Effect of disulfiram

One fascinating aspect of the effect of the genetic polymorphisms described earlier is that acculturation can partially overcome the protective factor, and Asian groups born in North America may have only partial protection (Goldman 1993 Tu and Israel 1995). In individuals who consume small amounts of alcohol over time, the aversive effects diminish, an effect similar to that described in clinical reports of patients who developed a resistance to the effects of disulfiram. 

Disulfiram produces a variety of adverse effects, which commonly include drowsiness, lethargy, and fatigue (Chick 1999). Other more serious adverse effects, such as optic neuritis, peripheral neuropathy, and hepatotoxicity, are rare. Psychiatric effects of disulfiram are also uncommon. They probably occur only at higher dosages of the drug and may result from the inhibition by disulfiram of a variety of enzymes in addition to ALDH. Included among the enzymes inhibited by disulfiram is dopamine P-hydroxylase, inhibition of which increases dopamine levels, which in turn can exacerbate psychotic symptoms in patients with schizophrenia and occasionally may result in psychotic or depressive symptoms in patients without schizophrenia. 

DISULFIRAM PROTON PUMP INHIBITORS -OMEPRAZOLE Possible T adverse effects of disulfiram Accumulation of metabolites Monitor closely for T side-effects, although patients have received combinations without reported problems... 

Effects of disulfiram 523 6.6 Primary liver cell carcinoma 534... 

Several adverse effects of disulfiram itself (as opposed to the aldehyde that it allows to accumulate) have been described. They include neurological reactions and skin reactions, but hepatotoxicity is the only previously reported life-threatening reaction, and it is rare (3). 

The neurotoxic effects of disulfiram have been compared with those of carbon disulfide, a disulfiram metabolite (9). The results suggested that carbon disulfide may be responsible for the behavioural and neurological adverse effects of disulfiram. If so, other toxic effects of carbon disulfide might follow administration of high doses of disulfiram, such as parkinsonism, psychotic behaviour, and encephalopathy. 

Helander A, Carlsson S. Use of leukocyte aldehyde dehydrogenase activity to monitor inhibitory effect of disulfiram treatment. Alcohol Clin Exp Res 1990 14(l) 48-52. 

Keplinger ML, Wells JA. The effect of disulfiram on the action and metabolism of paraldehyde. J Pharmacol Exp Ther 1957 119(l) 19-25. 

Nagendra SN, Shetty KT, Subhash MN, Udaya HB, Pradhan N (1993) Effect of disulfiram administration on brain tryptophan, serotonin and peripheral tryptophan content. Neurochem Int 22 31-36... 

Nilsson GE, Tottmar O (1989) Effects of disulfiram and coprine on rat brain tryptophan hydroxylation in vivo. Neurochem Res 14 537-540... 

Fiala ES, Bobotas G, Lukakis C, et al. 1977. Effects of disulfiram and related compounds on the metabolism in vivo ofthe colon carcinogen, 1,2-dimethylhydrazine. Biochem Pharmacol 26 1763-1768. 

There seems to be only one report (with temazepam) of a olinieally signif-ieant interaction between disiifiram and the benzodiazepines, and this report is unconfirmed, as the patient did not take temazepam alone. The other reports only describe potential interactions that have been identified by single-dose studies. These do not necessarily reliably predict what will happen in practice. However, it seems possible that some patients will experience increased drowsiness, possibly because of this interaction, and because drowsiness is a very common adverse effect of disulfiram. Reduce the dosage of the benzodiazepine if necessary. Benzodiazepines that are metabolised by similar pathways to diazepam and chlordiazepoxide, may possibly interact in the same way (e.g. bromazepam, clonazepam, clorazepate, prazepam, ketazolam, clobazam, flurazepam, nitrazepam, medazepam) but this needs confirmation. Alprazolam, oxazepam and lo-razepam appear to be non-interacting alternatives. 

Drug-drug interactions Disulfiram A pharmacokinetics study (n=40) examined the effect of disulfiram (DIS) on EFV, ritonavir and ATV, concluding that ATV co-administration reduced the effect of DIS on aldehyde dehydrogenase (which mediates the DIS-alcohol reaction) [286 j. This happens possibly as a result of ATV s inihibition of CYP 3A4, what may render DIS ineffective in the treatment of alcoholism. 

The effects of warfarin may increase when administered with acetaminophen, NSAIDs, beta blockers, disulfiram, isoniazid, chloral hydrate, loop diuretics, aminoglycosides, cimetidine, tetracyclines, and cephalosporins. Oral contraceptives, ascorbic acid, barbiturates, diuretics, and vitamin K decrease the effects of warfarin. Because die effects of warfarin are influenced by many drugp, die patient must notify die nurse or die primary healdi care provider when taking a new drug or discontinuing... 

