Peptic Ulcer Disease and Gastro-oesophageal Reflux Disease

Classification

PPIs: omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole. H2 antagonists: ranitidine(prototype, restricted many markets), famotidine, cimetidine. Antacids: Al(OH)3, Mg(OH)2, CaCO3, NaHCO3. Mucosal protectants: sucralfate, misoprostol, bismuth. Anti-H.pylori: combination regimens(below).

Mechanism

PPIs: irreversible H+/K+-ATPase(“proton pump”) inhibitors — FINAL COMMON step regardless of stimulus(histamine/H2, gastrin, ACh/M3 all converge here) → MOST POTENT acid suppression(blocks downstream of ALL pathways simultaneously). PRODRUGS, weak bases, ION-TRAPPED in acidic parietal cell canaliculus(same principle as chloroquine/urinary alkalinization) → acidic environment activates to sulfenamide form → covalent IRREVERSIBLE pump binding. Recovery needs NEW pump synthesis(~24-48h) → sustained suppression despite short plasma t½(PD vs PK distinction).

H2 antagonists: competitive REVERSIBLE H2 block → reduces ONLY histamine-mediated pathway(gastrin/ACh intact) → LESS complete than PPI → lower potency, PPIs now preferred 1st-line.

Antacids: DIRECT neutralization of EXISTING acid(simple acid-base chemistry) — rapid but short-lived, does NOT reduce acid PRODUCTION at all — fundamental distinction from suppressant classes.

Sucralfate: polymerizes in ACIDIC environment → sticky paste, adheres to ULCER CRATER specifically(exposed proteins) → physical barrier vs acid/pepsin. DIFFERENT logic(protects damaged tissue, not ↓acid) → REQUIRES acidic environment to activate → LESS effective +PPI/H2-blocker/antacid(raises pH, impairs activation) — specific timing consideration.

Misoprostol: synthetic PGE1 analogue — replaces protective PG that NSAIDs deplete(same COX-1 mechanism as aspirin’s GI toxicity) → restores mucus/bicarbonate/mucosal blood flow. Specific use: PREVENT NSAID-induced ulceration in patients needing continued NSAID. Uterotonic/abortifacient(same PG action) → CI in PREGNANCY — directly traceable to own mechanism, not unrelated SE.

H. pylori Eradication

Standard triple therapy: PPI + 2 antibiotics(clarithromycin+amoxicillin, or metronidazole if penicillin-allergic), 10-14 days — acid suppression(less hostile environment+promotes healing) + dual antibiotics(↓resistance-emergence risk) = SAME combination-therapy resistance-prevention logic as TB/leprosy, applied to single bacterial species. Bismuth quadruple therapy(bismuth subsalicylate+metronidazole+tetracycline+PPI): clarithromycin-resistance areas/triple-therapy failure — bismuth has DIRECT antibacterial action + mucosal-coating protection, independent contribution.

Adverse Effects

PPIs long-term(all traceable to ONE fact: acid serves physiological functions beyond digestion): hypomagnesaemia(↓intestinal Mg2+ absorption) · ↑fracture risk(↓Ca2+ absorption theory, debated exact mechanism) · B12 deficiency(acid needed to release B12 from dietary protein, years-long suppression) · ↑C. diff/enteric infection susceptibility(acid = 1st-line pathogen defence, chronic suppression removes barrier).

H2 blockers: CIMETIDINE specifically = notable CYP450 inhibitor(↑warfarin, phenytoin, theophylline) + anti-androgenic(gynaecomastia, ↓libido — weak androgen receptor binding, off-target, NOT shared by ranitidine/famotidine) → largely superseded despite pioneering the class.

Antacids: ALUMINIUM→CONSTIPATION; MAGNESIUM→DIARRHOEA(useful mnemonic pairing — combination products deliberately pair both to cancel effects). CaCO3: milk-alkali syndrome(excessive/prolonged — hypercalcaemia+metabolic alkalosis+renal impairment). All antacids CHELATE co-drugs(same cation-chelation as fluoroquinolones/tetracyclines) → timing separation needed.

