Overview
Clinical Meaning
PPIs and H2 receptor antagonists suppress gastric acid through fundamentally different mechanisms that determine their clinical profiles.
PPIs and H2 receptor antagonists suppress gastric acid through fundamentally different mechanisms that determine their clinical profiles. H2 blockers (famotidine, ranitidine — withdrawn due to NDMA contamination) competitively and reversibly block histamine H2 receptors on the basolateral membrane of parietal cells, reducing cAMP-mediated acid secretion. Because histamine is only one of three secretagogues (the others being acetylcholine via M3 receptors and gastrin via CCK-B receptors), H2 blockers provide only partial acid suppression (~70% reduction), are most effective against basal (nocturnal) acid secretion, and develop pharmacological tolerance (tachyphylaxis) within 2-6 weeks as parietal cells upregulate alternative stimulatory pathways. PPIs irreversibly inhibit the H+/K+ ATPase proton pump — the final common pathway for all acid secretion regardless of the stimulating pathway — producing more potent (>95%) and sustained acid suppression without tolerance. PPIs require an acidic environment for activation and only bind actively secreting pumps, necessitating pre-meal dosing when parietal cells are stimulated. Their duration of action (24-48 hours) exceeds their plasma half-life (1-2 hours) because new pump protein synthesis is required to restore acid secretion. Clinical selection depends on the condition...