2 minutes. Child - Diphenhydramine 1 mg/kg/dose IV over 2 minutes (maximum 5 mg/kg/day or 50 mg/m(2)/day).
    I) ENHANCED ELIMINATION
    1) Disulfiram is not cleared by hemodialysis or hemoperfusion, however ethanol is, so it might be beneficial in severe reaction, but is rarely, if ever, indicated. Fomepizole would generally be preferred in these cases, as it is less invasive.
    J) PATIENT DISPOSITION
    1) HOME CRITERIA: Accidental ingestions in asymptomatic patients who have no synergistic co-ingestions may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with deliberate ingestions, synergistic co-ingestions, unclear history, symptomatic or intoxicated patients, or those in unstable social situations should be sent to a health care facility for observation.
    3) ADMIT CRITERIA: Patients with persistent or worsening gastrointestinal irritation, CNS agitation or depression, seizures, respiratory depression, or dysrhythmias should be admitted. Intensive care unit is indicated for aggressive airway and cardiac monitoring.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (respiratory depression, progressive agitation, coma or dysrhythmias), or in whom the diagnosis is unclear.
    K) PITFALLS
    1) Obtain a detailed history of occult exposures, as ethanol containing commercial products such as cough syrup and personal hygiene products can cause the disulfiram-ethanol reaction. Decontamination with charcoal or gastric lavage is rarely necessary as ethanol is rapidly absorbed and these patients often present with vomiting. The reaction is typically short-lived, therefore careful supportive care is usually sufficient.
    L) PHARMACOKINETICS
    1) Disulfiram: Protein binding 50%. Disulfiram is slowly eliminated from the body via oxidation and glucuronidation in the liver and reduction in erythrocytes; elimination half-life is approximately 7 hours. Excreted in urine 63%; high lipid solubility.
    2) Disulfiram-ethanol reaction: Onset usually within 5 to 10 minutes, but may be delayed several hours. Disulfiram-ethanol reactions have occurred up to 14 days after disulfiram has been discontinued. Duration of effect varies from 30 minutes to several hours.
    M) DIFFERENTIAL DIAGNOSIS
    1) Anticholinergic poisoning, toxic alcohol ingestions, allergic reactions, gastroenteritis, sepsis, scombroid poisoning. Exposure to some other substances (some cephalosporins, monoamine oxidase inhibitors, some sulfonylureas, coprinus mushrooms, tetrachloroethylene, trichloroethylene) can cause a similar reaction when ethanol is ingested concomitantly.

Range Of Toxicity

    A) Dose response is variable. In general, mild reactions may occur with as little as 5 to 10 mg disulfiram/100 mL ethanol. More dramatic reactions predicted after exposure to 50 mg disulfiram/100 mL ethanol, and severe reactions at 125 to 150 mg disulfiram/100 mL ethanol (Prod Info ANTABUSE(R) oral tablets, 2006). Ingestions as little as 7 mL of ethanol have been associated with death.

Clinical Effects

Summary Of Exposure

    A) USES: Disulfiram is used to treat alcoholism by causing adverse effects when ethanol is ingested.
    B) PHARMACOLOGY: Disulfiram blocks hepatic aldehyde dehydrogenase. Acetaldehyde, the major metabolite of ethanol by liver alcohol dehydrogenase, reaches high levels, causing many adverse effects. Disulfiram also impairs norepinephrine synthesis as its metabolite, diethyldithiocarbamate, inhibits dopamine beta-hydroxylase, the rate-limiting step in norepinephrine synthesis. Disulfiram also inhibits the liver cytochrome P450, CYP2E1.
    C) TOXICOLOGY: The disulfiram-ethanol reaction can be precipitated after exposure to ethanol by any route.
    D) EPIDEMIOLOGY: Disulfiram-ethanol reactions are common; most reactions are self-limiting, lasting several hours. Rarely, reactions are severe or life threatening.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Diaphoresis, cutaneous warmth, flushing, pruritus, nausea and vomiting, blurred vision, conjunctival injection, tachycardia, hypotension including orthostasis, hypertension, palpitations, chest pain, altered mentation, confusion, anxiety, somnolence, headache, anxiety, vertigo, tremor, bronchospasm, dyspnea, hyperventilation, respiratory depression.
    2) SEVERE TOXICITY: Severe vomiting, esophageal rupture, hypotension, tachydysrhythmias, myocardial infarction, sudden cardiac death, fulminant polyneuropathy, visual hallucinations, seizures, delirium, coma, respiratory depression.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, hypotension, and hypertension have been reported following concomitant use of ethanol and disulfiram.
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Hypertension has been reported following concomitant use of ethanol and disulfiram (Park & Riggio, 2001; Zapata & Orwin, 1992; Volicer & Nelson, 1984; Dalessio, 1968).
    2) Hypotension has been reported following concomitant use of ethanol and disulfiram (Ho et al, 2007; Prod Info ANTABUSE(R) oral tablets, 2006; Harry et al, 1998; vonKrogh et al, 2002).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Tachycardia has been reported with concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Ho et al, 2007; Heath et al, 1992; Harry et al, 1998; vonKrogh et al, 2002).

