Disulfiram-alcohol Reaction Research Articles

Disulfiram-alcohol reaction in 49 year old patient

Disulfiram-alcohol reaction in 49 year old patient

SY18-1 * ETHNIC DIFFERENCES OF DISULFIRAM PHARMACOGENETIC EFFECT IN ASIAN POPULATION

Introduction. The development of alcoholism results from multiple risk factors involving complex gene-gene and gene-environment interactions. Alcohol sensitivity is a well-known trait marker predisposing toward alcoholism via regulating the reinforcing and certain intoxicating effects of ethanol. The compound promoting acute ethanol intoxicating effect could contribute to the alcoholism treatment. The ethnic variations of aldehyde dehydrogenase (ALDH), the principal enzyme for acetaldehyde elimination in alcohol metabolism, will provide an opportunity to clarify the pharmacogenetic effect of disulfiram for the Asian population. Method. In preclinical animal studies, the male C57BL/6J mice were adapted to assess the effect of disulfiram on ethanol sensitivity by using a battery of three behavioral assays: Rotarod for ethanol-induced ataxia, hypothermia and sedation. Clinically, we recruited alcoholic patients with ALDH2\*1/\*1 and ALDH2\*1/\*2 genotypes identified by PCR-RFLP and confirmed by direct nucleotide sequencing. Before and after disulfiram treatment in one-week interval, the participants received an oral dose of ethanol (0.2 g/kg). The blood ethanol and acetaldehyde, cardiovascular hemodynamic parameters were measured following ethanol ingestion. Result. The disulfiram increased ethanol-induced hypothermia and sedation in C57BL/6J mice.In human study, no acetaldehyde accumulation in ALDH2\*1/\*1 alcoholic subjects and mild elevation (∼40 uM) in ALDH2\*1/\*2 alcoholics following low dose ethanol ingestion. After the disulfiram treatment, there were significantly higher levels of blood acetaldehyde (peak concentration ∼200 uM in ALDH2\*1/\*1 group and ∼500 uM in ALDH2\*1/\*2 group). Consistently, the cardiovascular hemodynamic parameters showed marked alterations (∼50% increase of heart rate) after disulfiram treatment. Conclusion. The disulfiram-alcohol reaction is sufficiently potent to make alcoholics stop alcohol drinking, but should reduce treatment dose for subjects with variant ALDH2*2 and be aware of the potential hazard consequences for uncontrollable alcohol drinking in the treatment course.

Alcohol-Medication Interactions: The Acetaldehyde Syndrome

Medications that inhibit aldehyde dehydrogenase when coadministered with alcohol produce accumulation of acetaldehyde. Acetaldehyde toxic effects are characterized by facial flushing, nausea, vomiting, tachycardia and hypotension, symptoms known as acetaldehyde syndrome, disulfiram-like reactions or antabuse effects. Severe and even fatal outcomes are reported. Besides the aversive drugs used in alcohol dependence disulfiram and cyanamide (carbimide), several other pharmaceutical agents are known to produce alcohol intolerance, such as certain anti-infectives, as cephalosporins, nitroimidazoles and furazolidone, dermatological preparations, as tacrolimus and pimecrolimus, as well as chlorpropamide and nilutamide. The reactions are also observed in some individuals after the simultaneous use of products containing alcohol and disulfiram-like reactions inducers. Depending on the pharmacological inducer, reactions may occur several days after treatment completion. Disulfiram-alcohol reaction includes moderate decrease in blood pressure, but severe life-threatening arterial hypotension and shock sometimes develop. Myocardial infarction secondary to disulfiram-alcohol reaction has been also reported. For severe hypotension resulting from a disulfiram-ethanol reaction, adrenaline or noradrenaline have been employed as the pressor agent of choice. Fomepizole, an alcohol dehydrogenase inhibitor, may be a safe and effective treatment of severe reactions. When medications that produce antabuse effects are prescribed or dispensed, patients should be instructed to avoid medicines and other products containing alcohol, such as syrups, fermented vinegar, sauces and lotions. It is essential that doctors, nurses and pharmacists instruct patients to avoid alcohol during treatment with aversive drugs and disulfiram-like reactions inducers. Likewise, even when scientific evidence is inconclusive, such instructions should be provided in leaflets, which are often the only source of information for patients and a guide for health professionals.

