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DISULFIRAM-LIKE REACTION

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Disulfiram-like reaction is used to describe symptoms that are similar in presentation to disulfiram-ethanol reaction. With disulfiram-like reactions, the patient has been exposed to an agent that can inhibit alcohol dehydrogenase and an alcohol (ie, ethanol, isopropyl alcohol, organic solvents). A wide variety of agents can cause a disulfiram-like reaction when administered with ethanol.

Specific Substances

    1) Antabuse reaction
    2) Antabuse-like reaction
    3) Alcohol intolerance
    4) Alcohol reaction
    5) Ethanol intolerance
    6) Disulfiram (reaction)

Available Forms Sources

    A) SOURCES
    1) Disulfiram-like reaction is used to describe symptoms that are similar in presentation to disulfiram-ethanol reaction. With disulfiram-like reactions, the patient has been exposed to an agent that can inhibit alcohol dehydrogenase and an alcohol (ie, ethanol, isopropyl alcohol, organic solvents). A wide variety of agents can cause a disulfiram-like reaction when administered with ethanol (Kuffner, 2006).
    2) Ethanol is often a hidden component of products and pharmaceuticals; some pharmaceuticals for intravenous administration are solubilized in up to 10% ethanol bases (Edwards et al, 1986). In diverse medicinal preparations, which include OTC and prescription, alcohol content may vary from less than 1% to 68%. Topical application of ethanol-containing products may cause a reaction (Kuffner, 2006).
    3) CAUSATIVE AGENTS
    a) The significance of drug-induced disulfiram-like reactions is described as: (1) CLINICALLY SIGNIFICANT (documented to cause the disulfiram reaction), (2) POSSIBLE (documented to cause a disulfiram-like reaction, but occurrence is rare), and (3) POTENTIAL (drugs and chemicals which inhibit aldehyde dehydrogenase to varying extents and may or may not cause a reaction). The following list may not be all inconclusive (Prod Info AMARYL(R) oral tablets, 2008; Jang & Harris, 2007; Barber et al, 2007; Kuffner, 2006; Berger & Guss, 2005; Tatro, 1988; Benjamin, 1995; Hansten, 1985; Kautz, 1960; Prod Info Tindamax(TM),, 2004; Edwards et al, 1986; Alexander, 1985; Neu, 1983; Abramowicz, 1983; Budmiger & Kochler, 1982; Foster et al, 1980; Buening et al, 1981; Reeves & Davies, 1980; Foster et al, 1980a; Neu & Prince, 1980; Portier et al, 1980; Boyd, 1960).
    b) ANTIMICROBIAL AGENTS
    1) Cephalosporins (clinically significant)
    a) Cefamandole (clinically significant)
    b) Cefoperazone (clinically significant)
    c) Cefotetan (clinically significant)
    d) Cefmenoxine (clinically significant)
    e) Moxalactam (clinically significant)
    2) Chloramphenicol (potential)
    3) Furazolidone (potential)
    4) Griseofulvin (possible)
    5) Ketoconazole (possible)
    6) Metronidazole (possible)
    7) Nitrofurantoin (potential)
    8) Quinacrine (potential)
    9) Sulfonamide (potential)
    10) Tinidazole
    11) Trimethoprim/sulfamethoxazole (potential)
    c) ANTIRETROVIRAL
    1) Abacavir (potential)
    d) MAO INHIBITORS
    1) Procarbazine (clinically significant)
    2) Pargyline (clinically significant)
    3) Tranylcypromine (clinically significant)
    e) SULFONYLUREAS
    1) Chlorpropamide (clinically significant)
    2) Tolbutamide (clinically significant)
    3) Glyburide (clinically significant)
    4) Glipizide (clinically significant)
    5) Tolazamide (clinically significant)
    6) Acetohexamide (clinically significant)
    f) MISCELLANEOUS
    1) Animal charcoal (possible)
    2) Calcium carbimide (possible)
    3) Chloral hydrate (potential)
    4) Isosorbide dinitrate (case reports)
    5) Nitroglycerin (case reports)
    6) Tacrolimus
    7) Tolazoline/Phentolamine (potential)
    g) MUSHROOMS
    1) Coprinus atramentarius (clinically significant)
    2) Coprinus insignis (clinically significant)
    3) Coprinus quadrifidus
    4) Coprinus variegatus
    5) Boletus luridus (possible)
    6) Clitocybe clavipes (clinically significant)
    7) Polyporus sulphureus
    8) Pholiota squarosa
    9) Tricholoma aurantum
    10) Verpa bohemica (possible)
    h) INDUSTRIAL CHEMICALS
    1) Bisethylxanthogen (unknown)
    2) Butanol oxime (clinically significant)
    3) N-butyraldoxine (potential)
    4) Calcium cyanamide (potential)
    5) Carbamide (potential)
    6) Carbamate fungicides (unknown)
    7) Carbamate herbicides (unknown)
    8) Carbon disulfide (potential)
    9) Carmofur (-1-Hexyl carbamoyl-5-fluorouracil) (possible)
    10) Demethylformaide (clinically significant)
    11) Diethylthiocarbamate (unknown)
    12) Ethylene dibromide (potential)
    13) Hydrogen sulfide (clinically significant)
    14) Irgopyrine (potential)
    15) Paraldehyde (potential)
    16) Phentolamide (potential)
    17) Tetraethyl lead (clinically significant)
    18) Tetramethylthiuram disulfide (clinically significant)
    19) Tetrachlorolethylene (clinically significant)
    20) Thiram analogs unknown)
    21) Thiuram derivatives (potential)
    22) Trichlorethylene (clinically significant)
    4) PREDISPOSING MEDICAL CONDITIONS
    a) FACIAL FLUSHING: Certain individuals have an inherent tendency to flush in the facial areas, particularly in response to alcohol, coffee, very cold or hot drinks, and highly spiced foods. In rosacea, the flush becomes permanent and marked, usually after the age of 40. Patients with rosacea display an intense erythema of the face and abdomen upon consumption of alcohol (Pillsbury & Heaton, 1980; Wilkin, 1980).

