A-34. Drugs used in peptic ulcer diseases

Question 1

Anti-secretory agents

Answer 1

1. H2 antagonists: from longest to shortest half-life.
   Famotidine, Nizatidine, Ranitidine and Cimetidine.
2. Proton pump inhibitors: from longest to shortest half-life.
   Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole and Omeprazole.
3. M1 antagonists:
   Pirenzepine and Telenzepine

Question 2

Antacids

Answer 2

1. Sodium bicarbonate and sodium citrate.
2. Magnesium hydroxide.
3. Aluminum hydroxide, basic Al carbonate gel and Al phosphate gel.
4. Calcium carbonate.

Question 3

Mucosal defense enhancers

Answer 3

1. Bismuth chelate.
2. Sucralfate.
3. Misoprostol.

Question 4

H. pylori eradication

Answer 4

1. Classic triple therapy: metronidazole + bismuth citrate + tetracycline or amoxicillin
   * given for 14 days, or 7 days with omeprazole added; highest sfx risk
2. Modified triple tx: PPI + clarithromycin + metronidazole
   * given for 7 days; lowest sfx risk
3. Alternative triple tx: PPI + clarithromycin + amoxicillin
   * given for 7 days; middle sfx risk

Question 5

Histamine H2 receptor antagonists

Drugs, MOA, kinetics, dosage, indications, SE

Answer 5

1. Drugs: Famotidine, Ranitidine, Nizatidine and Cimetidine
   (longest to shortest half-life).
2. MOA: inhibit H2 on parietal cells → ↓ cAMP → ↓ H/K-ATPase activity
   inhibit both basal + stimulated (via food / pH increase) gastric acid secretion, as well as pepsin and intrinsic factor secretion.
   also antagonize effects of histamine on heart + vessels; may enhance immune responses.
3. Kinetics: well absorbed by gastric mucosa, but absorption is inhibited by antacids / food.
4. Dosage: Famotidine 2 x 20 mg/day or 1 x 40 mg/day (on doses list)!
5. Indications:
   a. ulcer - both gastric and duodenal; effective for both, but more effective for duodenal.
   b. Zollinger-Ellison syndrome - gastrinoma; high doses needed.
   c. Reflux esophagitis, stress ulcers and pre-anesthetic in emergency procedures.
6. Side Effects:
   a. HA, dizziness, nausea, diarrhea, constipation, myalgia, rashes and pruritus
   b. CNS disturbances - mainly in elderly
   c. Hypochlorhydria - low gastric HCl; ↑ bacterial survival; candidal peritonitis; can favor growth of bacteria which produce carcinogenic nitrosamines
   d. Rarely - thrombo-/leukocytopenia, hepatorenal toxicity and bradycardia (if given i.v.)
   e. May slow the detection of gastric cancers
   
   • Cimetidine only:
   • Anti-androgenic effects - binds androgen R → ↓ libido, gynecomastia, impotence.
   • CYP450 inhibition.

Question 6

Proton pump inhibitors

Drugs, MOA, indications, dosage, SE, interactions

Answer 6

1. Drugs: Rabeprazole, Pantoprazole, Lansoprazole, Esomeprazole and Omeprazole
   (long to short T1/2).
2. MOA: inhibit the H+/K+-ATPase proton pump on the luminal surface of parietal cells.
3. Indications: same as H2 atgs (except stress ulcer + pre-anesthesia);
   better than H2 atgs for reflux esophagitis.
4. Dosage: pantoprazole 20-40 mg 1-2x/day (on doses list) !
5. Side Effects:
   a. Hypergastrinemia - may cause hyperplasia of G cells or carcinoid tumors
   b. Pneumonia - ↑ risk of nosocomial + community-acquired respiratory infections
   c. Diarrhea - ↑ risk of C. diff and others (Salmonella, Shigella, E. coli, Campylobacter) or overgrowth of normal flora
   d. Osteoporosis - with long-term use, ↑ hip fracture risk
   e. HA, dizziness, skin rash, leukopenia
6. Interaction: Omeprazole inhibits anti-aggregation effect of Clopidogrel because both are pro-drugs activated by CYP2C19 + thus compete with each other for activation.