Disulfiram reaction in an artist exposed to solvents

This case report describes an artist on treatment for alcoholism with disulfiram (Antabuse) who suffered chronic symptoms similar to those of a disulfiram alcohol reaction, which we attribute to his occupational exposure to products containing alcohol and other solvents. Symptoms abated with strict precautions to prevent exposure, although gradually returned over the course of months, causing him eventually to stop the medication. Medical practitioners should be aware of possible adverse interactions between occupational solvent exposures and disulfiram.

Cardiovascular Complications of Disulfiram Alcohol Reaction

Cardiovascular Complications of Disulfiram Alcohol Reaction

Divergence of Ethanol and Acetaldehyde Kinetics and of the Disulfiram‐Alcohol Reaction between Subjects with and without Alcoholic Liver Disease

Despite standardization, marked interindividual variation in the severity of the disulfiram-alcohol reaction (DAR) has been observed. We studied the DAR in 51 consecutive alcoholics with (n = 16) and without (n = 35) significant alcoholic liver disease. Clinical signs of the DAR were much weaker in the patients with compared with those patients without liver disease. Because acetaldehyde is thought to be the main cause of the DAR, we studied ethanol and acetaldehyde kinetics in 13 patients (6 females, 7 males) with alcoholic liver disease (documented by biopsy, clinical and/or radiological findings, and by quantitative liver function) [galactose elimination capacity (GEC) 4.2 +/- SD 1.0 mg/min/kg; aminopyrine breath test (ABT) 0.14 +/- 0.10% dose x kg/mmol CO2] and 13 age- and sex-matched controls (alcoholics without significant liver disease, GEC 7.1 +/- 0.7; ABT 0.81 +/- 0.35). Clinical signs of acetaldehyde toxicity during the DAR (flush, nausea, tachycardia, and blood pressure drop) were absent in alcoholic liver disease, but clearly evident in controls. Blood ethanol kinetics were similar in both groups, Cmax and area under the concentration-time curve (AUC) being 6.27 +/- 1.82 and 368.9 +/- 72.9 mmol x min/liter in alcoholic liver disease, and 6.62 +/- 1.71 and 377.6 +/- 124.5 in controls, respectively. In contrast, there was a strong (p < 0.001) difference in Cmax and AUC of acetaldehyde, respective values being 33.46 +/- 21.52 and 1463.8 +/- 762.5 mumol x min/liter in alcoholic liver disease, and 110.87 +/- 56.00 and 4162.0 +/- 2424.6 in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

An exceptional case of lethal disulfiram-alcohol reaction

A case of fatal disulfiram-alcohol reaction due to ingestion of ethanol and antabuse is presented. Unusual autopsy findings and toxicological results are described. This case represents a report of corrosion lesion in the lower oesophagus and stomach due to a violent chemical reaction in situ and also the highest blood concentration of acetaldehyde (41 mg/l) ever recorded.

Dose-effect relationship of disulfiram in human volunteers. II: A study of the relation between the disulfiram-alcohol reaction and plasma concentrations of acetaldehyde, diethyldithiocarbamic acid methyl ester, and erythrocyte aldehyde dehydrogenase activity.

