Disulfiram


Article Author:
Maranda Stokes


Article Editor:
Sara Abdijadid


Editors In Chief:
Steven Anderson


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
4/10/2019 12:36:46 PM

Indications

Disulfiram is one of three drugs approved by the FDA for treatment of alcohol dependence. It is a second-line option (acamprosate and naltrexone are first-line treatments) in patients with sufficient physician supervision. Disulfiram is safe and efficient in supervised short-term and long-term treatment of individuals dependant on alcohol but who are motivated to discontinue alcohol use. Current studies for use in treating patients with comorbid alcohol dependence with post-traumatic stress disorder, alcohol and cocaine dependence, and cocaine dependence alone are underway.[1][2][3]

Recent studies of disulfiram as a proteasome inhibitor and DNA demethylating agent show promise for new potential therapeutic uses for malignancy and fungal infections. Disulfiram may have a primary or adjuvant role in the treatment of drug-resistant fungal infections (particular candida) and malignancy by inhibiting ABC drug transport protein responsible for resistance. Evidence shows metabolites of disulfiram induce p53, mediating apoptosis and cell death. Investigations of the role of disulfiram as an anti-cancer agent are ongoing.

Mechanism of Action

Disulfiram is converted to an active metabolite, diethyldithiocarbamate, in the stomach. In the blood, it is converted to diethyldithiocarbamic acid (DDC), which is degraded to form diethylamine and carbon disulfide. DDC undergoes phase II metabolism forming sulfoxide and sulfone metabolites. These S-oxidized compounds are potent active metabolites producing the effects of disulfiram.[4][5][6]

Alcohol Dependence

Disulfiram irreversibly inhibits aldehyde dehydrogenase (ALDH1A1) by competing with nicotinamide adenine dinucleotide (NAD) at the cysteine residue in the active site of the enzyme. ALDH1A1 is a hepatic enzyme of the major oxidative pathway of alcohol metabolism converting ethanol to acetaldehyde. At therapeutic doses of disulfiram, alcohol consumption results in increased serum acetaldehyde causing diaphoresis, palpitations, facial flushing, nausea, vertigo, hypotension, and tachycardia. This collection of symptoms is known as the disulfiram-alcohol reaction and discourages alcohol intake. The reaction is proportional to both the dose of disulfiram and alcohol. Disulfiram is not an anti-craving drug and does not modulate the neurobiological mechanism of addiction.

Cocaine Dependence

Disulfiram also inhibits dopamine beta-hydroxylase (DBH), an enzyme that converts dopamine to noradrenaline, causing an accumulation of dopamine. Increased dopamine corrects the underlying deficit in patients addicted to cocaine. Recent studies have shown reduced frequency and amount of cocaine use in patients treated with disulfiram.

Administration

Disulfiram is available only via oral administration. Tablets are available in 250 mg to 500 mg forms. Tablets may be crushed and mixed with liquids (water, coffee, milk, fruit juice) and should be taken once per day. Disulfiram should never be administered until patient abstained from alcohol for at least 12 hours. Patients should abstain from alcohol and alcohol-containing products for at least 14 days after discontinuing disulfiram as disulfiram-alcohol reactions have been reported within 2 weeks of discontinuation. There is no benefit to increasing dose of disulfiram to greater than 500 mg/day.

A trial of disulfiram and alcohol to produce a disulfiram-alcohol reaction is no longer recommended. The patient should be extensively educated on symptoms of disulfiram-alcohol reaction before administration.