Overview

Life Support

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

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) DESCRIPTION: Disulfiram-like reaction is used to describe symptoms that are similar in presentation to disulfiram-ethanol reaction. With disulfiram-like reactions, the patient has been exposed to an agent that can inhibit alcohol dehydrogenase and an alcohol (ethanol, isopropyl alcohol, organic solvents). A wide variety of agents can cause a disulfiram-like reaction when administered with ethanol. Commonly implicated agents include the following: antimicrobial agents (eg, metronidazole, cephalosporins, nitrofurantoin, ketoconazole, sulfonamides, trimethoprim/sulfamethoxazole), antiviral agents (eg, abacavir), sulfonylureas (eg, glyburide, glipizide), MAO-inhibitors (eg, pargyline), various mushrooms (eg, Coprinus atramentarius, Clitocybe clavipes), and industrial chemicals (eg, trichloroethylene, tetraethyl lead, tetrachloroethylene, hydrogen sulfide, butanol oxime, dimethylformamide, tetramethylthiuram disulfide).
    B) PHARMACOLOGY: These agents or their metabolites inhibit aldehyde dehydrogenase and dopamine beta-hydroxylase.
    C) TOXICOLOGY: Toxicity occurs when aldehyde dehydrogenase is inhibited resulting in accumulation of acetaldehyde after ethanol ingestion. Inhibition of dopamine beta-hydroxylase results in norepinephrine depletion at presynaptic sympathetic nerve endings.
    D) EPIDEMIOLOGY: Disulfiram-like reactions are commonly described in the medical setting but are usually self-limited. Severe manifestations of toxicity are very rare. Reactions to these drugs are usually milder than the disulfiram-ethanol reaction.
    E) WITH POISONING/EXPOSURE
    1) ADVERSE EFFECTS: The disulfiram-like reaction occurs after exposure to the implicated substance along with ethanol or ethanol containing products and includes the following:
    a) MILD TO MODERATE TOXICITY: Diaphoresis, cutaneous warmth, flushing, pruritus, nausea and vomiting, blurred vision, conjunctival injection, tachycardia, hypotension, hypertension, palpitations, chest pain, altered mentation, confusion, anxiety, somnolence, headache, anxiety, vertigo, tremor, bronchospasm, dyspnea, and hyperventilation.
    b) SEVERE TOXICITY: Extremely rare, but could include profound hypotension, tachydysrhythmia, myocardial infarction, visual hallucinations, seizures, delirium, coma, respiratory depression, and sudden cardiac death.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Dysrhythmias, syncope, hypotension, hypertension, tachycardia, chest pain, and myocardial infarction have been reported with disulfiram-like reactions.
    0.2.7) NEUROLOGIC
    A) WITH POISONING/EXPOSURE
    1) Confusion, dizziness, headache, and weakness have been reported with disulfiram-like reaction.
    0.2.8) GASTROINTESTINAL
    A) WITH POISONING/EXPOSURE
    1) Abdominal pain and nausea/vomiting have been reported with disulfiram-like reaction.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Diaphoresis, cutaneous warmth, flushing, and pruritus have been reported with disulfiram-like reaction.

Laboratory Monitoring

    A) Monitor vital signs.
    B) Obtain an ECG and institute continuous cardiac monitoring in patients with chest pain or hypotension.
    C) In general, laboratory studies are not needed for patients with mild to moderate reactions. For patients with severe reactions, laboratory tests such as serum electrolytes, glucose, BUN, creatinine, lactate, liver function tests, ethanol concentration, and venous blood gas, may assist the provider in evaluating for other causes of the patients symptoms.
    D) Specific serum drug concentrations are difficult to obtain and no help in managing patients in the acute setting.

