Bankole A. Johnson
Department of Psychiatry and Neurobehavioral Sciences, University of Virginia, Charlottesville, VA, USA
Disulfiram is one of several aldehyde dehydrogenase (ALDH) inhibitors that increase the plasma level of ► acetaldehyde in the body following the ingestion of ethanol. Disulfiram is currently used in the treatment of alcoholism.
As early as 1937, it was realized that exposure to disulfi-ram (tetraethylthiuram disulphide) resulted in abstinence from alcohol. Tetraethylthiuram disulphide has been used since the 1880s in the manufacturing process of rubber (Suh et al. 2006). E. E. Williams, an American physician working at a chemical plant, was the first to observe that workers who were exposed to disulfiram experienced unpleasant effects after drinking alcohol and, as a result, involuntarily abstained from alcohol. Williams (1937) sent a letter to the editor of the Journal of the American Medical Association (JAMA) suggesting that the compound could be beneficial as a cure for alcoholism. The discovery remained overlooked until 1945 when Hald, Jacobsen, and Larsen, experimenting with disulfiram as an antihelminthic drug, ingested the drug and alcohol and experienced the unpleasant side effects firsthand. Realizing the potential of the drug, they went into collaboration with a clinician, Martensen-Larsen, to expand the research of disulfiram to alcoholics (Petersen 1992). The results were promising, pointing to disulfiram as a potential pharmacological treatment for alcoholism.
► Pharmacokinetics Absorption and Biotransformation
Following oral administration, disulfiram is rapidly absorbed from the gastrointestinal tract and is distributed across the mucosa into the blood. Endogenous thiols and the glutathione reductase system of erythrocytes then reduce disulfiram to its monomer, diethyldithiocarbamic acid (DDC). DDC, while unstable in the extremely acidic environment of the stomach, is a strong metal-chelating agent that has an affinity for cupric ions, forming a bis (diethyldithiocarbamato) copper complex (Cu(DDC)2). Cu(DDC)2 is rapidly degraded after its formation during the simultaneous reformation of DDC. DDC is itself unstable in biological tissues and is degraded into diethyl-amine (DEA) and CS2, both of which are eliminated without further degradation.
Another metabolite of disulfiram, diethylthiomethyl-carbamate (Me-DTC), is formed by oxidative desulfura-tion, which is mediated by microsomal ► cytochrome P450 mono-oxygenases. The last oxidative biotransformation of disulfiram produces formaldehyde, inorganic sulfate, and methanethiol (Johansson 1992).
Distribution, Protein Binding, and Excretion
Following absorption, disulfiram and its metabolites are evenly distributed throughout the body in a variety of tissues including the kidney, heart, liver, thyroid gland, adrenal gland, pancreas, and muscle, with lesser amounts observed in blood and the brain. Disulfiram and its metabolite DDC are bound to proteins by an interaction with protein-free thiol groups, while, in the blood, disul-firam and its metabolite Me-DTC are extensively bound to plasma albumin.
The metabolites of disulfiram are excreted by means of the lungs, kidney, and feces. Less than a quarter ofthe intact drug is excreted in the feces. The majority of metabolites, especially DDC, are eliminated by the kidneys. Although no excretion data are available for Me-DTC, the CS2 produced from the degradation of DDC in tissues is eliminated from the lungs. Only minor amounts of DDC, Me-DTC, CS2, and DEA are detectable in urine (Johansson 1992).
Aldehyde Dehydrogenase (ALDH) Inhibition -Mechanism of Action
Following consumption of ethanol, the first oxidation metabolite produced is ► acetaldehyde. Because acetalde-hyde is toxic to cells, it is essential that it is metabolized further. The next step in the elimination of ethanol is made possible by the enzyme ALDH, which almost instantaneously metabolizes the toxic acetaldehyde to the nontoxic acetate. There are four different ► isozyme forms of ALDH although the two main forms involved in the oxidation of acetaldehyde are ALDH1 and ALDH2, both of which are found mainly in the liver.
Disulfiram has a preference for ALDH1, and this preferential inhibition causes a marked increase in acetaldehyde following the ingestion of ethanol. The rapid accumulation of acetaldehyde occurs not only because the enzyme that degrades it is inhibited, but also because the enzyme that degrades ethanol into acetaldehyde, ► alcohol dehy-drogenase (ADH), has a faster turnover rate than ALDH. Not only does disulfiram block ALDH1, but its metabolites play a role in inhibiting ALDH as well. Specifically, Me-DTC has been characterized as an irreversible inactiva-tor of ALDH1. The overall inhibition of ALDH by dis-ulfiram and its metabolites is via a quick competitive inactivation, which is then followed by the irreversible inhibition of the enzyme, halting its activity (Johansson 1992).
The consequential buildup of acetaldehyde from blocking its metabolism by ALDH is responsible for the negative effects associated with combining disulfiram and ethanol. These negative effects are proportional to the amount of ethanol ingested. Immediately after drinking, the person experiences facial flushing, a mild headache, and sweating. The effects may then worsen to include nausea, vomiting, palpitation, hyperventilation, and hypotension. The most severe effects may include respiratory depression, arrhythmias, unconsciousness, convulsions, congestive heart failure, cardiovascular collapse, and even death (Suh et al. 2006).
