Disulfiram

Last updated
Disulfiram
Disulfiram.svg
Disulfiram-from-xtal-Mercury-3D-bs.png
Clinical data
Trade names Antabuse, Antabus, other
Other namestetraethyldisulfanedicarbothioamide; 1-(Diethylthiocarbamoyldisulfanyl)-N,N-diethyl-methanethioamide
AHFS/Drugs.com Monograph
MedlinePlus a682602
Pregnancy
category
  • AU:B2
Routes of
administration
By mouth, subdermal implant
ATC code
Legal status
Legal status
Pharmacokinetic data
Metabolism Liver to diethylthiocarbamate
Elimination half-life 60–120 hours
Identifiers
  • 1,1′-disulfanediylbis(N,N-diethylmethanethioamide)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
CompTox Dashboard (EPA)
ECHA InfoCard 100.002.371 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C10H20N2S4
Molar mass 296.52 g·mol−1
3D model (JSmol)
  • CCN(CC)C(=S)SSC(=S)N(CC)CC
  • InChI=1S/C10H20N2S4/c1-5-11(6-2)9(13)15-16-10(14)12(7-3)8-4/h5-8H2,1-4H3 Yes check.svgY
  • Key:AUZONCFQVSMFAP-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Disulfiram is a medication which is used to support the treatment of chronic alcoholism because it induces an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death. [3]

Contents

In the body, alcohol is converted to acetaldehyde, which is then broken down by acetaldehyde dehydrogenase. When the dehydrogenase enzyme is inhibited, acetaldehyde builds up, causing unpleasant side effects (see Disulfiram-alcohol reaction). Disulfiram should be used in conjunction with counseling and support.[ citation needed ]

Medical uses

Disulfiram is used as a second-line treatment, behind acamprosate and naltrexone, for alcohol dependence. [4]

Under normal metabolism, alcohol is broken down in the liver by the enzyme alcohol dehydrogenase to acetaldehyde, which is then converted by the enzyme acetaldehyde dehydrogenase to a harmless acetic acid derivative (acetyl coenzyme A). Disulfiram blocks this reaction at the intermediate stage by blocking acetaldehyde dehydrogenase. After alcohol intake under the influence of disulfiram, the concentration of acetaldehyde in the blood may be five 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. About 5 to 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 usually include flushing of the skin, accelerated heart rate, low blood pressure, nausea, and vomiting. Uncommon adverse events include shortness of breath, throbbing headache, visual disturbance, mental confusion, postural syncope, and circulatory collapse. [5]

Disulfiram should not be taken if alcohol has been consumed in the last 12 hours. [6] There is no tolerance to disulfiram: the longer it is taken, the stronger its effects. [3] 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. [7]

Disulfiram does not reduce alcohol cravings, so a major problem associated with this drug is extremely poor compliance. Methods to improve compliance include subdermal implants, which release the drug continuously over a period of up to 12 weeks, and supervised administration practices, for example, having the drug regularly administered by one's spouse.[ medical citation needed ]

Although disulfiram remained the most common pharmaceutical treatment of alcohol abuse until the end of the 20th century, today it is often replaced or accompanied with newer drugs, primarily the combination of naltrexone and acamprosate, which directly attempt to address physiological processes in the brain associated with alcohol abuse.[ citation needed ]

Side effects

The most common side effects in the absence of alcohol are headache, and a metallic or garlic taste in the mouth, though more severe side effects may occur. [8] Tryptophol, a chemical compound that induces sleep in humans, is formed in the liver after disulfiram treatment. [9] Less common side effects include decrease in libido, liver problems, skin rash, and nerve inflammation. [10] Liver toxicity is an uncommon but potentially serious side effect, and risk groups e.g. those with already impaired liver function should be monitored closely. That said, the rate of disulfiram-induced hepatitis are estimated to be in between 1 per 25,000 to 1 in 30,000, [11] and rarely the primary cause for treatment cessation.

Cases of disulfiram neurotoxicity have also occurred, causing extrapyramidal and other symptoms. [12] Disulfiram can produce neuropathy in daily doses of less than the usually recommended 500 mg. Nerve biopsies showed axonal degeneration and the neuropathy is difficult to distinguish from that associated with ethanol abuse. Disulfiram neuropathy occurs after a variable latent period (mean 5 to 6 months) and progresses steadily. Slow improvement may occur when the drug's use is stopped; often there is complete recovery eventually. [13]

Disulfiram disrupts metabolism of several other compounds, including paracetamol (acetaminophen), [14] theophylline [15] and caffeine. [16] However, in most cases, this disruption is mild and presents itself as a 20–40% increase in the half-life of the compound at typical dosages of disulfiram.[ citation needed ]

