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

(Mendelson and Mello, 1979), thus not supporting the idea that alcoholics
drink to relieve tension.
Tolerance, Physical Dependence, and Withdrawal. Mild intoxication by
alcohol is familiar to almost everyone, but the symptoms vary among
individuals. Some simply experience motor incoordination and sleepiness.
Others initially become stimulated and garrulous. As the blood
level increases, the sedating effects increase, with eventual coma and
death occurring at high alcohol levels. The initial sensitivity (innate
tolerance) to alcohol varies greatly among individuals and is related to
family history of alcoholism (Wilhelmsen et al., 2003). Experience
with alcohol can produce greater tolerance (acquired tolerance) such
that extremely high blood levels (300-400 mg/dL) can be found in
alcoholics who do not appear grossly sedated. In these cases, the lethal
dose does not increase proportionately to the sedating dose, and thus
the margin of safety (therapeutic index) is decreased.
Heavy consumers of alcohol not only acquire tolerance but also
inevitably develop a state of physical dependence. This often leads to
drinking in the morning to restore blood alcohol levels diminished during
the night. Eventually, they may awaken during the night and take a
drink to avoid the restlessness produced by falling alcohol levels. The
alcohol-withdrawal syndrome (Table 24–4) generally depends on the
size of the average daily dose and usually is “treated” by resumption of
alcohol ingestion. Withdrawal symptoms are experienced frequently
but usually are not severe or life-threatening until they occur in conjunction
with other problems, such as infection, trauma, malnutrition, or
electrolyte imbalance. In the setting of such complications, the syndrome
of delirium tremens becomes likely.
Alcohol addiction produces cross-tolerance to other sedatives
such as benzodiazepines. This tolerance is operative in abstinent
alcoholics, but while the alcoholic is drinking, the sedating effects of
alcohol add to those of other sedatives, making the combination
more dangerous. This is particularly true for benzodiazepines, which
Table 24–4
Alcohol Withdrawal Syndrome
Alcohol craving
Tremor, irritability
Nausea
Sleep disturbance
Tachycardia
Hypertension
Sweating
Perceptual distortion
Seizures (6-48 hours after last drink)
Visual (and occasionally auditory or tactile) hallucinations
(12-48 hours after last drink)
Delirium tremens (48-96 hours after last drink; rare in
uncomplicated withdrawal)
Severe agitation
Confusion
Fever, profuse sweating
Tachycardia
Nausea, diarrhea
Dilated pupils
are relatively safe in overdose when given alone but potentially are
lethal in combination with alcohol.
The chronic use of alcohol and other sedatives is associated
with the development of depression (McLellan et al., 1979), and the
risk of suicide among alcoholics is one of the highest of any diagnostic
category. Cognitive deficits have been reported in alcoholics
tested while sober. These deficits usually improve after weeks to
months of abstinence. More severe recent memory impairment is
associated with specific brain damage caused by nutritional deficiencies
common in alcoholics (e.g., thiamine deficiency).
Alcohol is toxic to many organ systems. As a result, the medical
complications of alcohol abuse and dependence include liver disease,
cardiovascular disease, endocrine and GI effects, and
malnutrition, in addition to the CNS dysfunctions outlined earlier.
Ethanol readily crosses the placental barrier, producing the fetal alcohol
syndrome, a major cause of mental retardation (Chapter 23).
Pharmacological Interventions.
Detoxification. A patient who presents in a medical setting with an
alcohol-withdrawal syndrome should be considered to have a potentially
lethal condition. Although most mild cases of alcohol withdrawal
never come to medical attention, severe cases require general evaluation;
attention to hydration and electrolytes; vitamins, especially highdose
thiamine; and a sedating medication that has cross-tolerance with
alcohol. To block or diminish the symptoms described in Table 24–4,
a short-acting benzodiazepine such as oxazepam can be used at a dose
of 15-30 mg every 6-8 hours according to the stage and severity of
withdrawal; some authorities recommend a long-acting benzodiazepine
unless there is demonstrated liver impairment. Anticonvulsants such as
carbamazepine have been shown to be effective in alcohol withdrawal,
although they appear not to relieve subjective symptoms as well as benzodiazepines.
After medical evaluation, uncomplicated alcohol withdrawal
can be treated effectively on an outpatient basis. When there are
medical problems, a history of seizures, or simultaneous dependence on
other drugs, hospitalization is required.
Pharmacotherapy. Detoxification is only the first step of treatment.
Complete abstinence is the objective of long-term treatment, and this
is accomplished mainly by behavioral approaches. Medications that
aid in the prevention of relapse are under development. Disulfiram
(ANTABUSE; Chapter 23) has been useful in some programs that focus
behavioral efforts on ingestion of the medication. Disulfiram blocks
aldehyde dehydrogenase, the second step in ethanol metabolism,
resulting in the accumulation of acetaldehyde, which produces an
unpleasant flushing reaction when alcohol is ingested. Knowledge of
this unpleasant reaction helps the patient to resist taking a drink.
Although quite effective pharmacologically, disulfiram has not been
found to be effective in controlled clinical trials because so many
patients failed to ingest the medication.
Naltrexone (REVIA; Chapter 23), an opioid receptor antagonist
that blocks the reinforcing properties of alcohol, is FDAapproved
as an adjunct in the treatment of alcoholism. Chronic
administration of naltrexone resulted in a decreased rate of relapse
to alcohol drinking in the majority of published double-blind clinical
trials (Pettinati et al., 2006). It works best in combination with
behavioral treatment programs that encourage adherence to medication
and abstinence from alcohol. A depot preparation with a
duration of 30 days (VIVITROL) was approved by the FDA in 2006;
it greatly improves medication adherence, the major problem with
the use of medications in alcoholism.
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CHAPTER 24
DRUG ADDICTION