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CHAPTER 23 The Alcohols 397

The societal and medical costs of alcohol abuse are staggering.
It is estimated that more than 600,000 emergency department vis- Ethanol
its and approximately 85,000 deaths in the USA annually are due NAD + CH CH OH NADPH + O 2
3
2
to alcohol use. Once in the hospital, people with chronic alcohol-
ism generally have poorer outcomes. In addition, each year, tens of Alcohol MEOS
thousands of children are born with morphologic and functional dehydrogenase
defects resulting from prenatal exposure to ethanol. Despite the
investment of many resources and much basic research, alcohol- – NADH Acetaldehyde NADP + H O
+
2
ism remains a common chronic disease that is difficult to treat. CH 3 CHO
Ethanol and many other alcohols with potentially toxic effects Fomepizole
are used as fuels and in industry—some in enormous quantities. In NAD +
addition to ethanol, methanol and ethylene glycol toxicity occurs Aldehyde
with sufficient frequency to warrant discussion in this chapter. dehydrogenase
NADH
■ BASIC PHARMACOLOGY OF Acetate –
ETHANOL CH COO – Disulfiram
3
Pharmacokinetics FIGURE 23–1 Metabolism of ethanol by alcohol dehydrogenase

Ethanol is a small water-soluble molecule that is absorbed rap- and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehy-
idly from the gastrointestinal tract. After ingestion of alcohol in drogenase and aldehyde dehydrogenase are inhibited by fomepizole
+
the fasting state, peak blood alcohol concentrations are reached and disulfiram, respectively. NAD , nicotinamide adenine dinucleo-
within 30 minutes. The presence of food in the stomach delays tide; NADPH, nicotinamide adenine dinucleotide phosphate.
absorption by slowing gastric emptying. Distribution is rapid,
with tissue levels approximating the concentration in blood. The the conversion of alcohol to acetaldehyde (Figure 23–1, left).
volume of distribution for ethanol approximates total body water These enzymes are located mainly in the liver, but small amounts
(0.5–0.7 L/kg). After an equivalent oral dose of alcohol, women are found in other organs such as the brain and stomach. There
have a higher peak concentration than men, in part because is considerable genetic variation in ADH enzymes, affecting the
women have a lower total body water content and in part because rate of ethanol metabolism and also appearing to alter vulnerabil-
of differences in first-pass metabolism. In the central nervous sys- ity to alcohol-abuse disorders. For example, one ADH allele (the
*
tem (CNS), the concentration of ethanol rises quickly, since the ADH1B 2 allele), which is associated with rapid conversion of etha-
brain receives a large proportion of total blood flow and ethanol nol to acetaldehyde, has been found to be protective against alcohol
readily crosses biologic membranes. dependence in several ethnic populations, especially East Asians.
Over 90% of alcohol consumed is oxidized in the liver; much of Some metabolism of ethanol by ADH occurs in the stomach
the remainder is excreted through the lungs and in the urine. The in men, but a smaller amount occurs in women, who appear to
excretion of a small but consistent proportion of alcohol by the lungs have lower levels of the gastric enzyme. This difference in gastric
can be quantified with breath alcohol tests that serve as a basis for a metabolism of alcohol in women probably contributes to the sex-
legal definition of “driving under the influence” (DUI) in many coun- related differences in blood alcohol concentrations noted above.
tries. In most states in the USA, the alcohol level for driving under During conversion of ethanol by ADH to acetaldehyde, hydro-
the influence is set at 80 mg/dL (0.08%). At levels of ethanol usually gen ion is transferred from ethanol to the cofactor nicotinamide
+
achieved in blood, the rate of oxidation follows zero-order kinetics; adenine dinucleotide (NAD ) to form NADH. As a net result,
that is, it is independent of time and concentration of the drug. The alcohol oxidation generates an excess of reducing equivalents
typical adult can metabolize 7–10 g (150–220 mmol) of alcohol in the liver, chiefly as NADH. The excess NADH production
per hour, the equivalent of approximately one “drink” [10 oz (300 appears to contribute to the metabolic disorders that accompany
mL) beer, 3.5 oz (105 mL) wine, or 1 oz (30 mL) distilled 80-proof chronic alcoholism and to both the lactic acidosis and hypoglyce-
spirits]. A commercial product (“Palcohol”), approved in the USA in mia that frequently accompany acute alcohol poisoning.
2015, consists of a powder to be mixed to form a drink containing
10% ethanol (approximately equivalent to wine). B. Microsomal Ethanol-Oxidizing System (MEOS)
Two major pathways of alcohol metabolism to acetaldehyde This enzyme system, also known as the mixed function oxidase
have been identified (Figure 23–1). Acetaldehyde is then oxidized system, uses NADPH as a cofactor in the metabolism of ethanol
to acetate by a third metabolic process. (Figure 23–1, right) and consists primarily of cytochrome P450
2E1, 1A2, and 3A4 (see Chapter 4).
A. Alcohol Dehydrogenase Pathway During chronic alcohol consumption, MEOS activity is
The primary pathway for alcohol metabolism involves alcohol induced. As a result, chronic alcohol consumption results in sig-
dehydrogenase (ADH), a family of cytosolic enzymes that catalyze nificant increases not only in ethanol metabolism but also in the