Disulfiram

Products

Disulfiram is commercially available in the form of water-suspendable tablets called dispersible tablets (Antabus). It has been approved in many countries since 1949.

Structure and properties

Disulfiram or tetraethylthiuram disulfide (C10H20N2S4, Mr = 296.54 g/mol) is a white to almost white crystalline powder that is practically insoluble in water. Prior to its medical use, it was used in the vulcanization of rubber in the manufacture of rubber as early as the 19th century. In the process, it was discovered in 1937 that it caused factory workers to be intolerant to alcoholic beverages. In 1949 it was approved as a drug in many countries. Among other things, it is biotransformed to the active metabolite diethylthiocarbamate.

Effects

Disulfiram (ATC N07BB01) selectively blocks acetaldehyde dehydrogenase in the liver. After ingestion of alcohol, the concentration of acetaldehyde increases. This leads to the typical antabuse-alcohol interaction after approximately 5 to 30 minutes:

The symptoms subside after 1-3 hours. Complications include severe reactions with marked vasodilatation, circulatory collapse, pallor, weakness, visual disturbances, dizziness, disorientation, nausea, vomiting, heart failure, myocardial infarction, cardiac arrhythmias, impaired consciousness, epileptic seizures and death. The extent of symptoms depends on the amount of alcohol ingested and the disulfiram dose.

Mechanism of action

Disulfiram is rapidly converted in the body to its active metabolite diethylthiocarbamate, which binds metal ions with high affinity and selectively and irreversibly inhibits aldehyde dehydrogenase. This results in alcohol not being completely degraded to acetic acid, but only to the intermediate product, toxic acetaldehyde, which triggers the intolerance reaction. Disulfiram also inhibits the enzyme dopamine-β-hydroxylase, which converts dopamine to norepinephrine. This results in an increase in dopamine and a decrease in norepinephrine in peripheral and central tissues. Inhibition of DBH is thought to be partly responsible for the effectiveness of disulfiram in treating alcohol and cocaine dependence. The rare psychiatric side effects may also be attributed to the dopamine increase.

Indications

Supportive treatment of chronic alcoholism, periodic recurrent alcoholism in conjunction with nonpharmacologic methods. Disulfiram has also shown some efficacy in cocaine withdrawal but is not approved for this indication in many countries.

Dosage

No alcohol should be consumed for 3 days before starting therapy. The tablets are dissolved in a glass of water, producing a milky and tasteless dispersion that should be taken immediately. The dosage range is 200 mg to 800 mg per day. It is advisable to take the drug before a therapy companion, so that the intake is controlled. It should be noted that the effect can last up to 4 days after discontinuation, and in some cases even up to two weeks.

Contraindications

Disulfiram is contraindicated in hypersensitivity, severe myocardial, coronary, and circulatory affections, manifest psychosis, epilepsy, and severe brain injury. Patients who have responded to previous administration of disulfiram with subclinical or clinically manifest hepatitis should not be treated with the drug. Disulfiram must not be used in the presence of preexisting nonaethylated hepatopathy such as viral hepatopathy or marked elevation of transaminases. Likewise, the drug is contraindicated for children and adolescents under 18 years of age. Caution should be exercised in patients with diabetes mellitus and renal insufficiency. Full precautions can be found in the SmPC.

Interactions

The active metabolite diethylthiocarbamate is formed by CYP450 isozymes. Interactions are possible with anticoagulant drugs, phenytoin, theophylline, tricyclic antidepressants, amitriptyline, MAO inhibitors, diazepam, and chlordiazepoxide, among others. Antihistamines, some neuroleptics, and tranquilizers may attenuate antabuse syndrome.Metronidazole and other nitroimidazoles may possibly increase alcohol intolerance. Of course, alcohol should not be drunk before, during and after treatment. It should be noted that alcohol is also contained in some medicines and foods (e.g. tinctures, cherry sticks). Intolerance reactions occur from an amount of about 3 g of pure ethanol.

Adverse effects

In addition to the antabuse syndrome, adverse effects can occur without alcohol. Disulfiram is usually tolerated. Rare serious side effects include life-threatening hepatitis. If symptoms such as loss of appetite, fatigue, vomiting, itching, and jaundice occur, the drug should be discontinued and the doctor contacted. Common: