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

patients with chronic alcoholism. Additionally, many chronic alcoholics
develop testicular atrophy and decreased fertility. The mechanism
involved in this is complex and likely involves altered
hypothalamic function and a direct toxic effect of alcohol on Leydig
cells. Gynecomastia is associated with alcoholic liver disease and is
related to increased cellular response to estrogen and to accelerated
metabolism of testosterone.
Sexual function in alcohol-dependent women is less clearly
understood. Many female alcoholics complain of decreased libido,
decreased vaginal lubrication, and menstrual cycle abnormalities.
Their ovaries often are small and without follicular development.
Some data suggest that fertility rates are lower for alcoholic women.
The presence of comorbid disorders such as anorexia nervosa or
bulimia can aggravate the problem. The prognosis for patients who
abstain is favorable in the absence of significant hepatic or gonadal
failure (O’Farrell et al., 1997).
Hematological and Immunological
Effects
Chronic alcohol use is associated with a number of anemias.
Microcytic anemia can occur because of chronic
blood loss and iron deficiency. Macrocytic anemias and
increases in mean corpuscular volume are common and
may occur in the absence of vitamin deficiencies.
Normochromic anemias also can occur owing to effects
of chronic illness on hematopoiesis. In the presence of
severe liver disease, morphological changes can include
the development of burr cells, schistocytes, and ringed
sideroblasts. Alcohol-induced sideroblastic anemia may
respond to vitamin B 6
replacement (Wartenberg, 1998).
Alcohol use also is associated with reversible thrombocytopenia,
although platelet counts under 20,000/mm 3
are rare. Bleeding is uncommon unless there is an
alteration in vitamin K 1
–dependent clotting factors
(Chapter 30); proposed mechanisms have focused on
platelet trapping in the spleen and marrow.
Alcohol also affects granulocytes and lymphocytes
(Schirmer et al., 2000). Effects include leukopenia, alteration of
lymphocyte subsets, decreased T-cell mitogenesis, and changes in
immunoglobulin production. These disorders may play a role in
alcohol-related liver disease. In some patients, depressed leukocyte
migration into inflamed areas may account in part for the poor
resistance of alcoholics to some types of infection (e.g., Klebsiella
pneumonia, listeriosis, and tuberculosis). Alcohol consumption
also may alter the distribution and function of lymphoid cells by
disrupting cytokine regulation, in particular that involving interleukin
2 (IL-2). Alcohol appears to play a role in the development
of infection with the human immunodeficiency virus-1 (HIV). In
vitro studies with human lymphocytes suggest that alcohol can suppress
CD4 T-lymphocyte function and concanavalin A–stimulated
IL-2 production and enhance in vitro replication of HIV. Moreover,
persons who abuse alcohol have higher rates of high-risk sexual
behavior.
ACUTE ETHANOL INTOXICATION
Signs of intoxication typical of CNS depression are
seen in most people following 2-3 drinks, with the
most prominent effect seen at the times of peak BEL,
~30-60 minutes following consumption on an empty
stomach. These symptoms include an initial feeling of
stimulation (perhaps due to inhibition of CNS
inhibitory systems), giddiness, muscle relaxation, and
impaired judgment. Higher blood levels (~80 mg/dL
or ~17 mM) are associated with slurred speech, incoordination,
unsteady gait, and potential impairments
of attention; levels between 80 and 200 mg/dL
(~17-43 mM) are associated with more intense mood
lability, and greater cognitive deficits, potentially
accompanied by aggressiveness, and anterorgrade
amnesia (an alcoholic blackout) (Schuckit, 2009c).
Blood ethanol levels >200 mg/dL can produce nystagmus
and unwanted falling asleep; levels of 300 mg/dL
(~65 mM) and higher can produce failing vital signs,
coma, and death. All of these symptoms are likely to
be exacerbated and occur at a lower BEC when
ethanol is taken along with other CNS depressants
(e.g., diazepam or similar benzodiazepines), or with
any drug or medication for which sleepiness and uncoordination
are likely.
An increased reaction time, diminished fine motor control,
impulsivity, and impaired judgment become evident when the concentration
of ethanol in the blood is 20-30 mg/dL. More than 50%
of persons are grossly intoxicated by a concentration of 150 mg/dL.
In fatal cases, the average concentration is about 400 mg/dL,
although alcohol-tolerant individuals often can withstand comparable
blood alcohol levels. The definition of intoxication varies by state
and country. In the U.S., most states set the ethanol level defined as
intoxication at 80 mg/dL. There is increasing evidence that lowering
the limit to 50-80 mg/dL can reduce motor vehicle injuries and fatalities
significantly. While alcohol can be measured in saliva, urine,
sweat, and blood, measurement of levels in exhaled air remains the
primary method of assessing the level of intoxication.
Many factors, such as body weight and composition and the
rate of absorption from the GI tract, determine the concentration of
ethanol in the blood after ingestion of a given amount of ethanol.
On average, the ingestion of 3 standard drinks (42 g ethanol) on
an empty stomach results in a maximum blood concentration of
67-92 mg/dL in men. After a mixed meal, the maximal blood concentration
from three drinks is 30-53 mg/dL in men. Concentrations
of alcohol in blood will be higher in women than in men consuming
the same amount of alcohol because, on average, women are smaller
than men, have less body water per unit of weight into which ethanol
can distribute, and have less gastric ADH activity than men. For individuals
with normal hepatic function, ethanol is metabolized at a
rate of one standard drink every 60-90 minutes.
The characteristic signs and symptoms of alcohol intoxication
are well known. Nevertheless, an erroneous diagnosis of drunkenness
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CHAPTER 23
ETHANOL AND METHANOL