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Blurred vision and conjunctival injection have been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Phillips, 1987).
    2) CASE REPORT: Miosis occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has been reported following concomitant use of ethanol and disulfiram (Ho et al, 2007; Prod Info ANTABUSE(R) oral tablets, 2006; Srinivasan et al, 1986; Heath et al, 1992; Harry et al, 1998; vonKrogh et al, 2002).
    b) CASE REPORT: A 48-year-old man underwent a disulfiram-ethanol test, a week after starting disulfiram 250 mg twice daily, in his physician's office, and immediately developed atrial fibrillation and non-sustained ventricular tachycardia of 7 to 8 beats/min. Biochemical analysis revealed hypokalemia of 2.9 mEq/L, which may have helped to precipitate the dysrhythmias. The patient recovered with lidocaine administration and potassium supplementation (Savas & Gullu, 1997; Savas, 1997)
    c) CASE REPORT: A 50-year-old woman with a history of type I bipolar disorder and alcohol dependence presented with a 3 to 4 day history of delirium (deficits in orientation, concentration, and visual hallucinations) after drinking at least 2 glasses of wine and alcoholic fruit punch while taking 250 mg/day of disulfiram (taken for 3 months prior to admission). Physical examination revealed tachycardia (123 beats/min) and nonfocal neurologic signs. Extensive metabolic, infectious, and endocrine work-up showed no abnormalities (Park & Riggio, 2001a).
    d) A dose-response study (n=52 healthy non-alcoholic volunteers) reported that 200 mg or less of disulfiram and 0.15 g of ethanol/kg body weight caused a fall of the diastolic blood pressure of 20 or more mm Hg in 31 volunteers and an increase in the heart rate of 20 or more beats/min in 40 volunteers (Fuller & Gordis, 2004).
    e) CASE REPORT: Tachycardia (126 beats/min) occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986).
    f) CASE REPORT/SOLVENTS: A 46-year-old artist, taking disulfiram for treatment of alcoholism, reported nausea, palpitations, left-sided chest discomfort, and fatiguability of the upper extremities following occupational exposure to artist products containing organic solvents (ie, dichloromethane, toluene, xylene, acetone, hexane) and an alcohol (ie, ethanol, methanol, isopropyl alcohol). Six weeks after adhering to strict precautions against inhalation and dermal exposure, including the use of disposable gloves, long sleeves, regular hand washing, ventilation of the artist's studio, and use of a cartridge respirator while spray painting, the patient reported resolution of symptoms (Ehrlich et al, 2012).
    g) CASE REPORT: A 45-year-old industrial painter, with a 5-year history of alcoholism, developed vomiting, intense shivering, and altered mental status while painting; he received parenteral metoclopramide and paracetamol at his factory health center. Due to a subsequent drop in his blood pressure, he was transferred to the emergency department. At admission, he was delirious, dyspneic, febrile, and had diffuse erythema over his forearm and face. He was tachycardic (120 bpm) and hypotensive (60/40 mmHg). An ECG indicated sinus tachycardia with ST depression, and arterial blood gases revealed metabolic acidosis (pH 7.24). His blood pressure stabilized following administration of fluids and vasopressors. The patient's personal history revealed that disulfiram 100 mg daily was initiated 9 months before admission. Due to his occupation, he was exposed to a variety of solvents and alcohols without the use of any personal protective equipment. He was subsequently discharged with advice to use a cartridge respirator and wear gloves while painting (Senthilkumaran et al, 2013).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Dysrhythmias and sudden death have been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).
    b) CASE REPORT: A 48-year-old man underwent a disulfiram-ethanol test, a week after starting disulfiram 250 mg twice daily, in his physician's office, and immediately developed atrial fibrillation and non-sustained ventricular tachycardia of 7 to 8 beats/min. Biochemical analysis revealed hypokalemia of 2.9 mEq/L, which may have helped to precipitate the dysrhythmias. The patient recovered with lidocaine administration and potassium supplementation (Savas & Gullu, 1997; Savas, 1997).
    C) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension, including orthostatic hypotension has been reported following concomitant use of ethanol and disulfiram (Moreels et al, 2012; Ho et al, 2007; Prod Info ANTABUSE(R) oral tablets, 2006; Srinivasan et al, 1986; Harry et al, 1998; vonKrogh et al, 2002).
    b) Severe hypotension (60/40 mm Hg) and dysrhythmias occurred in a 48-year-old man following administration of a disulfiram-ethanol test performed under close medical supervision. The patient recovered with supportive care. Laboratory testing showed hypokalemia of 2.9 mEq/L, which also may have contributed to his reaction (Savas & Gullu, 1997; Savas, 1997).
    c) A dose-response study (n=52 healthy non-alcoholic volunteers) reported that 200 mg or less of disulfiram and 0.15 g of ethanol/kg body weight caused a fall of the diastolic blood pressure of 20 or more mm Hg in 31 volunteers and an increase in the heart rate of 20 or more beats per minute in 40 volunteers (Fuller & Gordis, 2004).