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 IV fluids and antiemetics; however, 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 pressor such as norepinephrine. For patients with life-threatening reactions not responding to supportive care, consider fomepizole to decrease production of acetaldehyde by inhibiting ethanol metabolism, or hemodialysis to remove ethanol, but such aggressive modalities are almost never needed.
    C) DECONTAMINATION
    1) GI decontamination is generally not warranted. These reactions are generally not recognized until absorption has occurred, and ethanol is not well adsorbed by charcoal.
    D) AIRWAY MANAGEMENT
    1) Administer 100% oxygen as needed for respiratory support. Intubate and provide assisted ventilation as necessary in patients with mental status depression.
    E) ANTIDOTE
    1) Fomepizole (4-Methylpyrazole) has been used to treat severe disulfiram reactions. It should be considered only in patients with severe toxicity not responding to supportive care. It decreases production of acetaldehyde by directly inhibiting alcohol dehydrogenase. Initial loading dose is 15 mg/kg followed by a maintenance dose of 10 mg/kg every 12 hours for 4 doses (48 hours). Then, increase the dose to 15 mg/kg because of auto-induction of alcohol dehydrogenase. Fomepizole may be discontinued when serum ethanol is below limits of detection.
    F) SEIZURE
    1) IV benzodiazepines; barbiturates or propofol if seizures recur or persist.
    G) HYPOTENSIVE EPISODE
    1) Keep patient supine, administer IV 0.9% NS 20 mL/kg, norepinephrine if hypotension persists.
    H) ENHANCED ELIMINATION PROCEDURE
    1) In rare patients with severe toxicity not responding to supportive care, dialysis could be used to clear serum ethanol, but this is rarely necessary.
    I) PATIENT DISPOSITION
    1) HOME MANAGEMENT: Patients may be observed at home for mild symptoms but should be evaluated for any concerning symptoms (confusion, lethargy, hypotension, or any signs of distress).
    2) OBSERVATION CRITERIA: Any patient who manifests persistent nausea and vomiting, flushing, headache, anxiety, vertigo, hypotension, confusion, seizure, or coma should be sent to a healthcare facility for observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged.
    3) ADMISSION CRITERIA: Patients with persistent or worsening symptoms despite treatment in the emergency department should be admitted to the appropriate level of care.
    4) CONSULT CRITERIA: Consult a medical toxicologist for patients with severe toxicity or on whom the diagnosis in unclear.
    J) PITFALLS
    1) Pitfalls include failure to recognize a disulfiram-like reaction, underestimation of clinical severity of symptoms or utilization of pharmaceutical agents containing ethanol during patient treatment. Patients are at risk of a reaction to ethanol for several days after the use of the implicated drug.
    K) TOXICOKINETICS
    1) The above agents produce acetaldehyde dehydrogenase inhibition. Only generation of new enzymes allows metabolism of acetaldehyde to continue. Ingestion of ethanol or ethanol containing products results in adverse reaction for as long as the serum acetaldehyde dehydrogenase activity is diminished, which may persist for several days after the implicated drug is consumed.
    L) DIFFERENTIAL DIAGNOSIS
    1) Allergic reaction and sepsis.

Range Of Toxicity

    A) When these drugs are used at therapeutic doses, reactions can occur after exposure to small amounts of ethanol. Reactions are usually relatively mild and severe toxicity is rare.

