Disulfiram is an antioxidant industrial chemical produced since 1881 for the vulcanization of rubber. It has been used in the United States since 1951 as a drug in the treatment of alcoholism. Ingestion of ethanol while taking disulfiram causes a well-defined unpleasant reaction, the fear of which provides a negative incentive to drink alcohol. Clinical toxicity is caused by overdose or occurs as a result of a disulfiram-ethanol drug interaction. Disulfiram is also being investigated for the treatment of cocaine addiction. The toxicities resulting from disulfiram overdose differ from those of disulfiram-ethanol interaction.

Is based on a history of acute ingestion and the presence of CNS symptoms with vomiting. The disulfiram-ethanol interaction is diagnosed in a patient with a history of disulfiram use and possible exposure to ethanol who exhibits a characteristic hypotensive flushing reaction.

1. Specific levels. A serum ethanol level may help predict the degree of a disulfiram-ethanol reaction and determine if fomepizole administration may be beneficial. Plasma disulfiram levels are not of value in diagnosis or treatment. Plasma acetaldehyde levels will be elevated during the disulfiram-ethanol reaction but this does not change clinical management and testing is not readily available.
2. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine and liver aminotransferases.

1. Disulfiram is rapidly metabolized to diethyldithiocarbamate which causes inhibition of two critical enzymes. It binds irreversibly to aldehyde dehydrogenase, leading to accumulation of toxic acetaldehyde after ethanol ingestion. Inhibition of dopamine beta-hydroxylase (necessary for norepinephrine synthesis from dopamine) results in norepinephrine depletion at presynaptic sympathetic nerve endings, leading to vasodilation and orthostatic hypotension. The resulting surplus of dopamine may potentiate psychosis and provides a theoretic basis for the use of disulfiram in treating cocaine dependence.
2. Diethyldithiocarbamate is further metabolized to carbon disulfide which may play a role in central and peripheral nervous system toxicity.
3. Disulfiram and its metabolites contain either sulfhydryl (S-H) or thiocarbonyl (C=S) moieties common to chelating agents. Chronic use may cause depletion of certain essential metals (copper, zinc). This may in part be the cause of the enzyme-inhibiting effects of disulfiram, as both of these enzymes require copper as a cofactor. Idiosyncratic fulminant hepatic failure or distal sensory-motor and optic neuropathy may also occur with chronic use.
4. Pharmacokinetics. Disulfiram is absorbed rapidly and completely, but because enzyme inhibition is the mechanism of action, peak effects may be delayed for 8-12 hours. Although the elimination half-life is 7-8 hours, clinical effects may persist for days because of high lipid solubility and slow enzyme resynthesis. Disulfiram is metabolized in the liver. It inhibits multiple cytochrome P450 enzymes, thus inhibiting the metabolism of many other drugs, including isoniazid, phenytoin, theophylline, warfarin, and many benzodiazepines.

1. Disulfiram overdose. A typical therapeutic dose of disulfiram is 250 mg/day. Ingestion of 2.5 g or more has caused toxicity in children after a delay of 3-12 hours.
2. Disulfiram-ethanol interaction. Ingestion of as little as 7 mL of ethanol can cause a severe reaction in patients taking as little as 200 mg of disulfiram per day. Mild reactions have been reported after use of cough syrup, aftershave lotions, and other alcohol-containing products.

1. Acute disulfiram overdose (without ethanol) is uncommon and exhibits primarily neurologic symptoms, with headache, ataxia, confusion, lethargy, seizures, and prolonged coma. Multiple authors report neuropathy and basal ganglia lesions. Neuropsychological impairment may be chronic. A garlic-like breath odor, vomiting, and hypotension have been reported with acute disulfiram overdose.
2. Disulfiram-ethanol interaction. The severity of the reaction usually depends on the doses of disulfiram and ethanol. Mild reactions (mild headache, facial flushing) may occur almost immediately after ethanol ingestion or at a plasma ethanol level of 10 mg/dL. Moderate reactions occur with ethanol levels of about 50 mg/dL and manifest with anxiety, nausea, tachycardia, hypotension, throbbing headache, and dyspnea. Severe reactions have resulted in coma and seizures as well as respiratory and cardiovascular failure and death. ECG findings of ischemia are well described. Reactions do not usually occur unless the patient has been on oral disulfiram therapy for at least 1 day; the reaction may occur up to 14 days after the last dose of disulfiram, as aldehyde dehydrogenase is resynthesized very slowly.

1. Emergency and supportive measures
   1. Acute disulfiram overdose
      1. Maintain an open airway and assist ventilation if necessary.
      2. Treat coma and seizures if they occur.
   2. Disulfiram-ethanol interaction
      1. Maintain an open airway and assist ventilation if necessary.
      2. Treat hypotension with supine position and IV fluids (eg, saline). If a pressor agent is needed, a direct-acting agent such as norepinephrine is preferred over indirect-acting drugs such as dopamine because neuronal norepinephrine stores are reduced.
      3. Administer benzodiazepine anxiolytics (eg, lorazepam) and reassurance as needed.
      4. Treat vomiting with a 5-HT₃ receptor antagonist or metoclopramide and headache with IV analgesics if needed. Avoid antiemetics (which have an alpha receptor-blocking effect) such as prochlorperazine.
      5. Histamine receptor antagonists may alleviate flushing.
2. Specific drugs and antidotes. Fomepizole inhibits alcohol dehydrogenase, and in the presence of ethanol will prevent additional formation of acetaldehyde. Case series support the use of fomepizole to rapidly reverse disulfiram-ethanol toxicity including the need for vasopressor support.
3. Decontamination
   1. Acute disulfiram overdose. Administer activated charcoal orally if conditions are appropriate (see Table I-37). Rapid drug absorption argues against gastric lavage except for ingestions both large and very recent.
   2. Disulfiram-ethanol interaction. Decontamination procedures are not likely to be of benefit once symptoms occur.
4. Enhanced elimination. Hemodialysis is not indicated for disulfiram overdose, but it may remove ethanol and acetaldehyde and has been reported to be effective in treating the acute disulfiram-ethanol interaction. It is unlikely to be necessary in patients receiving adequate fluid and pressor support.