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 blocks dopamine β-hydroxylase and limits synthesis of norepinephrine from dopamine:
- Relative excess of dopamine may contribute to altered behavior
- Relative depletion of norepinephrine may contribute to hypotension
Disulfiram metabolite (carbon disulfide) interacts with pyridoxal 5-phosphate:
- Diminishes concentration of pyridoxine available for formation of γ-aminobutyric acid (GABA) in CNS
- Potentially lowers seizure threshold
- Carbon 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:
  - Metronidazole
  - Cephalosporins (with nMTT side chain)
    - Cefoperazone, Cefotetan, Cefmetazole
  - Nitrofurantoin
- Oral hypoglycemics:
  - Sulfonylureas
- Industrial agents:
  - Carbon disulfide
  - Hydrogen sulfide
- Mushrooms:
  - Coprinus atramentarius
  - Clitocybe clavipes

Diagnosis

Signs and Symptoms

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

History
Ingestion of disulfiram or agents listed above may provide essential clues to diagnosis �
Physical Exam

Vital signs:
- Hypotensive, tachycardic, tachypneic
Cardiovascular:
- Tachycardia, arrhythmias
Pulmonary:
- Pulmonary edema, dyspnea
Abdominal:
- Diffuse abdominal pain, nausea, vomiting
Skin:
- Flushed, diaphoretic
Neurologic:
- Dysphoria, confusion, signs of cerebellar dysfunction, seizures

Essential Workup

Suspect disulfiram-ethanol reaction with the following: �

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/seizure
- Basal 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 necessary
- Supplemental oxygen
- Mechanical ventilation as needed
- Resuscitation 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 depression
  - Caution if vomiting (potential for aspiration)
  - Do not intubate solely to give activated charcoal
- Gastric lavage is unnecessary
- Whole-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 enzyme
  - Not indicated for routine disulfiram-ethanol reactions or mild disulfiram overdose
  - May improve the hemodynamic profile in moderate to severe overdoses
Hemodialysis:
- Consider after massive ingestion of disulfiram and ethanol with refractory hypotension
- No 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 μg/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 reactions
- Abstain 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 alcohol
- Includes: 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 �H, Loft �S, Andersen �JR, et al. Disulfiram therapy-adverse drug reactions and interactions. Acta Psychiatr Scand Suppl. 1992;369:59-65.
Kuffner �EK. Chapter 79. Disulfiram and disulfiram-like reactions. In: Hoffman �RS, Nelson �LS, Goldfrank �LR, Howland �MA, Lewin �NA, Flomenbaum �NE, eds. Goldfranks Toxicologic Emergencies. 9th ed. New York, NY: McGraw-Hill; 2011.
Leikin �J, Paloucek �F. Disulfiram. Poisoning and Toxicology Handbook. Hudson, OH: Lexi-Comp; 2002;502-503.
Park �CW, Riggio �S. Disulfiram-ethanol induced delirium. Ann Pharmacother. 2001;35:32-35.
Sande �M, Thompson �D, Monte �AA. Fomepizole for severe disulfiram-ethanol reactions. Am J Emerg Med. 2012;30(1):262.e3-e5.

Codes

ICD9

977.3 Poisoning by alcohol deterrents �

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)

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