Drugs Used in Peptic Ulcer & GERD

Acid-peptic disorders (peptic ulcer disease, GERD, stress ulcers, Zollinger–Ellison syndrome) are managed by suppressing acid, neutralising acid, protecting mucosa, or eradicating Helicobacter pylori. This is one of the highest-yield Pharmacology chapters under autacoids — expect questions on PPI mechanism, CYP2C19 interactions, and eradication regimens.

The acid-secretion target

Gastric acid is secreted by the parietal cell H⁺/K⁺-ATPase (proton pump) — the final common pathway. Three stimulatory inputs converge on the parietal cell:

1. Histamine → H₂ receptor → Gs → ↑cAMP (the dominant physiological stimulus; potentiates the other two)
2. Acetylcholine (vagal, M₃ receptor) → ↑Ca²⁺
3. Gastrin (from antral G-cells; CCK₂ receptor) → ↑Ca²⁺; gastrin also acts indirectly via ECL-cell histamine release

High-yield: Because histamine is the final amplifying signal, H₂ blockers reduce acid evoked by all three stimuli to some extent, but the proton pump is the true final step — hence PPIs are more complete acid suppressors than H₂ blockers.

Drug classes acting here:

Class	Prototype	Site/Mechanism	Potency of acid suppression
Proton pump inhibitors	Omeprazole	Irreversible H⁺/K⁺-ATPase block	Most powerful (>90–95%)
H₂ receptor blockers	Ranitidine, famotidine	Competitive H₂ antagonism	Moderate (good for nocturnal acid)
Antacids	Mg/Al hydroxide	Chemical neutralisation in lumen	Symptomatic only
Mucosal protectives	Sucralfate, bismuth	Physical/chemical barrier	No acid suppression
Prostaglandin analogue	Misoprostol	↑Mucus/bicarbonate, ↓acid	Mild
Anticholinergics (obsolete)	Pirenzepine	M₁ block	Weak

Proton pump inhibitors (PPIs)

Drugs: Omeprazole, esomeprazole (S-isomer of omeprazole), lansoprazole, pantoprazole, rabeprazole, dexlansoprazole.

Mechanism — the key exam concept

PPIs are prodrugs that are weak bases and require an acidic environment for activation.

Flow: Oral PPI (enteric-coated, acid-labile) → absorbed in small intestine → enters blood → concentrates selectively in the acidic secretory canaliculus of the parietal cell → protonated and converted to the active sulphenamide/cyclic sulfenamide → forms a covalent disulphide bond with cysteine residues of H⁺/K⁺-ATPase → irreversible inhibition.

High-yield: PPIs cause irreversible enzyme inhibition. Acid secretion resumes only when new pump molecules are synthesised → this is why the duration of action (~24–48 h) far exceeds the plasma half-life (~1–2 h). Classic MCQ point.

Critical pharmacokinetic/clinical pearls

• Take 30–60 min before a meal (ideally before breakfast). The drug must be present when pumps are activated by food. Pumps not active during the dosing window escape inhibition.
• Enteric coating prevents degradation by gastric acid; do not crush.
• Full antisecretory effect takes 3–4 days (steady state of pump turnover).
• Metabolised by CYP2C19 and CYP3A4. Pantoprazole and rabeprazole have the least CYP-mediated drug interactions (rabeprazole is largely non-enzymatic).
• CYP2C19 genetic polymorphism affects response — poor metabolisers have higher levels/efficacy.

High-yield (interaction): PPIs (especially omeprazole/esomeprazole) inhibit CYP2C19 and reduce conversion of clopidogrel (a prodrug) to its active metabolite → ↓antiplatelet effect. If a PPI is needed with clopidogrel, prefer pantoprazole (least CYP2C19 inhibition).

Indications

GERD (drug of choice), PUD, H. pylori eradication (as part of regimen), NSAID-induced ulcer prevention and healing, Zollinger–Ellison syndrome (high-dose PPI is treatment of choice), stress-ulcer prophylaxis, bleeding peptic ulcer (high-dose IV pantoprazole/esomeprazole after endoscopic haemostasis).

