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 acid 2- Parietal cells: secrete hydrochloric acid! 3- Chief cells: secrete pepsin, a proteolytic enzyme 4- 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
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. Side effects antiandrogenic blood dyscrasias blood dyscrasias
(Tagament)
(Zantac)
(Pepcid)
(Axid)
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 contaminated food 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
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

51. Antacids
Magnesium hydroxide
Aluminum hydroxide
Calcium carbonate

52. Antacids: neutralizing HCl
Most widely used: mixture of aluminum hydroxide and magnesium hydroxide (neutralizes HCl)

53. Antacids: side effects
Aluminum hydroxide:
constipation
systemic phosphate depletion (weakness, malaise, anorexia)
Magnesium hydroxide:
loose stools
ionic magnesium stimulates gastric release ("acid rebound")
Calcium carbonate:
milk-alkali syndrome with elevation of:
serum calcium, phosphate, urea, creatinine, bicarbonate levels
may result in renal calcinosis
Systemic alkalosis may occur

54. Coating Agents:

55. Coating Agents: Sucralfate (Carafate)
Sucralfate (Carafate)-complex polyaluminum hydroxide salt of sucrose sulfate
highly polar antacid pH: binds to ulcer bed (granulation tissue, not to gastric or duodenal mucosa)
decreases proton diffusion to the ulcer base
may increase endogenous tissue prostaglandins and may bind epidermal growth factors and other growth factors-- improving mucosal defense

56. Coating Agents: Colloidal bismuth
Colloidal bismuth: -- bismuth-protein coagulant
may protect also from pepsin and acid digestion
may inhibit pepsin activity
prevents proton diffusion into the ulcer
Stimulates gastric mucosal secretion of protective agents:
Colloidal bismuth only class of antiulcer drugs that can eradicate H. pylori and cure associated gastritis

57. Prostaglandins:

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

59. Prostaglandins: Mechanism of action
reduction in basal and stimulated gastric acid secretion; enhanced mucosa resistance to injury (PGE1/PGE2).

60. Misoprostol (CYTOTEC),
misoprostol is moderately effective in treating duodenal and gastric ulcers.
inhibits gastric acid secretion and is higher than the dose needed to produce cytoprotective effects (enhanced secretion of mucus and HCO3-).
Dose: 200 mg, four times daily with food

61. Misoprostol: therapeutic use
Although prostaglandin analogs remain second-line agents in the treatment of peptic ulcer, they are valuable as cytoprotective agents in patients who require NSAIDS agents.
Misoprostol is used for the prevention of gastric ulcer disease induced by NSAIDS in patients who must take aspirin-like drugs for the treatment of arthritis or other diseases and who are at high risk for complicated gastric ulcer disease.

62. Misoprostol: Side Effects
Diarrhea in up to 30% of patients at therapeutic doses, a side effect that may limit its use somewhat.
Some abdominal cramping also may occur.
These compounds are potential abortifacients and should NOT be used in women who are pregnant or in whom conception is a possibility.

63. THE END