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

630 (the “proof” of an alcoholic beverage is twice its percentage
of alcohol; e.g., 40% alcohol is 80 proof). A
glass of beer or wine, a mixed drink, or a shot of spirits
contains about 14 g alcohol, or about 0.3 mol
ethanol. Consumption of 1-2 mol over a few hours is
not uncommon. Thus, alcohol is consumed in gram
quantities, whereas most other drugs are taken in milligram
or microgram doses.
Since the ratio of ethanol in end-expiratory alveolar
air and ethanol in the blood is relatively consistent,
blood ethanol levels (BELs) in humans can be estimated
readily by the measurement of alcohol levels in expired
air; the partition coefficient for ethanol between blood
and alveolar air is approximately 2000:1. Because of the
causal relationship between excessive alcohol consumption
and vehicular accidents, there has been a
near-universal adoption of laws attempting to limit the
operation of vehicles while under the influence of
alcohol. Legally allowed BELs typically are set at or
below 80 mg% (80 mg ethanol per 100 mL blood; 0.08%
w/v), which is equivalent to a concentration of 17 mM
ethanol in blood. A 12-oz bottle of beer, a 5-oz glass of
wine, and a 1.5-oz “shot” of 40% liquor each contains
approximately 14 g ethanol, and the consumption of one
of these beverages by a 70-kg person would produce a
BEL of approximately 30 mg%. However, it is important
to note that this is approximate because the BEL is
determined by a number of factors, including the rate of
drinking, sex, body weight and water percentage, and the
rates of metabolism and stomach emptying (see “Acute
Ethanol Intoxication” later in the chapter).
SECTION II
NEUROPHARMACOLOGY
PHARMACOLOGICAL PROPERTIES
Absorption, Distribution,
and Metabolism
Ethanol. After oral administration, ethanol is absorbed
rapidly into the bloodstream from the stomach and
small intestine and distributes into total-body water
(0.5-0.7 L/kg). Peak blood levels occur about 30 minutes
after ingestion of ethanol when the stomach is
empty. Because absorption occurs more rapidly from
the small intestine than from the stomach, delays in
gastric emptying (owing, e.g., to the presence of food)
slow ethanol absorption. Because of first-pass metabolism
by gastric and liver alcohol dehydrogenase (ADH),
oral ingestion of ethanol leads to lower BELs than
would be obtained if the same quantity were administered
intravenously. Gastric metabolism of ethanol is
lower in women than in men, which may contribute to
the greater susceptibility of women to ethanol (Lieber,
2000; Schukit, 2006a). Aspirin increases ethanol
bioavailability by inhibiting gastric ADH.
Ethanol is metabolized largely by sequential hepatic
oxidation, first to acetaldehyde by ADH and then to acetic
acid by aldehyde dehydrogenase (ALDH) (Figure 23–1).
Each metabolic step requires NAD + ; thus oxidation of
1 mol ethanol (46 g) to 1 mol acetic acid requires 2 mol
NAD + (approximately 1.3 kg). This greatly exceeds the
supply of NAD + in the liver; indeed, NAD + availability
limits ethanol metabolism to about 8 g or 10 mL (approximately
170 mmol) per hour in a 70-kg adult, or approximately
120 mg/kg per hour. Thus, hepatic ethanol
metabolism functionally saturates at relatively low blood
levels compared with the high BELs achieved, and
ethanol metabolism is a zero-order process (constant
amount per unit time). Small amounts of ethanol are
excreted in urine, sweat, and breath, but metabolism to
acetate accounts for 90-98% of ingested ethanol, mostly
owing to hepatic metabolism by ADH and ADLH.
A hepatic cytochrome P450, CYP2E1, also can
contribute (Figure 23–1), especially at higher ethanol concentrations
and under conditions such as alcoholism,
where its activity may be induced. Catalase also can produce
acetaldehyde from ethanol, but hepatic H 2
O 2
availability
usually is too low to support significant flux of
ethanol through this pathway. Although CYP2E1 usually
is not a major factor in ethanol metabolism, it can be an
important site of interactions of ethanol with other drugs.
CYP2E1 is induced by chronic consumption of ethanol,
increasing the clearance of its substrates and the activation
of certain toxins such as CCl 4
. There can be decreased
clearance of the same drugs, however, after acute consumption
of ethanol because ethanol competes with them
for oxidation by the enzyme system (e.g., phenytoin and
warfarin).
The large increase in the hepatic NADH:NAD +
ratio during ethanol oxidation has profound consequences
in addition to limiting the rate of ethanol
metabolism. Enzymes requiring NAD + are inhibited;
thus lactate accumulates, activity of the tricarboxylic
acid cycle is reduced, and acetyl coenzyme A (acetyl
CoA) accumulates (and it is produced in quantity from
ethanol-derived acetic acid; Figure 23-1). The combination
of increased NADH and elevated–acetyl CoA supports
fatty acid synthesis and the storage and
accumulation of triacylglycerides. Ketone bodies
accrue, exacerbating lactic acidosis. Ethanol metabolism
by the CYP2E1 pathway produces elevated
NADP + , limiting the availability of NADPH for the
regeneration of reduced glutathione (GSH), thereby
enhancing oxidative stress.