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Disulfiram Reaction, Emergency Medicine

Basics

Description

- Inhibits various enzymes and its active metabolites exert additional effects. - Disulfiram-ethanol reaction: - Usually occurs 8-12 hr after taking the drug; should not be observed >24 hr after dosing - Competitively and irreversibly inactivates aldehyde dehydrogenase - Ethanol metabolism is blocked, resulting in accumulation of acetaldehyde - Acetaldehyde produces release of histamine resulting in vasodilation and hypotension - Severe reactions may occur in drinkers with ethanol levels of 50-100 mg/dL - Severity and duration of reaction is proportional to amount of ethanol ingested

- Disulfiram metabolite (carbon disulfide) interacts with pyridoxal 5-phosphate: - Diminishes concentration of pyridoxine available for formation of Оі-aminobutyric acid (GABA) in CNS - Potentially lowers seizure threshold - Carbon disulfide is also cardiotoxic, hepatotoxic, and inhibits cytochrome P-450 (CYP2E1)

- Disulfiram is used as a deterrent in the treatment of chronic ethanol abuse - Many users of the medication wear a medical alert bracelet - Other agents producing disulfiram-like reactions: - Antibiotics: - Metronidazole - Cephalosporins (with nMTT side chain) - Cefoperazone, Cefotetan, Cefmetazole

- Oral hypoglycemics: - Industrial agents: - Carbon disulfide - Hydrogen sulfide

- Mushrooms: - Coprinus atramentarius - Clitocybe clavipes

- Disulfiram-ethanol reaction: - Hypotension, tachycardia, tachypnea - Flushing of face, neck, torso - Pruritus, diaphoresis, sensation of warmth - Nausea, vomiting, abdominal pain, diarrhea - Headache, ataxia, confusion, anxiety, dizziness - Dyspnea, pulmonary edema, chest pain, dysrhythmias, myocardial infarction

- Disulfiram overdose: - Symptoms rare with <3 g ingested - 10-30 g may be lethal - May mimic shock and/or sepsis - Tachycardia, hypotension, tachypnea - Abdominal pain, diarrhea, garlic, or rotten-egg breath - Agitation, irritability, ataxia - Dysarthria, hallucinations - Lethargy, coma, seizures, flaccidity - Parkinsonism

- ABCs: - Airway protection if necessary - Supplemental oxygen - Mechanical ventilation as needed - Resuscitation with 0.9% NS IV for hypotension

- Gastric lavage is unnecessary - Whole-bowel irrigation is not indicated

  • Inhibits various enzymes and its active metabolites exert additional effects.
  • Disulfiram-ethanol reaction:Usually occurs 8-12 hr after taking the drug; should not be observed >24 hr after dosingCompetitively and irreversibly inactivates aldehyde dehydrogenaseEthanol metabolism is blocked, resulting in accumulation of acetaldehydeAcetaldehyde produces release of histamine resulting in vasodilation and hypotensionSevere reactions may occur in drinkers with ethanol levels of 50-100 mg/dLSeverity and duration of reaction is proportional to amount of ethanol ingested
  • Disulfiram blocks dopamine β-hydroxylase and limits synthesis of norepinephrine from dopamine:Relative excess of dopamine may contribute to altered behaviorRelative depletion of norepinephrine may contribute to hypotension
  • Disulfiram metabolite (carbon disulfide) interacts with pyridoxal 5-phosphate:Diminishes concentration of pyridoxine available for formation of Оі-aminobutyric acid (GABA) in CNSPotentially lowers seizure thresholdCarbon disulfide is also cardiotoxic, hepatotoxic, and inhibits cytochrome P-450 (CYP2E1)
  • Disulfiram metabolites may chelate important metals (copper, zinc, iron) essential in various enzyme systems
  • Disulfiram metabolites may cause peripheral neuropathies that are dose and duration dependent

