Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women. These effects are specific to cimetidine and do not occur with the other H2 antagonists.
Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H2 antagonists are secreted into breast milk and may therefore affect nursing infants.
H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause
Drugs Used in the Treatment of Gastrointestinal Diseases 1091 bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous infusions should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry.
Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4–10 times less avidly than cimetidine to cytochrome P450. Negligible CYP interaction occurs with nizatidine and famotidine.
H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels.
Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acid-peptic disorders. PPIs are now among the most widely prescribed drugs worldwide.
Six PPIs are available for clinical use: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62–3) but have a completely different mechanism of action. Omeprazole and lansoprazole are racemic mixtures of Rand S-isomers. Esomeprazole is the S-isomer of omeprazole and dexlansoprazole the R-isomer of lansoprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62–2).