1. PEPTIC ULCER DISEASE
From pH to Hp by
Dr G Muntingh

2. Gastric Physiology Gastric Acid Secretion
Histamine
Most important stimulant of gastric acid secretion
released from ECL cells by gastrin and cholinergic activity
Acetylcholine
PG and somatostatin
inhibit acid secretion

3. Gastric Acid Secretion
Histamine
increases parietal cell cAMP
activates cAMP dependent protein kinase
Gastrin
direct stimulation of parietal cells
stimulation of histamine release from ECL cells
Acetylcholine
increases parietal cell cytosolic calcium
PG and somatostatin
inhibits G proteins
decreased generation of cAMP

4. Phases of Gastric Acid Secretion
Cephalic
Gastric
Intestinal
Basal or interdigestive
unrelated to feeding
peaks at about midnight and ebbs at about 7 AM
mediated by neural pathways

5. Gastric acid secretion
Inhibitors
Acid
induces feedback inhibition of gastrin release
somatostatin reduces acid secretion by
inhibiting gastrin release
inhibiting parietal cell secretion
inhibiting release of histamine
stimulates release of secretin
hyperglycemia
Hypertonic fluids
Fats
gastric inhibitory peptide

6. CLASSIFICATION OF PEPTIC LESIONS
Erosions
superficial, does not penetrate the mucosa
Ulcers
deeper lesions, penetrates beyond the muscularis mucosa
Acute - less than 2 weeks, not associated with any fibrotic reaction in the submucosa
Chronic- more than 2 weeks and associated with fibrosis and formation of granulation tissue
Inflammation

7. PEPTIC ULCER
ulcerative disorders of the upper gastrointestinal tract involving principally the most proximal portion of the duodenum and the stomach
Major Forms
Duodenal Ulcer
Gastric Ulcer
4/22/2017

8. Pathogenesis of Peptic Ulcer Disease
Aggressive Factors
Acid
Pepsin
Bile
Helicobacter pylori
Aspirin and NSAIDs
Defensive Factors
Gastric mucus
Mucus Gel layer
Bicarbonate
Mucosal barrier
mucosal blood flow
endogenous PGs
cell restitution

9. Aggressive Factors Acid Pepsin Bile Helicobacter pylori
secreted by parietal (oxyntic) cells
principal aggressive factor
pepsin is active only in a low pH
acid by itself can damage the mucosa
Pepsin
secreted by peptic or chief cells
Bile
Helicobacter pylori
Aspirin and NSAIDs

10. Pathogenesis of PUD Aggressive Factors
Aspirin and NSAIDs
direct toxicity to gastric mucosa
depletes protective endogenous PG
inhibits PG synthesis
interrupts gastric mucosal barrier
permit H+ ion back diffusion
decrease gastric mucus and bicarbonate secretion
increased gastric acid secretion
impaired epithelial cell replacement

11. Pathogenesis of PUD Defensive
Gastric mucus gel layer
stimulated by
mechanical & chemical irritation
cholinergic stimulation
slows down ionic diffusion
impermeable to macromolecule
continuously secreted and solubilized by pepsin
increased by prostaglandin
decreased by aspirin and NSAIDs

12. Pathogenesis of PUD Defensive Factors
Gastric mucosal barrier
luminal surface
intercellular tight junctions
almost impermeable to H ion back diffusion from the lumen
interrupted by
bile acids, salicylates, alcohol, weak organic acids

13. Pathogenesis of PUD Defensive Factors
Gastric mucosal blood flow
Cell restitution
Endogenous Prostaglandins
stimulates
gastric mucus secretion
gastric/duodenal HCO3 secretion
maintains good mucosal blood flow
maintains integrity of mucosal barrier
promotes epithelial cell renewal

14. Duodenal Ulcer Chronic and recurrent disease
Deep and sharply demarcated
> 95% in the duodenal bulb
6-15% of western populations
Natural history
Spontaneous healing and recurrence
Recurrence may be asymptomatic

