Drugs in Peptic Ulcer Disease - 2nd MBBS Pharmacology (KDT Standard)

TOPIC 1: DRUGS USED IN PEPTIC ULCER DISEASE

Pathophysiology - Acid & Defense

Diagram: Pharmacological Basis of Gastric Acid Regulation

Diagram: Parietal Cell - How Drugs Act

CLASSIFICATION OF DRUGS USED IN PEPTIC ULCER

A. Drugs That Reduce Gastric Acid

• Aluminum hydroxide, Magnesium hydroxide, Calcium carbonate
• Mechanism: Neutralize HCl → raise gastric pH → inactivate pepsin
• Use: Symptomatic relief, adjunct therapy
• Adverse effects:
  • Aluminium - constipation, hypophosphatemia
  • Magnesium - diarrhea (so combination "Maalox" balances both)
  • Calcium - rebound acid hypersecretion, milk-alkali syndrome
• Precautions: Renal failure (Mg antacids avoided), avoid 2 hours before other drugs (reduces absorption)

• Cimetidine, Ranitidine*, Famotidine, Nizatidine
• Mechanism: Competitive blockade of H2 receptors on parietal cells → reduces histamine-stimulated acid → reduces basal, nocturnal, and food-stimulated secretion by ~70%
• (Note: Ranitidine was withdrawn from several markets due to NDMA carcinogen contamination; famotidine is now preferred)

• Omeprazole*, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole, Dexlansoprazole
• Mechanism: Irreversible inhibition of H+/K+-ATPase → suppress basal + stimulated acid by >90%

• Pirenzepine (M1 selective) - reduces acid secretion via ENS ganglia
• Rarely used now due to atropine-like side effects

B. Drugs That Protect the Mucosa (Cytoprotective)

• Misoprostol (PGE1 analog)
• Mechanism: Stimulates EP3 receptor on parietal cells → inhibits acid secretion; stimulates mucus and HCO3- secretion from superficial epithelial cells → cytoprotection
• Use: Prevention of NSAID-induced gastric ulcers
• Adverse effect: Diarrhea (dose-related), uterine contractions
• Contraindication: Pregnancy (causes miscarriage/abortion)

• Mechanism: In acidic pH, polymerizes into a viscous gel that binds to positively charged proteins in ulcer base → forms a protective coating barrier. Also stimulates PG synthesis and binds bile salts.
• Use: Duodenal ulcer, stress ulcer prophylaxis
• Precaution: Take on empty stomach; separate from other drugs by 2 hours (reduces absorption); not effective if gastric pH is raised (avoid combining with antacids/PPIs)

• Bismuth subsalicylate (Pepto-Bismol), Colloidal bismuth subcitrate (CBS)
• Mechanism: Antimicrobial (against H. pylori), inhibits pepsin activity, increases mucus secretion, coats ulcer base
• Use: Component of quadruple therapy for H. pylori; traveler's diarrhea

C. Antibiotics for H. pylori Eradication

• Amoxicillin, Clarithromycin, Metronidazole, Tetracycline (used in combination regimens)

TOPIC 1 (CONTINUED): OMEPRAZOLE - DETAILED

Chemical Nature

Mechanism of Action (MOA) - MOST IMPORTANT

1. Oral administration - Enteric-coated capsule (protects from premature degradation in stomach acid)
2. Absorbed in the small bowel (alkaline duodenum dissolves enteric coat)
3. Transported via bloodstream to parietal cell
4. Concentrated in the acidic secretory canaliculus of the parietal cell (acid environment, pH <4)
5. Converted to active sulfenamide intermediate (via sulfenic acid)
6. Active sulfenamide forms a covalent disulfide bond with the cysteine -SH groups of H+/K+-ATPase
7. Irreversible inhibition of the proton pump
8. Acid secretion suppresses for 24-48 hours until NEW enzyme is synthesized

Key fact for exams: PPIs are prodrugs; activation requires acid; they bind covalently (irreversibly) to H+/K+-ATPase; should be taken 30-60 min BEFORE meals for maximum effect (food stimulates acid production which activates the drug in the canaliculus).