There are a large number of reported compounds that adversely interact with disulfiram. Those drugs that interfere with the dopamine/norepinephrine system should not be administered with disulfiram because this may cause sleeplessness, paranoia, and even ► psychosis. Examples of drugs that interfere with the dopamine/ norepinephrine system include ► bupropion, ► amphetamines, ► methylphenidate, and ► cocaine. Interestingly, the pesticide thiram acts as a disulfiram analog, and its use should be avoided by anyone taking disulfiram. The Coprinus atramentarius species of mushroom should also be avoided since it is an ALDH inhibitor (Johansson 1992).
Drugs that use cytochrome P450 for oxidative metabolism have been found to change their biotransformation rate when coadministered with disulfiram. In particular, warfarin and some of the ► tricyclic antidepressants such as ► amitriptyline and ► imipramine have prolonged plasma clearance rates when given with disulfiram.
Other drugs that do not utilize cytochrome P450 for metabolic oxidation still show a prolonged clearance rate when coadministered with disulfiram. These drugs include ► barbiturates, many of the ► benzodiazepines including diazepam. ► Caffeine metabolism is also prolonged in persons taking disulfiram. Patients on the bronchodilator theophylline should also be aware that concurrent use with disulfiram will cause them to experience a prolonged effect of the bronchodilating methylxan-thine (Johansson 1992).
While disulfiram is a useful aversion therapy drug, there are other variables at work. The efficacy of disulfiram is more dependent on compliance than only on the drug itself. When patients are closely monitored during the course of treatment, the efficacy of disulfiram is quite good. In fact, a review by Brewer et al. (2000) reported that 17 out of 18 disulfiram studies demonstrated the effectiveness of disulfiram when subjects were directly supervised. Without supervision, the adherence rate can be as low as 20% (Suh et al. 2006).
Another factor that influences the efficacy of disulfi-ram is the patient. When patients have stability in the home and family, are not uncontrolled heavy drinkers, and are motivated to abstain from alcohol, they display better adherence to disulfiram treatment. Although disul-firam no longer holds the key to a cure for alcoholism, it can be a very helpful tool when combined with appropriate supervision and support (Johnson 2008).
When disulfiram was first being evaluated as a treatment for alcoholism, the dose range was between 1,000 and 3,000 mg/day. At such high doses, severe ► adverse effects were not uncommon. Such adverse effects included psychosis, sudden circulatory collapse, and sudden respiratory collapse. It is important to note, however, that most of the patients who suffered a fatal disulfiram-ethanol reaction were reported to have consumed large amounts of alcohol following disulfiram administration, a combination that undoubtedly contributed to their deaths (Suh et al. 2006).
Besides the high doses of disulfiram, early treatments also involved an initial aversion trial in which the patient would purposefully be given disulfiram and ethanol. The point was to demonstrate to the patient, under controlled medical conditions, how the disulfiram-ethanol interaction would feel and thus prevent patients from drinking while being treated with disulfiram. The practice of the initial aversion trial was later discontinued, and patients were only given verbal descriptions of the side effects of the disulfiram-ethanol reaction. This change in practice ushered in the use of disulfiram as strictly a psychological deterrent to drinking while reinforcing the importance of close supervision during treatment.
Current treatment guidelines state that the lowest possible dose of disulfiram should be given in order to obtain the required result. The FDA recommends a daily dose of 250 mg, but some patients can take as little as 125 mg or up to as much as 500 mg. At these doses, disulfiram is safe and well tolerated for both short- and long-term treatment of alcoholism (Suh et al. 2006).
The most frequently reported side effects of disulfiram in the absence of alcohol include headache, drowsiness, dermatitis, and a garlic-like aftertaste. Another less common side effect is ► hepatotoxicity, especially in persons with liver disease. This adverse effect can, however, be avoided by providing the patient with educational materials and by conducting frequent liver function testing.
Disulfiram is contraindicated in persons with cardiovascular as well as cerebrovascular disease. Patients with severe liver function abnormalities should also refrain from taking disulfiram. Disulfiram is a pregnancy category C compound and should not be given to women who are or may become pregnant during the course of treatment.
In conclusion, disulfiram continues to play an important role in helping people who abuse alcohol to achieve abstinence. Although disulfiram is in no way a panacea, its use as an aversion therapeutic in conjunction with appropriate supervision can help people to effectively abstain from alcohol consumption. It is up to the clinician to determine whether the patient would be successful in adhering to the disulfiram course of treatment and to make sure that the patient has all the necessary resources to be successful.
► Alcohol Abuse and Dependence
► Drug Interactions
Brewer C, Meyers RJ, Johnsen J (2000) Does disulfiram help to prevent relapse in alcohol abuse? CNS Drugs 14:329-341
Johansson B (1992) A review of the pharmacokinetics and pharmacody-namics ofdisulfiram and its metabolites. Acta Psychiatr Scand Suppl 369:15-26
Johnson BA (2008) update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings. Biochem Pharmacol 75:34-56
Petersen EN (1992) The pharmacology and toxicology of disulfiram and its metabolites. Acta Psychiatr Scand Suppl 369:7-13
Suh JJ, Pettinati HM, Kampman KM, O'Brien CP (2006) The status of disulfiram: a half of a century later. J Clin Psychopharmacol 26:290-302
Williams EE (1937) Effects of alcohol on workers with carbon disulfide. JAMA 109:1472-1473
A diuretic is any drug that elevates the rate of urination and thus provides a means of forced diuresis.
Diversion refers to a prescribed drug being given or sold to other people instead of being consumed by the person for whom it was prescribed.
► Abuse Liability
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