17. GASTRIC ULCER
60% of GU are located within 6 cm. of the pylorus, at or near the right-hand region of the stomach and most frequently on the posterior wall.
Appears as an eroded or "punched out" area of mucosa surrounded by inflamed and swollen tissue.
Malignant- lesser curve, larger ulcers
1 - 8% that are radiographically benign are maligant
4/22/2017

25. HELICOBACTER PYLORI
A bacteria, Gm-, microoerophilic, spiral bacillus, secretes toxins that cause chronic inflammation and contribute to the formation of ulcers
Also secretes proteins that attract cells that cause inflammation
Cause almost all cases of ulcer disease that are not medication related
4/22/2017

26. Pathogenesis of PUD Aggressive Factors
Helicobacter pylori
Urease
Surface proteins
Proteases and phospholipases
Adhesins
Cytoxin associated gene A
Vacuolating cytotoxin A

30. Monocytes and lymphocytes
Evasion of the host chronic inflammatory reaction by H. pylori leads to chronic active gastritis
Evasion of the host chronic inflammatory reaction by H. pylori leads to chronic active gastritis
In time, the acute inflammatory response to H. pylori infection – acute gastritis, predominantly in the gastric antrum – is down-regulated as monocytes and lymphocytes infiltrate the mucosa, initiating a chronic inflammatory reaction.20 Antibodies are produced, but they fail to eradicate the bacterium (though animal studies suggest that oral vaccines may, in future, be able to generate an effective immune response)21 Continuing to evade the host immune system, H. pylori perpetuates the chronic inflammation by stimulating polymorph activity and further release of proteolytic enzymes and free oxygen radicals.
Continued chronic inflammation progresses to chronic active gastritis in nearly all affected individuals, but may continue in the presence of risk factors such as increased host susceptibility pathogenesis, leading to peptic ulcer or even gastric carcinoma.5, 6, 20
Antibodies
Monocytes and lymphocytes

31. H. pylori is a causal factor in most cases of peptic ulcer disease
Duodenal ulcer
Gastric ulcer 5% 1% 2%
25% 3%
H. pylori is a causal factor in most cases of peptic ulcer disease
While only one in six individuals infected with H. pylori develops peptic ulcer disease, the bacterium is a major cause of the disease.6, 22 Over 90% of patients with duodenal ulcer and some 70% of patients with gastric ulcer are infected with H. pylori. The other major cause of peptic ulcer disease, particularly gastric ulcer disease, is the use of nonsteroidal anti-inflammatory drugs (NSAIDs).
A key common factor in ulcerogenesis is gastric acid. Consequently, effective 24-hour control of gastric acid secretion with the acid pump inhibitor omeprazole achieves the primary treatment aims of rapid symptom resolution and predictable healing irrespective of whether a peptic ulcer is caused by H. pylori infection or NSAID use.23 2%
92%
70%
H. pylori
NSAID
Cancer (Zollinger Ellison)
Other
Marshall 1994

32. Consequences of Hp Infection
H. pylori infection
Acute gastritis
Chronic Superficial Gastritis
PUD
Lymphoproliferative
Disease
Chronic Atrophic Gastritis
Chronic Superficial
gastritis
Gastric
Adenocarcinoma

33. What can you do for your patients?

34. Drugs that neutralize existing acid
Antacids
Drugs that suppress acid formation
H2 receptor antagonists
PPI
Antimuscarinic agents
Drugs for Mucosal protection
Prostaglandins Sucralfate Carbenoxolone colloidal bismuth
Miscellaneous

35. Antacids Calcium bicarbonate Sodium bicarbonate Aluminum hydroxide
Magnesium hydroxide
Rarely used as a primary therapeutic agent but for symptomatic relief only
Mostly used in combination

36. PHYSIOLOGY OF HCl SECRETION
Figure Stimulation of the Parietal Cells
4/22/2017

37. HOW H2-RECEPTOR ANTAGONISTS WORK
Figure H2 Receptor Antagonist Mechanism of Action
4/22/2017

38. H2 Receptor Antagonists
Cimetidine Famotidine
Ranitidine
Structures share homology with histamine
Different potency but all significantly inhibit basal and stimulated acid secretion
Similar ulcer healing rates
Often used for active ulcers (4 - 6 wks) in combination with antibitiotics for H.Pylori

