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

632 methanol is taken along with ethanol. As little as 15 mL of methanol
can produce toxicity, including blindness, with doses in excess of
70 mL capable of producing death. Methanol poisoning consists of
headache, GI distress, and pain (partially related to pancreatic
injury), difficulty breathing, restlessness, and blurred vision associated
with hyperemic optic disks. Severe metabolic acidosis can
develop due to the accumulation of formic acid, and the respiratory
depression can be severe, especially in the context of coma. The
visual disturbances associated with methanol intoxication are a
prominent part of the picture, and occur as a consequence of injury
to ganglion cells of the retina by the metabolite, formic acid, with
subsequent inflammation, atrophy, and potential bilateral blindness.
The clinical picture can also include necrosis of the pancreas.
SECTION II
NEUROPHARMACOLOGY
Genetic Variation in Ethanol Metabolism. The enzymes involved in
ethanol metabolism (Figure 23–1) are mainly ADH and ALDH, and
secondarily, catalase and CYP2E1. Several of these enzymes have
genetic variants that alter alcohol metabolism and susceptibility to
its effects.
The genetics of the ADH isoforms are important for understanding
risk factors for severe repetitive ethanol problems. The three
relevant forms are ADH1A, 1B, and 1C (genes on chromosome 4
q22). These class I ADHs have K m
<34 mmol (0.15 g/dL) and are
responsible for 70% of the ethanol metabolizing capacity at BECs of
22 mM (i.e., ~0.10 g/dL) (Edenberg et al., 2006). These ADH forms
are the rate-limiting step in ethanol metabolism, reducing the blood
ethanol concentrations by ~4-5 mM (0.015-0.020 g/dL) per hour,
the approximate levels of alcohol resulting from the consumption of
one standard drink.
The ADH1A gene has no polymorphisms known to significantly
affect the rate of alcohol metabolism. The ADH1B gene has a polymorphism,
ADH1B*2, with arginine 47 replaced by histidine to produce a
variant form of ADH with a 40-fold higher V max
than ADH1B. This
polymorphism is seen in 30-45% of Chinese, Japanese, and Koreans,
less than 10% of most Europeans, but in 50-90% of Russians and Jews
(Edenberg et al., 2006). The potential faster metabolism of ethanol may
result in a transient slightly higher blood level of acetaldehyde and is
reported to be associated with a lower risk for heavy drinking and
ethanol-related problems. A second polymorphism for ADH1B,
ADH1B*3 (arginine 269 replaced by cysteine), has a 30-fold higher
V max
. ADHlB*3 is seen in about 30% of Africans and also is associated
with lower risk of heavy drinking and ethanol problems.
A third ADH gene found in the chromosome 4q22 cluster,
ADH1C, exhibits two polymorphisms in high linkage disequilibrium,
the 1 and 2 forms. The V max
of 1 is twice that of 2, and
this ADH1C*1 allele is hypothesized to be associated with a slightly
faster metabolism of ethanol and/or a higher level of acetaldehyde.
The independent effects of ADH1C*1 and ADH1B*2 alleles are difficult
to determine. The ADH cluster on chromosome 4 also contains
class II ADHs with K m
= 34 mM (~0.15 g/dL). The class II forms contribute
about 30% of the ethanol metabolizing capacity noted above.
There are polymorphisms hypothesized to be associated with the
alcoholism risk, but less information is known about these forms (Luo
et al., 2007).
Other systems also contribute to the metabolism of ethanol
to acetaldehyde including via catalase (Kuo et al., 2008). In addition,
at higher BELs, the microsomal ethanol metabolizing system
(MEOS) is important, especially CYP2E1, but also CYPs1A2 and
3A4. Variations of the CYP2E1 gene located on chromosome 10
have been hypothesized to relate to the level of sensitivity or reaction
to the ethanol observed in the brain.
Acetaldehyde is produced from the breakdown of ethanol at
the rate of approximately one standard drink per hour. As shown in
Figure 23–1, the acetaldehyde is then rapidly broken down through
the actions of ALDH2, primarily in the mitochondria of liver cells.
The actions of ALDH2, a phase 2 enzyme (Chapter 6), are important
because low levels of acetaldehyde may be perceived as rewarding
and stimulating, while high blood levels of this substance produce
severe adverse reactions that can include vomiting, diarrhea, and
unstable blood pressure (Husemoen et al., 2008). There is a mutation
in the ALDH2 gene (12q24), ALDH2*2 (resulting from a substitution
of glycine 487 with lysine). Homozygotes with a nonfunctional
ALDH2*2 occur in 5-10% of Japanese, Chinese, and Korean individuals,
for whom severe adverse reactions occur after consumption
of one drink or less. Consequently, their risk for severe repetitive
heavy drinking is close to zero. This reaction operates through the
same mechanism that occurs with drinking after taking the ALDH2
inhibitor, disulfiram. Heterozygotes for this polymorphism
(ALDH2*2, 2*1) make up 30-40% of Asian individuals who, after
consuming ethanol experience a facial flush and an enhanced sensitivity
to beverage alcohol, but who do not necessarily report an overall
adverse response to the drug (Wall and Ehlers, 1995). The
heterozygotes tend to drink lower quantities of ethanol than the general
population, although repeated intake may relate to an enhanced
risk for adverse ethanol-related organ damage (including esophageal
cancer and, perhaps, pancreatitis), possibly associated with higher
acetaldehyde levels. While additional ALDH mutations occur, less is
known about potential associations between these polymorphisms
and the risk from alcohol.
EFFECTS OF ETHANOL ON
PHYSIOLOGICAL SYSTEMS
William Shakespeare described the acute pharmacological
effects of imbibing ethanol in the Porter scene (act 2,
scene 3) of Macbeth. The Porter, awakened from an
alcohol-induced sleep by Macduff, explains three
effects of alcohol and then wrestles with a fourth effect
that combines the contradictory aspects of soaring overconfidence
with physical impairment:
Porter: . . . and drink, sir, is a great provoker of three things.
Macduff: What three things does drink especially provoke?
Porter: Marry, sir, nose-painting [cutaneous vasodilation],
sleep [CNS depression], and urine [a consequence of the inhibition
of antidiuretic hormone (vasopressin) secretion, exacerbated by
volume loading]. Lechery, sir, it provokes and unprovokes: it provokes
the desire but it takes away the performance. Therefore much
drink may be said to be an equivocator with lechery: it makes him
and it mars him; it sets him on and it takes him off; it persuades him
and disheartens him, makes him stand to and not stand to [the
imagination desires what the corpus cavernosum cannot deliver];
in conclusion, equivocates him in a sleep, and, giving him the lie,
leaves him.