    d) Severe cardiovascular collapse occurred in a 50-year-old man taking disulfiram 800 mg/day when he consumed a bottle of wine. The patient initially presented in cardiopulmonary arrest; administration of sodium bicarbonate and epinephrine restored the pulse, but severe hypotension persisted. Arterial hypotension and urinary output worsened despite maximal doses of dopamine, dobutamine, and fluid challenge. Norepinephrine was infused, resulting in rapid improvement in blood pressure, urinary output, and core temperature. Although cardiovascular status remained stable, the patient developed a pulmonary infection and remained in severe postanoxic coma, and expired 16 days later. The mechanism of hypotension induced by concomitant use of ethanol and disulfiram was thought to be vasodilation due to acetaldehyde accumulation. In addition, diethyldithiocarbamate, a metabolite of disulfiram, inhibits dopamine beta-hydroxylase, the rate-limiting step in norepinephrine synthesis; the resulting norepinephrine depletion would attenuate the adrenergic response to hypotension (Motte et al, 1986a).
    e) CASE REPORTS: Two patients with a history of alcohol abuse were being treated with disulfiram 500 mg/day. Both ingested ethanol while receiving treatment, and approximately 1/2 to 1 hour after the ethanol ingestion developed symptoms of vomiting, flushing, hypotension, and tachycardia. ECG revealed ST segment depression. Both patients were given fomepizole 7 mg/kg, and heart rate and blood pressure normalized within 45 minutes. ECG and all other symptoms normalized within 1 hour of fomepizole administration, with no adverse effects to treatment in either patient (Harry et al, 1998).
    f) CASE REPORT: A 42-year-old woman, who presented to the emergency department due to mental status changes and alcohol abuse after consuming a bottle of wine and 80 mg of prazepam, experienced a severe headache, nausea, and chest pain approximately 30 minutes after unintentionally ingesting 400 mg of disulfiram. She developed hypotension (60 mmHg systolic) and tachycardia (110 beats/min) , and an ECG demonstrated ST-segment depression. Her troponin I level increased to a peak of 2.47 mcg/L. With supportive care, including IV fluids and vasopressor administration, the patient recovered with normalization of her blood pressure and resolution of her ECG abnormalities and chest pain (Moreels et al, 2012).
    g) CASE REPORT: A 45-year-old industrial painter, with a 5-year history of alcoholism, developed vomiting, intense shivering, and altered mental status while painting; he received parenteral metoclopramide and paracetamol at his factory health center. Due to a subsequent drop in his blood pressure, he was transferred to the emergency department. At admission, he was delirious, dyspneic, febrile, and had diffuse erythema over his forearm and face. He was tachycardic (120 bpm) and hypotensive (60/40 mmHg). An ECG indicated sinus tachycardia with ST depression, and arterial blood gases revealed metabolic acidosis (pH 7.24). His blood pressure stabilized following administration of fluids and vasopressors. The patient's personal history revealed that disulfiram 100 mg daily was initiated 9 months before admission. Due to his occupation, he was exposed to a variety of solvents and alcohols without the use of any personal protective equipment. He was subsequently discharged with advice to use a cartridge respirator and wear gloves while painting (Senthilkumaran et al, 2013).
    D) CARDIAC ARREST
    1) WITH POISONING/EXPOSURE
    a) Cardiovascular collapse has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).
    b) Severe cardiovascular collapse occurred in a 50-year-old man taking disulfiram 800 mg/day when he consumed a bottle of wine. The patient initially presented in cardiopulmonary arrest; administration of sodium bicarbonate and epinephrine restored the pulse, but severe hypotension persisted. Arterial hypotension and urinary output worsened despite maximal doses of dopamine, dobutamine, and fluid challenge. Norepinephrine was infused, resulting in rapid improvement in blood pressure, urinary output, and core temperature. Although cardiovascular status remained stable, the patient developed a pulmonary infection and remained in severe postanoxic coma, and expired 16 days later. The mechanism of hypotension induced by concomitant use of ethanol and disulfiram was thought to be vasodilation due to acetaldehyde accumulation. In addition, diethyldithiocarbamate, a metabolite of disulfiram, inhibits dopamine beta-hydroxylase, the rate-limiting step in norepinephrine synthesis; the resulting norepinephrine depletion would attenuate the adrenergic response to hypotension (Motte et al, 1986a).
    E) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Chest pain has been reported following concomitant use of ethanol and disulfiram (Moreels et al, 2012; Prod Info ANTABUSE(R) oral tablets, 2006).
    b) CASE REPORT/SOLVENTS: A 46-year-old artist, taking disulfiram for treatment of alcoholism, reported nausea, palpitations, left-sided chest discomfort, and fatiguability of the upper extremities following occupational exposure to artist products containing organic solvents (ie, dichloromethane, toluene, xylene, acetone, hexane) and an alcohol (ie, ethanol, methanol, isopropyl alcohol). Six weeks after adhering to strict precautions against inhalation and dermal exposure, including the use of disposable gloves, long sleeves, regular hand washing, ventilation of the artist's studio, and use of a cartridge respirator while spray painting, the patient reported resolution of symptoms (Ehrlich et al, 2012).
    F) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Heath et al, 1992).
    G) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) Myocardial infarction has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).
