Page 418 - Basic _ Clinical Pharmacology ( PDFDrive )

404 SECTION V Drugs That Act in the Central Nervous System

TREATMENT OF ALCOHOLISM reduces its absorption even further. Acamprosate is widely distrib-
uted and is eliminated renally. It does not appear to participate
After detoxification, psychosocial therapy either in intensive inpa- in drug-drug interactions. The most common adverse effects are
tient or in outpatient rehabilitation programs serves as the primary gastrointestinal (nausea, vomiting, diarrhea) and rash. It should
treatment for alcohol dependence. Other psychiatric problems, not be used in patients with severe renal impairment.
most commonly depressive or anxiety disorders, often coexist
with alcoholism and, if untreated, can contribute to the tendency Disulfiram
of detoxified alcoholics to relapse. Treatment for these associated
disorders with counseling and drugs can help decrease the rate of Disulfiram acts by inhibiting aldehyde dehydrogenase. Alcohol is
relapse for alcoholic patients. metabolized as usual, but acetaldehyde accumulates. Thus, disul-
Three drugs—disulfiram, naltrexone, and acamprosate—have firam causes extreme discomfort in patients who drink alcoholic
FDA approval for adjunctive treatment of alcohol dependence. beverages. Disulfiram alone has little effect; however, flushing,
throbbing headache, nausea, vomiting, sweating, hypotension, and
confusion occur within a few minutes after an individual taking
Naltrexone disulfiram drinks alcohol. The effects may last 30 minutes in mild
cases or several hours in severe ones. Because adherence to disulfi-
Naltrexone, a relatively long-acting opioid antagonist, blocks ram therapy is low and because evidence from clinical trials for its
μ-opioid receptors (see Chapter 31). Alone and in combination effectiveness is weak, disulfiram is no longer commonly used.
with behavioral counseling, naltrexone has been shown in a num- Disulfiram is rapidly and completely absorbed from the gas-
ber of short-term (12- to 16-week), placebo-controlled trials to trointestinal tract; however, a period of 12 hours is required for
reduce the rate of relapse to either drinking or alcohol dependence its full action. Its elimination is slow, and its action may persist
and to reduce craving for alcohol, especially in patients with high for several days after the last dose. The drug inhibits the metabo-
rates of naltrexone adherence. Naltrexone is approved by the FDA lism of many other therapeutic agents, including phenytoin, oral
for treatment of alcohol dependence. Nalmefene, another opioid anticoagulants, and isoniazid. It should not be administered with
antagonist, appears to have similar effects in alcohol-use disorder medications that contain alcohol, including nonprescription med-
but is not yet approved by the FDA for this indication. ications such as those listed in Table 63–3. Disulfiram can cause
Naltrexone is generally taken once a day in an oral dose of small increases in hepatic transaminases. Its safety in pregnancy
50 mg for treatment of alcoholism. An extended-release formu- has not been demonstrated.
lation administered as an intramuscular injection once every 4
weeks is also effective. The drug can cause dose-dependent hepato- Other Drugs
toxicity and should be used with caution in patients with evidence
of abnormalities in serum aminotransferase activity. The combina- Several other drugs have shown efficacy in maintaining abstinence
tion of naltrexone plus disulfiram should be avoided, since both and reducing craving in chronic alcoholism, although none has
drugs are potential hepatotoxins. Administration of naltrexone to FDA approval yet for this use. Such drugs include antiseizure
patients who are physically dependent on opioids precipitates an agents (topiramate, gabapentin, and valproate, see Chapter 24);
acute withdrawal syndrome, so patients must be opioid-free before and baclofen, a GABA receptor antagonist used as a spasmolytic
initiating naltrexone therapy. Naltrexone also blocks the therapeu- (see Chapter 27). Studies of varenicline (see Chapter 7) indicate
tic analgesic effects of usual doses of opioids. that this nicotinic agonist drug can reduce binge drinking in mice.
Clinical trials of selective serotonin reuptake inhibitors (SSRIs, see
Chapter 30) and ondansetron, a 5-HT antagonist (see Chapter 62)
3
Acamprosate yielded negative results overall, but suggested that these agents may
have benefits in certain subgroups of patients. Based on evidence
Acamprosate has been used in Europe for a number of years to from model systems, efforts are under way to explore agents that
treat alcohol dependence and is approved for this use by the FDA. receptors, corticotropin-releasing fac-
Like ethanol, acamprosate has many molecular effects including modulate cannabinoid CB 1
tor receptors, and GABA receptor systems, as well as several other
actions on GABA, glutamate, serotonergic, noradrenergic, and possible targets. Rimonabant, a CB receptor antagonist, has been
1
dopaminergic receptors. Probably its best-characterized actions shown to suppress alcohol-related behaviors in animal models and
are as a weak NMDA-receptor antagonist and a GABA -receptor is being tested in clinical trials of alcoholism.
A
activator. In European clinical trials, acamprosate reduced short-
term and long-term (more than 6 months) relapse rates when
combined with psychotherapy. However, in a large American trial
that compared acamprosate with naltrexone and with combined ■ PHARMACOLOGY OF OTHER
acamprosate and naltrexone therapy (the COMBINE study), ALCOHOLS
acamprosate did not show a statistically significant effect alone or
in combination with naltrexone. Other alcohols related to ethanol have wide applications as indus-
Acamprosate is administered as one or two enteric-coated trial solvents and occasionally cause severe poisoning. Of these,
333-mg tablets three times daily. It is poorly absorbed, and food methanol and ethylene glycol are two of the most common