Question 7

M1 muscarinic receptor antagonists

Drugs, MOA, kinetics, indications, SE

Answer 7

1. Drugs: Pirenzepine and Telenzepine.
2. MOA: selective M1 muscarinic atgs → block cholinergic vagal stimulation of gastric secretions at the level of the parasympathetic ganglia
   * block gastric secretion at lower doses than those which block other cholinergic functions → ↓ sfx
3. Kinetics: poor oral absorption.
4. Indications: duodenal or gastric ulcers (higher dose for gastric).
5. Side Effects:
   a. Frequent - constipation / diarrhea, dry mouth, HA, CNS effects
   b. Less frequent - blurred vision

Question 8

Antacids- Sodium compounds:

Answer 8

Sodium bicarbonate and Sodium citrate

• Sodium bicarb + HCl forms NaCl, water and CO2.
• Can cause systemic alkalosis and fluid retention (via ↑ Na+).

Question 9

Antacids- Magnesium compounds:

Answer 9

Magnesium hydroxide forms MgCl2 and water; poorly soluble, long DOA and cathartic effect (diarrhea).

Question 10

Antacids- Aluminum compounds:

Answer 10

Aluminum hydroxide, basic Al carbonate gel and Al phosphate gel.

• AlCl3 formed from Al-OH and HCl; Al-OH has slow action and AlCl3 is poorly soluble → constipation, binding of tetracyclines + phosphate; can cause encephalopathy in kidney dysfunction.

Question 11

Antacids- Calcium compounds:

Answer 11

Calcium carbonate.

* 10% of formed CaCl2 is absorbed and can cause hypercalcemia and milk-alkali syndrome; only given short-term.

Question 12

Bismuth chelate (MOA, indications, SE)

Answer 12

1. MOA: chelates with proteins to form a protective coating over ulcers; also acts weakly as an antacid
   * taken 30 mins before or 2 hours after last meal
2. Indication: gastric and duodenal ulcers; combined with H2 atgs → less relapse
3. Side Effects:
   a. Darkening of oral cavity
   b. In renal impairment - encephalopathy and osteodystrophy

Question 13

Sucralfate (MOA, indications, SE, interactions)

Answer 13

Basic aluminum salt of sucrose octasulfate.

1. MOA: negatively charged sucrose octasulfate binds (+) charges on proteins, forming a gel; decreases back-diffusion of H+ into mucosa; stimulates PG synthesis; taken before meals
2. Indications: gastric and duodenal ulcers
3. Side Effects: obstipation - severe or complete constipation
4. Interaction: only effective in acidic environment → not given with antacids / H2 blockers!

Question 14

Misoprostol (MOA, indications, SE, CI)

Answer 14

Synthetic PGE1

1. MOA: stimulates mucus secretion; enhances mucosal blood flow; prevents back diffusion; enhances cell replication; inhibits acid secretion (via ↓ cAMP).
2. Indication: NSAID-induced gastric mucosa damage
   
   • (Prophylaxis of NSAID ulcers can also be via COX2-selective NSAIDs, PPIs and H2 atgs)
3. Side Effects: diarrhea
4. Contraindication: pregnancy - stimulates uterine contractions!

Question 15

H. pylori eradication

Answer 15

H. pylori infects the gastric mucosa by neutralization of gastric acid with urease, breaking down urea to NH3 and CO2 which neutralizes gastric acid, forming NH4Cl.

Other factors in H. pylori pathogenicity are cytotoxins, PLA2 / PLAC, induction of leukotriene + PAF release, and endotoxin-induced endothelial damage.

H. pylori infection increases risk of gastric carcinoma.

Therapy is by any of the combinations mentioned above in the drug list.