    b) CASE REPORT: A 42-year-old woman, who presented to the emergency department due to mental status changes and alcohol abuse after consuming a bottle of wine and 80 mg of prazepam, experienced a severe headache, nausea, and chest pain approximately 30 minutes after unintentionally ingesting 400 mg of disulfiram. She developed hypotension (60 mmHg systolic) and tachycardia (110 beats/min) , and an ECG demonstrated ST-segment depression. Her troponin I level increased to a peak of 2.47 mcg/L. With supportive care, including IV fluids and vasopressor administration, the patient recovered with normalization of her blood pressure and resolution of her ECG abnormalities and chest pain (Moreels et al, 2012).
    H) CONGESTIVE HEART FAILURE
    1) WITH POISONING/EXPOSURE
    a) Acute congestive heart failure has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).
    I) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension has been reported following concomitant use of ethanol and disulfiram (Park & Riggio, 2001; Zapata & Orwin, 1992; Volicer & Nelson, 1984; Dalessio, 1968).
    b) CASE REPORT: A 59-year-old man with a history of alcohol abuse voluntarily received disulfiram 125 mg/day. Prior to disulfiram therapy, the patient's blood pressure was 124/74 mm Hg. After disulfiram therapy with concurrent abuse of alcohol in mouthwash and pre-shave lotion, the patient's blood pressure increased to 188/100 mm Hg. The disulfiram was discontinued and the patient's blood pressure decreased (Volicer & Nelson, 1984).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) BRONCHOSPASM
    1) WITH POISONING/EXPOSURE
    a) Bronchospasm has been reported following concomitant use of ethanol and disulfiram (Park & Riggio, 2001; Zapata & Orwin, 1992; Dalessio, 1968).
    B) DYSPNEA
    1) WITH POISONING/EXPOSURE
    a) Dyspnea has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Savas & Gullu, 1997; Savas, 1997).
    C) HYPERVENTILATION
    1) WITH POISONING/EXPOSURE
    a) Hyperventilation has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).
    D) DECREASED RESPIRATORY FUNCTION
    1) WITH POISONING/EXPOSURE
    a) Respiratory depression has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DELIRIUM
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 50-year-old woman with a history of type I bipolar disorder and alcohol dependence presented with a 3 to 4 day history of delirium (deficits in orientation, concentration, and visual hallucinations) after drinking at least 2 glasses of wine and alcoholic fruit punch while taking 250 mg/day of disulfiram (taken for 3 months prior to admission). Physical examination revealed tachycardia (123 BPM) and nonfocal neurologic signs. Extensive metabolic, infectious, and endocrine work-up showed no abnormalities (Park & Riggio, 2001a).
    b) CASE REPORT: A 45-year-old industrial painter, with a 5-year history of alcoholism, developed vomiting, intense shivering, and altered mental status while painting; he received parenteral metoclopramide and paracetamol at his factory health center. Due to a subsequent drop in his blood pressure, he was transferred to the emergency department. At admission, he was delirious, dyspneic, febrile, and had diffuse erythema over his forearm and face. He was tachycardic (120 bpm) and hypotensive (60/40 mmHg). An ECG indicated sinus tachycardia with ST depression, and arterial blood gases revealed metabolic acidosis (pH 7.24). His blood pressure stabilized following administration of fluids and vasopressors. The patient's personal history revealed that disulfiram 100 mg daily was initiated 9 months before admission. Due to his occupation, he was exposed to a variety of solvents and alcohols without the use of any personal protective equipment. He was subsequently discharged with advice to use a cartridge respirator and wear gloves while painting (Senthilkumaran et al, 2013).
    B) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Dystonia, akinesia, hypophonia, and slowness and shuffling of the gait were reported in a 30-year-old woman after a suicide attempt with approximately 20 g disulfiram along with ethanol. Computed tomography and magnetic resonance scans revealed hypodense lesions of the pallidum and putamen. Treatment with levodopa 1000 mg/day ameliorated the akinesia, but caused severe oromandibular hyperkinesis and blepharospasm. Bromocriptine and lisuride were not helpful, nor were biperiden or amantadine. The etiology of these symptoms was unclear, but were thought to be due to either hypoperfusion of the basal ganglia during the reaction of disulfiram and ethanol, or to neurotoxicity from accumulation of carbon disulfide (Krauss et al, 1991).
    C) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures have been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Heath et al, 1992).
    b) 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. Fifty percent of the cases (n=11) were not associated with the disulfiram-ethanol reaction (McConchie et al, 1983).
    c) CASE REPORT: Generalized seizures occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986).
    D) NEUROPATHY
    1) WITH POISONING/EXPOSURE
    a) Fulminant polyneuropathy following disulfiram-ethanol ingestion may be irreversible in some cases (Rothrock et al, 1984).
    E) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Throbbing headache has been reported following concomitant use of ethanol and disulfiram. Throbbing head and neck pain have also been reported (Moreels et al, 2012; Prod Info ANTABUSE(R) oral tablets, 2006; Park & Riggio, 2001; Zapata & Orwin, 1992; Phillips, 1987; Srinivasan et al, 1986; Dalessio, 1968).
    F) ANXIETY
    1) WITH POISONING/EXPOSURE
    a) Anxiety has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Park & Riggio, 2001; Zapata & Orwin, 1992).
    G) VERTIGO
    1) WITH POISONING/EXPOSURE
    a) Vertigo has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Park & Riggio, 2001; Zapata & Orwin, 1992).
    H) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Confusion and somnolence have been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006; Park & Riggio, 2001; Savas & Gullu, 1997; Savas, 1997; Zapata & Orwin, 1992; Kirubakaran et al, 1986).
