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

may be responsible for some of the lack of judgment and control
that is expressed as obsessive alcohol consumption. The loss of brain
volume and impairment of function seen in the chronic alcoholic is
at least partially reversible by abstinence but will worsen with continued
drinking. Early diagnosis and treatment of alcoholism are
important in limiting the brain damage that promotes the progression
to severe addiction.
Etiology of Alcohol Use Disorders
and the Role of Genes
A wide range of social, cultural, interpersonal, and biological
factors combine to contribute to the risk for heavier
drinking and alcohol use disorders (Schuckit,
2009b). The initial decision to consume alcohol is predominantly
a response to the environment and culture
in which one lives. Environmental and cultural factors
that contribute to alcohol use include stress, expectations
regarding the effects alcohol is likely to produce,
drinking patterns within one’s culture and peer group,
availability of alcohol, and attitudes toward drunkenness.
These nonbiological forces contribute to perhaps
70-80% of the initial decision to drink and at least 40%
of the transition from drinking to alcohol-related problems
and alcohol use disorders. Correspondingly, ~60%
of the susceptibility to alcohol use disorders results from
heritable factors (Table 23–2).
The search for the genes and alleles responsible for alcoholism
is complicated by the polygenetic nature of the disease and the general
difficulty in defining multiple genes responsible for complex diseases.
As noted earlier in the chapter, polymorphisms in the enzymes of
ethanol metabolism seem to explain why some populations (mainly
Asian) are protected from alcoholism. This has been attributed to
genetic differences in alcohol- and aldehyde-metabolizing enzymes.
Specifically, genetic variants of ADH that exhibit high activity and
Table 23–2
Genes for Intermediate Phenotypes Affecting Risk
for Alcohol Use Disorder
PHENOTYPE
GENES
Facial flush after drinking ALDH2
ADH1B, ADH1C
Impulsivity and disinhibition GABRA2
ADH4
CHRM2
DRD2, DRD4
Low level of response to ethanol GABRA1, GABRA6
5HTT promoter
KCNMA1
CHRN cluster
variants of ALDH that exhibit low activity protect against heavy drinking,
probably because alcohol consumption by individuals who have
these variants results in accumulation of acetaldehyde, which produces
a variety of unpleasant effects (Li, 2000).
In contrast to these protective genetic variants, there are few
consistent data about genes responsible for increased risk for
alcoholism. A genetic mechanism associated with an enhanced risk
for both alcohol and other drug use disorders operates through the
intermediate characteristic (or phenotype) of impulsivity and
disinhibition (King et al., 2004). The identified polymorphisms
include two variations of the GABA A
receptors (Dick et al.,
2006a,b), a variation in ADH4 hypothesized to be related to personality
characteristics (Edenberg et al., 2006), and a muscarinic cholinergic
receptor gene, CHRM2 (Jones et al., 2006).
Another phenotype related to an enhanced risk for alcohol
use disorders (but not other drug use disorders) is associated with a
low level of response (perhaps reflecting low sensitivity) to ethanol
(Schuckit, 2009b). The need for higher amounts of ethanol to achieve
the desired effects may contribute to the decision to drink more per
occasion, which in turn leads to altered expectations of the effects of
beverage alcohol, an enhanced probability of selecting heavierdrinking
peers, as well as problematic approaches to dealing with
stress (Schuckit et al., 2008). To date, genetic contributions to the
level of response have been tentatively identified for two GABA A
subunits (Dick et al., 2006a,b), a polymorphism in the promoter
region of the 5-HT transporter that is associated with lower levels
of 5-HT in the synaptic space (Barr et al., 2005), a polymorphism of
the K + channel-related KCNMA1 (Schuckit et al., 2005), and a variant
nicotinic Ach receptor that is also related to an increased risk for
heavy smoking and related consequences (Joslyn et al., 2008).
Antisocial alcoholism has been linked with polymorphisms of several
5-HT receptors (Ducci et al, 2009). Polymorphisms in dopaminergic
and opioid systems and in genes that correlate with a
predisposition to bipolar disorder, schizophrenia, and several anxiety
disorders may also contribute to a general vulnerability to a range
of substance abuse disorders.
TERATOGENIC EFFECTS: FETAL
ALCOHOL SYNDROME
Children born to alcoholic mothers display a common
pattern of distinct dysmorphology known as fetal alcohol
syndrome (FAS) (Jones and Smith, 1973; Lemoine
et al., 1968). The diagnosis of FAS typically is based
on the observance of a triad of abnormalities in the
newborn, including:
• a cluster of craniofacial abnormalities
• CNS dysfunction
• pre- and/or postnatal stunting of growth
Hearing, language, and speech disorders also may
become evident as the child ages (Church and Kaltenbach,
1997). Children who do not meet all the criteria
for a diagnosis of FAS still may show physical and
mental deficits consistent with a partial phenotype,
641
CHAPTER 23
ETHANOL AND METHANOL