H2 blocker

MECHANISM: Reversible competitive antagonists of H2 receptors on parietal cells (Gs-coupled → ↑adenylyl cyclase → ↑cAMP → ↑H+/K+ ATPase activity). Blocking H2 lowers cAMP and decreases acid secretion. They mainly reduce basal and nocturnal acid secretion, and are less effective than PPIs because gastrin and ACh (M3) can still stimulate parietal cells via Ca2+ pathways.

AGENTS: Cimetidine, famotidine, nizatidine, and ranitidine. Ranitidine was withdrawn from the US market in 2020 because of NDMA (a probable carcinogen) contamination. Remember "-tidine" = H2 blocker.

CLINICAL USES: GERD (mild or intermittent), peptic ulcer disease (duodenal and gastric), stress ulcer prophylaxis, and Zollinger-Ellison syndrome (PPIs preferred), plus dyspepsia. They are used less often today because PPIs are more effective. Famotidine is the one most commonly used now.

ADVERSE EFFECTS: - Cimetidine is a potent CYP450 inhibitor (CYP1A2, 2C9, 2D6, 3A4), so it raises levels of warfarin, theophylline, phenytoin, and others. Famotidine, nizatidine, and ranitidine have minimal CYP effects. - Cimetidine is antiandrogenic: gynecomastia, decreased libido, impotence, and galactorrhea (↑prolactin) in men. It displaces androgens from their receptors and inhibits estradiol metabolism. - Cimetidine crosses the blood-brain barrier and the placenta. CNS effects include confusion, dizziness, headache, and delirium, especially in elderly patients and those with renal impairment. - Cimetidine and ranitidine reduce renal creatinine secretion, which can falsely raise serum creatinine without a true change in GFR. - Rare effects include thrombocytopenia and other cytopenias, and bradycardia or arrhythmias with rapid IV administration. - Tachyphylaxis (tolerance) can develop with continued use.

DRUG INTERACTIONS: Because they raise gastric pH, H2 blockers decrease absorption of drugs that need an acidic environment (ketoconazole, itraconazole, atazanavir, some iron preparations). They are renally cleared, so dose adjustment is needed in renal impairment.

COMPARISON WITH OTHER ACID-SUPPRESSING AGENTS: - PPIs (omeprazole): irreversibly inhibit H+/K+ ATPase and are more effective. Risks include C. difficile infection, fractures, hypomagnesemia, and decreased B12 absorption. - Antacids: neutralize acid directly and work quickly. - Sucralfate: forms a protective barrier over ulcers and needs an acidic pH. - Misoprostol (PGE1 analog): increases mucus and bicarbonate production and decreases acid secretion.

HIGH-YIELD PEARL: Cimetidine = "Cimetidine inhibits CYP450 and androgen receptors" (gynecomastia). Of the acid-suppressing drugs, H2 blockers are better than antacids but less potent than PPIs.