Clinical Relevance

Proton pump = FINAL COMMON convergence of every acid-stimulatory pathway → why PPIs are mechanistically MOST potent, not just newest. Sucralfate/misoprostol’s genuinely DIFFERENT logic(physical protection vs prostaglandin replacement, NOT acid suppression) correctly predicts their specific niches(sucralfate needs acidic environment; misoprostol’s NSAID-ulcer-prevention role+pregnancy CI) — not one undifferentiated “antiulcer drug” category.

Classification

Proton pump inhibitors (PPIs): omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole
H2 receptor antagonists: ranitidine (largely withdrawn/restricted in many markets over an NDMA contamination concern, still taught as the prototype), famotidine, cimetidine
Antacids: aluminium hydroxide, magnesium hydroxide, calcium carbonate, sodium bicarbonate
Mucosal protective agents: sucralfate, misoprostol, bismuth compounds
Anti-H. pylori regimens: combination therapy (below)

Mechanism of Action

Proton pump inhibitors: irreversible inhibitors of the H⁺/K⁺-ATPase (“proton pump”) on the gastric parietal cell’s luminal (canalicular) membrane — the final common step of acid secretion regardless of what stimulated the parietal cell (histamine via H2 receptors, gastrin, or acetylcholine via M3 receptors all ultimately converge on this same pump), making PPIs the most potent acid-suppressing class available, since they block acid secretion downstream of every stimulatory pathway simultaneously rather than blocking just one. PPIs are prodrugs, weak bases that accumulate specifically in the highly acidic parietal cell canaliculus (the same ion-trapping principle already seen for chloroquine under Antimalarial Drugs and for renal urinary alkalinization under Renal Pharmacology, here concentrating the drug precisely where it needs to act), where the acidic environment converts them to their active sulfenamide form, which then covalently and irreversibly binds the pump. Because the binding is irreversible, acid secretion recovery after a dose depends on synthesis of new pump protein (roughly 24–48 hours), which is why PPIs achieve more sustained acid suppression than their relatively short plasma half-life would otherwise suggest — a specific, examined pharmacodynamic-versus-pharmacokinetic distinction.

H2 receptor antagonists: competitively and reversibly block histamine H2 receptors on the parietal cell, reducing acid secretion specifically through the histamine-mediated pathway — since histamine is a major (though not the only) physiological driver of acid secretion, H2 blockers meaningfully reduce acid output, but less completely than PPIs (gastrin- and acetylcholine-driven secretion remain largely intact), explaining their comparatively lower potency and the general shift toward PPIs as first-line therapy for most acid-related indications today.

Antacids: directly neutralize existing gastric acid by simple acid-base chemistry, providing rapid but short-lived symptomatic relief — they do not reduce acid production at all, only neutralize acid already present, the fundamental mechanistic distinction from every acid-suppressing class above.

Sucralfate: in an acidic environment, polymerizes into a sticky, viscous paste that adheres specifically to the ulcer crater/damaged mucosa (preferentially binding exposed proteins at the site of injury rather than healthy mucosa), forming a physical protective barrier against acid/pepsin — a genuinely different mechanism from acid suppression altogether (protecting damaged tissue rather than reducing the acid attacking it), which is why sucralfate specifically requires an acidic environment to activate and is therefore less effective if given concurrently with a PPI/H2 blocker/antacid (which raise gastric pH and impair sucralfate’s own activation) — a specific, examined drug-drug interaction/timing consideration.

Misoprostol: a synthetic prostaglandin E1 analogue, replacing the protective prostaglandin activity that NSAIDs deplete (NSAIDs’ COX-1 inhibition removes the same cytoprotective gastric prostaglandins already discussed under Antiplatelet Drugs’ aspirin-GI-toxicity mechanism) — misoprostol restores mucus/bicarbonate secretion and mucosal blood flow, specifically used to prevent NSAID-induced peptic ulceration in patients who must continue NSAID therapy, a genuinely mechanism-targeted preventive use rather than a generic antiulcer drug. Uterotonic/abortifacient property (the same prostaglandin action that protects gastric mucosa also stimulates uterine contraction) makes misoprostol contraindicated in pregnancy for its GI indication, a specific, high-yield contraindication directly traceable to the drug’s own mechanism rather than an unrelated side effect.

