proton pump inhibitor

MECHANISM: PPIs are weak-base prodrugs absorbed in the small intestine, then reach parietal cells via the bloodstream. In the acidic secretory canaliculus they are protonated and converted to an active sulfenamide, which forms covalent disulfide bonds with cysteine residues on the H+/K+ ATPase (the proton pump). Inhibition is irreversible, so acid secretion resumes only after new pumps are synthesized (about 24-48 h or longer). Because PPIs act on the final common pathway of acid secretion (stimulated by histamine, ACh, and gastrin), they are more effective than H2 blockers.

PHARMACOKINETICS/ADMINISTRATION: Take 30-60 min before a meal (usually breakfast). Pumps are most active after fasting and are activated by food, so this timing lets the drug inhibit the most active pumps. Full effect takes about 3-5 days. Most are acid-labile and given as enteric-coated or delayed-release formulations. Hepatic metabolism is via CYP2C19 and CYP3A4. Omeprazole and esomeprazole inhibit CYP2C19.

INDICATIONS: GERD and erosive esophagitis; peptic ulcer disease (gastric and duodenal); H. pylori triple therapy (PPI + clarithromycin + amoxicillin or metronidazole) or bismuth quadruple therapy (PPI + bismuth + tetracycline + metronidazole); NSAID ulcer prophylaxis; stress ulcer prophylaxis in ICU patients at high risk; Zollinger-Ellison syndrome (gastrinoma; high doses); upper GI bleeding (IV PPI after endoscopic therapy); and Barrett esophagus (often used).

ADVERSE EFFECTS (high-yield): - Hypomagnesemia (can cause secondary hypocalcemia, arrhythmias, QT prolongation) - Decreased absorption of vitamin B12, iron, calcium (as calcium carbonate), and possibly an increased fracture risk (hip, wrist, spine) - Increased risk of C. difficile infection and other enteric infections (loss of the gastric acid barrier) - Community-acquired pneumonia (association) - Acute interstitial nephritis, with possible association with CKD - Rebound acid hypersecretion after abrupt discontinuation (hypergastrinemia; taper if long-term) - Fundic gland polyps and hypergastrinemia - Possible enterochromaffin-like cell hyperplasia (not proven to cause carcinoid in humans) - Atrophic gastritis and the masking of gastric cancer symptoms (a reason to evaluate alarm features before empiric therapy) - Microscopic (lymphocytic) colitis (association)

DRUG INTERACTIONS: Omeprazole/esomeprazole inhibit CYP2C19, which reduces activation of clopidogrel (a prodrug) and may reduce its antiplatelet effect; pantoprazole has less interaction. Reduced gastric acidity decreases absorption of drugs requiring acid (ketoconazole, itraconazole, atazanavir, iron salts, levothyroxine). Can increase levels of warfarin, diazepam, and phenytoin (CYP2C19 inhibition). Methotrexate levels may rise with high doses.

COMPARISON: H2 blockers (cimetidine, ranitidine, famotidine, nizatidine) block histamine H2 receptors and are less potent; cimetidine inhibits CYP450 and has antiandrogen effects (gynecomastia, impotence). Antacids provide quick, short-term neutralization. Sucralfate and misoprostol are mucosal protectants. Potassium-competitive acid blockers (P-CABs; vonoprazan) bind K+ site reversibly, work without acid activation, and have a faster onset; they are increasingly used for erosive esophagitis and H. pylori therapy.

LABORATORY/DIAGNOSTIC PEARLS: PPIs raise serum gastrin (negative feedback loss), which can cause a false-positive secretin/gastrin screening in suspected gastrinoma. Hold PPIs 1-2 weeks before urea breath test, stool antigen, or rapid urease testing for H. pylori (false negatives). Hold before pH-impedance testing as indicated.

CLINICAL PEARL: Use the lowest effective dose for the shortest duration. Alarm features (dysphagia, weight loss, GI bleeding, anemia, age >60 with new-onset symptoms) warrant endoscopy rather than empiric PPI therapy alone.