Disulfiram is usually given orally. Because there is an increased risk of side effects and toxic hazards as the dosage is increased, the daily dosage prescribed in the United States has been limited to 250—500 mg/day. However, efforts to titrate the dosage of disulfiram in relation to a challenge dose of ethanol indicated that some patients require in excess of 1 g/day of disulfiram to reach blood levels sufficient to produce a DER (Brewer 1984). 

Anton RF, Pettinati H, Zweben A, et al A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 24 421 28, 2004 Aragon CM, Stotland LM, Amit Z Studies on ethanol-brain catalase interaction evidence for central ethanol oxidation. Alcohol Clin Exp Res 15 165-169, 1991 Arizzi MN, Correa M, Betz AJ, et al Behavioral effects of intraventricular injections of low doses of ethanol, acetaldehyde, and acetate in rats studies with low and high rate operant schedules. Behav Brain Res 147 203—210, 2003 Azrin NH, Sisson RW, Meyers R, et al Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psychiatry 13 105—112, 1982 Babor TF, Kranzler HR, Lauerman RL Social drinking as a health and psychosocial risk factor Anstie s limit revisited, in Recent Developments in Alcoholism, Vol 5. Edited by Galanter M. New York, Plenum, 1987, pp 373 02... 

Brewer C How effective is the standard dose of disulfiram a review of the alcohol-disulfiram reaction in practice. Br J Psychiatry 144 200—202, 1984... 

Chester JA, Cunningham CL GABA(A) receptor modulation of the rewarding and aversive effects of ethanol. Alcohol 26 131—143, 2002 Chick J Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf 20 427 35, 1999... 

Azrin NH, Sisson RW, Meyers R, et al Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psy 13 105-112, 1982 Bickel WK, Amass L, Higgins ST, et al Effects of adding behavioral treatment to opioid detoxification with buprenorphine. J Consult Clin Psychol 65 803—810, 1997 Bien TH, Miller WR, Tonigan JS Brief interventions for alcohol prohlems a review. Addiction 88 315-335, 1993... 

Bartonicek V, Teisinger J. 1962. Effect of tetraethyl thiram disulphide (disulfiram) on metabolism of trichloroethylene in man. Br JIndMed 19 216-221. 

MacDonnell. M.F and Fessock, L. Some effects of ethanol, amphetamine, disulfiram and p-CPA on seizing of prey in feline predatory attack and on associated motor pathways. Q J Stud Ale 33 437-450, 1972. 

Disulfiram works by irreversibly blocking the enzyme aldehyde dehydrogenase, a step in the metabolism of alcohol, resulting in increased blood levels of the toxic metabolite acetaldehyde. As levels of acetaldehyde increase, the patient experiences decreased blood pressure, increased heart rate, chest pain, palpitations, dizziness, flushing, sweating, weakness, nausea and vomiting, headache, shortness of breath, blurred vision, and syncope. These effects are commonly referred to as the disulfiram-ethanol reaction. Their severity increases with the amount of alcohol that is consumed, and they may warrant emergency treatment. Disulfiram is contraindicated in patients who have cardiovascular or cerebrovascular disease, because the hypotensive effects of the disulfiram-alcohol reaction could be fatal in such patients or in combination with antihypertensive medications. Disulfiram is relatively contraindicated in patients with diabetes, hypothyroidism, epilepsy, liver disease, and kidney disease as well as impulsively suicidal patients. 

Bourdelat-Parks B., Anderson G., Donaldson Z. et al. (2005). Effects of dopamine beta-hydroxylase genotype and disulfiram inhibition on catecholamine homeostasis in mice. Psychopharmacol. (Berl). 183, 72-80. 

Hematologic Effects. Effects of 1,2-dibromoethane on the hematopoietic system of humans exposed by inhalation, oral, or dermal routes have not been described. Results of animal studies are equivocal except that, based on a study in rats, individuals taking disulfiram for alcoholism might be a susceptible human subpopulation at higher risk for adverse hematopoietic effects (Wong et al. 1982) (See Sections 2.6 and 2.7). 

Disulfiram is the generic name for Antabuse, a drug used in the treatment of chronic alcoholism. Disulfiram potentiates the toxic and carcinogenic effects of 1,2-dibromoethane in experimental animals. Presumably, this occurs by blocking conversion of the aldehyde metabolite as with acetaldehyde from ethanol. There is no evidence that similar effects occur in humans. Based on animal data, however, Ayerst Laboratories, producers of Antabuse (disulfiram), recommended the following in the package insert "Patients taking Antabuse tablets should not be exposed to ethylene dibromide or its vapors" (PDR 1991). 

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