The study was designed to elucidate the basic pharmacological and biochemical effects of the disulfiram dose (Antabus) provoking disulfiram-alcohol reaction (DAR) in 52 human volunteers after ethanol challenge. Disulfiram was given daily in increasing doses (1, 100, 200, and 300 mg) in successive 14 day periods, with ethanol challenge at the end of each period, until a DAR was achieved. Irrespective of dose (except the 1 mg dose), the DAR was always accompanied by almost complete inactivation (about 97%) of aldehyde dehydrogenase (ALDH) activity in erythrocytes, plasma concentrations of diethyldithiocarbamic acid methyl ester (Me-DDC) in the range of 8-472 nmol/l and accumulated plasma concentrations of acetaldehyde in the range of 7-197 mumol/l. In four of the volunteers, the cardiovascular effects of the DAR were recorded as a decrease in diastolic blood pressure (14-47 mmHg) and an increase in pulse rate (9-40 beats/min.), accompanied by a two- to fourfold increase in the plasma concentrations of adrenaline and noradrenaline. The enzyme kinetics of ALDH in erythrocytes were regularly analysed in eight volunteers during DSF intake. In addition to the expected decrease in oxidizing capacity, the Km values were also impaired, which suggests that the inhibitor is implicated in an active site directed reaction.

Dose‐Effect Relationship of Disulfiram in Human Volunteers. I: Clinical Studies

The aim of this study was to investigate the relation between Antabus dosage and the disulfiram-alcohol reaction (DAR) after ethanol challenge. Fifty-two healthy volunteers, 29 men and 23 women, aged 20-61 years, were treated with increasing doses of Antabuse (1, 100, 200, 300 mg) for 14 days each. At the end of each 14 days the volunteers were challenged with 0.15 g ethanol/kg body weight. Blood pressure, pulse rate, respiration rate, and symptoms such as flushing, heat sensation, nausea, vomiting, palpitations, breathlessness, and headache were monitored for the next 50 min. The volunteers left the study when they had experienced a valid DAR. A valid DAR, which was principally defined on the basis of the patients' feeling of discomfort, but for safety reasons also on the basis of unacceptable circulatory changes, was reached in 21 out of 52 volunteers after 100 mg Antabuse, in 27 after 200 mg, and in 4 after 300 mg. Most of them left the study after flushing and circulatory changes, but did not feel ill enough to be convinced that they should abstain from drinking. Ten volunteers with weak subjective symptoms, but with a valid DAR, were therefore rechallenged after the next increased dose and experienced a somewhat stronger reaction. We conclude that a daily dose of 200 mg Antabuse brings about a substantial reaction in volunteers in the presence of alcohol. The possible need for a 300 mg dose of Antabuse to prevent a patient from drinking was discussed.

Inhibition of erythrocyte aldehyde dehydrogenase activity and elimination kinetics of diethyldithiocarbamic acid methyl ester and its monothio analogue after administration of single and repeated doses of disulfiram to man

The elimination kinetics of the methyl esters of diethyldithiocarbamic acid (Me-DDC) and its monothio analogue (Me-DTC) has been compared in ten alcoholic patients after a single oral dose of 400 mg disulfiram (Antabuse). Erythrocyte aldehyde dehydrogenase (ALDH) activity was continuously followed in the subjects until complete inactivation. The relation between individual steady-state concentrations of Me-DTC in plasma, blood acetaldehyde concentration and the dose of disulfiram sufficient to give the disulfiram alcohol reaction was investigated in 12 healthy volunteers treated with increasing doses of disulfiram and then challenged with ethanol. The mean peak plasma concentration of Me-DDC occurred at 1.8 h and its plasma half-life was 6.3 h. The corresponding values for Me-DTC were 3.3 h and 11.2 h, respectively. This suggests oxidative formation of Me-DTC from Me-DDC. In alcoholics with a rapid decrease in erythrocyte ALDH activity (in less than 5 days), the mean peak plasma concentration of Me-DTC was 278 nmol.l-1, whereas the peak concentration was below the detection limit in subjects with a prolonged inactivation time (7-20 days). The healthy volunteers were divided into three groups of four subjects, with clinically valid disulfiram alcohol reactions at 100, 200, and 300 mg doses of disulfiram, respectively. The mean plasma concentrations of Me-DTC at steady-state were proportional to the disulfiram doses given, compared within groups at different doses, and between groups at equal and different optimal doses of the drug. The concentrations of Me-DTC were significantly increased, as compared above, whereas the blood concentrations of acetaldehyde were not significantly increased.(ABSTRACT TRUNCATED AT 250 WORDS)

The disulfiram-alcohol reaction: factors determining and potential tests predicting severity.

