H2-Receptor Antagonists - Agents that Reduce Intragastric Acidity

H₂-RECEPTOR ANTAGONISTS

From their introduction in the 1970s until the early 1990s, H₂-receptor antagonists (commonly referred to as H₂ blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of proton pump inhibitors, the use of prescription H₂ blockers has declined markedly.

Chemistry & Pharmacokinetics

Four H₂ antagonists are in clinical use: cimetidine, ranitidine, famo-tidine, 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, dura-tion 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 vol-ume of distribution.

Pharmacodynamics

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 . The volume of gastric secretion and the concentra-tion 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 stimu-lated 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 less than 6 hours.

Clinical Uses

H₂-receptor antagonists continue to be prescribed but proton pump inhibitors  are steadily replacing H₂ antagonists for most clinical indications. However, the over-the-counter preparations of the H₂ antagonists are heavily used by the public.

A. Gastroesophageal Reflux Disease (GERD)

Patients with infrequent heartburn or dyspepsia (fewer than 3 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 prophylac-tically before meals in an effort to reduce the likelihood of heart-burn. Frequent heartburn is better treated with twice-daily H₂ antagonists (Table 62–1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H₂ antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition.

B. Peptic Ulcer Disease

Proton pump inhibitors have largely replaced H₂ antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H₂ antagonists are still sometimes used. Nocturnal acid suppression by H₂ antagonists affords effective ulcer healing in most patients

Pharmacodynamics

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 . The volume of gastric secretion and the concentra-tion 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 stimu-lated 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 less than 6 hours.

Clinical Uses

H₂-receptor antagonists continue to be prescribed but proton pump inhibitors  are steadily replacing H₂ antagonists for most clinical indications. However, the over-the-counter preparations of the H₂ antagonists are heavily used by the public.

A. Gastroesophageal Reflux Disease (GERD)

Patients with infrequent heartburn or dyspepsia (fewer than 3 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 prophylac-tically before meals in an effort to reduce the likelihood of heart-burn. Frequent heartburn is better treated with twice-daily H₂ antagonists (Table 62–1) or proton pump inhibitors. In patients with erosive esophagitis (approximately 50% of patients with GERD), H₂ antagonists afford healing in less than 50% of patients; hence proton pump inhibitors are preferred because of their superior acid inhibition.

B. Peptic Ulcer Disease

Proton pump inhibitors have largely replaced H₂ antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H₂ antagonists are still sometimes used. Nocturnal acid suppression by H₂ antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80–90% after 6–8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a pro-ton pump inhibitor should be given instead of an H₂ antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H₂ antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10-to 14-day course of therapy including a proton pump inhibitor and two antibiotics . This regimen achieves ulcer heal-ing and eradication of the infection in more than 90% of patients. For the minority of patients in whom H pylori cannot be success-fully eradicated, H₂ antagonists may be given daily at bedtime in half of the usual ulcer therapeutic dose to prevent ulcer recurrence (eg, ranitidine, 150 mg; famotidine, 20 mg).

C. Nonulcer Dyspepsia

H₂ antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated.

D. Prevention of Bleeding from Stress-Related Gastritis

Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1–5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H₂ antagonists or proton pump inhibitors) reduce the incidence of clinically significant bleeding. However, the opti-mal agent is uncertain at this time. For patients without a nasoen-teric tube or with significant ileus, intravenous H₂ antagonists are preferable over intravenous proton pump inhibitors because of their proven efficacy and lower cost. Continuous infusions of H₂ antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH.

Adverse Effects

H₂ antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H₂ antagonists (or proton pump inhibitors) may increase the risk of nosocomial pneumonia in critically ill patients.

Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H₂ antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients.

Cimetidine inhibits binding of dihydrotestosterone to andro-gen 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 brady-cardia and hypotension through blockade of cardiac H₂ receptors; therefore, intravenous injections should be given over 30 minutes. H₂ antagonists rarely cause reversible abnormalities in liver chemistry.

Drug Interactions

Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 . Hence, the half-lives of drugs metabolized by these pathways may be prolonged. Ranitidine binds 4–10 times less avidly than cime-tidine to cytochrome P450. Negligible 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.