H. pylori Eradication

Standard triple therapy: a PPI plus two antibiotics (typically clarithromycin and amoxicillin, or metronidazole in penicillin-allergic patients), for 10–14 days — combining an acid suppressant (creating a less hostile environment for the antibiotics to work, and directly promoting ulcer healing) with dual antibiotic coverage specifically to reduce the resistance-emergence risk that monotherapy would carry against this organism, the identical combination-therapy resistance-prevention logic already established repeatedly across Antimicrobials — General Considerations, Antitubercular Drugs, and Antileprotic Drugs, here applied to a single bacterial species rather than a mycobacterium. Bismuth-based quadruple therapy (bismuth subsalicylate, metronidazole, tetracycline, plus a PPI) is used where clarithromycin resistance is prevalent or triple therapy has failed — bismuth itself has direct antibacterial action against H. pylori plus a mucosal-coating protective effect, contributing independently to the regimen beyond the antibiotics alone.

Adverse Effects

PPIs: generally well tolerated short-term; long-term use carries specific, increasingly-recognized risks worth knowing as a set — hypomagnesaemia (impaired intestinal Mg²⁺ absorption with prolonged use), increased fracture risk (proposed mechanism: reduced gastric acidity impairing calcium absorption, though the exact mechanism remains debated), B12 deficiency (gastric acid is needed to release B12 from dietary protein for absorption, so chronic acid suppression can impair this over years), and increased susceptibility to certain enteric infections including Clostridioides difficile (gastric acid normally provides a first-line defence against ingested pathogens, and its chronic suppression removes this barrier) — all mechanistically traceable to the same underlying fact (acid serves physiological functions beyond digestion, and suppressing it long-term has predictable downstream consequences), rather than being an unrelated list of side effects.

H2 blockers: cimetidine specifically is a notable CYP450 inhibitor (raising levels of warfarin, phenytoin, theophylline among others — a specific, examined property distinguishing it from the other, more selective H2 blockers) and has a distinctive anti-androgenic effect (gynaecomastia, reduced libido — from weak binding to androgen receptors, an off-target effect not shared by ranitidine/famotidine), both specific reasons cimetidine has been largely superseded by other agents in this class despite pioneering it.

Antacids: aluminium-containing antacids cause constipation; magnesium-containing antacids cause diarrhoea — a genuinely useful, frequently-taught mnemonic pairing (and the reason many combination antacid products deliberately combine both, aiming for the opposing GI effects to cancel out). Calcium carbonate can cause milk-alkali syndrome with excessive/prolonged use (hypercalcaemia, metabolic alkalosis, renal impairment). All antacids chelate/reduce absorption of numerous co-administered drugs (the same cation-chelation interaction mechanism already seen with fluoroquinolones and tetracyclines), requiring timing separation.

Clinical Relevance

The proton pump’s role as the final common convergence point of every acid-secretion stimulatory pathway is what makes PPIs mechanistically the most potent acid suppressants available, not merely the newest — and recognizing sucralfate/misoprostol’s genuinely different logic (physical protection and prostaglandin replacement, respectively, rather than acid suppression) is what correctly predicts their specific niches (sucralfate needing an acidic environment to work, misoprostol’s specific NSAID-ulcer-prevention role and pregnancy contraindication) rather than lumping every “antiulcer drug” into one undifferentiated category.

Parietal cell with histamine/gastrin/acetylcholine pathways all converging on the H+/K+-ATPase, marking where PPIs (final pump) vs H2 blockers (one upstream pathway only) act.
PPI ion-trapping activation in the acidic parietal cell canaliculus.