Adverse Effects

Disulfiram has an acceptable risk profile. However, it is associated with many adverse events and drug-drug interactions, including death. Most common of less serious adverse effects include headache, sleepiness, tiredness, and halitosis (or metallic taste).[5][7][8][9]

Dermatological, neurological, psychiatric, and cardiac events have been reported. Serious side effects include hepatitis, hepatotoxicity, psychosis, seizures, peripheral neuropathy, and optic neuritis. Dermatological adverse effects are rare and include exfoliative dermatitis, rash, and pruritis. Hepatic failure may develop after many months of therapy. Cases of fatal fulminant hepatic failure have been reported despite discontinuation of medication (1 case in 30,000 patients treated per year). Psychiatric adverse effects are rare. Psychosis, confusional states, mutism, head banging, memory impairment, and rarely stupor have been reported, and effects are dose-dependent. Symptoms usually resolve after discontinuation of disulfiram and a short-course of anti-psychotic medication. Psychosis may occur as a result of an interaction between disulfiram and cannabis. Neurological adverse effects may occur as early as 10 days after initiation. Axonal polyneuropathy is a rare adverse effect. Some cases of severe sensory-motor polyneuropathy with the involvement of cranial nerves have been reported within weeks of initiation of disulfiram 500 mg. Neuropathy occurs in 1 case per 10,000 patients treated with disulfiram per year.

Drug interactions occur with compounds utilizing the cytochrome P450 enzyme system for oxidative metabolism. This has been demonstrated with the following medications: amitriptyline, imipramine, phenytoin, chlordiazepoxide, diazepam, omeprazole, and acetaminophen. Drug-drug interactions may occur with other medications not listed.

Slow elimination of disulfiram may give rise to the disulfiram-alcohol reaction up to fourteen days after the discontinuation. Disulfiram-alcohol reactions have been reported in patients exposed to environmental chemical compounds containing alcohol.

Contraindications

Disulfiram is not a safe option for everyone. Disulfiram is contraindicated absolutely in patients with significant coronary artery disease or heart failure. Cases of heart failure and death were reported in patients with the severe myocardial disease shortly after initiation of disulfiram. Disulfiram is contraindicated with psychosis as it may worsen patient's psychosis. Caution should be used in patients with a history of liver disease and risks versus benefits should be weighed by a physician. Patient's receiving metronidazole, paraldehyde, alcohol, or alcohol-containing preparations (sauces, cough mixtures, vinegar) should not receive disulfiram and should be educated in advance to avoid a disulfiram-alcohol reaction. Never administer to a patient if alcohol use is suspected or without patient's consent and understanding of disulfiram-alcohol reaction. Disulfiram may be used with caution in patients with seizures, diabetes, thyroid disorders, traumatic brain injury, and renal disease due to the possibility of an accidental disulfiram-alcohol reaction.

Monitoring

Close monitoring of adverse events is necessary, in particular, in patients with polysubstance abuse. Patients taking disulfiram should be monitored for signs and symptoms of hepatitis including fatigue, weakness, anorexia, nausea, vomiting, jaundice, malaise, and dark urine. Baseline and follow-up liver function tests should be monitored ten days to one month following initiation of disulfiram. Complete blood count and serum chemistries should also be routinely monitored.

Toxicity

Contact local Poison Control Center in case of overdose. No information available on the treatment of disulfiram overdose and there is no antidote available. Supportive care via supplemental oxygen, cardiac monitoring, and intravenous fluids may be necessary. Consult a physician if symptoms are severe. Cases of ingestion equal to or greater than 5 gm, resulted in parkinsonism, choreoathetosis, and thalamic syndrome. Doses should not exceed 500 mg/day for treatment of alcohol dependence, and doses for malignancy have not been determined.

Enhancing Healthcare Team Outcomes

Dulsulfiram may be prescribed by the nurse practitioner, primary care provider, emergecy department physician or the internist. However, all healthcare workers including the pharmacist must be familiar with its adverse effect profile. The agent is not well tolerated and when consumed with alcohol can produce severe side effects that can even lead to a heart attack. Today, this drug is not used to treat alcoholism because it is not deemed to be safe.[10]


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Disulfiram - Questions

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When an alcoholic is administered disulfiram, what is the toxic byproduct that causes the nausea and vomiting?



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Which of the following agents would not be expected to cause nausea, vomiting, flushing, dizziness, headache, and abdominal discomfort after the consumption of alcohol?