Adverse effects (long-term, frequently tested)

• Hypomagnesaemia (can cause tetany/arrhythmia)
• Vitamin B12 deficiency (acid needed to release B12 from food)
• Iron malabsorption
• ↑Risk of enteric infections — Clostridioides difficile and community-acquired pneumonia (reduced acid barrier)
• Rebound acid hypersecretion on stopping (gastrin-driven ECL/parietal hyperplasia)
• Hypergastrinaemia → enterochromaffin-like (ECL) cell hyperplasia; carcinoid in rats (not proven in humans)
• Increased fracture risk (hip/spine) with long-term high dose; possible interstitial nephritis; acute kidney injury
• Headache, diarrhoea (most common short-term)

H₂ receptor antagonists

Drugs: Cimetidine (first, most interactions), ranitidine, famotidine (most potent), nizatidine, roxatidine.

Mechanism: Competitive, reversible block of parietal-cell H₂ receptors → ↓cAMP → reduced acid, especially basal and nocturnal acid secretion.

High-yield: H₂ blockers are particularly good at suppressing nocturnal acid (which is largely histamine-driven). They are weaker than PPIs for daytime/meal-stimulated acid. Tachyphylaxis/tolerance develops within days of regular use — a reason PPIs are preferred for sustained suppression.

Cimetidine — the "exception" drug

• Potent CYP450 inhibitor → ↑levels of warfarin, phenytoin, theophylline, diazepam, etc.
• Antiandrogenic: gynaecomastia, impotence, ↓libido (binds androgen receptor; also ↑prolactin)
• Confusion in elderly/renal failure (crosses BBB)

Mnemonic for cimetidine toxicity: "Cimetidine Causes Confusion, Cytochrome inhibition, and CC-cup (gynaecomastia)." Famotidine and ranitidine lack these.

Note: Ranitidine was largely withdrawn owing to NDMA (N-nitrosodimethylamine) carcinogen contamination — a recent, exam-relevant fact. Famotidine is now the preferred H₂ blocker.

Antacids

Weak bases that chemically neutralise secreted acid; raise gastric pH, inhibit pepsin (pepsin inactive above pH 4), and weakly stimulate mucosal prostaglandins/bicarbonate.

Antacid	Notable effect	Caution
Sodium bicarbonate	Rapid, systemic; CO₂ → belching; systemic alkalosis	Avoid in HTN/CHF (Na⁺ load); milk-alkali syndrome
Calcium carbonate	Potent, fast; acid rebound (↑gastrin)	Hypercalcaemia, milk-alkali syndrome, constipation
Magnesium hydroxide	Fast acting	Diarrhoea (osmotic); Mg accumulation in renal failure
Aluminium hydroxide	Slow; binds phosphate	Constipation; hypophosphataemia; binds drugs

High-yield: Mg salts → diarrhoea; Al salts → constipation. Combination Mg + Al hydroxide balances bowel effects — the classic combined antacid.

Interaction pearl: Antacids chelate/reduce absorption of tetracyclines, fluoroquinolones, iron, ketoconazole, and digoxin — separate dosing by ≥2 hours. Milk-alkali syndrome = hypercalcaemia + metabolic alkalosis + renal impairment (classically with CaCO₃ + milk).

Mucosal protective (cytoprotective) agents

Sucralfate

• Sucrose octasulphate + aluminium hydroxide; an aluminium salt of sulphated sucrose.
• Requires acidic pH (<4) for activation → polymerises to a sticky gel that binds to ulcer base proteins (esp. positively charged albumin/fibrinogen at the ulcer crater) forming a protective coat. Also stimulates prostaglandins, mucus, bicarbonate.

