DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

644 metabolites of the drug, especially diethylthiomethylcarbamate,
behave as suicide-substrate inhibitors of ALDH in vitro. These
metabolites reach significant concentrations in plasma following the
administration of disulfiram (Johansson, 1992).
The ingestion of alcohol by individuals previously treated with
disulfiram gives rise to marked signs and symptoms of acetaldehyde
poisoning. Within 5-10 minutes, the face feels hot and soon afterward
becomes flushed and scarlet in appearance. As the vasodilation spreads
over the whole body, intense throbbing is felt in the head and neck, and
a pulsating headache may develop. Respiratory difficulties, nausea,
copious vomiting, sweating, thirst, chest pain, considerable hypotension,
orthostatic syncope, marked uneasiness, weakness, vertigo,
blurred vision, and confusion are observed. The facial flush is replaced
by pallor, and the blood pressure may fall to shock levels.
Alarming reactions may result from the ingestion of even
small amounts of alcohol in persons being treated with disulfiram.
The use of disulfiram as a therapeutic agent thus is not without
danger, and it should be attempted only under careful medical and
nursing supervision. Patients must be warned that as long as they are
taking disulfiram, the ingestion of alcohol in any form will make
them sick and may endanger their lives. Patients must learn to avoid
disguised forms of alcohol, as in sauces, fermented vinegar, cough
syrups, and even after-shave lotions and back rubs.
The drug never should be administered until the patient has
abstained from alcohol for at least 12 hours. In the initial phase of
treatment, a maximal daily dose of 500 mg is given for 1-2 weeks.
Maintenance dosage then ranges from 125-500 mg daily depending
on tolerance to side effects. Unless sedation is prominent, the daily
dose should be taken in the morning, the time when the resolve not
to drink may be strongest. Sensitization to alcohol may last as long
as 14 days after the last ingestion of disulfiram because of the slow
rate of restoration of ALDH (Johansson, 1992).
Disulfiram and/or its metabolites can inhibit many enzymes
with crucial sulfhydryl groups, and it thus has a wide spectrum of
biological effects. It inhibits hepatic CYPs and thereby interferes
with the metabolism of phenytoin, chlordiazepoxide, barbiturates,
warfarin, and other drugs.
Disulfiram by itself usually is innocuous, but it may cause acneform
eruptions, urticaria, lassitude, tremor, restlessness, headache,
dizziness, a garlic-like or metallic taste, and mild GI disturbances.
Peripheral neuropathies, psychosis, and ketosis also have been reported.
SECTION II
NEUROPHARMACOLOGY
Other Agents
Ondansetron, a 5-HT 3
-receptor antagonist and antiemetic drug
(Chapters 13 and 46), reduces alcohol consumption in laboratory
animals and currently is being tested in humans. Preliminary findings
suggest that ondansetron is effective in the treatment of early-onset
alcoholics, who respond poorly to psychosocial treatment alone,
although the drug does not appear to work well in other types of
alcoholics. Ondansetron administration lowers the amount of alcohol
consumed, particularly by drinkers who consume fewer than
10 drinks per day (Sellers et al., 1994). It also decreases the subjective
effects of ethanol on 6 of 10 scales measured, including the
desire to drink (Johnson et al., 1993), while at the same time not having
any effect on the pharmacokinetics of ethanol.
Topiramate, a drug used for treating seizure disorders
(Chapter 21), appears useful for treating alcohol dependence.
Compared with the placebo group, patients taking topiramate
achieved more abstinent days and a lower craving for alcohol
(Johnson et al., 2003). The mechanism of action of topiramate is not
well understood but is distinct from that of other drugs used for
the treatment of dependence (e.g., opioid antagonists), suggesting
that it may provide a new and unique approach to pharmacotherapy
of alcoholism.
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