39. Cimetidine- Competitive Inhibition
% bioavailability (oral)
not affected by food
oral = parenteral
metabolized in liver
excreted in urine (48% -oral dose; 75% IV or IM dose); faeces and bile ( 10%)
caution with warfarin, phenytoin, theophylline ( inhibition of P450)

40. Cimetidine Dose: 300 mg QID 800 mg for active ulcer- healing
Rate of 80% in 4 weeks
AE: gynecomastia (high doses, prolonged)
Loss of libido; Impotence; Decrease in
Sperm count, confusion, elev. Of
aminotransferases, creatinine, prolactin
* Rare toxicities: neutropenia, pancytopenia, anemia, thrombocytopenia

41. Ranitidine 5 X more potent Less adverse effects
No significant drug interaction
No antiandrogenic activity
Cimetidine and ranitidine can bind to hepatic cytochrome P450, famotidine does not

42. HOW PROTON PUMP INHIBITORS WORK
Figure Proton Pump Inhibitor Mechanism of Action
4/22/2017

43. Proton Pump Inhibitors
Omeprazole Lanzoprazole
Pantoprazole
Substituted benzimidazole derivatives that covalently bind and IRREVERSIBLY inhibit H+,K+, ATPase
Most potent acid inhibitors

44. PPI - Omeprazole, Lanzoprazole
Potently inhibit all phases of gastric secretion
Rapid onset of action, max acid inhibitory effect between 2 and 6 hrs and duration lasts for 72 to 96 hrs.
T1/2: 18 hrs, can take 2 and 5 d for gastric acid secretion to normalize after discontinuance

45. PPI - Omeprazole, Lanzoprazole
Given before meals- pumps need to be activated
SE: 1.Mild to mod hypergastrinemia
2.Carcinoid tumors in animals, none in
Humans
3.Interfere with absorption of ketoconazole,
ampicillin, iron, digoxin

46. Mucosal Protectors Sucralfate. Prostaglandins Colloidal Bismuth
Mucosal Protectors Sucralfate Prostaglandins Colloidal Bismuth Carbenoxolone
SUCRALFATE
Complex sucrose salt in which hydroxyl group substituted by AlOH and sulfate
Insoluble in water, becomes viscous paste that bind to site of active ulceration in ↓ pH
Toxicity- rare, constipation most reported, also hypophosphatemia

47. Sucralfate
Moa:
AlOH- binds to damaged tissues within ulcer bed and provides physicochemical barrier impeding further tissue damage
Induce trophic effect- enhance prostaglandin synthesis, stimulate mucus and bicarbonate secretion, enhance mucosal defense and repair

48. Colloidal Bismuth Potential mechanisms Ulcer coating
Prevention of further pepsin/HCl induced damage
Binding of pepsin
Stimulation of prostaglandins, bicarbonate, and mucous secretion
chelates with protein and granulation tissue

49. Colloidal Bismuth Healing rate comparable with H2 receptor antagonist
Produce darkening of stools

50. Prostaglandin Analogues- Misoprostol
Clinical use- prevention of NSAID-induced mucosal injury( only drug approved by FDA)
Rapidly absorbed after oral dose
Therapeutic effect is by enhancement of mucosal defense and repair
Enhance mucous bicarbonate secretion
Stimulate mucosal blood flow
Decrease mucosal cell turnover

51. Prostaglandin Analogues- Misoprostol
AE: diarrhea ( %)
Uterine bleeding and contraction
(Contraindicated in pregnancy)
Dose: 200ug four times a day

52. Carbenoxolone Enhances synthesis of gastric mucus
Decrease pepsin secretion
Increase life of mucosal cells and diminishes mucosal exfoliation
AE: sodium retention
Hypertension
hypokalemia

53. Miscellaneous 1. Anticholinergic- designed to inhibit activation
of muscarinic receptors in parietal cells
PIRENZEPINE - selective M1 receptor antagonist
> Synergistic with cimetidine
Cimetidine alone %
Pirenzepine alone - 58%
C P %
> Prolongs action of antacids

