Ethanol, a sedative-hypnotic drug, is the most important alcohol of pharmacologic interest. It has few medical applications, but its abuse causes major medical and socioeconomic problems. Other alcohols of toxicologic importance are methanol and ethylene glycol. Several important drugs discussed in this chapter are used to prevent the potentially life-threatening ethanol withdrawal syndrome, to treat chronic alcoholism, or to treat acute methanol and ethylene glycol poisoning.
After ingestion, ethanol is rapidly and completely absorbed; the drug is then distributed to most body tissues, and its volume of distribution is equivalent to that of total body water (0.5–0.7 L/kg). Two enzyme systems metabolize ethanol to acetaldehyde (Figure 23–1).
Metabolism of ethanol by alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. (Reproduced, with permission, from Katzung BG, Masters SB, Trevor AT, editors: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 23–1.)
1. Alcohol dehydrogenase (ADH)
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.
2. Microsomal ethanol-oxidizing system (MEOS)
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.
Acetaldehyde formed from the oxidation of ethanol by either ADH or MEOS is rapidly metabolized to acetate by aldehyde dehydrogenase, a mitochondrial enzyme found in the liver and many other tissues. Aldehyde dehydrogenase is inhibited by disulfiram and other drugs, including metronidazole, oral hypoglycemics, and some cephalosporins. Some individuals, primarily of Asian descent, have genetic deficiency of aldehyde dehydrogenase. After consumption of even small quantities of ethanol, these individuals experience nausea and a flushing reaction from accumulation of acetaldehyde.
High-Yield Terms to Learn
|Alcohol abuse ||An alcohol-use disorder characterized by compulsive use of ethanol in dangerous situations (eg, driving, combined with other CNS depressants) or despite adverse consequences ...|