High-yield: Because sucralfate needs acid to work, do NOT give with antacids/PPIs/H₂ blockers simultaneously (give 2 h apart). Adverse effects: constipation (Al), and it binds other drugs (give other drugs apart from it). Preferred for stress ulcer prophylaxis in ventilated patients as it may cause less pneumonia than acid suppressants.

Bismuth compounds (colloidal bismuth subcitrate / subsalicylate)

• Coats ulcer base, directly bactericidal against H. pylori, stimulates mucus/bicarbonate/PG.
• Side effects: black tongue and black stools (do not confuse with melaena), reversible. Neurotoxicity with prolonged high doses.

Misoprostol

• A PGE₁ analogue. ↑Mucus + bicarbonate secretion, ↑mucosal blood flow, and ↓acid (cytoprotection + mild antisecretion).
• Main use: prevention of NSAID-induced gastric ulcers, especially in high-risk patients (elderly, prior ulcer, on steroids/anticoagulants).

High-yield: Misoprostol is contraindicated in pregnancy — it causes uterine contractions (abortifacient; used with mifepristone for MTP, and for PPH). Dose-limiting side effect = diarrhoea and abdominal cramps. For routine NSAID-ulcer prevention, PPIs are now usually preferred (better tolerated) — but misoprostol remains the answer when "cytoprotective/PG analogue" is asked.

H. pylori eradication

H. pylori is the major cause of PUD (95% of duodenal, 70% of gastric ulcers), chronic gastritis, gastric adenocarcinoma, and MALT lymphoma. Eradication heals ulcers and prevents recurrence.

Standard triple therapy (14 days preferred)

PPI + Clarithromycin + Amoxicillin (PPI + Clarithromycin + Metronidazole if penicillin-allergic).

Bismuth quadruple therapy

PPI + Bismuth + Metronidazole + Tetracycline — preferred where clarithromycin resistance is high (now common in India) or as second-line after triple-therapy failure.

High-yield: Rising clarithromycin resistance has shifted first-line choice toward bismuth-based quadruple therapy in many regions. Concomitant (non-bismuth quadruple) therapy = PPI + Amoxicillin + Clarithromycin + Metronidazole.

Regimen	Components	Duration	When preferred
Triple	PPI + Clarithromycin + Amoxicillin	14 days	Low clarithromycin resistance
Bismuth quadruple	PPI + Bismuth + Tetracycline + Metronidazole	10–14 days	High resistance / penicillin allergy / 2nd line
Concomitant	PPI + Amoxicillin + Clarithromycin + Metronidazole	10–14 days	High resistance, no bismuth
Levofloxacin triple	PPI + Levofloxacin + Amoxicillin	10–14 days	Salvage/rescue

Confirm eradication ≥4 weeks after therapy (and after stopping PPI ≥2 weeks) by urea breath test or stool antigen test — these are the tests of choice for confirming cure. Serology does NOT confirm eradication (stays positive).

Mnemonic for triple therapy: "PAC" — PPI + Amoxicillin + Clarithromycin.

Clinical condition–specific drug of choice

Condition	Drug/approach of choice
GERD	PPI (best healing of erosive oesophagitis)
Uncomplicated PUD (H. pylori +)	Eradication regimen + PPI
NSAID-induced ulcer (treatment)	PPI (stop NSAID if possible)
NSAID ulcer prevention	PPI or misoprostol (or COX-2 selective NSAID)
Zollinger–Ellison syndrome	High-dose PPI
Bleeding peptic ulcer	Endoscopic haemostasis + high-dose IV PPI
Stress-ulcer prophylaxis (ICU)	PPI or H₂ blocker (sucralfate alternative)
Functional dyspepsia	PPI trial / prokinetic

High-yield (ZES): Zollinger–Ellison = gastrin-secreting tumour (gastrinoma, often pancreas/duodenum), part of MEN-1. Features: multiple/refractory ulcers, ulcers in unusual sites (jejunum), diarrhoea, ↑↑serum gastrin. Diagnosis: fasting serum gastrin + secretin stimulation test (paradoxical ↑gastrin). Treatment: high-dose PPI ± tumour resection.

