Acid Suppression and Peptic Ulcer Disease
Parietal cell physiology · Proton pump inhibitors · H2 receptor antagonists · Helicobacter pylori eradication · Cytoprotective agents
Parietal Cell: Three Inputs, One Pump
Input 1
Histamine
From ECL cells → H2 receptor → Gs → cAMP → PKA
Input 2
Gastrin
From G cells → CCK-B receptor → Ca2+ and ECL histamine release
Input 3
Acetylcholine
Vagal → M3 receptor → Gq → Ca2+
Final effector
H+/K+ ATPase
Secretes H+ into lumen → pH ~1.0
Acid-Suppressive Drug Classes Compared
Feature Proton Pump Inhibitors H2 Receptor Antagonists Notes
Target H+/K+ ATPase (pump) Histamine H2 receptor PPIs act downstream of all receptor inputs
Block type Irreversible covalent Competitive reversible PPIs suppress ~90%; H2RAs ~65%
Onset Delayed; days to full effect Rapid (1–2 hours) H2RAs better for on-demand relief
Timing rule 30–60 min before first meal With or without food PPI timing is non-negotiable
Tolerance No Yes (1–2 weeks) H2RAs not suitable for long-term maintenance
Preferred agent Any; pantoprazole if on clopidogrel Famotidine (not cimetidine) Cimetidine: multiple CYP interactions
Proton Pump Inhibitor: Key Pharmacology
Mechanism
Prodrug Activation
  • Absorbed in small intestine
  • Concentrated in acidic canaliculus
  • Acid converts prodrug to sulfenamide
  • Covalent bond to H+/K+ ATPase cysteine
  • Irreversible: new pump synthesis required (~18 hrs)
CYP2C19 Pharmacogenomics
Metabolizer Status Matters
  • Ultrarapid metabolizers: lower drug exposure, treatment failure risk
  • Poor metabolizers: higher exposure, greater acid suppression
  • Rabeprazole: least CYP2C19-dependent
  • Pantoprazole: minimal CYP2C19 inhibition — use with clopidogrel
  • Omeprazole/esomeprazole: inhibit CYP2C19 → reduce clopidogrel activation
Long-Term Adverse Effects
Monitor for These
  • Hypomagnesemia: oral Mg does not fix; stop PPI
  • Clostridioides difficile risk increased
  • Calcium malabsorption: use calcium citrate
  • Rebound hypersecretion on abrupt stop: taper
  • B12 malabsorption with very long-term use
Helicobacter pylori Eradication
First-Line Regimens (14 days)
Choose Based on Local Resistance
  • Triple therapy (clarithromycin resistance <15%): PPI + amoxicillin + clarithromycin
  • Bismuth quadruple (resistance >15% or prior macrolide): PPI + bismuth + metronidazole + tetracycline
  • Both for 14 days (not 7 days)
  • PPI dose twice daily; higher dose if CYP2C19 ultrarapid metabolizer
Diagnostic Testing
Urea Breath Test or Stool Antigen Test
  • Urea breath test: labeled urea → urease → labeled CO2 in breath; >95% sensitivity and specificity
  • Stool antigen test: equivalent accuracy
  • Stop PPI 2 weeks before testing
  • Stop antibiotics/bismuth 4 weeks before testing
  • Serology: cannot confirm eradication — do not use for post-treatment testing
Cytoprotective Agents
Antacids
Neutralize Acid Transiently
  • Al(OH)3: constipating; Mg(OH)2: laxative; combine to balance
  • Duration: 1–2 hours only
  • Chelate fluoroquinolones, tetracyclines, iron, bisphosphonates — separate by 2+ hours
  • Role: on-demand mild heartburn only
Sucralfate
Physical Barrier at Ulcer
  • Polymerizes at low pH → adheres to ulcer crater
  • Barrier lasts up to 6 hours per dose
  • Does not neutralize acid
  • Avoid in severe renal impairment (aluminum)
  • Separate from fluoroquinolones, warfarin, phenytoin, digoxin, thyroid hormone by 2 hours
  • Used for stress ulcer prophylaxis in ICU
Misoprostol
PGE1 Analog — Contraindicated in Pregnancy
  • Prostaglandin E1 analog: replaces COX-1-derived prostaglandins
  • Stimulates mucus, bicarbonate, mucosal blood flow
  • Used for NSAID gastroprotection (40% ulcer reduction)
  • Adverse effects: diarrhea, cramping (dose-dependent)
  • ABSOLUTE CI IN PREGNANCY: causes uterine contractions, miscarriage, preterm labor
Critical Rule — Misoprostol

Misoprostol is FDA Pregnancy Category X. Confirm absence of pregnancy and ensure reliable contraception before prescribing for any indication. In women of childbearing potential requiring NSAID gastroprotection, use a proton pump inhibitor instead.