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.
|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 directly related to the drinking|
|Alcohol dependence||An alcohol-use disorder characterized by alcohol abuse plus physical dependence on ethanol|
|Alcohol withdrawal syndrome||The characteristic syndrome of insomnia, tremor, agitation, seizures, and autonomic instability engendered by deprivation in an individual who is physically dependent on ethanol|
|Delirium tremens (DTs)||Severe form of alcohol withdrawal whose main symptoms are sweating, tremor, confusion, and hallucinations|
|Fetal alcohol syndrome||A syndrome of craniofacial dysmorphia, heart defects, and mental retardation caused by the teratogenic effects of ethanol consumption during pregnancy|
|Wernicke-Korsakoff syndrome||A syndrome of ataxia, confusion, and paralysis of the extraocular muscles that is associated with chronic alcoholism and thiamine deficiency|
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).
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.)
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.
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 ...