Clinical Effects

Heent

    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) BLURRED VISION: Blurred vision has been reported with disulfiram-like reaction (Kuffner, 2006).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Dysrhythmias, syncope, hypotension, hypertension, tachycardia, chest pain, and myocardial infarction have been reported with disulfiram-like reactions.
    3.5.2) CLINICAL EFFECTS
    A) TACHYCARDIA
    1) WITH POISONING/EXPOSURE
    a) Tachycardia has commonly been reported with disulfiram-like reaction (Barber et al, 2007; Kuffner, 2006; Heelon & White, 1998).
    b) FURAZOLIDONE: A disulfiram-like reaction may occur with the concurrent ingestion of ethanol and furazolidone, due to the inhibition of aldehyde dehydrogenase. Patients may experience flushing, palpitations, tachycardia, dyspnea, hyperventilation, nausea, and vomiting (USPDI , 2001; Tatro, 1988).
    B) LOW BLOOD PRESSURE
    1) WITH POISONING/EXPOSURE
    a) Hypotension has commonly been reported with disulfiram-like reaction (Kuffner, 2006; Alexander, 1985).
    b) METRONIDAZOLE: Case reports have described nausea, flushing, headache, dyspnea, and hypotension following inadvertent use of alcoholic beverages in patients receiving metronidazole (Alexander, 1985).
    C) HYPERTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypertension has rarely been reported with disulfiram-like reaction (Kuffner, 2006; Neu & Prince, 1980a).
    b) CASE REPORT: A 22-year-old woman became flushed, diaphoretic, felt faint, vomited, and had increased blood pressure (140/100 mmHg) after drinking a vodka cocktail while receiving intravenous moxalactam 2 g every eight hours for four days (Neu & Prince, 1980a).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) Dysrhythmias have been reported with disulfiram-like reaction (Kuffner, 2006).
    E) SYNCOPE
    1) WITH POISONING/EXPOSURE
    a) Syncope has been reported with disulfiram-like reaction (Kuffner, 2006).
    F) CHEST PAIN
    1) WITH POISONING/EXPOSURE
    a) Chest pain has been reported with disulfiram-like reaction (Kuffner, 2006).
    G) MYOCARDIAL INFARCTION
    1) WITH POISONING/EXPOSURE
    a) Myocardial infarction has been reported with disulfiram-like reaction (Kuffner, 2006).
    H) SUDDEN CARDIAC DEATH
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT (ORAL): There has been one case report of sudden death due to an interaction between metronidazole and ethanol. Postmortem serum ethanol level was 162 mg/dL, serum acetaldehyde level was 4.6 mg/dL (46 mg/L), and serum metronidazole level was 0.42 mg/L. An interaction between ethanol and metronidazole was suspected as the cause of death (Cina et al, 1996a).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY FINDING
    1) WITH POISONING/EXPOSURE
    a) Tachypnea has been reported with disulfiram-like reaction (Kuffner, 2006; Heelon & White, 1998; Penick et al, 1969; Tunguy-Desmarais, 1983; Alper et al, 1985; Plosker, 1987).
    b) FURAZOLIDONE: A disulfiram-like reaction may occur with the concurrent ingestion of ethanol and furazolidone, due to the inhibition of aldehyde dehydrogenase. Patients may experience flushing, palpitations, tachycardia, dyspnea, hyperventilation, nausea, and vomiting (Tatro, 1988; Hansten, 1985; Kautz, 1960).
    c) METRONIDAZOLE: Case reports have described nausea, flushing, headache, dyspnea, and hypotension following inadvertent use of alcoholic beverages in patients receiving metronidazole (Alexander, 1985).

Neurologic

    3.7.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Confusion, dizziness, headache, and weakness have been reported with disulfiram-like reaction.
    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH POISONING/EXPOSURE
    a) Headache has been reported with disulfiram-like reaction (Kuffner, 2006; Prod Info Tindamax(TM),, 2004; Neu & Prince, 1980a; Foster et al, 1980a).
    b) METRONIDAZOLE: Case reports have described nausea, flushing, headache, dyspnea, and hypotension following inadvertent use of alcoholic beverages in patients receiving metronidazole (Alexander, 1985).
    B) ASTHENIA
    1) WITH POISONING/EXPOSURE
    a) Asthenia has been reported with disulfiram-like reaction (Kuffner, 2006).
    C) CLOUDED CONSCIOUSNESS
    1) WITH POISONING/EXPOSURE
    a) Confusion has been reported with disulfiram-like reaction (Kuffner, 2006).
    D) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) Dizziness has been reported with disulfiram-like reaction (Kuffner, 2006; Neu & Prince, 1980a).