• Metabolized by hepatic CYP2C19 and CYP3A4
• Asians have higher frequency of "poor metabolizer" CYP2C19 genotype → higher drug levels
• Half-life: 1-2 hours (plasma), but effect lasts 24-48 h (enzyme turnover dependent)
• IV formulation available (omeprazole sodium, pantoprazole IV)
• Dose reduction needed in severe hepatic disease

Therapeutic Uses of Omeprazole

Adverse Effects of Omeprazole

Drug Interactions (Precautions)

• Clopidogrel: Omeprazole inhibits CYP2C19 → reduced activation of clopidogrel → reduced antiplatelet effect. AVOID combining omeprazole/esomeprazole with clopidogrel. Use pantoprazole instead (least CYP2C19 inhibition).
• Warfarin, Diazepam, Phenytoin: Increased plasma levels due to CYP inhibition
• Atazanavir, Ketoconazole, Itraconazole: Reduced absorption (require acidic pH)
• Methotrexate: Delayed clearance

Precautions

• Take on an empty stomach, 30-60 min before meals
• Not for immediate (rapid) symptom relief - antacids are faster
• Long-term use: monitor Mg2+, B12, bone density
• Reduce dose in severe liver disease
• Do not crush or chew enteric-coated capsules

TOPIC 2: H. PYLORI POSITIVE GASTRIC ULCER - TREATMENT REGIMENS

Why Eradicate H. pylori?

Diagnosis of H. pylori

• Non-invasive: Urea breath test (UBT) with ¹³C-labeled urea, fecal antigen test, serology
• Invasive (endoscopy): Rapid urease test, histology, culture

Treatment Regimens

1. Standard Triple Therapy (7-14 days)

• Omeprazole 20 mg BD + Amoxicillin 1 g BD + Clarithromycin 500 mg BD
• Preferred when clarithromycin resistance is low (<15%) and no prior macrolide use
• Eradication rate: 70-80% (declining due to resistance)

2. Bismuth Quadruple Therapy - FIRST LINE (10-14 days)

• Omeprazole 20 mg BD + Bismuth 525 mg QDS + Metronidazole 250-500 mg QDS + Tetracycline 500 mg QDS
• Eradication rate: >90% - recommended as preferred first-line in high-resistance areas
• Also used in penicillin-allergic patients

3. Sequential Therapy (10 days)

• Days 1-5: PPI + Amoxicillin
• Days 6-10: PPI + Clarithromycin + Metronidazole/Tinidazole
• Eradication rate: ~90%; evidence suggests superiority over standard triple therapy

4. Concomitant Therapy (5-7 days)

• PPI + Amoxicillin + Clarithromycin + Metronidazole all together
• Good eradication rates in high-resistance settings

5. Levofloxacin-based Rescue Therapy (2nd line)

• PPI + Levofloxacin + Amoxicillin (for failed first-line treatment)

Role of PPI in H. pylori Regimens

• Raises gastric pH → enhances antibiotic stability (amoxicillin is pH sensitive) and efficacy
• Promotes bacteriostatic conditions by raising pH above minimum inhibitory concentration

Precautions in H. pylori Treatment

• Check eradication 4-8 weeks after completing treatment (UBT or fecal antigen test)
• Antibiotic resistance: Clarithromycin resistance is rising globally; in high-resistance areas, use bismuth quadruple therapy
• Compliance: 14-day courses improve eradication rates
• NSAIDs: Avoid during treatment; both H. pylori and NSAIDs cause ulcers
• Penicillin allergy: Replace amoxicillin with metronidazole or tetracycline
• Test-of-cure UBT should be done at least 4 weeks after completing antibiotics and 2 weeks after stopping PPI (to avoid false negatives)

TOPIC 3: RANITIDINE - DETAILED

Note for exam context: Ranitidine was removed from markets (FDA 2020; other regulators followed) due to detection of N-nitrosodimethylamine (NDMA), a potential human carcinogen, in ranitidine products. This was an intrinsic instability issue with the ranitidine molecule itself (not a manufacturing issue). Famotidine is now the preferred H2 blocker. However, ranitidine pharmacology is still relevant for exams as it represents the class.

Pharmacology

• Class: H2 receptor antagonist (2nd generation after cimetidine)
• Structure: Contains a furan ring (unlike cimetidine's imidazole ring)
• Potency: 4-10 times more potent than cimetidine; fewer drug interactions

Mechanism of Action

• Basal acid secretion
• Food-stimulated acid secretion
• Nocturnal acid secretion (most effectively suppressed)

Indications (Therapeutic Uses)

Adverse Effects of Ranitidine

Cimetidine vs. Ranitidine - Key Comparison

Pharmacokinetics of Ranitidine

• Oral bioavailability ~50% (first-pass metabolism)
• Widely distributed including CSF, breast milk, placenta
• Excreted mainly by kidneys (renal dose adjustment needed)
• Half-life: ~2-3 hours