Etiology

  • Disulfiram is used as a deterrent in the treatment of chronic ethanol abuse
  • Many users of the medication wear a medical alert bracelet
  • Other agents producing disulfiram-like reactions:Antibiotics:MetronidazoleCephalosporins (with nMTT side chain)Cefoperazone, Cefotetan, CefmetazoleNitrofurantoinOral hypoglycemics:Industrial agents:Carbon disulfideHydrogen sulfideMushrooms:Coprinus atramentariusClitocybe clavipes

Diagnosis

Signs and Symptoms

  • Disulfiram-ethanol reaction:Hypotension, tachycardia, tachypneaFlushing of face, neck, torsoPruritus, diaphoresis, sensation of warmthNausea, vomiting, abdominal pain, diarrheaHeadache, ataxia, confusion, anxiety, dizzinessDyspnea, pulmonary edema, chest pain, dysrhythmias, myocardial infarction
  • Disulfiram overdose:Symptoms rare with <3 g ingested10-30 g may be lethalMay mimic shock and/or sepsisTachycardia, hypotension, tachypneaAbdominal pain, diarrhea, garlic, or rotten-egg breathAgitation, irritability, ataxiaDysarthria, hallucinationsLethargy, coma, seizures, flaccidityParkinsonism

History

Ingestion of disulfiram or agents listed above may provide essential clues to diagnosis пїЅ

Physical Exam

  • Vital signs:Hypotensive, tachycardic, tachypneic
  • Cardiovascular:
  • Pulmonary:
  • Abdominal:Diffuse abdominal pain, nausea, vomiting
  • Skin:
  • Neurologic:Dysphoria, confusion, signs of cerebellar dysfunction, seizures

Essential Workup

Suspect disulfiram-ethanol reaction with the following: пїЅ

  • Typical signs and symptoms are present
  • Treatment for chronic ethanol abuse in conjunction with recent ethanol ingestion, or exposure to ethanol-containing foods or medications, including mouthwash

Diagnosis Tests & Interpretation

Lab

  • Ethanol level
  • Electrolytes, BUN, creatinine, and glucose
  • Liver function tests if hepatitis is suspected
  • Creatine phosphokinase (CPK) if considering rhabdomyolysis in light of seizures or agitation
  • Urinalysis (myoglobin)
  • Serum levels of offending agent are NOT clinically useful

Imaging

  • ECG to assess cardiac ischemia or dysrhythmia
  • CT scan or MRI:Indicated with altered mental status/seizureBasal ganglia ischemia and infarction have been reported
  • EEG:Diffuse slowing without focal abnormalities has been seen in cases of acute toxicity with coma

Differential Diagnosis

  • Sepsis
  • Meningitis, encephalitis
  • Cardiogenic shock secondary to acute coronary syndrome
  • Anaphylactoid/anaphylactic reaction
  • Gastroenteritis/pancreatitis with dehydration
  • Ethanol withdrawal
  • Acute poisonings yield mainly severe CNS toxicity
  • Ataxia, weakness, lethargy, seizures
  • Reye syndrome-like encephalopathy in severe cases
  • Adult symptoms may also be present

Treatment

Pre-Hospital

  • ABCs, IV access
  • Begin resuscitation with IVF if no signs or symptoms of pulmonary edema
  • Rapid glucose determination (Accu-Chek)

Initial Stabilization/Therapy

  • ABCs:Airway protection if necessarySupplemental oxygenMechanical ventilation as neededResuscitation with 0.9% NS IV for hypotension
  • Pressor support with norepinephrine for refractory hypotension

Ed Treatment/Procedures

  • Management is primarily supportive with aggressive, appropriate care:No specific antidote available
  • GI decontamination:Activated charcoal in cases of disulfiram overdose:Caution if mental status depressionCaution if vomiting (potential for aspiration)Do not intubate solely to give activated charcoalGastric lavage is unnecessaryWhole-bowel irrigation is not indicated
  • Alleviation of flushing:Antihistamines (H1 and H2 antagonists)Prostaglandin inhibitors (indomethacin, ketorolac)
  • Antiemetics for intractable vomiting (ondansetron, metoclopramide)
  • Seizures:Benzodiazepines (diazepam, lorazepam)Pyridoxine (vitamin B6)4-methylpyrazole:Inhibits ethanol metabolism at alcohol dehydrogenase enzymeNot indicated for routine disulfiram-ethanol reactions or mild disulfiram overdoseMay improve the hemodynamic profile in moderate to severe overdoses
  • Hemodialysis:Consider after massive ingestion of disulfiram and ethanol with refractory hypotensionNo studies documenting beneficial effect

