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EC number: 202-607-8
CAS number: 97-77-8
Disulfiram was widely used (approx. since 1950) as a drug for treatment of alcoholismis, usually administered p.o. in daily doses of 100 - 400 mg. It causes a blockade of the enzyme aldehyde dehydrogenase with consequently increasing levels of acetaldehyde upon ethanol consumption. The unpleasant clinical signs are known as Disulfiram-ethanol reaction (DER). Disulfiram also blocks the enzymatic degradation of dopamine by inhibition of dopamine b-hydroxylase (DBH). This effect might be used in the pharmacotherapy for the treatment of cocaine dependence.
Adverse effects of disulfiram as well as contraindications are
well investigated, as disulfiram was used for decades as a therapeutic
drug against alcoholism. In recent publications (reviewed by Kampman,
2009) the pharmacological safety of disulfiram was evaluated again, as
it was shown to have the potential to treat cocaine dependence. Whereas
aldehyde dehydrogenase is the primary target in treating alcoholism,
human laboratory, genetic, and preclinical animal studies indicate that
its beneficial effects on cocaine use result from the inhibition of
dopamine b-hydroxylase (Gaval-Cruz, 2009).
Peachey (1981) summarized four areas of concern associated with
repeated disulfiram application:
Medical complications during disulfiram-ethanol reaction (DER)
Myocardial infarction, shock, and death can occur during the DER.
Cerebrovascular haemorrhage and infarction, causing loss of
consciousness during the DER followed by death after several days, are
also reported. Although most fatal DERs have been associated with
excessive dosages of disulfiram (> 1500 mg daily) followed by
consumption of large amounts of ethanol, deaths have also been reported
with therapeutic disulfiram dosages and relatively small amounts of
ethanol. Reversible electrocardiographic changes are recorded during the
Toxicity associated with disulfiram administration in humans
Disulfiram and its metabolite diethyldithiocarbamate (DDC) inhibit
dopamine-b-hydroxylase (DBH) causing increased dopamine levels and
decreased norepinephrine levels in the brain and other tissues.
Drowsiness, lethargy, disturbed sexual function, and neuropsychological
dysfunction occur as a result of the DBH inhibition. More serious
behavioural changes include psychosis and acute encephalopathy which
occur particularly in individuals with low cerebral spinal fluid DBH
activity or low pretreatment levels of platelet monoamine oxidase and
amine oxidase and high levels of red cell catechol-O-methyltransferase.
Patients with a diagnosis of depression or borderline schizophrenia may
manifest more psychopathology while taking disulfiram. The development
of neuropathy, muscle weakness, and motor incoordination are the result
of CS2-induced toxicity during disulfiram treatment. In addition,
disulfiram may cause hepatotoxicity, atherosclerosis, and increased
blood pressure. Limb anomalies have been reported in infants born on
disulfiram-treated alcoholic mothers.
Disulfiram inhibits the metabolism of other drugs including
antipyrine, phenytoin, warfarin, isoniazid, rifampin, diazepam, and
chlordiazepoxide causing increased blood levels of these drugs. It is
noteworthy that a similar reaction does not occur with short- and
intermediate acting benzodiazepines. The simultaneous administration of
disulfiram with warfarin may result in prolongation of the prothrombin
time with subsequent haemorrhage. Similarly, cumulative toxicity to
phenytoin has been reported in alcoholics receiving disulfiram. On the
other hand, with cessation of disulfiram administration, dosages of the
other drugs may need to be adjusted downward. Diazepam induces the
intensity of the DER, while amitriptyline enhances DER.
Toxicity due to acetaldehyde
Blood acetaldehyde levels are raised appreciably in
disulfiram-treated alcoholics following the ingestion of relatively
small amounts of ethanol. It is possible that alcoholics who receive
disulfiram and who continue to drink may experience some degree of
acetaldehyde-induced cardiotoxicity and/or hepatotoxicity.
Clinical cases are published, where delirium-associated neurotoxic
effects are described. However, neurotoxic effects occurred upon
combined exposure to disulfiram and ethanol (Mirsal, 2005).
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