Disulfiram aldehyde dehydrogenase inhibited

Ethanol is almost entirely metabolized in the liver. The first step, oxidation by alcohol dehydrogenase, yields acetaldehyde, a reactive and toxic compound. Essentially all of the acetaldehyde is converted to acetate by the liver enzyme aldehyde dehydrogenase. Aldehyde dehydrogenase is inhibited by the drag disulfiram. Given alone, disulfiram is a nontoxic substance. However, ethanol consumption in the presence of... 

Most of the human experience with disulfiram has come from its use as an avoidance therapy for alcoholism. Metabolites of disulfiram inhibit aldehyde dehydrogenase, resulting in elevated levels of acetaldehyde after ethanol ingestion. Side effects include flushing of the face, tachycardia, severe headache, apprehension, hyperpnea, hypotension, dizziness, nausea, vomiting, and fainting. Severe reactions may include convulsions, myocardial infarction, and marked respiratory depression. ... 

It exerts its action by inhibiting aldehyde dehydrogenase enz5une. Disulfiram thus increases the concentration of acetaldehyde in body when ethanol is ingested by an individual pretreated with disulfiram. The symptoms and signs produced... 

Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. NAD +, nicotinamide adenine dinucleotide NADPH, nicotinamide adenine dinucleotide phosphate. 

Disulfiram Inhibits aldehyde dehydrogenase, causes aldehyde accumulation during ethanol ingestion Deterrent to relapse in individuals with alcoholism Toxicity Little effect on its own but severe and potentially dangerous flushing, headache, nausea, vomiting, and hypotension when combined with ethanol... 

A similar effect is exerted by the drug disulfiram (Antabuse), which has been used to discourage drinking and whose metabolites are thought to inhibit aldehyde dehydrogenase.95... 

Disulfiram (Antabuse) inhibits aldehyde dehydrogenase irreversibly, causing an increase in the level of acetaldehyde, formed from ethanol by the enzyme alcohol dehydrogenase. This results in nausea, vomiting, and other symptoms in the human—hence its use as a deterrent in alcoholism. Inhibition by disulfiram appears to be irreversible, the level returning to normal only as a result of protein synthesis. 

In 1951, disulfiram was the first medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of alcohol dependence other than detoxification. Disulfiram inhibits a key enzyme, aldehyde dehydrogenase, involved in breakdown of ethyl alcohol. After drinking, the alcohol-disulfiram reaction produces excess blood levels of acetaldehyde, which is toxic in that it produces facial flushing, tachycardia, hypotension, nausea and vomiting, and physical discomfort. Opioid receptors antagonists, such as naloxone and naltrexone (see Chapter 47) that block opioid receptors have been found to decrease alcohol consumption (Cornish et al 2004). 

Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by alcohol-dependent patients undergoing treatment. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit aldehyde dehydrogenase and can cause a disulfiram-like reaction if combined with ethanol. 

In addition to its powerful synergistic action with alcohol by the inhibition of aldehyde dehydrogenase, Disulfiram exerts an equally strong synergistic toxic effect in the presence of ethylene dibromide (EDB, ref. 179) Laboratory rats exposed to 20 ppm EDB (inhalation)... 

Disulfiram appeared to act synergistically with tranquilizers, causing spontaneous miscarriages and/or malformations in the fetuses of five women. It also exerts powerful synergistic action with alcohol by inhibition of the enzyme of aldehyde dehydrogenase and acts similarly with EDB to magnify the toxicity and oncogenicity of the latter compound. 

METRONIDAZOLE ALCOHOL Disulfiram-like reaction Metronidazole inhibits aldehyde dehydrogenase Avoid co-ingestion... 

ALCOHOL METRONIDAZOLE Disulfiram-like reaction. Unsteadiness, and incoordination caused by metronidazole may be aggravated by alcohol Metronidazole inhibits aldehyde dehydrogenase. Additive side-effects Avoid co-ingestion... 

Disulfiram (Antabuse). In alcoholics who are well and motivated, an attempt may be made to discourage drinking by inducing immediate unpleasantness. Disulfiram inhibits the enzyme aldehyde dehydrogenase so that acetaldehyde (toxic metabolite of alcohol) accumulates. The objective of administering disulfiram is that patients will find the experience so unpleasant that they will avoid alcohol. It should be administered only under specialist supervision. 

A disulfiram-like effect (see p. 186) occurs with alcohol because metronidazole inhibits alcohol and aldehyde dehydrogenase patients should be warned appropriately. 

Cephalosporins that contain a methyltetrazole-thiol side chain (as in cefamandole, cefmenoxime, cefmeta-zole, cefonizid, cefoperazone, ceforanide, cefotetan, cefotiam, latamoxef, and moxalactam) and chemically similar structures (cefepime, ceftriaxone) co-adminis-tered with alcohol can produce a disulfiram-like syndrome by inhibiting aldehyde dehydrogenase (195,202,203). 

Disulfiram (tetraethylthiuram) has been widely used since the late 1940s to facilitate abstinence from alcohol (1). Concomitant use of alcohol during disulfiram therapy results in an autonomic symptom complex that can involve headache, flushing, nausea and vomiting, sweating, tachycardia, hypotension, and confusion. The mechanism of action of disulfiram is inhibition of aldehyde dehydrogenase alcohol is metabolized to acetaldehyde, which accumulates (2). 

Paraldehyde is metabolized in the liver to acetaldehyde (22), and the metabohsm of aldehyde by aldehyde dehydrogenase is inhibited by disulfiram, causing aldehyde toxicity. The adverse effects of this have been shown in experimental animals (23) and there have been reports of confusional psychosis in patients given disulfiram and paraldehyde (24). 

The MTT group has also been implicated in the intolerance to alcohol a.ssociatcd with certain injectable cephalosporins ccfamandole, cefotcian. ccfmetazolc, and cefoperazone. Thus, disulfiram-like reactions, attributed to the accumulation of acetaldehyde and resulting from the inhibition of aldehyde dehydrogenase-catalyzed oxidation of ethanol by M lT-contuining cephalo.sporins. " may occur in patients who have consumed alcohol before, during, or shortly after the course of therapy. 

Disulfiram has multiple mechanisms of toxicity. Its most well-defined 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-/f-hydroxylase has also been associated with its toxicity. 

Metronidazole possesses selective bactericidal and an-tiparasitic activity. Its mechanism of action is complex and not thoroughly understood but is thought to include interference with nucleic acid synthesis. Metronidazole is also capable of producing a disulfiram-type reaction with ethanol ingestion. This reaction is hypothesized to occur due to metronidazole inhibition of aldehyde dehydrogenase. 

Agents that can inhibit dopamine-P-hydroxylase include disulfiram, fusaric acid, phenylpropargylamine, FLA 63, FLA 57, LY 10853 and SKF 102698. These agents are of value in experimental investigations, but none Is used clinically for this purpose (though disulfiram is used to modify ethanol metabolism by a different mechanism see aldehyde DEHYDROGENASE INHIBITORS). 

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