    I) COMA
    1) WITH POISONING/EXPOSURE
    a) Unconsciousness has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).
    b) CASE REPORT: Coma occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986).
    J) VISUAL HALLUCINATIONS
    1) WITH POISONING/EXPOSURE
    a) Visual hallucinations have been reported following concomitant use of ethanol and disulfiram (Park & Riggio, 2001; Zapata & Orwin, 1992; Dalessio, 1968).
    K) LIGHTHEADEDNESS
    1) WITH POISONING/EXPOSURE
    a) Light-headedness has been reported following concomitant use of ethanol and disulfiram (Phillips, 1987).
    b) CASE REPORT: Dizziness occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986).
    L) TREMOR
    1) WITH POISONING/EXPOSURE
    a) Tremor has been reported following concomitant use of ethanol and disulfiram (Ho et al, 2007; Savas & Gullu, 1997; Savas, 1997).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have been reported following concomitant use of ethanol and disulfiram (Moreels et al, 2012; Prod Info ANTABUSE(R) oral tablets, 2006; Park & Riggio, 2001; Harry et al, 1998; Savas & Gullu, 1997; Savas, 1997; Zapata & Orwin, 1992; Srinivasan et al, 1986).
    b) DISULFIRAM OVERDOSE WITH ETHANOL: Nausea and vomiting occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986; vonKrogh et al, 2002).
    c) CASE REPORT/SOLVENTS: A 46-year-old artist, taking disulfiram for treatment of alcoholism, reported nausea, palpitations, left-sided chest discomfort, and fatiguability of the upper extremities following occupational exposure to artist products containing organic solvents (ie, dichloromethane, toluene, xylene, acetone, hexane) and an alcohol (ie, ethanol, methanol, isopropyl alcohol). Six weeks after adhering to strict precautions against inhalation and dermal exposure, including the use of disposable gloves, long sleeves, regular hand washing, ventilation of the artist's studio, and use of a cartridge respirator while spray painting, the patient reported resolution of symptoms (Ehrlich et al, 2012).
    B) GASTROINTESTINAL PERFORATION
    1) WITH POISONING/EXPOSURE
    a) Esophageal rupture secondary to profound vomiting has been reported in patients following concomitant use of ethanol and disulfiram (Fernandez, 1972).
    b) CASE REPORT: One report describes a case of a 60-year-old man who had received one month of disulfiram therapy who consumed a large quantity of alcohol. Subsequently, the patient began to vomit violently and was hospitalized in a state of shock. Chest x-ray revealed a left-sided pneumothorax, pleural effusion, and mediastinal air. The patient died 30 minutes after hospitalization and autopsy revealed a large perforation of the esophagus with gastric content contamination of the mediastinal and pleural spaces (Fernandez, 1972).
    C) THIRST
    1) WITH POISONING/EXPOSURE
    a) Thirst has been reported following concomitant use of ethanol and disulfiram (Prod Info ANTABUSE(R) oral tablets, 2006).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) METHEMOGLOBINEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: After drinking 3 bottles of white wine, a 49-year-old recovering alcoholic treated with disulfiram was found dead in her car. Toxicologic analysis showed ethanol concentrations of 0.15 g/dL in blood, 0.26 g/dL in the vitreous humor, and 0.25 g/dL in the urine. Methemoglobin level was 52.8% (Stransky et al, 1997).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DERMATOLOGICAL FINDING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis, cutaneous warmth, flushing (face, chest wall), and pruritus have been reported following concomitant use of ethanol and disulfiram (Ho et al, 2007; Prod Info ANTABUSE(R) oral tablets, 2006; Park & Riggio, 2001; Savas & Gullu, 1997; Savas, 1997; Zapata & Orwin, 1992; Phillips, 1987; Srinivasan et al, 1986).
    b) CASE REPORT: Diaphoresis occurred in a man after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day) (Kirubakaran et al, 1986).
    c) CASE REPORT/SOLVENTS: A 46-year-old artist, taking disulfiram for treatment of alcoholism, reported nausea, flushing, and malaise within 20 minutes after a bottle of lacquer thinner, containing methanol, acetone, toluene, xylene, and isopropyl alcohol, splashed in his face. Symptoms persisted for a few days (Ehrlich et al, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and mental status.
    B) Disulfiram and/or acetaldehyde concentrations are of little clinical value and are not readily available. Serum ethanol concentrations may help to confirm exposure, but very low ethanol levels are occasionally associated with severe reactions.
    C) No specific lab work is needed in most patients. If diagnosis is unclear, or patient has significant vomiting or cardiac ectopy, check general labs including serum electrolytes and ECG.
    D) Obtain a CT scan of the chest with water soluble oral contrast to exclude esophageal perforation in patients with severe chest pain after vomiting.
    E) In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography) and ECG.
    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 levels to toxic effects have not been established. Levels may be useful to document exposure.
    2) ACETALDEHYDE - Blood levels of acetaldehyde are elevated during a disulfiram-ethanol reaction, but acetaldehyde levels are not generally available (Kuffner, 2006).
    3) BLOOD ETHANOL - Blood or breath ethanol concentration should be performed to assist in making the diagnosis of disulfiram ethanol interaction (Kuffner, 2006).
    a) Blood ethanol concentration may be useful in confirming the interaction, but very low ethanol levels are occasionally associated with severe reactions.