54. Miscellaneous 2.Tricyclic antidepressants
> Toxicity precludes utility

55. H. Pylori Eradication Therapy
Treatment
Efficacy
H2-blockers alone
No effect
Omeprazole alone
Bismuth+amoxycillin
44%
Bismuth+metronidazole
55%
Omeprazole+amoxycillin
58%
Bismuth+metronidazole+amoxycillin
73%
Bismuth+metronidazole+tetracycline
94%

56. Regimen-1 for H. Pylori Triple Therapy
Bismuth subsalicylate – 30ml QID +
Metronidazole – 250mg QID
Tetracycline 500mg QID Or
Amoxycillin 500mg QID

57. Regimen-2 for H. Pylori Triple Therapy
Lansoprazole – 30mg BD Or
Omeprazole 20 BD +
Clarithromycin 500mg BD
Amoxycillin 1g BD
Metronidazole 400mg BD

58. Regimen-3 for H. Pylori Triple Therapy
Ranitidine - 300mg BD +
Tetracycline - 500mg QID
Clarithromycin - 500mg BD Or
Metronidazole - 400mg BD

59. Regimen-4 for H. Pylori Quadruple Therapy
Omeprazole/Lansoprazole +
Metronidazole
Tetracycline
Bismuth subsalicylate

60. Eradication of H. pylori results in long-term remission of peptic ulcer disease
Duodenal ulcer
Gastric ulcer
Patients in remission %
Patients in remission %
100
100
H. pylori eradicated
H. pylori eradicated 75 75 50 50
H. pylori-positive 25 25
Eradication of H. pylori results in long-term remission of peptic ulcer disease
Successful eradication of H. pylori results in long-term remission (up to 7 years) of both duodenal and gastric non-NSAID-associated peptic ulcer disease.32, 33 In a study of duodenal ulcer patients in whom the bacterium was eliminated with omeprazole and amoxycillin, 93% of patients remained in remission at 2 years, but after healing without eradication only 24% of patients remained in remission after 2 years.32 Annual relapse rates in duodenal ulcer after eradication were only 1.7% in one study,34 and 2.6% in a meta-analysis of 27 studies involving 1900 patients.35 Comparable results have been found in non-NSAID-associated gastric ulcer, where annual relapse rates were 2% with eradication of H. pylori and 53% in patients with persistent infection.36
H. pylori-positive
0.5 1
1.5 2 2 4 6 8 10 12
Years after termination
of treatment
Months after termination
of treatment
Miehlke et al 1995, © by Karger, Basel 1995; Axon et al 1997

61. Eradicating H. pylori effectively reduces complications
Complication H.pylori Present Absent (% patients) (% patients)
Recurrent ulcer (p<0.001)
Recurrent bleeding (p<0.001)
Eradicating H. pylori effectively reduces complications
Eradicating H. pylori not only promotes long-term remission of peptic ulcer disease, but also prevents disease complications.37 For example, ulcer relapse rate was reduced to only 4% after a median follow-up period of 18 months among patients with severe bleeding peptic ulcer disease who were healed and in whom H. pylori was eradicated by omeprazole-based therapy.38 Furthermore, no recurrence of haemorrhage occurred in these patients during a median follow-up period of 20 months. By contrast, 50% of patients who were H. pylori-positive suffered ulcer relapse and 33% experienced haemorrhage recurrence.
Labenz & Börsch 1994

62. Gastroesophageal Reflux Disease (GERD)
Non-pharmacological interventions:
Elimination of agents that  acid production:
coffee
NSAID’s ( causes ulceration)
Delayed gastric emptying (narcotics, fatty foods)
lower oesophageal sphincter pressure ( cigarettes, alcohol & certain drugs)

63. Drugs that decrease lower oesophageal sphincter pressure
Anticholinergic drugs
Antispasmodic drugs
Anti-histamines & antiemetics
TAD’s
Phenothiazine neuroleptics
Nitrates and Ca-channel blockers

64. Useful drugs in treating GERD