Medication

  • Diazepam: 5-10 mg (peds: 0.2-0.5 mg/kg) IV
  • Diphenhydramine: 25-50 mg (peds: 1-2 mg/kg) IV
  • Indomethacin: 50 mg PO (peds: 0.6 mg/kg PO for age >14 yr)
  • Lorazepam: 2-6 mg (peds: 0.03-0.05 mg/kg) IV
  • Metoclopramide: 10 mg (peds: 1-2 mg/kg) IV
  • Norepinephrine: 4 mL in 1,000 mL of D5W, infused at 0.1-0.2 Ојg/kg/min
  • Ondansetron: 4 mg (peds: 0.1 mg/kg for >2 yr old) IV
  • Pyridoxine: 1 g (peds: 500 mg) IV, repeat PRN

Follow-Up

Disposition

Admission Criteria

  • ICU admission for mechanical ventilation, coma, refractory hypotension requiring pressors, cardiac ischemia, refractory seizures, and severe agitation
  • Persistent vomiting, abdominal pain, or flushing
  • Elderly patients or those who have pre-existing cardiac disease

Discharge Criteria

  • Mild reactions that resolve with supportive care after observation period of 8-12 hr:Symptoms may recur on rechallenge with ethanol up to 7-10 days after last dose of disulfiram or agents that cause disulfiram-like reactionsAbstain from ethanol use until at least 2 wk after last dose of such agents
  • Appropriate follow-up needed to assess development of hepatic or neurologic sequelae

Follow-Up Recommendations

  • Psychiatry follow-up for intentional overdose with disulfiram
  • Detox follow-up for patients with disulfiram-ethanol reactions

Pearls and Pitfalls

  • Educate patients who are prescribed medications with potential for disulfiram-like reactions to avoid ALL alcoholIncludes: Mouthwash, alcohol-based hand gels, alcohol-based aftershaves, some cough syrups, and elixir-based liquid medications
  • Recommend abstinence for 3 days longer than the course of treatment to ensure low likelihood of reaction

Additional Reading

  • Enghusen Poulsen пїЅH, Loft пїЅS, Andersen пїЅJR, et al. Disulfiram therapy-adverse drug reactions and interactions. Acta Psychiatr Scand Suppl. 1992;369:59-65.
  • Kuffner пїЅEK. Chapter 79. Disulfiram and disulfiram-like reactions. In: Hoffman пїЅRS, Nelson пїЅLS, Goldfrank пїЅLR, Howland пїЅMA, Lewin пїЅNA, Flomenbaum пїЅNE, eds. Goldfranks Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011.
  • Leikin пїЅJ, Paloucek пїЅF. Disulfiram. Poisoning and Toxicology Handbook. Hudson, OH: Lexi-Comp; 2002;502-503.
  • Park пїЅCW, Riggio пїЅS. Disulfiram-ethanol induced delirium. Ann Pharmacother. 2001;35:32-35.
  • Sande пїЅM, Thompson пїЅD, Monte пїЅAA. Fomepizole for severe disulfiram-ethanol reactions. Am J Emerg Med. 2012;30(1):262.e3-e5.

See Also (Topic, Algorithm, Electronic Media Element)

Alcohol Poisoning пїЅ

Codes

ICD9

977.3 Poisoning by alcohol deterrents пїЅ

ICD10

  • T50.6X1A Poisoning by antidotes and chelating agents, acc, init
  • T50.6X4A Poisoning by antidotes and chelating agents, undet, init
  • T50.6X5A Adverse effect of antidotes and chelating agents, initial encounter

SNOMED

  • 292417007 Disulfiram adverse reaction (disorder)
  • 293960001 Disulfiram allergy (disorder)
  • 278025004 Antabuse poisoning (disorder)