TREATMENT OF PEPTIC ULCERS & CONTROL OF GASTRIC ACIDITY

1. TREATMENT OF PEPTIC ULCERS & CONTROL OF GASTRIC ACIDITY Prof. Riad Agbaria

2. Microscopic Anatomy of the Stomach Four secretory epithelial cells: 1- Mucous cells: secrete an alkaline mucus that protects the epithelium against shear stress and acid2-Parietal cells: secrete hydrochloric acid!3- Chief cells: secrete pepsin, a proteolytic enzyme4- G cells: secrete the hormone gastrin 5-Entrochromaffin-Like Cells (ECL)- HISTAMINE

3. Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.

4. Physiological stimulants of gastric acid secretion:

5. Physiological stimulants of gastric acid secretion: • Major physiologic stimulus: food intake -- three phases: • cephalic phase • gastric acid secretion responds to anticipation of food, sight, smell, taste • gastric phase • stimulation of mechanical and chemical gastric wall receptors by luminal contents. • intestinal phase • gastrin release (small amount); release of other peptides that stimulate gastric acid secretion

6. Food constituents: • Coffee (both caffeine containing and caffeine free) stimulates gastric acid secretion by stimulating gastric release • Beer and wine: stimulation of gastric acid secretion

7. Physiologic inhibition- gastric acid release: • Factors that inhibit gastric acid secretion include: • hyperglycemia • hypertonic fluids • duodenal fat • duodenal acid • intragastric pH = 3; partial inhibition • intragastric pH < or = 1.5; complete blockade of gastrin release

8. Basolateral parietal cells membranes contain receptors for: • histamine-- stimulation gastric acid secretion • gastrin-- stimulation gastric acid secretion • acetylcholine-- stimulation gastric acid secretion • prostaglandins --inhibition of gastric acid secretion • somatostatin -- inhibition of gastric acid secretion

9. Peptic Ulcer Disease

10. Pathogenic Factors: Peptic ulcer disease • Peptic ulcer disease: an imbalance between aggressive factors (gastric acid and pepsin) and protective factors (gastric mucus, bicarbonate, prostaglandins)

11. Role of pepsin in peptic ulcer disease: • Secreted gastric acid plus effects of pepsin promote tissue injury • Gastric acid promotes cleavage of pepsinogen (inactive) to proteolytically-active pepsins • Pepsinogen classification: • Direct correlation between pepsinogen I serum concentrations and maximal gastric acid secretion

12. Pharmacological Management of Ulcer Disease

13. Pharmacological Management of Ulcer Disease • Overview • Peptic ulcer: stomach or duodenal mucosal lesion -- acid and pepsin: major pathogenic roles • Classification of peptic ulcer: • Duodenal (DU) • Gastric (GU) • Major causative factor: bacterium Helicobacter pylori •  Helicobacter pylori: risk factor for: • gastric cancer • certain types of gastric lymphoma

14. Gastric Physiology Gastric mucosa: acid secretion • Oxidative phosphorylation dependent secretion by parietal cells. • Parietal cells: found in mucosal glands of the body and fundus of the stomach.

15. Regulation of gastric acid secretion Many factors: chemical, neural, hormonal stimulation: • Gastrin-most potent stimulant •  Activation of postganglionic vagal fibers (muscarinic cholinergic parietal cells receptor activation)

16. 1: Proton Pump Inhibitors: The most effective suppressors of gastric acid secretion

17. Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.

18. Proton Pump • Parietal cells H+ ion secretion depends on a H+,K+-ATPase pump-- promoting H K exchange • H+,K+-ATPase located in apical membraneto and tubulovesicular apparatus of parietal cells • Luminal surface of the membrane enzyme: exposed to gastric luminal acid

19. Proton Pump Inhibitors: • Omeprazole (Prilosec),20mg • Lansoprazole (Prevacid),30mg • Rapeprazole 20mg • All given daily before breakfast

20. Proton Pump Inhibitors: Mechanism of Action • Omeprazole (Prilosec) and lansoprazole (Prevacid) inhibit the proton pump, effectively irreversibly -- requiring synthesis of new enzyme protein • Omeprazole and lansoprazole approved for treatment of: • Duodenal ulcer • may be used in conjunction with triple therapy • Erosive esophagitis • Gastric acid hypersecretory states, including Zollinger-Ellison syndrome (Gastrinomas that cause secretion of large amounts of acids)

21. Proton Pump Inhibitors: Side effects • Long acting (irreversible) • Hypergastrinemia: because no acids, Bacteria may enter to the body • In rats: omeprazole cause tumors in GI.

22. Inhibitory effect of omeprazole on secretion of gastric acid.

23. H2 receptor antagonists

24. Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.