Gastrointestinal

    3.8.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Abdominal pain and nausea/vomiting have been reported with disulfiram-like reaction.
    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH POISONING/EXPOSURE
    a) Nausea and vomiting have been reported with disulfiram-like reaction (Barber et al, 2007; Kuffner, 2006; Prod Info Tindamax(TM),, 2004; Neu & Prince, 1980a; Neu & Prince, 1980a).
    b) METRONIDAZOLE: Case reports have described nausea, flushing, headache, dyspnea, and hypotension following inadvertent use of alcoholic beverages in patients receiving metronidazole (Alexander, 1985).
    c) FURAZOLIDONE: A disulfiram-like reaction may occur with the concurrent ingestion of ethanol and furazolidone, due to the inhibition of aldehyde dehydrogenase. Patients may experience flushing, palpitations, tachycardia, dyspnea, hyperventilation, nausea, and vomiting (Tatro, 1988; Hansten, 1985) .
    B) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) Abdominal pain has been reported with disulfiram-like reaction (Kuffner, 2006).
    b) TINIDAZOLE: Nausea, vomiting, abdominal cramps, headaches, and flushing may occur when ethanol is used during tinidazole therapy (Prod Info Tindamax(TM),, 2004).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Diaphoresis, cutaneous warmth, flushing, and pruritus have been reported with disulfiram-like reaction.
    3.14.2) CLINICAL EFFECTS
    A) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) Flushing (on the face and chest wall) has been reported with disulfiram-like reaction (Barber et al, 2007; Kuffner, 2006; Foster et al, 1980a; Neu & Prince, 1980a).
    b) Flushing has been reported with concurrent exposure to ethanol and the following agents: Furazolidone, metronidazole, tinidazole, abacavir, cefamandole (Barber et al, 2007; Prod Info Tindamax(TM),, 2004; Tatro, 1988; Alexander, 1985; Hansten, 1985; Portier et al, 1980a; Kautz, 1960).
    c) THIRAM: Dermal exposure to thiram in conjunction with ethanol ingestion may result in a disulfiram-like reaction, characterized by erythema, edema, and burning of the face and neck (Shelley, 1964).
    d) TOLAZOLINE: Concomitant ethanol and tolazoline therapy produces disulfiram reactions or ethanol intolerance, with symptoms such as tingling and flushing (Boyd, 1960).
    B) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Diaphoresis has been reported with disulfiram-like reaction (Kuffner, 2006; Foster et al, 1980a; Neu & Prince, 1980a).
    C) WARM SKIN
    1) WITH POISONING/EXPOSURE
    a) Cutaneous warmth has been reported with disulfiram-like reaction (Kuffner, 2006).
    D) ITCHING OF SKIN
    1) WITH POISONING/EXPOSURE
    a) Pruritus has been reported with disulfiram-like reaction (Kuffner, 2006; Boyd, 1960).
    E) ERUPTION
    1) WITH POISONING/EXPOSURE
    a) MOXALACTAM: A 16-year-old man received intravenous moxalactam 2 g every 8 hours for pneumonia. After 3 days of therapy, the patient became flushed and experienced nausea, headache, and a transient macular eruption on the face after drinking a can of beer (Neu & Prince, 1980a).

Summary Of Exposure

    A) DESCRIPTION: Disulfiram-like reaction is used to describe symptoms that are similar in presentation to disulfiram-ethanol reaction. With disulfiram-like reactions, the patient has been exposed to an agent that can inhibit alcohol dehydrogenase and an alcohol (ethanol, isopropyl alcohol, organic solvents). A wide variety of agents can cause a disulfiram-like reaction when administered with ethanol. Commonly implicated agents include the following: antimicrobial agents (eg, metronidazole, cephalosporins, nitrofurantoin, ketoconazole, sulfonamides, trimethoprim/sulfamethoxazole), antiviral agents (eg, abacavir), sulfonylureas (eg, glyburide, glipizide), MAO-inhibitors (eg, pargyline), various mushrooms (eg, Coprinus atramentarius, Clitocybe clavipes), and industrial chemicals (eg, trichloroethylene, tetraethyl lead, tetrachloroethylene, hydrogen sulfide, butanol oxime, dimethylformamide, tetramethylthiuram disulfide).
    B) PHARMACOLOGY: These agents or their metabolites inhibit aldehyde dehydrogenase and dopamine beta-hydroxylase.
    C) TOXICOLOGY: Toxicity occurs when aldehyde dehydrogenase is inhibited resulting in accumulation of acetaldehyde after ethanol ingestion. Inhibition of dopamine beta-hydroxylase results in norepinephrine depletion at presynaptic sympathetic nerve endings.
    D) EPIDEMIOLOGY: Disulfiram-like reactions are commonly described in the medical setting but are usually self-limited. Severe manifestations of toxicity are very rare. Reactions to these drugs are usually milder than the disulfiram-ethanol reaction.
    E) WITH POISONING/EXPOSURE
    1) ADVERSE EFFECTS: The disulfiram-like reaction occurs after exposure to the implicated substance along with ethanol or ethanol containing products and includes the following:
    a) MILD TO MODERATE TOXICITY: Diaphoresis, cutaneous warmth, flushing, pruritus, nausea and vomiting, blurred vision, conjunctival injection, tachycardia, hypotension, hypertension, palpitations, chest pain, altered mentation, confusion, anxiety, somnolence, headache, anxiety, vertigo, tremor, bronchospasm, dyspnea, and hyperventilation.
    b) SEVERE TOXICITY: Extremely rare, but could include profound hypotension, tachydysrhythmia, myocardial infarction, visual hallucinations, seizures, delirium, coma, respiratory depression, and sudden cardiac death.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs.
    B) Obtain an ECG and institute continuous cardiac monitoring in patients with chest pain or hypotension.
    C) In general, laboratory studies are not needed for patients with mild to moderate reactions. For patients with severe reactions, laboratory tests such as serum electrolytes, glucose, BUN, creatinine, lactate, liver function tests, ethanol concentration, and venous blood gas, may assist the provider in evaluating for other causes of the patients symptoms.
    D) Specific serum drug concentrations are difficult to obtain and no help in managing patients in the acute setting.

