Disulfiram
Encyclopedia
Disulfiram is a drug
discovered in the 1920s and used to support the treatment of chronic alcoholism
by producing an acute sensitivity to alcohol
. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals. Disulfiram is also being studied as a treatment for cocaine
dependence, as it prevents the breakdown of dopamine
(a neurotransmitter whose release is stimulated by cocaine); the excess dopamine results in increased anxiety, higher blood pressure, restlessness and other unpleasant symptoms. Several studies have reported that it has anti-protozoal
activity as well.
Research for possible disulfiram use in cancer therapy has been announced.
drug company Medicinalco. The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.
, alcohol is broken down in the liver
by the enzyme
alcohol dehydrogenase
to acetaldehyde
, which is then converted by the enzyme acetaldehyde dehydrogenase
to the harmless acetic acid
. Disulfiram blocks this reaction at the intermediate stage by blocking the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a "hangover
" this produces immediate and severe negative reaction to alcohol intake. Some 5–10 minutes after alcohol intake, the patient may experience the effects of a severe hangover
for a period of 30 minutes up to several hours. Symptoms include flushing
of the skin, accelerated heart rate, shortness of breath, nausea
, vomiting
, throbbing headache, visual disturbance, mental confusion, postural fainting, and circulatory collapse
.
Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body the effects may last for up to two weeks after the initial intake; consequently, medical ethics
dictate that patients must be fully informed about the disulfiram-alcohol reaction.
A nine-year study published in 2006 found that incorporation of supervised disulfiram and a related compound calcium carbimide into a comprehensive treatment program resulted in an abstinence rate of over 50%.
infection. Another study found that it had activity against Trichomonas vaginalis
which was resistant to the most common treatment, metronidazole
.
It is also useful in the treatment of scabies
as a combination drug of Benzyl benzoate/disulfiram.
ocular melanoma
was successfully treated by disulfiram with zinc gluconate
.
This can be explained as disulfiram creating complexes with metals (dithiocarbamate
complexes) is proteasome inhibitor
and can represent a new approach to proteasome
inhibition.
Clinical trials are recommended.
There is ongoing clinical trial of disulfiram with copper gluconate
against liver cancer in Utah (ClinicalTrials.gov Identifier: NCT00742911) and clinical trial of disulfiram as adjuvant against lung cancer in Israel (ClinicalTrials.gov Identifier: NCT00312819).
is a chemical compound that induces sleep in humans. It is formed in the liver after disulfiram treatment.
Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal
and other symptoms.
with iodine
:
, the term "disulfiram effect" refers to an adverse effect of a particular medication in causing an unpleasant hypersensitivity to alcohol
, similar to the effect caused by disulfiram administration.
Examples:
Coprine (N5-1-hydroxycyclopropyl-L-glutamine), which metabolises to 1-aminocyclopropanol, a closely related chemical having the same metabolic effects, occurs naturally in the common ink cap (Coprinopsis atramentaria
), an otherwise edible mushroom
. Similar reactions have been recorded with Clitocybe clavipes
and Boletus luridus
, although the agent in those species is unknown.
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
discovered in the 1920s and used to support the treatment of chronic alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
by producing an acute sensitivity to alcohol
Ethanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
. Trade names for disulfiram in different countries are Antabuse and Antabus manufactured by Odyssey Pharmaceuticals. Disulfiram is also being studied as a treatment for cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...
dependence, as it prevents the breakdown of dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
(a neurotransmitter whose release is stimulated by cocaine); the excess dopamine results in increased anxiety, higher blood pressure, restlessness and other unpleasant symptoms. Several studies have reported that it has anti-protozoal
Antiprotozoal agent
Antiprotozoal agents is a class of pharmaceuticals used in treatment of protozoan infection.Protozoans have little in common with each other and so agents effective against one pathogen may not be effective against another...
activity as well.
Research for possible disulfiram use in cancer therapy has been announced.
History
The drug's action was discovered by accident in 1948 by the researchers Erik Jacobsen, Jens Hald, and Keneth Ferguson at the DanishDenmark
Denmark is a Scandinavian country in Northern Europe. The countries of Denmark and Greenland, as well as the Faroe Islands, constitute the Kingdom of Denmark . It is the southernmost of the Nordic countries, southwest of Sweden and south of Norway, and bordered to the south by Germany. Denmark...
drug company Medicinalco. The substance was intended to provide a remedy for parasitic infestations; however, workers testing the substance on themselves reported severe symptoms after alcohol consumption.
Alcohol abuse
Under normal metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
, alcohol is broken down in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
by the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
alcohol dehydrogenase
Alcohol dehydrogenase
Alcohol dehydrogenases are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide...
to acetaldehyde
Acetaldehyde
Acetaldehyde is an organic chemical compound with the formula CH3CHO or MeCHO. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale industrially. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants as part...