13 ambulatory alcoholics (3 women, 10 men) who consented to alcohol-aversive treatment with disulfiram were subjected to detailed investigations before, during, and after the disulfiram-alcohol reaction (DAR). The studies included quantitative estimation of liver function (aminopyrine breath test, ABT; galactose elimination capacity, GEC) prior to the DAR, measurement of alcohol and acetaldehyde plasma levels together with pulse rate and blood pressure during the DAR, and the effects of disulfiram on erythrocyte acetaldehyde-oxidizing capacity (AOC). As expected, the severity of the DAR showed considerable interindividual variation. However, the maximal fall in diastolic blood pressure was closely (r = 0.83; p less than 0.001; n = 13) related to peak acetaldehyde plasma level (AAPL). The decrease in systolic blood pressure was age dependent, individuals greater than 40 years exhibiting a larger drop for a given AAPL. The dependence of acetaldehyde formation on liver function was suggested by a significant correlation (r = 0.88; p less than 0.01; n = 8) between ABT and AAPL; this relationship was influenced by the prior intake of enzyme-inducing drugs. Measurements of AOC indicated that a disulfiram-induced maximal suppression is achieved already after 6 days of treatment reaching levels of 0.7 +/- 0.6 nmol/ml/min (SD) (compared to pretreatment values of 4.1 +/- 0.9). Mean values in untreated alcoholics and in subjects with alcoholic or nonalcoholic liver disease were not significantly different from controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Cutaneous Reactions to Lower Aliphatic Alcohols Before and During Disulfiram Therapy

Cutaneous reactions to ethyl alcohol (ethanol), N-propyl alcohol (1-propanol), isopropyl alcohol (2-propanol), and acetaldehyde were evaluated in a control group and in patients before and while they were receiving disulfiram therapy. Local cutaneous erythema was observed from patch tests with ethyl alcohol, N-propyl alcohol, and isopropyl alcohol in hydrated skin, and from acetaldehyde in dry skin. Since reactions noted from topically applied alcohols before and while the patients were receiving disulfiram therapy were not statistically different, a localized disulfiram-alcohol reaction is unlikely. Erythema resulting from topically applied alcohols occurred in a dose-related manner and was caused by a direct vasodilatory effect on the cutaneous microvasculature. We believe that all true disulfiram-alcohol reactions are systemic, rather than local, in nature and require a substantial amount of alcohol to enter the system.

Reevaluation of the disulfiram-alcohol reaction in man.

The intensity of the disulfiram-alcohol reaction is found to depend on the blood acetaldehyde level, a disulfiram-induced predisposition reflected by alkalosis, and an individual predisposition reflected by dopamine-beta-hydroxylase activity.

Drug therapy reviews: Management of the disulfiram-alcohol reaction

A review of the proposed mechanisms of the disulfiram-alcohol interaction and recommended management of the interaction is presented. The efficacy of disulfiram in the management of alcoholism, the signs and symptoms of the disulfiram-alcohol interaction, and other agents with disulfiram-like activity are discussed. Recommended treatment consists of supportive measures such as Trendelenberg posture, administration of oxygen and intravenous infusion of fluid, solute, colloid, and, if needed, a pressor agent such as norepinephrine. Iron salts, ascorbic acid, antihistamines and phenothiazines are of no established benefit.