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 persistent or worsening gastrointestinal irritation, CNS agitation or depression, seizures, respiratory depression, or dysrhythmias should be admitted. Intensive care unit is indicated for aggressive airway and cardiac monitoring.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Accidental ingestions in asymptomatic patients who have no synergistic co-ingestions may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity (respiratory depression, progressive agitation, coma or dysrhythmias), or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with deliberate ingestions, synergistic co-ingestions, unclear history, symptomatic or intoxicated patients, or those in unstable social situations should be sent to a health care facility for observation.

Monitoring

    A) Monitor vital signs and mental status.
    B) Disulfiram and/or acetaldehyde concentrations are of little clinical value and are not readily available. Serum ethanol concentrations may help to confirm exposure, but very low ethanol levels are occasionally associated with severe reactions.
    C) No specific lab work is needed in most patients. If diagnosis is unclear, or patient has significant vomiting or cardiac ectopy, check general labs including serum electrolytes and ECG.
    D) Obtain a CT scan of the chest with water soluble oral contrast to exclude esophageal perforation in patients with severe chest pain after vomiting.
    E) In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography) and ECG.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Vomiting typically occurs as part of the disulfiram-like reaction, thus induction of vomiting is generally unnecessary. Activated charcoal has limited usefulness due to the rapid systemic absorption of ethanol, the poor absorption of ethanol to the activated charcoal, and possible aspiration due to spontaneous vomiting.
    6.5.2) PREVENTION OF ABSORPTION
    A) Vomiting typically occurs as part of the disulfiram-like reaction, thus induction of vomiting or orogastric lavage is generally unnecessary. Activated charcoal has limited usefulness due to the rapid systemic absorption of ethanol, the poor absorption of ethanol to the activated charcoal, and possible aspiration due to spontaneous vomiting.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment of the disulfiram-ethanol reaction is mainly symptomatic and supportive; no specific FDA approved antidote for disulfiram-ethanol reaction is commercially available. Fomepizole (15 mg/kg IV) has been used to treat disulfiram-ethanol reactions, and should be considered in severe reactions refractory to standard treatments.
    B) MONITORING OF PATIENT
    1) Monitor vital signs and mental status.
    2) Disulfiram and/or acetaldehyde concentrations are of little clinical value and are not readily available. Serum ethanol concentrations may help to confirm exposure, but very low ethanol levels are occasionally associated with severe reactions.
    3) No specific lab work is needed in most patients. If diagnosis is unclear, or patient has significant vomiting or cardiac ectopy, check general labs including serum electrolytes and ECG.
    4) Obtain a CT scan of the chest with water soluble oral contrast to exclude esophageal perforation in patients with severe chest pain after vomiting.
    5) In those with worsening symptoms or known large ingestions, closely monitor airway, breathing, circulation, cardiac ectopy via continuous cardiac monitoring (including pulse oximetry, capnography) and ECG.
    C) 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).
    D) HYPOTENSIVE EPISODE
    1) Postural repositioning with the patient supine may be used to combat effects of vasodilation. Consider use of both H1 and H2 antagonists to reverse possible histamine-induced vasodilation resulting in hypotension.
    2) Norepinephrine is a more logical choice than dopamine, since dopamine acts partially by releasing endogenous norepinephrine stores, which may be depleted by disulfiram. Disulfiram blocks dopamine beta-hydroxylase, which becomes rate-limiting in norepinephrine synthesis. Severe hypotension was reported to be resistant to dopamine in one patient but responded dramatically to high-dose norepinephrine infusion (2 mcg/kg/min) (Motte et al, 1986).
    a) A man developed disulfiram-ethanol reaction (generalized flushing, tremor, tachycardia, and hypotension 85/43 mm Hg) after drinking half a bottle of whisky 18 hours after disulfiram treatment. Fluid resuscitations and dopamine infusion failed to correct the unstable hemodynamics. However, norepinephrine caused a return of blood pressure to 125/68 mm Hg (Ho et al, 2007).
    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).
    E) 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).
    F) EXPERIMENTAL THERAPY
    1) FOMEPIZOLE
    a) Fomepizole (4-Methylpyrazole) is a FDA approved drug for treatment of methanol or ethylene glycol overdose(Prod Info ANTIZOL(R) IV injection, 2006), and has been used to treat the disulfiram-ethanol reaction, although it is not currently approved for this indication. Fomepizole prevents the metabolism of ethanol to acetaldehyde by inhibiting alcohol dehydrogenase (Kuffner, 2006; Lindros et al, 1981). The acetaldehyde levels dropped markedly, and symptoms decreased in one reported case (Anon, 1981), the benefits of this drug for a disulfiram-ethanol reaction resulting in hypotension appear limited.
    b) Fomepizole should be considered in patients with life-threatening signs or symptoms of a disulfiram-ethanol reaction and who are unresponsive to standard treatments.
    c) CASE REPORT - A 31-year-old man ingested 20 g disulfiram after drinking 330 g of ethanol over the previous 12 hours. Four hours later, the patient was vomiting, hypotensive (99/44 mm Hg), and tachycardic (100 beats/min). Initial treatment included activated charcoal, promethazine, and fluids. The patient's symptoms persisted, and at 10 hours post-ingestion, 1000 mg fomepizole was administered. The patient became more alert and stable approximately 1.5 hours after fomepizole administration. Two more doses of fomepizole (700 mg each) were given in the following 24 hours, and the patient made a full recovery with no sequelae at a 4 month follow-up (vonKrogh et al, 2002).
    d) CASE REPORTS - Two patients with a history of alcohol abuse were being treated with disulfiram 500 mg/day. Both ingested ethanol while receiving treatment, and approximately 1/2 to 1 hour after the ethanol ingestion developed symptoms of vomiting, flushing, hypotension, and tachycardia. ECG revealed ST segment depression. Both patients were given fomepizole 7 mg/kg, and heart rate and blood pressure normalized within 45 minutes. ECG and all other symptoms normalized within 1 hour of fomepizole administration, with no adverse effects to treatment in either patient (Harry et al, 1998).
    e) ADVERSE EFFECTS
    1) Adverse effects are generally mild and transient. Fomepizole, dosed at 10 and 20 mg/kg, caused no side effects in 8 adult males. Three of 4 subjects dosed with 50 mg/kg experienced mild nausea and dizziness within 2 hours of dosing. All subjects dosed at 100 mg/kg experienced nausea, dizziness, and vertigo that lasted up to 30 hours after dosing. No changes in vital signs or blood or urine chemistries were noted in any of the subjects (Jacobsen et al, 1988).
    2) In a study of 22 patients who received doses of 600 to 8650 mg, the following adverse effects were noted: Pain on injection (n=2); abdominal pain (n=1); skin rash (n=1); nausea (n=1); headache (n=1) (Baud et al, 1992).