Aldehyde dehydrogenase inhibitors (ALDH inhibitors) like disulfiram inhibit the metabolism and consequent detoxification of 3,4-dihydroxyphenylacetaldehyde (DOPAL). [17] [18] [19] DOPAL is the major metabolite of the monoamine neurotransmitter dopamine and is a known potent dopaminergic neurotoxin. [17] [18] It is thought to be involved in aging-related dopaminergic neurodegeneration and Parkinson's disease. [17] [18] By inhibiting ALDH, disulfiram and other ALDH inhibitors may accelerate aging-related dopaminergic neurodegeneration. [17] [20] [19] This has been demonstrated with disulfiram in preclinical research, although dopaminergic neurotoxicity caused by the drug in humans has not been studied or shown and preclinical findings with disulfiram are conflicting. [17] [19] [20] [21] In any case, environmental exposure to known ALDH inhibitors, such as various pesticides, have been associated with dopaminergic neurodegeneration and incidence of Parkinson's disease, among other findings. [17] [19]

Similarly acting substances

In medicine, 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.[ citation needed ]

Examples:[ citation needed ]

Pharmacology

Pharmacodynamics

Disulfiram acts as an irreversible aldehyde dehydrogenase (ALDH) inhibitor. [22] ALDH is an enzyme that catalyze the oxidation of aldehydes. [22] It is known to inactivate acetaldehyde, a toxic metabolite of alcohol. [22] By inhibiting ALDH, disulfiram prevents the inactivation and detoxification of acetaldehyde and thereby induces a variety of unpleasant symptoms when alcohol is consumed. [22]

Besides inhibiting ALDH, disulfiram is a dopamine β-hydroxylase (DBH) inhibitor. [23] [24] DBH is an enzyme that converts the monoamine neurotransmitter dopamine into norepinephrine. [23] [24] By inhibiting DBH, disulfiram may increase dopamine levels in the brain and periphery but decrease levels of norepinephrine and its metabolite epinephrine in the brain and periphery. [23] [24] However, it is also possible that disulfiram may actually decrease brain dopamine levels. [24] DBH inhibition by disulfiram may explain its possible therapeutic benefits in cocaine dependence as well as cases of psychosis and mania associated with the drug. [23] [24] [25] There are also cases of disulfiram producing stimulant psychosis in combination with the psychostimulants methylphenidate and amphetamine. [25] DBH inhibition by disulfiram might also explain the hypotension side effect when alcohol is ingested in people taking disulfiram. [23]

Disulfiram is also known to inhibit the cytochrome P450 enzymes CYP2E1 and CYP1A2. [25]

History

The synthesis of disulfiram, originally known as tetraethylthiuram disulfide, was first reported in 1881. By around 1900, it was introduced to the industrial process of sulfur vulcanization of rubber and became widely used. In 1937, a plant physician in the American rubber industry described adverse reactions to alcohol in workers exposed to tetramethylthiuram monosulfide and disulfide, and proposed that this effect of disulfiram and related compounds might lead to ”the cure for alcoholism”; the effect was also noticed in workers at a Swedish rubber boot factory. [26]

In the early 1940s it had been tested as a treatment for scabies, a parasitic skin infection, as well as intestinal worms. [26]

Around that time, during the German occupation of Denmark, Erik Jacobsen and Jens Hald at the Danish drug company Medicinalco picked up on that research and began exploring the use of disulfiram to treat intestinal parasites. The company had a group of enthusiastic self-experimenters that called itself the "Death Battalion", and in the course of testing the drug on themselves, accidentally discovered that drinking alcohol while the drug was still in their bodies made them mildly sick. [26] [27] :98–105

They made that discovery in 1945, and did nothing with it until two years later, when Jacobsen gave an impromptu talk and mentioned that work, which was discussed afterwards in newspapers at the time, leading them to further explore the use of the drug for that purpose. [26] [27] :98–105 That work included small clinical trials with Oluf Martensen-Larsen, a doctor who worked with alcoholics. [26] They published their work starting in 1948. [26] [28]

The chemists at Medicinalco discovered a new form of disulfiram while trying to purify a batch that had been contaminated with copper. This form turned out to have better pharmacological properties, and the company patented it and used that form for the product that was introduced as Antabus (later anglicized to Antabuse). [26]

This work led to renewed study of the human metabolism of ethanol. It was already known that ethanol was mostly metabolized in the liver, with it being converted first to acetaldehyde and then acetaldehyde to acetic acid and carbon dioxide, but the enzymes involved were not known. By 1950 the work led to the knowledge that ethanol is oxidized to acetaldehyde by alcohol dehydrogenase and acetaldehyde is oxidized to acetic acid by aldehyde dehydrogenase (ALDH), and that disulfiram works by inhibiting ALDH, leading to a buildup of acetaldehyde, which is what causes the negative effects in the body. [26]

