H2 antihistamine

**Mechanism:** Reversible, competitive antagonists of the H2 receptor (Gs-coupled) on the basolateral membrane of gastric parietal cells. Blocking H2 decreases adenylyl cyclase activity, lowering cAMP and PKA signaling, which reduces H+/K+ ATPase (proton pump) activity. Net effect: decreased acid secretion, especially basal and nocturnal acid. Less effective than PPIs because ACh (M3, via Gq/Ca2+) and gastrin (CCK-B, via Gq/Ca2+) still stimulate the parietal cell.

**Drugs:** Cimetidine, famotidine, nizatidine, ranitidine (withdrawn in the US in 2020 because of NDMA contamination). Mnemonic: "Take H2 blockers before you dine. Tagament (cimetidine) is the worst."

**Clinical uses:** - GERD (mild or intermittent) - Peptic ulcer disease (duodenal and gastric ulcers) - Gastritis - Stress ulcer prophylaxis - Zollinger-Ellison syndrome (PPIs preferred) - Adjunct for urticaria or allergic reactions (H1 + H2 combination) - Nocturnal acid breakthrough

**Adverse effects and board-relevant points:** - **Cimetidine** is a potent **CYP450 inhibitor** (CYP3A4, 2D6, 1A2). It increases levels of warfarin, theophylline, phenytoin, and others. - Cimetidine is **antiandrogenic**: gynecomastia, galactorrhea, decreased libido, and impotence in men. It inhibits androgen receptors and displaces estradiol from binding. It also increases prolactin. - Cimetidine and ranitidine **decrease renal creatinine secretion**, which raises serum creatinine without a true change in GFR. - Crosses the BBB, especially in elderly or renally impaired patients: confusion, delirium, and headache. - Famotidine rarely causes QT prolongation in renal failure. - Other effects: Rare cytopenias (thrombocytopenia) and dose adjustment is needed in renal impairment, because the drugs are renally cleared. - **Tachyphylaxis** (tolerance) can develop with continued use. - Decreased gastric acidity can reduce absorption of drugs that need acid (ketoconazole, itraconazole, iron).

**Comparison with other agents:** - **PPIs** (omeprazole, etc.) irreversibly inhibit H+/K+ ATPase and are more effective for healing ulcers and erosive esophagitis. - **H1 antihistamines** (diphenhydramine, loratadine) treat allergy and are unrelated to acid suppression. - **Antacids** neutralize acid directly. - **Sucralfate** and **misoprostol** are mucosal protectants.

**Key physiology tie-in:** Parietal cell stimulation comes from three pathways: histamine (H2, Gs, cAMP), gastrin (CCK-B, Gq), and ACh (M3, Gq). Histamine is released from ECL cells. H2 blockers address only the histamine pathway, which is why they are less potent than PPIs.