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Ethanol, a sedative-hypnotic drug, is the most important alcohol of pharmacologic interest. Its abuse causes major medical and socioeconomic problems. Other alcohols of toxicologic importance are methanol and ethylene glycol. Several drugs discussed in this chapter are used to prevent the potentially life-threatening ethanol withdrawal syndrome, to treat chronic alcohol-use disorders, or to treat acute methanol and ethylene glycol poisoning.
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After ingestion, ethanol is rapidly and completely absorbed; the drug is then distributed to most body tissues. Two enzyme systems metabolize ethanol to acetaldehyde (Figure 23–1).
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Alcohol Dehydrogenase (ADH)
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This family of cytosolic, NAD+-dependent enzymes, found mainly in the liver and gut, accounts for the metabolism of low to moderate doses of ethanol. Because of the limited supply of the coenzyme NAD+, the reaction has zero-order kinetics, resulting in a fixed capacity for ethanol metabolism of 7–10 g/h. Gastrointestinal metabolism of ethanol is lower in women than in men. Genetic variation in ADH affects the rate of ethanol metabolism and vulnerability to alcohol-use disorders.
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Microsomal Ethanol-Oxidizing System (MEOS)
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At blood ethanol levels higher than 100 mg/dL, the liver microsomal mixed function oxidase system that catalyzes most phase I drug-metabolizing reactions (see Chapter 2) contributes significantly to ethanol metabolism (Figure 23–1). Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and MEOS activity; this is partially responsible for the development of tolerance to ethanol. The primary isoform of cytochrome P450 induced by ethanol—2E1 (see Table 4–3)—converts acetaminophen to a hepatotoxic metabolite.
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Acetaldehyde formed from the oxidation of ethanol by either ADH ...