Four H2 antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%. Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62–1). H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency. In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution.
TABLE 62–1 Clinical comparisons of H2-receptor blockers.
bid, twice daily; HS, bedtime.
The H2 antagonists exhibit competitive inhibition at the parietal cell H2 receptor and suppress basal and meal-stimulated acid secretion (Figure 62–2) in a linear, dose-dependent manner. They are highly selective and do not affect H1 or H3 receptors (see Chapter 16). The volume of gastric secretion and the concentration of pepsin are also reduced.
H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H2 receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2-receptor blockade.
The potencies of the four H2-receptor antagonists vary over a 50-fold range (Table 62–1). When given in usual prescription doses, however, all inhibit 60–70% of total 24-hour acid secretion. H2 antagonists are especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine), but they have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine). Therefore, nocturnal and fasting intragastric pH is raised to 4–5, but the impact on the daytime, meal-stimulated pH profile is less. Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours; hence, these drugs are commonly given twice daily. At doses available in over-the-counter formulations, the duration of acid inhibition is 6–10 hours.
H2-receptor antagonists continue to be prescribed, but PPIs (see below) are more commonly prescribed than H2 antagonists for most clinical indications. The over-the-counter preparations of the H2 antagonists are heavily used by the public.
1.
Gastroesophageal reflux disease (GERD)—Patients with infrequent heartburn or dyspepsia (fewer than three times per week) may take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1–2 hours) compared with H2 antagonists (6–10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62–1) or PPIs. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence PPIs are preferred because of their superior acid inhibition.
2.