Disulfiram Hypersensitivity Hepatitis

DISULFIRAM is widely used as adjunctive therapy in the outpatient treatment of chronic alcoholism. Except for the disulfiram-alcohol reaction, disulfiram alone appears to be well tolerated by man. In a compilation by Ayerst Laboratories (New York) of more than 160 reports from the literature of 1948 to 1971, and in a personal search of the English literature, no reference to hepatic toxicity could be found. The following case, therefore, is reported because it included two episodes of acute hepatitis that were temporally related to the administration of disulfiram. Report of a Case A 44-year-old white salesman was transferred from the White City domiciliary to the Portland Veterans Administration Hospital for evaluation of a rising level of serum glutamic oxaloacetic transaminase (SGOT) and two recent episodes of hepatitis that occurred after the administration of disulfiram. From November 1971 to March 1972 he was hospitalized at the Palo Alto Veterans Administration Hospital

Alcohol and Disulfiram

To the Editor.— The LETTER of Koff et al ( 215 :1988-1989, 1971) is a timely reminder of the precautions which the physician prescribing disulfiram must impress upon his patient. I discuss this with the patient when he is first administered this medication, and I also write out for him a list of proscribed alcohol-containing substances. The list goes like this: no alcohol, hard liquor, wine, beer, liqueurs, aperitifs, cider, wine vinegar, cooking wine, alcohol sponges, extensive applications of body lotions, eau de Cologne, mouthwashes, after-shave lotion, cough medication unless prescribed by a physician, or paraldehyde. It may be that I err on the over-cautious side, but I have never had a patient report a disulfiram-alcohol reaction from substances he was forewarned about.

Alcohol in cough medicines hazard to disulfiram user.

To the Editor.— The use of disulfiram (Antabuse) as an adjunct to alcoholism treatment programs is well known in this country, and may be increasing. 1 The minimal dose of alcohol necessary to evoke a reaction in the disulfiram treated patient is somewhat controversial, 2 although it has been suggested that as little as 7 ml of alcohol may cause typical reactions. 3 Thus, in disguised forms, alcohol could represent a serious hazard for patients receiving disulfiram. Our experience with a patient who had a disulfiram-alcohol reaction following the ingestion of a single dose of an over-the-counter, widely advertised cough medication, containing 25% alcohol, serves to emphasize the dangers of alcohol-containing preparations in these unique patients. Report of a Case.— The patient, a 46-year-old white man, was admitted to the hospital because of the abrupt onset of nausea, vomiting, and flushing of several hours' duration. He had been a heavy

Sudden Death during Disulfiram—Alcohol Reaction

A 44-year-old healthy alcoholic had been taking 0.5 g of disulfiram daily for 8 weeks. On day 1 he drank a “quart” of whisky, was arrested for drunkenness and released. On day 2 he drank a “pint” o...

Effect of disulfiram (tetraethylthiuram disulfide) on mitochondrial oxidations

Disulfiram inhibits the oxidation of NAD-linked substrates by mitochondria but does not affect their succinoxidase activity. The oxidation of β-hydroxybutyrate was totally blocked by 0·27 mM disulfiram. Disulfiram did not change the P/O ratios. Uncoupled mitochondria were less sensitive to disulfiram than phosphorylating mitochondria. Disulfiram inhibited the dinitrophenol-activated ATPase of mitochondria by about 60 per cent whilst having little effect on Mg 2+-activated ATPase. The ATP-P i exchange reaction was approximately 50 per cent inhibited by disulfiram. The inhibitory effect of disulfiram on mitochondria is irreversible. 2-Mercaptoethanol protected the mitochondria if present before the addition of disulfiram. The mechanism of action of disulfiram and the implications of the results for the understanding of the disulfiram-alcohol reaction and the mechanism of oxidative phosphorylation are discussed.

Acetoin as a metabolite of ethanol.

AbstractBlood acetoin concentrations in rabbits were followed after administration of ethanol to animals receiving disulfiram and to control animals. Disulfiram increased blood acetoin before and after the administration of alcohol. No increase was observed in animals receiving alcohol alone. Acetoin formation from acetaldehyde and pyruvate or ethanol and pyruvate was investigated in vitro. In liver homogenates and minced liver acetoin was formed from ethanol and pyruvate, but not from ehtanol or pyruvate alone. Disulfiram inhibited acetoin synthesis from theanol and pyruvate under aerobic conditions, but not anaerobically or when acetaldehyde and pyruvate were used as substrates. The role of acetoinin alcohol metabolism and disulfiramalcohol reaction is discussed.