Disulfiram

Absorption

Disulfiram is absorbed slowly from the gastrointestinal tract (80 to 90% of oral dose).

Toxicity

LD50=8.6g/kg (orally in rats). Symptoms of overdose include irritation, slight drowsiness, unpleasant taste, mild GI disturbances, and orthostatic hypotension.

Description

Disulfiram was first synthesized in the 1800s to improve the manufacturing process of rubber. A physician working in a rubber factory plant first observed in 1937 that factory workers who were exposed to disulfiram were intolerant to ethanol. In the 1940s, two scientists rediscovered the disulfiram– ethanol effects while researching antiparasitic therapies. This finding eventually led to the approval of the medication to be used as an ethanol deterrent by the Food and Drug Administration in 1951.

Chemical properties

yellow-white crystals or grey powder

Originator

Esperal,Millot Solac,France,1950

The Uses of Disulfiram

Disulfiram is a copper and zinc chelator and an irreversible inhibitor of aldehyde dehydrogenase (IC50 = 0.1 mM) that has been indicated for the treatment of alcohol dependence. It also inhibits the copper-dependent enzyme dopamine β-hydroxylase, which prevents the breakdown of dopamine and has been considered as a treatment for cocaine dependence. When in complex with copper, disulfiram has been shown to inhibit purified 20S proteasome (IC50 = 7.5 μM) and 26S proteasome (IC50 = 20 μM) from MDA-MB-0231 breast cancer cells. Because disulfiram targets the ubiquitin-proteasome pathway, it has been investigated as an anti-cancer agent. Furthermore, at 250 nM it has been shown to induce reactive oxygen species, to activate JNK and p38 pathways, and to inhibit NF-κB activity, which suppresses self-renewal in cancer stem cells.

The Uses of Disulfiram

It is used as rubber accelerator; vulcanizer; seed disinfectant; fungicide; alcohol deterrent.

The Uses of Disulfiram

Alcohol deterrent;Dopamine beta-hydroxylase inhibitor;For the treatment and management of chronic alcoholism.

Background

A carbamate derivative used as an alcohol deterrent. It is a relatively nontoxic substance when administered alone, but markedly alters the intermediary metabolism of alcohol. When alcohol is ingested after administration of disulfiram, blood acetaldehyde concentrations are increased, followed by flushing, systemic vasodilation, respiratory difficulties, nausea, hypotension, and other symptoms (acetaldehyde syndrome). It acts by inhibiting aldehyde dehydrogenase.

Indications

For the treatment and management of chronic alcoholism

What are the applications of Application

Disulfiram is an ALDH and tumor cell growth inhibitor

Definition

ChEBI: An organic disulfide that results from the formal oxidative dimerisation of N,N-diethyldithiocarbamic acid. A multi-enzyme inhibitor that is used in alcohol aversion therapy and also exhibits anticancer properties.

Manufacturing Process

Disulfiram may be made by the reaction of diethyl amine with carbon disulfide in the presence of sodium hydroxide. The (C2H5)2NCSSNa intermediate is oxidatively coupled using hydrogen peroxide to give disulfiram.

brand name

Antabuse (Odyssey) .

Therapeutic Function

Alcohol deterrent

General Description

Odorless or almost odorless white or almost white to tan powder. Unpleasant taste with metallic or garlic aftertaste. pH of a solution obtained by shaking 1 g with 30 mL of water is 6 to 8.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Disulfiram is sensitive to light. Disulfiram is incompatible with strong acids, strong oxidizers and nitrosating agents (e.g. N-Nitrosodiphenylamine). .

Hazard

Toxic symptoms when ingested with alcohol; animal teratogen. Vasodilation and nausea. Questionable carcinogen.

Health Hazard

Disulfiram affects the central nervous system, thyroid, and skin; in combination with alcohol it causes an “Antabusealcohol” syndrome.
Small doses of disulfiram reportedly can cause effects on thyroid iodine uptake and thyroid gland hypertrophy. It may also produce dermatitis and acneform rashes.

Fire Hazard

Flash point data for Disulfiram are not available; however, Disulfiram is probably combustible.

Flammability and Explosibility

Not classified

Biological Activity

Inhibitor of aldehyde dehydrogenase that displays antialcoholism activity. Shown to reversibly stimulated Ca 2+ -ATPase activity and inhibit V-ATPase (EC 50 = 26 μ M). Also inhibits expression of MMP-2 and MMP-9 and displays anti-invasive activity.

