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

similar to mild alcohol withdrawal, dehydration, and/or mild acidosis
(Stephens et al., 2008).
Chronic heavy drinking reportedly increases the probability
of developing a more permanent cognitive deficit often referred to as
alcoholic dementia. However, the signs of cognitive deficits and
brain atrophy observed soon after a heavy drinking period often
reverse over the subsequent several weeks to months following
abstinence (Bartsch et al., 2007). The thiamine depletion that can
accompany heavy ethanol consumption contributes to Wernicke-
Korsakoff syndromes; however, the ataxia and ophalmoparesis of
Wernicke’s, and the severe anterograde and retrograde amnesias of
Korsakoff’s, are seen in <<1% of chronic alcohol-dependent individuals.
Additional severe neurological syndromes associated with
chronic heavy use of alcohol include cerebellar degeneration with
associated atrophy of the cerebellar vermis (seen in ~1% of alcoholics),
and a peripheral neuropathy (observed in ~10% of alcoholics)
(Alexander-Kaufman et al., 2007; Peters et al., 2006). The
specific mechanisms associated with damage to the cerebellum and
peripheral nerves have not been definitively identified.
Heavy doses of ethanol over multiple days or weeks are also
associated with several temporary but disturbing “alcohol-induced”
psychiatric syndromes (Schuckit, 2006a). As many as 40% of alcoholdependent
humans develop severe alcohol-related depressive
symptoms that can include temporary suicidal thoughts and
behaviors. Similarly, a range of anxiety conditions, including those
characterized by panic attacks and generalized anxiety, are likely in
a large minority of alcohol-dependent individuals during the withdrawal
syndrome. Perhaps 3% of alcohol-dependent men and women
report experiencing temporary auditory hallucinations and paranoid
delusions that resemble schizophrenia beginning during periods of
heavy intoxication; all of these psychiatric syndromes are likely to
markedly improve within several days to a month of abstinence, with
residual mild symptoms continuing to diminish thereafter. While no
definitive data on the mechanisms for these alcohol-induced psychiatric
conditions are available, it is logical to assume that alcoholrelated
changes in CNS pathways (NE and 5-HT levels, the balance
between GABA A
and NMDA receptor activity, dopaminergic activity)
may operate here in a manner similar to those seen in depression,
anxiety, and schizophrenic disorders.
Cardiovascular System
Ethanol intake greater than three standard drinks per day
elevates the risk for heart attacks and bleeding-related
strokes (Hvidtfeldt et al., 2008). Indeed, vascular-related
diseases are among the leading causes of early death in
alcohol-dependent individuals. The risk includes a 6-fold
increased risk for coronary artery disease, a heightened
risk for cardiac arrhythmias, and an elevated rate of
congestive heart failure. The causes are complex and
observations are complicated by certain positive effects
of small amounts of ethanol.
Serum Lipoproteins and Cardiovascular Effects. In
most countries, the risk of mortality due to coronary
heart disease (CHD) is correlated with a high dietary
intake of saturated fat and elevated serum cholesterol
levels. France is an exception to this rule, with relatively
low mortality from CHD despite the consumption of
high quantities of saturated fats (the “French paradox”).
Epidemiological studies suggest that widespread wine
consumption (20-30 g ethanol per day) is one of the factors
conferring a cardioprotective effect, with 1-3 drinks
per day resulting in a 10-40% decreased risk of coronary
heart disease compared with abstainers. In contrast,
daily consumption of greater amounts of alcohol
leads to an increased incidence of non-coronary causes
of cardiovascular failure, such as arrhythmias, cardiomyopathy,
and hemorrhagic stroke, offsetting the
beneficial effects of alcohol on coronary arteries; that
is, alcohol has a J-shaped dose-mortality curve.
Reduced risks for CHD are seen at intakes as low as
one-half drink per day (Libby et al., 2007). Young
women and others at low risk for heart disease derive
little benefit from light to moderate alcohol intake,
whereas those of both sexes who are at high risk and
who may have had a myocardial infarction clearly benefit.
Data based on a number of prospective, cohort,
cross-cultural, and case-control studies in diverse populations
consistently reveal lower rates of angina pectoris,
myocardial infarction, and peripheral artery
disease in those consuming light (1-20 g/day) to moderate
(21-40 g/day) amounts of alcohol.
One possible mechanism by which alcohol could reduce the
risk of CHD is through its effects on blood lipids. Changes in plasma
lipoprotein levels, particularly increases in high-density lipoprotein
(HDL; Chapter 31), have been associated with the protective effects
of ethanol. HDL binds cholesterol and returns it to the liver for elimination
or reprocessing, decreasing tissue cholesterol levels. Ethanolinduced
increases in HDL-cholesterol thus could antagonize
cholesterol accumulation in arterial walls, lessening the risk of
infarction. Approximately half the risk reduction associated with
ethanol consumption is explained by changes in total HDL levels
(Langer et al., 1992). HDL is found as two subfractions, named
HDL 2
and HDL 3
. Increased levels of HDL 2
(and possibly also
HDL 3
) are associated with reduced risk of myocardial infarction.
Levels of both subfractions are increased following alcohol consumption
and decrease when alcohol consumption ceases.
Apolipoproteins A-I and A-II are constituents of HDL. Increased
levels of both apolipoproteins A-I and A-II are associated with individuals
who are daily heavy drinkers. In contrast, there are reports
of decreased serum apolipoprotein(a) levels following acute alcohol
consumption. Elevated apolipoprotein(a) levels have been associated
with an increased risk for the development of atherosclerosis.
All forms of alcoholic beverages confer cardio-protection.
A variety of alcoholic beverages increase HDL levels while decreasing
the risk of myocardial infarction. The flavonoids found in red
wine (and purple grape juice) may have an additional antiatherogenic
role by protecting low-density lipoprotein (LDL) from oxidative
damage. Oxidized LDL has been implicated in several steps of
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CHAPTER 23
ETHANOL AND METHANOL