Precautions

• Renal impairment: Reduce dose (renally excreted); risk of CNS effects
• Elderly: Risk of confusion with IV administration
• H. pylori-associated ulcers: H2 blockers alone are insufficient - require antibiotic co-therapy; high recurrence without eradication
• NSAID users: PPIs are superior to H2 blockers for both treatment and prevention
• Masking of malignancy: Symptom relief without H. pylori eradication may mask gastric cancer
• Drug interactions with itraconazole/ketoconazole (reduced absorption due to raised pH)
• Can be given IV in acute upper GI bleeding (less effective than high-dose PPI)

TOPIC 4: OMEPRAZOLE IN ZOLLINGER-ELLISON SYNDROME - PHARMACOLOGICAL BASIS & PRECAUTIONS

What is Zollinger-Ellison Syndrome (ZES)?

• Extreme hyperacidity (basal acid output >15 mEq/hr; normally <5)
• Multiple, refractory peptic ulcers (often in unusual locations - jejunum, multiple)
• Diarrhea (60-70% of patients) due to acid inactivation of pancreatic enzymes and direct mucosal damage
• Heartburn (20%)
• Elevated fasting serum gastrin levels (>1000 pg/mL diagnostic; normal <100)

Why Omeprazole (PPI) is the Drug of Choice in ZES

1. Acts at the final common pathway: The H+/K+-ATPase is the terminal step of acid secretion - it is activated regardless of which stimulus (gastrin, histamine, ACh) drives parietal cells. In ZES, the driver is continuously elevated gastrin. Blocking the final step (proton pump) is more effective than blocking upstream receptors (H2 blockers).
2. Maximal acid suppression (>90%): PPIs suppress both basal and stimulated acid far more than H2 blockers (~70%). In ZES, massive continuous acid output requires this potent suppression.
3. Duration of action: One dose suppresses acid for 24-48 hours (until new enzyme synthesis). This makes management practical.
4. H2 blockers are insufficient in ZES:
   • Require very high doses (ranitidine 6-12 g/day was required historically)
   • Tolerance (tachyphylaxis) develops with H2 blockers, further reducing efficacy
   • These problems are overcome by PPIs
5. Dose of omeprazole in ZES: Higher than standard - typically 60-360 mg/day depending on acid output. Dose is titrated to maintain basal acid output <10 mEq/hr (or <5 mEq/hr if prior esophageal surgery).
6. Long-term use is safe: Prospective studies (Maton et al., Gastroenterology 1989) confirmed safety and efficacy of long-term omeprazole in ZES.

Diagram: Why PPI beats H2 Blockers in ZES

Gastrinoma → Continuous Gastrin ↑↑↑
           ↓
Gastrin → G-cell → ECL cell → Histamine↑
           ↓                       ↓
     Parietal Cell (CCK2R)   H2 Receptor
           ↓                       ↓
     Ca2+ pathway →→→→→→→→→ cAMP pathway
                    ↓↓↓↓↓↓↓↓↓
              H+/K+-ATPase (Proton Pump) ← OMEPRAZOLE blocks HERE
                    ↓
                  H+ → Lumen
                  
H2 blockers only block the cAMP branch.
Omeprazole blocks the FINAL step = blocks ALL acid regardless of stimulus.

Additional Treatments in ZES

• Surgery: Localization and resection of gastrinoma (curative if single tumor, no mets)
• Somatostatin analogs: Octreotide (suppresses gastrin release, used when surgery not feasible)
• Chemotherapy: For malignant gastrinomas with metastases

Precautions with Omeprazole in ZES

• Higher doses needed - titrate to acid output; dose far exceeds standard 20-40 mg/day
• Long-term monitoring for:
  • Hypomagnesemia (may cause tetany, cardiac arrhythmia)
  • Vitamin B12 and iron deficiency (monitor annually with long-term use)
  • Bone density (long-term PPI - increase hip fracture risk; supplement calcium + Vitamin D)
  • Hypergastrinemia (PPIs raise gastrin further by removing acid-negative feedback - but this is secondary and managed as part of the underlying disease)
  • ECL cell hyperplasia (from gastrin trophic effects - theoretical concern; not clinically significant at PPI doses used)
• Do not stop abruptly in ZES - rebound acid hypersecretion and risk of ulcer perforation/bleeding
• Drug interactions: Avoid co-prescription of clopidogrel with omeprazole (use pantoprazole instead for antiplatelet patients); monitor warfarin INR

SUMMARY TABLE: Anti-Ulcer Drugs at a Glance