Enhanced Elimination

    A) SUMMARY
    1) Disulfiram is not cleared by hemodialysis or hemoperfusion, however ethanol is, so it might be beneficial in severe reaction, but is rarely, if ever, indicated. Fomepizole would generally be preferred in these cases, as it is less invasive.

Abstracts

Case Reports

    A) ADULT
    1) A 43-year-old man developed nausea and vomiting, weakness, dizziness, somnolence, diaphoresis, miosis, generalized seizures, and coma after ingesting disulfiram (eleven 250 mg tablets one day before admission and 5 more the next day, several hours before admission) with ethanol (a pint/day). His vital signs on presentation were: respirations 16 breaths/min and shallow; pulse 126 beats/min; blood pressure 132/92 mm Hg; temperature 35 degrees Celsius. He also developed slight hypokalemia (3.1 mEq/L), fever (38 degrees Celsius), leukocytosis (WBC 14,800 cells/mm(3) with a left-shift), and increased serum amylase and serum glutamic oxaloacetic transaminase (SGOT) (208 Units/mL and 71 Units/mL, respectively). Following supportive care, he regained consciousness on the third hospital day (Kirubakaran et al, 1986).
    2) In a pilot study of two alcoholic volunteers, alcohol challenges (0.15 g/kg) before treatment with a single subcutaneous dose of disulfiram (1 g or 2 g) performed on days 7, 14, 21, and 28 resulted in persistent and statistically significant changes in the subjective and objective responses to alcohol in posttreatment period. One patient (1 g disulfiram) developed only diaphoresis on day 7; however, the other patient (2 g disulfiram) developed headache, dizziness, flushing, conjunctival injection, and blurring of vision (Phillips, 1987).

Range Of Toxicity

Summary

    A) Dose response is variable. In general, mild reactions may occur with as little as 5 to 10 mg disulfiram/100 mL ethanol. More dramatic reactions predicted after exposure to 50 mg disulfiram/100 mL ethanol, and severe reactions at 125 to 150 mg disulfiram/100 mL ethanol (Prod Info ANTABUSE(R) oral tablets, 2006). Ingestions as little as 7 mL of ethanol have been associated with death.

Minimum Lethal Exposure

    A) Deaths have been reported following the ingestion of ethanol and disulfiram doses of 1 to 3 grams (Fuller & Gordis, 2004).
    B) Death has been reported following a test dose of 15 mL of ethanol in a patient taking disulfiram (Becker & Sugarman, 1952).

Maximum Tolerated Exposure

    A) The severity of the reaction correlates poorly with the amount of ethanol ingested; as little as 7 mL of ethanol has produced mild reactions (Frank & Lovejoy, 1984); reactions have occurred following use of cough syrups, after-shave lotions, ethanol-based rubbing compounds, and fermented vinegar.
    B) Disulfiram doses of 500 mg, 1000 mg, and 1500 mg inhibit aldehyde dehydrogenase for up to 4 days, 6 days, and 8 days, respectively (Kuffner, 2006).
    C) One study reported that 250 to 500 mg of disulfiram are insufficient to cause a disulfiram-ethanol reaction in some patients. However, a dose-response study (n=52 healthy non-alcoholic volunteers) reported that 200 mg or less of disulfiram and 0.15 g of ethanol/kg body weight caused a fall of the diastolic blood pressure of 20 or more mm Hg in 31 volunteers and an increase in the heart rate of 20 or more beats/min in 40 volunteers (Fuller & Gordis, 2004).
    D) In a retrospective review of charts of 61 alcoholics, 60 patients on 500 mg/day of disulfiram developed a positive response (flushing, tachycardia, headache, nausea, a slight fall in blood pressure) when exposed to alcohol. Forty-five patients experienced a positive response to the first challenge dose of alcohol (12 mL of ethanol [30 mL of whisky]); however, 15 patients needed a second dose. A moderate to severe reaction developed in 6 patients (hypotension in 5 patients; Mallory-Weiss syndrome in 1 patient) requiring medical intervention (Srinivasan et al, 1986).