The drug was first marketed in Denmark and as of 2008, Denmark is the country where it is most widely prescribed. It was approved by the FDA in 1951. [26] [29] The FDA later approved other drugs for treatment of alcoholism, namely naltrexone in 1994 and acamprosate in 2004. [26]

Society and culture

Though the Occupational Safety and Health Administration (OSHA) in the US has not set a permissible exposure limit (PEL) for disulfiram in the workplace, the National Institute for Occupational Safety and Health has set a recommended exposure limit (REL) of 2 mg/m3 and recommended that workers avoid concurrent exposure to ethylene dibromide. [30]

Research

Disulfiram has been studied as a possible treatment for cancer, [31] parasitic infections, [32] anxiety disorder, [33] and latent HIV infection. [34]

Cancer

When disulfiram creates complexes with metals (dithiocarbamate complexes), it is a proteasome inhibitor and as of 2016 it had been studied in in vitro experiments, model animals, and small clinical trials as a possible treatment for liver metastasis, metastatic melanoma, glioblastoma, non-small cell lung cancer, and prostate cancer. [31] [35] Various clinical trials of copper depletion agents have been carried out.[ citation needed ]

Parasitic infections

In the body, disulfiram is rapidly metabolized to diethyldithiocarbamate (ditiocarb), which binds to metal ions such as zinc or copper to form zinc or copper diethyldithiocarbamate (zinc or copper ditiocarb). The zinc diethyldithiocarbamate (zinc-ditiocarb) metabolite of disulfiram is extremely potent against the diarrhea and liver abscess-causing parasite Entamoeba histolytica and might be active against other deadly parasites. [32] [36]

HIV

Disulfiram has also been identified by systematic high-throughput screening as a potential HIV latency reversing agent (LRA). [37] [38] Reactivation of latent HIV infection in patients is part of an investigational strategy known as "shock and kill" which may be able to reduce or eliminate the HIV reservoir. [34] Recent phase II dose-escalation studies in patients with HIV who are controlled on antiretroviral therapy have observed an increase in cell-associated unspliced HIV RNA with increasing exposure to disulfiram and its metabolites. [37] [39] Disulfiram is also being investigated in combination with vorinostat, another investigational latency reversing agent, to treat HIV. [40]

Related Research Articles

<span class="mw-page-title-main">Acetaldehyde dehydrogenase</span> Class of enzymes

Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:

<span class="mw-page-title-main">CYP2E1</span> Protein-coding gene in the species Homo sapiens

Cytochrome P450 2E1 is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. This class of enzymes is divided up into a number of subcategories, including CYP1, CYP2, and CYP3, which as a group are largely responsible for the breakdown of foreign compounds in mammals.

<span class="mw-page-title-main">Cocaethylene</span> Chemical compound

Cocaethylene (ethylbenzoylecgonine) is the ethyl ester of benzoylecgonine. It is structurally similar to cocaine, which is the methyl ester of benzoylecgonine. Cocaethylene is formed by the liver when cocaine and ethanol coexist in the blood. In 1885, cocaethylene was first synthesized, and in 1979, cocaethylene's side effects were discovered.

<span class="mw-page-title-main">Alcohol flush reaction</span> Effect of alcohol consumption on the human body

Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, ears, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Fomepizole</span> Medication

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<span class="mw-page-title-main">Alcohol tolerance</span> Bodily responses to the functional effects of ethanol in alcoholic beverages

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<span class="mw-page-title-main">Tolcapone</span> Chemical compound

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<span class="mw-page-title-main">Aldehyde dehydrogenase</span> Group of enzymes

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

<span class="mw-page-title-main">Pargyline</span> Chemical compound

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<span class="mw-page-title-main">ALDH2</span> Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.

<span class="mw-page-title-main">Hangover</span> Discomfort following alcohol consumption

A hangover is the experience of various unpleasant physiological and psychological effects usually following the consumption of alcohol, such as wine, beer, and liquor. Hangovers can last for several hours or for more than 24 hours. Typical symptoms of a hangover may include headache, drowsiness, concentration problems, dry mouth, dizziness, fatigue, gastrointestinal distress, absence of hunger, light sensitivity, depression, sweating, hyper-excitability, irritability, and anxiety.

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Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde. This polymorphism is most often reported in patients of East Asian descent. Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. Severe pain after drinking alcohol may indicate a more serious underlying condition.

<span class="mw-page-title-main">Disulfiram-like drug</span> Drug that causes an adverse reaction to alcohol

A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects are caused by accumulation of acetaldehyde, a major but toxic metabolite of alcohol formed by the enzyme alcohol dehydrogenase. The reaction has been variously termed a disulfiram-like reaction, alcohol intolerance, and acetaldehyde syndrome.

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