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

CH 3 OH
Methanol
H 3 C CH 2 OH
Ethanol
NAD + NADPH
631
Fomepizole
NADH
+
H +
NADH
+
H +
Folate-dependent
pathway
CO 2
+
H 2 O
H 2 C O
X
Formaldehyde
O
HC OH
Formic acid
β-hydroxy-β-methyl
glutaryl CoA
AMP + 2P;
NAD +
+ O 2
NADPH
H 2 O 2
Alcohol
dehydrogenase
Aldehyde
dehydrogenase
H 3 C
O
CH
Acetaldehyde
X
O
H 3 C C OH
Acetic acid
Thiokinase
C
CoA S C CH 3
Acetyl CoA
CYP2E1
+ H 2 O
Disulfiram
CoA + ATP
Catalase
Tricarboxylic
acid cycle
2H 2 O
CHAPTER 23
ETHANOL AND METHANOL
Ketone
bodies
Figure 23–1. Metabolism of ethanol and methanol.
Cholesterol
Fatty acids
The mechanisms underlying hepatic disease
resulting from heavy ethanol use probably reflect a
complex combination of these metabolic factors,
CYP2E1 induction (and enhanced activation of toxins
and production of H 2
O 2
and oxygen radicals), and possibly
enhanced release of endotoxin as a consequence
of ethanol’s effect on gram-negative flora in the GI
tract. Effects of heavy ethanol ingestion on various
organs are summarized in the following discussion;
damage to tissues very likely reflects the poor nutritional
status of alcoholics (malabsorption and lack of
vitamins A and D and thiamine), suppression of
immune function by ethanol, and a variety of other generalized
effects.
Methanol. One carbon alcohol, methanol (CH 3
OH), is also known
as methyl and wood alcohol. It is an important industrial reagent and
solvent found in products such as paint removers, shellac, and
antifreeze (Lushine et al., 2003); methanol is added to industrial-use
ethanol to mark it unsafe for human consumption.
Methanol is rapidly absorbed via the oral route, inhalation,
and through the skin, with the latter two routes most relevant to
industrial settings. Methanol also is metabolized by ADH and
ALDH, with damaging consequences (described later in the chapter).
Competition between methanol and ethanol for ADH forms the
basis of the use of ethanol in methanol poisoning. Several drugs
inhibit alcohol metabolism, including fomepizole (4-methylpyrazole)
an ADH inhibitor useful in ethylene glycol poisoning, and disulfiram,
an ALDH inhibitor used in treating alcoholism (described later
in the chapter). Ethanol also can competitively inhibit the metabolism
of other substrates of ADH and CYP2E1, such as methanol and
ethylene glycol, and therefore is an effective antidote.
FOMEPIZOLE
Feelings of intoxication from methanol, while similar in
many ways to those with ethanol, are less intense, and often delayed
by 8 or more hours from ingestion, progressing even more slowly if