Contact allergens

TETD is a rubber accelerator of the thiuram group, contained in “thiuram mix.” It can cross-react with other thiurams, especially TMTD. TETD is used to aid those trying to break their dependence on alcohol. The disulfiram-alcohol reaction is not allergic but due to the accumulation of toxic levels of acetaldehyde. The implanted drug can, however, lead to local or generalized dermatitis, for example ingested disulfiram, mainly in previously rubber-sensitized patients. As an adjunctive treatment of alcoholism, it caused occupational contact dermatitis in a nurse.

Pharmacokinetics

Disulfiram produces a sensitivity to alcohol which results in a highly unpleasant reaction when the patient under treatment ingests even small amounts of alcohol. Disulfiram blocks the oxidation of alcohol at the acetaldehyde stage during alcohol metabolism following disulfiram intake, the concentration of acetaldehyde occurring in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. Accumulation of acetaldehyde in the blood produces a complex of highly unpleasant symptoms referred to hereinafter as the disulfiram-alcohol reaction. This reaction, which is proportional to the dosage of both disulfiram and alcohol, will persist as long as alcohol is being metabolized. Disulfiram does not appear to influence the rate of alcohol elimination from the body. Prolonged administration of disulfiram does not produce tolerance; the longer a patient remains on therapy, the more exquisitely sensitive he becomes to alcohol.

Clinical Use

Adjunct in the treatment of chronic alcohol dependence

Safety Profile

A human poison by ingestion. An experimental poison by intraperitoneal route. Toxic symptoms when accompanied by ingestion of alcohol. Human systemic effects by ingestion: jaundtce, joint changes. An experimental teratogen. Other experimental reproductive effects. Questionable carcinogen with experimental neoplastigenic data. See also THIRAM.

Potential Exposure

AgriculturalChemical; Drug, Tumorigen, Mutagen; ReproductiveEffector; Human Data; Hormone, Primary Irritant. Somethiurams have been used as rubber components. Disulfiramis used as an accelerator in compounding natural, styrenebutadiene, and Neoprene? rubbers as a rubber acceleratorand vulcanizer; as a seed disinfectant and fungicide; in therapy; as an alcohol deterrent; in adhesives.

Drug interactions

Potentially hazardous interactions with other drugs
Alcohol: risk of severe disulfiram reaction.
Anticoagulants: enhanced anticoagulant effect with coumarins.
Antiepileptics: inhibition of metabolism of fosphenytoin and phenytoin (increased risk of toxicity).
Paraldehyde: increased risk of toxicity with paraldehyde.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit.Note: For alcohol/disulfiram or ethylene dibromide/disulfiram reaction, remove the person from exposure. Begin rescue breathing (using universal precautions, includingresuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility.

Carcinogenicity

In a lifetime carcinogenicity bioassay, disulfiram was not carcinogenic in either rats or mice when fed in the diet. The highest doses were 600 ppm in rats and 2000ppm in mice.
Increased fetal resorptions, but no teratogenic effects, were seen in rats exposed at 100mg/kg/day from day 3 of gestation. A weak genotoxic response was observed in mice treated in vivo as evidenced by an increase in sister chromatid exchanges in bone marrow and spermatogonial cells.9
The 2003 ACGIH threshold limit valuetime- weighted average (TLV-TWA) is 2mg/m3.

Metabolism

Hepatic.

Metabolism

Disulfiram is rapidly reduced to diethyldithiocarbamate, mainly by the glutathione reductase system in erythrocytes; reduction may also occur in the liver.
Diethyldithiocarbamate is metabolised in the liver to its glucuronide and methyl ester and to diethylamine, carbon disulfide, and sulfate ions. Metabolites are excreted mainly in the urine; carbon disulfide is exhaled in the breath.

storage

+4°C

Shipping

Toxic solids, flammable, organic, n.o.s. requiresa shipping label of “POISONOUS/TOXIC MATERIALS.”They fall into Hazard Class 6.1.

Toxicity evaluation

Disulfiram has multiple mechanisms of toxicity. Its most welldefined action is inhibition of aldehyde dehydrogenase, which thereby diminishes the breakdown of acetaldehyde. Accumulation of carbon disulfide, a disulfiram metabolite, as well as inhibition of dopamine-b-hydroxylase has also been associated with its toxicity in particular related to use for cocaine dependence.