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 H2 blockers (famotidine, ranitidine — withdrawn due to NDMA contamination) competitively and reversibly block histamine H2 receptors on the basolateral membrane of parietal cells, reducing cAMP-mediated acid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...