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Which one of the following sulfonylureas should not be administered to treat an alcoholic's Type 2 diabetes?



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Which is not a characteristic adverse effect of alcohol intake with disulfiram?



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A patient is prescribed disulfiram. Which of the following is not a feature of alcohol intake with disulfiram?



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What is the effect of disulfiram?



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When combined with sulfonylurea, which of the following causes disulfiram-like reactions?



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Which is least likely to occur if a person taking disulfiram consumes alcohol?



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Which diabetic medication when combined with alcohol can cause symptoms similar to a disulfiram-alcohol reaction?



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Which of the following will cause nausea and vomiting if a person drinks alcohol?



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Which is a sedative drug that can interact with disulfiram?



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To prevent acetaldehyde syndrome, the drug disulfiram should not be administered to patients who have consumed alcohol within what period of time?



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A patient has come to pick up his prescription for metronidazole to treat his diverticulitis. He says that he would also like to pay for his diphenhydramine elixir, that contains alcohol, along with his prescription. What should he be told?



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A middle-aged patient with alcoholism comes to the emergency department with numerous complaints. He was at a company party a few hours ago and suddenly developed flushing, headache, vomiting, profuse sweating, blurred vision, and confusion. The only thing he remembers is taking an antibiotic a few hours before going to the party. Which of the following may be responsible for his symptoms?



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A heavily inebriated student is brought into the emergency department. He was out partying all night and fell through a plate glass store window while roughhousing with some friends. He presents with several deep lacerations, and antibiotic therapy is indicated. Which of the following would be a poor choice because it could cause a disulfiram-like reaction with ethanol that could lead to pulmonary or cardiac failure?



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Which of the following medications will produce a powerful adverse effect if alcohol is used while the patient is taking the medication?



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Disulfiram - References

References

Butler K,Le Foll B, Impact of Substance Use Disorder Pharmacotherapy on Executive Function: A Narrative Review. Frontiers in psychiatry. 2019;     [PubMed]
Williams JB, Use of Disulfiram for Treatment of Alcohol Addiction in Patients With Psychotic Illness. The American journal of psychiatry. 2019 Jan 1;     [PubMed]
Warren D, Prescription Drug and Alcohol Use Disorders: Alcohol Use Disorder. FP essentials. 2019 Mar;     [PubMed]
Budworth L,Prestwich A,Lawton R,Kotzé A,Kellar I, Preoperative Interventions for Alcohol and Other Recreational Substance Use: A Systematic Review and Meta-Analysis. Frontiers in psychology. 2019;     [PubMed]
Williams EC,Matson TE,Harris AHS, Strategies to increase implementation of pharmacotherapy for alcohol use disorders: a structured review of care delivery and implementation interventions. Addiction science     [PubMed]
Heldal AT,Skurtveit S,Lobmaier PPK,Vederhus JK,Bramness JG, Use of drugs for alcohol use disorder in Norway 2004–16. Tidsskrift for den Norske laegeforening : tidsskrift for praktisk medicin, ny raekke. 2018 Nov 13;     [PubMed]
Kranzler HR,Soyka M, Diagnosis and Pharmacotherapy of Alcohol Use Disorder: A Review. JAMA. 2018 Aug 28;     [PubMed]
Blanco-Gandía MC,Rodríguez-Arias M, Pharmacological treatments for opiate and alcohol addiction: A historical perspective of the last 50 years. European journal of pharmacology. 2018 Oct 5;     [PubMed]
Guerzoni S,Pellesi L,Pini LA,Caputo F, Drug-drug interactions in the treatment for alcohol use disorders: A comprehensive review. Pharmacological research. 2018 Jul;     [PubMed]
Antonelli M,Ferrulli A,Sestito L,Vassallo GA,Tarli C,Mosoni C,Rando MM,Mirijello A,Gasbarrini A,Addolorato G, Alcohol addiction - the safety of available approved treatment options. Expert opinion on drug safety. 2018 Feb;     [PubMed]

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