Treatment

Monitoring

    A) Monitor vital signs.
    B) Obtain an ECG and institute continuous cardiac monitoring in patients with chest pain or hypotension.
    C) In general, laboratory studies are not needed for patients with mild to moderate reactions. For patients with severe reactions, laboratory tests such as serum electrolytes, glucose, BUN, creatinine, lactate, liver function tests, ethanol concentration, and venous blood gas, may assist the provider in evaluating for other causes of the patients symptoms.
    D) Specific serum drug concentrations are difficult to obtain and no help in managing patients in the acute setting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI decontamination is generally not warranted. These reactions are generally not recognized until absorption has occurred, and ethanol is not well adsorbed by charcoal.
    6.5.2) PREVENTION OF ABSORPTION
    A) GI decontamination is generally not warranted. These reactions are generally not recognized until absorption has occurred, and ethanol is not well adsorbed by charcoal.
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs.
    2) Obtain an ECG and institute continuous cardiac monitoring in patients with chest pain or hypotension.
    3) In general, laboratory studies are not needed for patients with mild to moderate reactions. For patients with severe reactions, laboratory tests such as serum electrolytes, glucose, BUN, creatinine, lactate, liver function tests, ethanol level, and venous blood gas, may assist the provider in evaluating for other causes of the patients symptoms.
    4) Specific serum drug concentrations are difficult to obtain and no help in managing patients in the acute setting.
    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, 2009; 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 the patient supine may be used to combat effects of vasodilation. Administer IV 0.9% NaCl 10 to 20 mL/kg.
    2) If hypotension persists, administer a vasopressor. Norepinephrine is a more logical choice than dopamine, since dopamine acts partially by releasing endogenous norepinephrine stores. Severe hypotension as been reported to be resistant to dopamine but responded dramatically to norepinephrine infusion (2 mcg/kg/min) is some cases (Motte et al, 1986; 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).
    D) 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 severe disulfiram reactions. 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-like reaction resulting in hypotension appear limited.
    b) Fomepizole should be considered in patients with life-threatening signs or symptoms of a disulfiram-like reaction and who are unresponsive to standard treatments.
    2) ADVERSE EFFECTS
    a) 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).
    b) 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) In rare patients with severe toxicity not responding to supportive care, dialysis could be used to clear serum ethanol, but this is rarely necessary.

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 symptoms despite treatment in the emergency department should be admitted to the appropriate level of care.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Patients may be observed at home for mild symptoms but should be evaluated for any concerning symptoms (confusion, lethargy, hypotension, or any signs of distress).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for patients with severe toxicity or in whom the diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Any patient who manifests persistent nausea and vomiting, flushing, headache, anxiety, vertigo, hypotension, confusion, seizure, or coma should be sent to a healthcare facility for observation. If symptoms resolve in the emergency department and the home social situation permits, the patient may be discharged.

Abstracts

Case Reports

    A) ADULT
    1) CASE REPORT (ORAL): One study described the case of a 31-year-old woman who died after receiving metronidazole. Postmortem serum ethanol level was 162 mg/dL, serum acetaldehyde level was 4.6 mg/dL (46 mg/L), and serum metronidazole level was 0.42 mg/L. An interaction between ethanol and metronidazole was suspected as the cause of death (Cina et al, 1996).
    2) CASE REPORT: Disulfiram-like reaction or reduced alcohol tolerance have been reported in patients taking abacavir-containing antiretroviral regimens. One patient experienced disulfiram-like reaction (nausea, facial flushing, tachycardia) after ingesting alcohol one week after starting abacavir; his symptoms re-occurred on rechallenge. Two other patients who have been taking abacavir for 5 to 11 months experienced severe alcohol intolerance after ingesting alcohol. It is suggested that abacavir may also be an inhibitor of alcohol dehydrogenase which can increase the possibility of disulfiram-like reactions in patient using alcohol (Barber et al, 2007).

Range Of Toxicity

Summary

    A) When these drugs are used at therapeutic doses, reactions can occur after exposure to small amounts of ethanol. Reactions are usually relatively mild and severe toxicity is rare.

Minimum Lethal Exposure

    A) CASE REPORT (ORAL): One study described the case of a 31-year-old woman who died after receiving metronidazole. Postmortem serum ethanol level was 162 mg/dL, serum acetaldehyde level was 4.6 mg/dL (46 mg/L), and serum metronidazole level was 0.42 mg/L. An interaction between ethanol and metronidazole was suspected as the cause of death (Cina et al, 1996).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) These agents or their metabolites inhibit aldehyde dehydrogenase and dopamine beta-hydroxylase (Kuffner, 2006).