, which is then converted by the enzyme acetaldehyde dehydrogenase
Acetaldehyde dehydrogenase
Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetic acid. The oxidation of acetaldehyde to acetate can be summarized as follows:...
to the harmless acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
. Disulfiram blocks this reaction at the intermediate stage by blocking the enzyme acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be 5 to 10 times higher than that found during metabolism of the same amount of alcohol alone. As acetaldehyde is one of the major causes of the symptoms of a "hangover
Hangover
A hangover describes the sum of unpleasant physiological effects following heavy consumption of alcoholic beverages. The most commonly reported characteristics of a hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst, typically after the...
" this produces immediate and severe negative reaction to alcohol intake. Some 5–10 minutes after alcohol intake, the patient may experience the effects of a severe hangover
Hangover
A hangover describes the sum of unpleasant physiological effects following heavy consumption of alcoholic beverages. The most commonly reported characteristics of a hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst, typically after the...
for a period of 30 minutes up to several hours. Symptoms include flushing
Flushing (physiology)
For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...
of the skin, accelerated heart rate, shortness of breath, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, throbbing headache, visual disturbance, mental confusion, postural fainting, and circulatory collapse
Circulatory collapse
A circulatory collapse is defined as a general or specific failure of the circulation, either cardiac or peripheral in nature. A common cause of this could be shock or trauma from injury or surgery...
.
Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. As disulfiram is absorbed slowly through the digestive tract and eliminated slowly by the body the effects may last for up to two weeks after the initial intake; consequently, medical ethics
Medical ethics
Medical ethics is a system of moral principles that apply values and judgments to the practice of medicine. As a scholarly discipline, medical ethics encompasses its practical application in clinical settings as well as work on its history, philosophy, theology, and sociology.-History:Historically,...
dictate that patients must be fully informed about the disulfiram-alcohol reaction.
A nine-year study published in 2006 found that incorporation of supervised disulfiram and a related compound calcium carbimide into a comprehensive treatment program resulted in an abstinence rate of over 50%.
Antiprotozoal and anti-scabies
A study reported that it may be potentially useful in the treatment of GiardiaGiardia
Giardia is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada in the supergroup "Excavata" that colonise and reproduce in the small intestines of several vertebrates, causing giardiasis, commonly known as Beaver fever...
infection. Another study found that it had activity against Trichomonas vaginalis
Trichomonas vaginalis
Trichomonas vaginalis is an anaerobic, flagellated protozoan, a form of microorganism. The parasitic microorganism is the causative agent of trichomoniasis, and is the most common pathogenic protozoan infection of humans in industrialized countries. Infection rates between men and women are the...
which was resistant to the most common treatment, metronidazole
Metronidazole
Metronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
.
It is also useful in the treatment of scabies
Scabies
Scabies , known colloquially as the seven-year itch, is a contagious skin infection that occurs among humans and other animals. It is caused by a tiny and usually not directly visible parasite, the mite Sarcoptes scabiei, which burrows under the host's skin, causing intense allergic itching...
as a combination drug of Benzyl benzoate/disulfiram.
Cancer
A patient with metastaticMetastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
ocular melanoma
Uveal melanoma
Uveal melanoma is a cancer of the eye involving the iris, ciliary body, or choroid . Tumors arise from the pigment cells that reside within the uvea giving color to the eye...
was successfully treated by disulfiram with zinc gluconate
Zinc gluconate
Zinc gluconate is the zinc salt of gluconic acid. It is an ionic compound consisting of two moles of gluconate for each mole of zinc...
.
This can be explained as disulfiram creating complexes with metals (dithiocarbamate
Dithiocarbamate
A dithiocarbamate is a functional group in organic chemistry. It is the analog of a carbamate in which both oxygen atoms are replaced by sulfur atoms. Sodium diethyldithiocarbamate is a common ligand in inorganic chemistry....
complexes) is proteasome inhibitor
Proteasome inhibitor
Proteasome inhibitors are drugs that block the action of proteasomes, cellular complexes that break down proteins, like the p53 protein. Proteasome inhibitors are being studied in the treatment of cancer.-Examples:...
and can represent a new approach to proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
inhibition.
Clinical trials are recommended.
There is ongoing clinical trial of disulfiram with copper gluconate
Copper gluconate
Copper gluconate is the copper salt of D-gluconic acid.- Uses :*Dietary supplement -- metabolizable copper to treat copper deficiency.*Used to treat acne vulgaris, common cold, hypertension, premature labor, Leishmaniasis, visceral postoperative complications.*Ingredient of Retsyn.- Side effects...
against liver cancer in Utah (ClinicalTrials.gov Identifier: NCT00742911) and clinical trial of disulfiram as adjuvant against lung cancer in Israel (ClinicalTrials.gov Identifier: NCT00312819).
