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

642 termed fetal alcohol effects (FAEs) or alcohol-related
neurodevelopmental disorders. FAS is seen in offspring
born to ~5% of heavy-drinking females. The incidence
of FAS is believed to be in the range of
0.5-1 per 1000 live births in the general U.S. population,
with rates as high as 2-3 per 1000 in African-American
and Native-American populations. A lower socioeconomic
status of the mother rather than racial background
per se appears to be primarily responsible for
the higher incidence of FAS observed in those groups
(Abel, 1995). The incidence of FAEs is likely higher
than that of FAS, making alcohol consumption during
pregnancy a major public health problem.
SECTION II
NEUROPHARMACOLOGY
Craniofacial abnormalities commonly observed in the diagnosis
of FAS consist of a pattern of microcephaly, a long and smooth
philtrum, shortened palpebral fissures, a flat midface, and epicanthal
folds. Magnetic resonance imaging studies demonstrate
decreased volumes in the basal ganglia, corpus callosum, cerebrum,
and cerebellum (Mattson et al., 1992). The severity of alcohol effects
can vary greatly and depends on the drinking patterns and amount of
alcohol consumed by the mother. Maternal drinking in the first
trimester has been associated with craniofacial abnormalities; facial
dysmorphology also is seen in mice exposed to ethanol at the equivalent
time in gestation.
CNS dysfunction following in utero exposure to alcohol manifests
in the form of hyperactivity, attention deficits, mental retardation,
and learning disabilities. FAS is the most common cause of
preventable mental retardation in the Western world (Abel and
Sokol, 1987), with afflicted children consistently scoring lower than
their peers on a variety of IQ tests. It now is clear that FAS represents
the severe end of a spectrum of alcohol effects. A number of studies
have documented intellectual deficits, including mental retardation,
in children not displaying the craniofacial deformities or retarded
growth seen in FAS. Although cognitive improvements are seen with
time, decreased IQ scores of FAS children tend to persist as they
mature, indicating that the deleterious prenatal effects of alcohol are
irreversible. Although a correlation exists between the amount of
alcohol consumed by the mother and infant scores on mental and
motor performance tests, there is considerable variation in performance
on such tests among children of mothers consuming similar
quantities of alcohol. The peak BEL reached may be a critical factor
in determining the severity of deficits seen in the offspring.
Although the evidence is not conclusive, there is a suggestion that
even moderate alcohol consumption (two drinks per day) in the second
trimester of pregnancy is correlated with impaired academic performance
of offspring at age 6 (Goldschmidt et al., 1996). Maternal
age also may be a factor. Pregnant women over age 30 who drink
alcohol create greater risks to their children than do younger women
who consume similar amounts of alcohol (Jacobson et al., 1996).
Children exposed prenatally to alcohol most frequently present
with attentional deficits and hyperactivity, even in the absence of
intellectual deficits or craniofacial abnormalities. Furthermore, attentional
problems have been observed in the absence of hyperactivity,
suggesting that the two phenomena are not necessarily related. Fetal
alcohol exposure also has been identified as a risk factor for alcohol
abuse by adolescents (Baer et al., 1998). Apart from the risk of FAS
or FAEs to the child, the intake of high amounts of alcohol by a pregnant
woman, particularly during the first trimester, greatly increases
the chances of spontaneous abortion.
Studies with laboratory animals have demonstrated many of the
consequences of in utero exposure to ethanol observed in humans,
including hyperactivity, motor dysfunction, and learning deficits. In
animals, in utero exposure to ethanol alters the expression patterns of
a wide variety of proteins, changes neuronal migration patterns, and
results in brain region–specific and cell type–specific alterations in neuronal
numbers. Indeed, specific periods of vulnerability may exist for
particular neuronal populations in the brain. Genetics also may play a
role in determining vulnerability to ethanol: There are differences
among strains of rats in susceptibility to the prenatal effects of ethanol.
Finally, multidrug abuse, such as the concomitant administration of
cocaine with ethanol, enhances fetal damage and mortality.
PHARMACOTHERAPY OF ALCOHOLISM
The core of care is a process of interventions and sessions
that help enhance changes in how the person
views their problem, along with efforts to help them
alter the problematic behaviors (Schuckit, 2009). With
cognitive-behavioral approaches serving as the core of
treatment, and a 20% or greater rate of spontaneous
remission in alcohol use disorders, the role of medications
can be difficult to evaluate. Thus, only those pharmacological
approaches that have been shown to be
superior to placebo through double-blind control trials
are worth considering in clinical practice.
Currently, three drugs are approved in the U.S.
for treatment of alcoholism: disulfiram (ANTABUSE),
naltrexone (REVIA), and acamprosate (Table 23–3).
Disulfiram has a long history of use but has fallen into
disfavor because of its side effects and problems with
patient adherence to therapy. Naltrexone and acamprosate
were introduced more recently. The goal of
these medications is to assist the patient in maintaining
abstinence.
Naltrexone
Naltrexone is chemically related to the highly selective
opioid-receptor antagonist naloxone (NARCAN) but has
higher oral bioavailability and a longer duration of
action. Neither drug has appreciable opioid-receptor
agonist effects. These drugs were used initially in the
treatment of opioid overdose and dependence because
of their ability to antagonize all the actions of opioids
(Chapters 18 and 24). There is evidence that naltrexone
blocks activation by alcohol of dopaminergic pathways
in the brain that are thought to be critical to reward.
Naltrexone helps to maintain abstinence by reducing the urge
to drink and increasing control when a “slip” occurs. It is not a