Toxicologic Mechanism

    A) Toxicity occurs when aldehyde dehydrogenase is inhibited resulting in accumulation of acetaldehyde after ethanol ingestion. Inhibition of dopamine beta-hydroxylase results in norepinephrine depletion at presynaptic sympathetic nerve endings (Kuffner, 2006).
    B) These agents produce an irreversible acetaldehyde dehydrogenase inhibition. Thus, only generation of new enzymes allows metabolism of acetaldehyde to continue. Ethanol ingestion will result in an adverse reaction for as long as the serum acetaldehyde dehydrogenase activity is diminished. This effect may be present for as long as 2 weeks after the last dose, depending on liver function. One week is a more typical duration of action with standard doses.

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
    2) Abramowicz M: Med Lett Drug Ther 1983; 25:58.
    3) Alexander I: 'Alcohol--antabuse' syndrome in patients receiving metronidazole during gynaecological treatment. Br J Clin Pract 1985; 39:292-293.
    4) Alper MM, Barwin BN, McLean WM, et al: Systemic absorption of metronidazole by the vaginal route. Obstet Gynecol 1985; 65:781-784.
    5) Anon: Chemical antidote aborts Antabuse-alcohol reaction. Med World News 1981; 22:28-33.
    6) Barber TJ, Marett B, Waldron S, et al: Are disulfiram-like reactions associated with abacavir-containing antiretroviral regimens in clinical practice?. AIDS 2007; 21(13):1823-1824.
    7) Baud FJ, Lambert C, & Bismuth C: Safety of oral or intra-venous 4 methyl-pyrazole (4 MP) in suspected ethylene-glycol (EG) intoxications (Abstract), In EAPCCT XV Congress, Istanbul, Turkey, 1992, pp 16.
    8) Benjamin DR: Mushrooms poisons and panaceas: A handbook for naturalists, mycologists and physicians, W. H. Freeman and Company, New York, NY, 1995.
    9) Berger KJ & Guss DA: Mycotoxins revisited: Part II. J Emerg Med 2005; 28(2):175-183.
    10) Boyd EM: A search for drugs with disulfiram-like activity. Q J Stud Alcohol 1960; 21:23.
    11) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    12) Budmiger H & Kochler F: Hexenrohrling (Boletus luridus) Mit Alcohol:Ein Kaslitischer Beitrag. Schweiz Med Wsch 1982; 112:1179-1181.
    13) Buening MK, Wold JS, Israel KS, et al: Disulfiram-like reaction to beta-lactams (letter). JAMA 1981; 245:2027.
    14) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    15) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
    16) Choonara IA & Rane A: Therapeutic drug monitoring of anticonvulsants state of the art. Clin Pharmacokinet 1990; 18:318-328.
    17) Cina SJ, Russell RA, & Conradi SE: Sudden death due to metronidazole/ethanol interaction. Am J Foren Med Pathol 1996; 17:343-346.
    18) Cina SJ, Russell RA, & Conradi SE: Sudden death due to metronidazole/ethanol interaction. Am J Forensic Med Pathol 1996a; 17:343-346.
    19) Edwards DL, Fink PC, & Van Dyke PO: Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole. Clin Pharm 1986; 5:999-1000.
    20) Foster TS, Raehl CL, & Wilson HD: Disulfiram-like reaction associated with a parenteral cephalosporin. Am J Hosp Pharm 1980; 37:858-859.
    21) Foster TS, Raehl CL, & Wilson HD: Disulfiram-like reaction associated with a parenteral cephalosporin. Am J Hosp Pharm 1980a; 37:858-859.
    22) Hansten PD: Drug Interactions, 5th ed, Lea & Febiger, Philadelphia, PA, 1985.
    23) Heelon MW & White M: Disulfiram-cotrimoxazole reaction. Pharmacother 1998; 18:869-870.
    24) Hegenbarth MA & American Academy of Pediatrics Committee on Drugs: Preparing for pediatric emergencies: drugs to consider. Pediatrics 2008; 121(2):433-443.
    25) Ho MP, Yo CH, Liu CM, et al: Refractive hypotension in a patient with disulfiram-ethanol reaction. Am J Med Sci 2007; 333(1):53-55.
    26) Hvidberg EF & Dam M: Clinical pharmacokinetics of anticonvulsants. Clin Pharmacokinet 1976; 1:161.
    27) Jacobsen D, Sebastian S, & Blomstrand R: 4-methylpyrazole: a controlled study of safety in healthy human subjects after single, ascending doses. Alcoholism 1988; 4:516-522.