Side effects
The most common side effects (in the absence of alcohol) are drowsiness, headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur. TryptopholTryptophol
Tryptophol is a chemical compound that induces sleep in humans. It is formed in the liver after disulfiram treatment. It is also produced by the trypanosomal parasite in sleeping sickness....
is a chemical compound that induces sleep in humans. It is formed in the liver after disulfiram treatment.
Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal
Extrapyramidal symptoms
The extrapyramidal system can be affected in a number of ways, which are revealed in a range of extrapyramidal symptoms , also known as extrapyramidal side-effects , such as akinesia and akathisia .Extrapyramidal symptoms are various movement disorders such as acute dystonic reactions,...
and other symptoms.
Dosage
Disulfiram is supplied in 200 mg, 250 mg, and 500 mg tablets. The usual initial dose is 500 mg a day for 1 to 2 weeks, followed by a maintenance dose of 250 mg (range 125 mg–500 mg) per day. The total daily dosage should not exceed 500 mg.Preparation
Disulfiram may be prepared from oxidation of sodium diethyldithiocarbamateSodium diethyldithiocarbamate
Sodium diethyldithiocarbamate is the organosulfur compound with the formula NaS2CN2.-Preparation:This salt is obtained by treating carbon disulfide with diethylamine in the presence of sodium hydroxide:Other dithiocarbamates can be prepared similarly from secondary amines and carbon disulfide...
with iodine
Iodine
Iodine is a chemical element with the symbol I and atomic number 53. The name is pronounced , , or . The name is from the , meaning violet or purple, due to the color of elemental iodine vapor....
:
- 2 NaS2CNEt2 + I2 → Et2NC(S)S-SC(S)NEt2 + 2 NaI (Et = C2H5)
Similarly acting substances
In medicineMedicine
Medicine is the science and art of healing. It encompasses a variety of health care practices evolved to maintain and restore health by the prevention and treatment of illness....
, the term "disulfiram effect" refers to an adverse effect of a particular medication in causing an unpleasant hypersensitivity to alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
, similar to the effect caused by disulfiram administration.
Examples:
- Antibiotics (Nitroimidazoles), e.g. metronidazoleMetronidazoleMetronidazole is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal....
- 1st generation sulphonylureas, e.g. tolbutamideTolbutamideTolbutamide is a first generation potassium channel blocker, sulfonylurea oral hypoglycemic drug sold under the brand name Orinase. This drug may be used in the management of type II diabetes if diet alone is not effective. Tolbutamide stimulates the secretion of insulin by the pancreas...
- Several CephalosporinCephalosporinThe cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
drugs, including cefoperazoneCefoperazoneCefoperazone is a third generation cephalosporin antibiotic, marketed by Pfizer under the name Cefobid, and also marked by pharco B international under the name of Cefazoneand also marketed by "sigmatec " under the name " cefoperazone"...
and cefotetanCefotetanCefotetan is an injectable antibiotic of the cephamycin type for prophylaxis and treatment of bacterial infections. It is often grouped together with second-generation cephalosporins and has a similar antibacterial spectrum, but with additional anti-anaerobe coverage.Cefotetan was developed by...
, that have a N-methylyhio-tetrazole moiety - GriseofulvinGriseofulvinGriseofulvin is an antifungal drug that is administered orally. It is used both in animals and in humans, to treat fungal infections of the skin and nails...
, an oral anti-fungal drug - Temposil, or citrated calcium carbimide, has the same function as disulfiram, but is weaker and safer.
Coprine (N5-1-hydroxycyclopropyl-L-glutamine), which metabolises to 1-aminocyclopropanol, a closely related chemical having the same metabolic effects, occurs naturally in the common ink cap (Coprinopsis atramentaria
Coprinopsis atramentaria
Coprinopsis atramentaria, commonly known as the common ink cap or inky cap, is an edible mushroom found in Europe and North America. Previously known as Coprinus atramentarius, it is the second best known ink cap and previous member of the genus Coprinus after C. comatus...
), an otherwise edible mushroom
Mushroom
A mushroom is the fleshy, spore-bearing fruiting body of a fungus, typically produced above ground on soil or on its food source. The standard for the name "mushroom" is the cultivated white button mushroom, Agaricus bisporus; hence the word "mushroom" is most often applied to those fungi that...
. Similar reactions have been recorded with Clitocybe clavipes
Clitocybe clavipes
Ampulloclitocybe clavipes, commonly known as the club-footed clitocybe, is a species of gilled mushroom from Europe.Although considered edible, antabuse-like reactions have been reported after consumption of alcohol after eating this mushroom...
and Boletus luridus
Boletus luridus
Boletus luridus, commonly known as the lurid bolete, is a fungus of the bolete family, found in deciduous woodlands in Europe and eastern North America. Fruiting bodies arise in summer and autumn and may be common. It is a solid bolete with an olive-brown cap, orange pores and stout ochre stem...
, although the agent in those species is unknown.
External links
- Disulfiram (patient information)