NSAID-induced ulcers — pathophysiology link

NSAIDs inhibit COX-1 → ↓protective gastric prostaglandins (PGE₂, PGI₂) → ↓mucus/bicarbonate, ↓mucosal blood flow → mucosal injury (gastric > duodenal). Prevention strategies: lowest dose/duration, add PPI or misoprostol, or use selective COX-2 inhibitors (less GI toxicity but ↑cardiovascular risk). Aspirin's antiplatelet effect adds bleeding risk.

Key differentials / "do not confuse" set

• PPI vs H₂ blocker: PPI irreversible/most potent/daytime+night; H₂ reversible/best for nocturnal/develops tolerance.
• Sucralfate vs misoprostol: both "cytoprotective," but sucralfate = physical barrier needing acid; misoprostol = PGE₁ analogue, abortifacient.
• Mg antacid (diarrhoea) vs Al antacid (constipation).
• Black stool from bismuth (harmless) vs melaena (GI bleed).
• Cimetidine (enzyme inhibitor, antiandrogen) vs other H₂ blockers (clean).
• Pantoprazole/rabeprazole (fewest interactions) vs omeprazole/esomeprazole (clopidogrel interaction).

Recently asked / exam angle

• Mechanism of PPI activation: "weak base, acid-activated prodrug forming covalent bond with cysteine of H⁺/K⁺-ATPase — irreversible." Why duration > half-life.
• PPI–clopidogrel interaction via CYP2C19 → choose pantoprazole.
• Drug requiring acidic pH for activation → both PPI and sucralfate (commonly paired in single-best-answer items).
• Ranitidine withdrawal due to NDMA contamination.
• Misoprostol = PGE₁ analogue, contraindicated in pregnancy, prevents NSAID ulcers; also used in MTP/PPH.
• Best test to confirm H. pylori eradication → urea breath test/stool antigen (not serology).
• Cimetidine adverse effects: gynaecomastia + enzyme inhibition.
• Long-term PPI: hypomagnesaemia, B12 deficiency, C. difficile, fracture, rebound hyperacidity.
• Zollinger–Ellison: high serum gastrin, secretin test, MEN-1 association, high-dose PPI.
• Antacid drug interactions (tetracycline/fluoroquinolone chelation) and milk-alkali syndrome.

Rapid revision

1. PPIs are irreversible H⁺/K⁺-ATPase inhibitors; duration of action exceeds plasma half-life because new pumps must be synthesised.
2. PPIs are acid-activated prodrugs — take 30–60 min before meals; full effect in 3–4 days.
3. Omeprazole/esomeprazole inhibit CYP2C19 → reduce clopidogrel activation; prefer pantoprazole.
4. Long-term PPI → hypomagnesaemia, B12 deficiency, C. difficile, pneumonia, fractures, rebound hyperacidity.
5. H₂ blockers best suppress nocturnal acid, develop tolerance/tachyphylaxis; cimetidine = enzyme inhibitor + antiandrogen.
6. Ranitidine withdrawn over NDMA carcinogen contamination; famotidine preferred.
7. Mg antacids → diarrhoea; Al antacids → constipation; combine to balance.
8. Sucralfate needs acid (<4) to form protective gel — don't combine with acid suppressants; causes constipation.
9. Misoprostol = PGE₁ analogue for NSAID-ulcer prevention; contraindicated in pregnancy (abortifacient); diarrhoea is dose-limiting.
10. Bismuth is directly anti-H. pylori; causes harmless black stool/tongue.
11. H. pylori first-line = PPI + clarithromycin + amoxicillin (PAC) ×14 d; bismuth quadruple for high resistance/penicillin allergy.
12. Confirm eradication with urea breath/stool antigen test (off PPI), not serology; Zollinger–Ellison treated with high-dose PPI.