25. Role of histamine: • Gastric mucosa contains large amounts of histamine in: • mast cell cytoplasmic granules • enterochromaffin-like cells (ECL)

26. H2 receptor antagonists • H2 receptor antagonists competitively inhibit histamine action on H2 receptors, located on: • gastric parietal cells • cardiac atrial cells • uterine smooth muscle cells

27. H2 receptor antagonists • H2 receptor antagonists: • Cimetidine (Tagamet) • Ranitidine (Zantac) • Famotidine (Pepcid) • Nizatidine (Axid) • Inhibit: • basal acid secretion • secretion in response to feeding, gastrin, histamine, hypoglycemia, or vagal stimulation

28. H2 Receptor Antagonists • Effective inhibitor of stimulated and NON-stimulated gastric acid secretion • Cimetidine (Tagamet) -- reduces acid secretion responses to: histamine, caffeine, hypoglycemia, gastrin • Healing rates: similar between antacids and H2 receptor antagonists (compliance better with receptor blockers)

29. H2 Antagonist: Cimetidine (Tagamet) • Side effects; • interaction with cytochrome P450 drug metabolizing system • tender gynecomastia: the two-week antiandrogenic effects (seen typically in Zollinger-Ellison disease patients following prolonged space or treatment with large doses. Due to pinding to androgen receptors and inhibition of P450 which catalyze hydroxylation of estradiol. • Reduction of sperm count is reversible

30. H2 Antagonist: Ranitidine (Zantac) • Ranitidine (Zantac)-- six times as potent as cimetadine in inhibiting gastric acid secretion • NO antiandrogenic properties • Side effect: Smaller inhibitory effect on cytochrome P450 system than cimetidine (Tagamet)

31. H2 Antagonist: Famotidine (Pepcid) • Famotidine (Pepcid) and nizatidine (Axid): potent H2 receptor blockers • Side effects: rare blood dyscrasias and rare hepatotoxicity (similarto that seen with cimetadine and ranitidine)

32. (Axid) (Tagament) (Zantac) (Pepcid) Side effects antiandrogenic SAMALL INHIBITION OF p450 blood dyscrasias blood dyscrasias Reduction of sperm Inhibition of P450

33. Effect of cimetidine on betazole-stimulated secretion of acid (upper panel) and of pepsin (lower panel) in human beings.

34. H2 antagonist therapeutic use • Promoting healing if Gastric & Duodenal Ulcer • Prophylaxis of stress ulcers • Gastroesophagal reflux Disease (GERD)

36. Anticholinergic drugs: • Atropine • Telenzepine (M1 antag) • Pirenzepine (M1 antag)

37. Physiological and pharmacological regulation of gastric secretions: the basis for therapy of peptic ulcer disease.

38. Muscarinic cholinergic antagonists can reduce basal secretion of gastric acid by 40% to 50%; stimulated secretion is inhibited to a lesser extent.

39. Anticholinergic drugs: • Atropine: not as effective as H2 receptor blockers • Side effects: • dryness of mouth • blurred vision • urinary retention • cardiac arrhythmias

40. Pirenzepine& telenzepine • pirenzepine is equivalent to cimetidine in preventing the recurrence of ulcers. • Both are hydrophilic and poorly penetrate the blood-brain barrier. • Dose: • Pirenzepine, oral, 50 mg 2-3Xdaily. • Telenzepine, oral, 3 mg/day.

41. Pirenzepine & telenzepine: Side effects • dry mouth • blurred vision • Constipation, may limit the utility of these drugs.

42. Helicobacter Pylori:

43. What is Helicobacter pylori? • H. pylori IS a bacterium causes chronic inflammation (gastritis) of the inner lining of the stomach in humans. • the most common cause of ulcers worldwide. • H. pylori infection is most likely acquired by ingesting contaminatedfood and water and through person to person contact. • In the United States, 30% of the adult population is infected. (50% of infected persons are infected by the age of 60.) • The infection is more common in crowded living conditions with poor sanitation. • In countries with poor sanitation, 90% of the adult population can be infected. • Infected individuals usually carry the infection indefinitely unless they are treated with medications to eradicate the bacterium. • One out of every six patients with H. pylori infection will develop ulcers of the duodenum or stomach. • H. pylori also is associated with stomach cancer and a rare type of lymphocytic tumor of the stomach called MALT lymphoma.

44. Helicobacter pylori: • Helicobacter pylori: a principal role in peptic ulcer pathogenesis • H. pylori: • causes active, chronic gastritis • Bacterial protein products appear damaging • Proteases and phospholipases produced by H. pylori degrade glycoprotein-lipid mucus layer complex

45. Management of H. pylori infection • Management of H. pylori infection: clinical consequences • 15% relapse rate for duodenal ulcer following H. pylori eradication • 75% relapse rate for duodenal ulcer following treatment with H2 receptor blockers only

46. Drug Treatment for H. pylori Patients with documented duodenal ulcers (upper GI contrast radiography or endoscopy) -- treat for H. pylori Drugs include: • bismuth compounds • amoxicillin • tetracycline (Achromycin) • clarithromycin (Biaxin) • metronidazole (Flagyl) • omeprazole (Prilosec), lansoprazole (Prevacid) • H2 antagonists

47. Bismuth compounds: Mechanism of Action • Mechanism of Action: • cytoprotective effects • compounds bind to the ulcer base, stimulating mucus and prostaglandin production • antibacterial effect: inhibition of proteolytic, lipolytic, and urease activities •  In monotherapy: bismuth compounds eradicate H. pylori in about 20% of patients • Bismuth compounds in combination with antibiotics eradicate H. pylori in up to 95% of patients.

48. Most successful protocol: triple therapy • bismuth compounds • metronidazole (Flagyl) • amoxicillin or tetracycline (Achromycin) • Triple therapy (two weeks) plus H2 blocker therapy (six weeks) is also a recommended protocol • Further increase in the rate of H. pylori eradication may be accomplished by the addition of omeprazole (Prilosec) to the regimen.

49. Drawbacks of triple therapy: • patient compliance (two-week treatment: 200 tablets) • Side effects