    28) Jang GR & Harris RZ: Drug interactions involving ethanol and alcoholic beverages. Expert Opin Drug Metab Toxicol 2007; 3(5):719-731.
    29) Kautz HD: New and unofficial drugs. J Am Med Assoc 1960; 172:1932.
    30) Kleinman ME, Chameides L, Schexnayder SM, et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Part 14: pediatric advanced life support. Circulation 2010; 122(18 Suppl.3):S876-S908.
    31) Kuffner EK: Disulfiram and disulfiramlike reactions. In: Flomenbaum NE, Goldfrank LR, Hoffman RS, et al , eds. Goldfrank's Toxicologic Emergencies. 8th ed., 8th ed. Mcgraw-Hill, New York, NY, 2006, pp 1176-1183.
    32) Lindros KO, Stowell A, & Pikkarainen P: The disulfiram (antabuse)-alcohol reaction in male alcoholics: Its efficient management by 4-methylpyrazole. Alcoholism: Clin Exp Res 1981; 5:528-530.
    33) Loddenkemper T & Goodkin HP: Treatment of Pediatric Status Epilepticus. Curr Treat Options Neurol 2011; Epub:Epub.
    34) Manno EM: New management strategies in the treatment of status epilepticus. Mayo Clin Proc 2003; 78(4):508-518.
    35) Motte S, Vincent J, & Gillet J: Refractory hyperdynamic shock associated with alcohol and disulfiram. Am J Emerg Med 1986; 4:323-325.
    36) Neu HC & Prince AS: Interaction between moxalactam and alcohol (letter). Lancet 1980a; 1:1422.
    37) Neu HC & Prince AS: Interaction between moxalactam and alcohol. Lancet 1980; 1:1422.
    38) Neu HC: Adverse effects of new cephalosporins. Ann Intern Med 1983; 98:415.
    39) Peberdy MA , Callaway CW , Neumar RW , et al: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care science. Part 9: post–cardiac arrest care. Circulation 2010; 122(18 Suppl 3):S768-S786.
    40) Penick SB, Carrier RN, & Sheldon JB: Metronidazole in the treatment of alcoholism. Am J Psychiatry 1969; 125:1063-1066.
    41) Pillsbury D & Heaton C: A Manual of Dermatology, 2nd ed, WB Saunders Co, Philadelphia, PA, 1980.
    42) Plosker GL: Possible interaction between ethanol and vaginally administered metronidazole. Clin Pharm 1987; 6:192-193.
    43) Portier H, Chalopin JM, & Fresyz M: Interaction between cephalosporins and alcohol. Lancet 1980; 2:263.
    44) Portier H, Chalopin JM, Freysz M, et al: Interaction between cephalosporins and alcohol. Lancet 1980a; 2:263.
    45) Product Information: AMARYL(R) oral tablets, glimepiride oral tablets. Sanofi-Aventis U.S. LLC, Bridgewater, NJ, 2008.
    46) Product Information: ANTIZOL(R) IV injection, fomepizole IV injection. Jazz Pharmaceuticals,Inc, Palo Alto, CA, 2006.
    47) Product Information: Tindamax(TM),, tinidazole,. Mikart, Inc.,, Atlanta,, GA, 2004.
    48) Product Information: diazepam IM, IV injection, diazepam IM, IV injection. Hospira, Inc (per Manufacturer), Lake Forest, IL, 2008.
    49) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    50) Product Information: norepinephrine bitartrate injection, norepinephrine bitartrate injection. Sicor Pharmaceuticals,Inc, Irvine, CA, 2005.
    51) Reeves DS & Davies AJ: Antabuse effect with cephalosporins. Lancet 1980; 2:540.
    52) Scott R, Besag FMC, & Neville BGR: Buccal midazolam and rectal diazepam for treatment of prolonged seizures in childhood and adolescence: a randomized trial. Lancet 1999; 353:623-626.
    53) Shelley WB: Golf-course dermatitis due to thiram fungicide - cross hazards of alcohol, disulfiram, and rubber. JAMA 1964; 188:415-417.
    54) Sreenath TG, Gupta P, Sharma KK, et al: Lorazepam versus diazepam-phenytoin combination in the treatment of convulsive status epilepticus in children: A randomized controlled trial. Eur J Paediatr Neurol 2009; Epub:Epub.
    55) Tatro DS: Drug Interaction Facts, JB Lippincott Co, St Louis, MO, 1988.
    56) Tunguy-Desmarais GP: Interaction between alcohol and metronidazole (letter). S Afr Med J 1983; 63:836.
    57) USPDI : Drug Information for the Health Care Professional (Internet Version). US Pharmacopeial Convention, Inc. Rockville, MD (Internet Version). Edition expires 2001; provided by Truven Health Analytics Inc., Greenwood Village, CO.
    58) Wilkin J: Epigastric rosacea. Arch Dermatol 1980; 116:584.