Serum Plasma Blood Concentrations

    7.5.1) THERAPEUTIC CONCENTRATIONS
    A) THERAPEUTIC CONCENTRATION LEVELS
    1) DISULFIRAM - Blood disulfiram levels in patients taking the drug therapeutically are generally 2 to 10 micrograms/milliliter (Reichelderfer, 1969).
    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) Disulfiram and/or acetaldehyde levels are of little clinical value. Ethanol levels may be useful to confirm the interaction but may not accurately reflect the duration or severity of the reaction (Kuffner, 2006).
    2) Intensity and duration depend on dosage of disulfiram, amount of alcohol ingested, and individual difference in response (Prod Info ANTABUSE(R) oral tablets, 2006; Lundwall, 1971). The following blood alcohol levels and reactions have been reported: mild reactions in a sensitive individual with as little as 5 to 10 mg/100 mL; fully developed symptoms with 50 mg/100 mL; unconsciousness with levels reaching 125-150 mg/100 mL(Prod Info ANTABUSE(R) oral tablets, 2006).
    3) ACETALDEHYDE LEVELS - Studies have reported that acetaldehyde levels in blood are usually lower than 1 mcg/mL in non-alcoholic subjects after moderate amounts of ethanol. However, a wide range (1 to 7 mcg/mL) has been reported. In at least 25 patients, acetaldehyde levels in blood increased 5 to 10 fold in the presence of disulfiram after ethanol ingestion (vanIeperen, 1984).
    4) A 24-year-old man treated with disulfiram was found dead after ingesting half a bottle of brandy. A post-mortem blood sample from the left femoral vein showed the following levels: ethanol, 0.39 g/dL; acetaldehyde level 0.01 g/dL (2270 mcmol/L) (vanIeperen, 1984).
    5) An adult man 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).
    6) After drinking 3 bottles of white wine, a 49-year-old recovering alcoholic treated with disulfiram was found dead in her car. Toxicologic analysis showed ethanol concentrations of 0.15 g/dL in blood, 0.26 g/dL in the vitreous humor, and 0.25 g/dL in the urine. Methemoglobin level was 52.8% (Stransky et al, 1997).
    7) OVERDOSE PLUS DISULFIRAM-ETHANOL REACTION: Plasma levels of disulfiram and its metabolites in a man 18 hours after admission for disulfiram overdose (eleven 250 mg tablets on one day and 5 more the next day) with ethanol (a pint/day) were: disulfiram 0 mcg/mL; diethyldithiocarbamate 0.76 mcg/mL, diethyldithiocarbamate methylester 0.26 mcg/mL, carbon disulfide 36.6 mcg/mL, diethylamine 324 mcg/mL. His blood ethanol level was 76 mg/dL. In a study of 15 sober alcoholic volunteers, without liver or renal disease, given 250 mg/day of disulfiram for 11 days, the following mean plasma levels of disulfiram and metabolites were obtained: disulfiram 0.41 mcg/mL (+/-SD 0.03); diethyldithiocarbamate 1.14 mcg/mL (+/-SD 0.07), diethyldithiocarbamate methylester 1.22 mcg/mL (+/-SD 0.13), carbon disulfide 24 mcg/mL (+/-SD 1.16), diethylamine 3.8 mcg/mL (+/-SD 0.28) (Kirubakaran et al, 1986).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Ethanol is primarily metabolized to acetaldehyde by liver alcohol dehydrogenase. Acetaldehyde is metabolized further to acetate by liver aldehyde dehydrogenase. Disulfiram is a thiuram derivative and inhibits liver aldehyde dehydrogenase, blocking the conversion of ethanol-derived acetaldehyde to acetate, and subsequent high levels of acetaldehyde occur after ethanol consumption. High acetaldehyde is responsible for many symptoms produced by the disulfiram-ethanol reaction. In addition, acetaldehyde may increase histamine release, responsible for some of the effects of the disulfiram-ethanol reaction (Prod Info ANTABUSE(R) oral tablets, 2006; AMA Department of Drugs, 1991; Kitson, 1977; Sauter et al, 1977).
    B) Intensity and duration of disulfiram-ethanol reaction depend on dosage of disulfiram, amount of alcohol ingested, and individual difference in response (Lundwall, 1971).
    C) Disulfiram also inhibits the liver microsomal cytochrome P450 enzyme, CYP2E1. CYP2E1 is responsible for the oxidative conversion of acetaminophen to N-acetyl-p-benzoquinone imine (NAPQI), which, in high concentrations, causes liver necrosis (Manyike et al, 2000).
    D) Diethyldithiocarbamate, a metabolite of disulfiram, inhibits dopamine beta-hydroxylase, the rate-limiting step in norepinephrine synthesis. The resulting norepinephrine depletion can attenuate the adrenergic response to hypotension (Motte et al, 1986).

References

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