Peptic Ulcer- Pathophysiology, Treatment (Anti-Ulcer agents)

1. Peptic Ulcer Disease

2. Introduction
Peptic ulcers are the areas of degeneration and necrosis in
the duodenum or the stomach.
The immediate cause of peptic ulcer disease is disturbance in normal
protective mucosal ‘barrier’ by acid-pepsin.
Site
• Lower esophagus
• Stomach
• Duodenum
• 10% of men, 4%
of women

3. Types
Acute Chronic
Superficial erosion Muscular wall erosion
with formation of
fibrous tissue
Minimal erosion Present continuously
for many months or
intermittently

5. Etiology and Pathophysiology
• The immediate cause of peptic ulcer disease is disturbance in normal
protective mucosal ‘barrier’ by acid-pepsin, resulting in digestion of the
mucosa. However, in contrast to duodenal ulcers, the patients of gastric
ulcer have low-to-normal gastric acid secretions, though true achlorhydria
in response to stimulants never occurs in benign gastric ulcer.
• Thus, the etiology of peptic ulcers possibly may not be explained on the
basis of a single factor but is multifactorial. Th ese factors are discussed
below but the first two—H. pylori gastritis and NSAIDs-induced injury are
considered most important.
1. Helicobacter pylori gastritis
2. NSAIDs-induced mucosal injury
3. Acid-pepsin secretions
4. Gastritis
5. Other local irritants
6. Psychological stress
7. Genetic factors
8. Hormonal factors
9. Dietary factors
10. Miscellaneous

6. Diffusion of Acid

7. Disruption of Gastric Mucosal Barrier

8. Protective Mechanism
• Mucus forms a layer that entraps or slows
diffusion of hydrogen ions across mucosal barrier
• Bicarbonate secreted Neutralizes HCl acid in
lumen of GI tract

9. Gastric Ulcers
Characterized by
• A normal to low secretion of gastric acid
• Back diffusion of acid is greater (chronic )
• Critical pathologic process is amount of acid able to
penetrate mucosal barrier
• H pylori is present in 50% to 70%
• Drugs --- Aspirin, corticosteroids, NSAIDs, reserpine,
Chronic alcohol abuse, chronic gastritis

10. Duodenal Ulcers
• Between ages of 35 to 45 years
• Account for 8 0% of all peptic ulcers
• Associated with ↑HCl acid secretion
• H.pylori associated in 9 0- 9 5 % of cases
• Diseases with ↑risk of duodenal ulcers
COPD, cirrhosis of liver, chronic pancreatitis,
hyperparathyroidism, chronic renal failure

11. Clinical Features
• Common to have no pain or other symptoms
– Gastric and duodenal mucosa not rich in sensory pain
fibers
– Duodenal ulcer pain
• Burning, cramp like
– Gastric ulcer pain
• Burning, gaseous

12. Diagnostic Studies
• Endoscopy procedure
– Determines degree of ulcer healing after treatment
– Tissue specimens can be obtained to identify H. pylori and to rule out
gastric cancer
• Tests for H.pylori
– Noninvasive tests
• Serum or whole blood antibody tests
– Immunoglobin G (I g G)
• Urea breath test
• C 14 breath test
– Invasive tests
• Biopsy of stomach
• Rapid urease test

13. • Barium contrast studies
– Widely used
• X- ray studies
– Ineffective in differentiating a peptic ulcer from a
malignant tumor
• Gastric analysis
• Lab analysis

14. Treatment
Medical regimen consists of
– Adequate rest
– Dietary modification
– Drug therapy
– Elimination of smoking
– Long-term follow-up care
Aim of treatment pro g ram
– ↓ degree of gastric acidity
– Enhance mucosal defense mechanisms
– Minimize harmful effects on mucosa

15. Pharmacology
• Approaches for the treatment of peptic ulcer are:
1. Reduction of gastric acid secretion
(a) H2 antihistamines: Cimetidine, Ranitidine, Famotidine, Roxatidine
(b) Proton pump inhibitors: Omeprazole, Esomeprazole, Lansoprazole,
Pantoprazole, Rabeprazole, Dexrabeprazole
(c) Anticholinergic drugs: Pirenzepine, Propantheline, Oxyphenonium
(d) Prostaglandin analogue: Misoprostol
2. Neutralization of gastric acid (Antacids)
(a) Systemic: Sodium bicarbonate, Sod. citrate
(b) Non-systemic: Magnesium hydroxide, Mag. trisilicate, Aluminium
hydroxide gel, Magaldrate, Calcium carbonate
3. Ulcer protectives: Sucralfate, Colloidal bismuth subcitrate (CBS)
4. Anti-H. pylori drugs: Amoxicillin, Clarithromycin, Metronidazole, Tinidazole,
Tetracycline

16. H2 ANTAGONISTS
• Cimetidine was the first H2 blocker to be
introduced clinically and is described as the
prototype, though other H2 blockers are more
commonly used now.
• Mechanism of Action
H2 Receptor on Parietal Cell
Gastric Acid secretion
H2 receptor antagonist
Eg- Cimetidine, Ranitidine

17. • Pharmacokinetics
Cimetidine is adequately absorbed orally,
though bioavailability is 60–80% due to first pass
hepatic metabolism.
It crosses placenta and reaches milk, but
penetration in brain is poor because of its
hydrophilic nature.
About 2/3 of a dose is excreted unchanged in
urine and bile, the rest as oxidized metabolites.
The elimination t½ is 2–3 hr. Dose reduction is
needed in renal failure

18. • Pharmacological Actions
1. H2 blockade- blocks histamine-induced gastric secretion, cardiac stimulation (guinea pig),
uterine relaxation (rat). Causes fall in BP.
2. Gastric Secretion- The only significant in vivo action of H2 blockers is marked inhibition of
gastric secretion.
• Adverse Effects
Headache, dizziness, bowel upset, dry mouth, rashes.
Cimetidine has antiandrogenic action increases plasma prolactin and inhibits degradation of
estradiol by liver. High doses given for long periods have produced gynecomastia, loss of libido,
impotence and temporary decrease in sperm count.
• Drug Interactions
1. Antacids reduce absorption of all H2 blockers.
2. Ketoconazole absorption is decreased by H2 blockers due to reduced gastric acidity.
3. Cimetidine inhibits several cytochrome P-450 isoenzymes and reduces hepatic blood flow. It
inhibits the metabolism of many drugs so that they can accumulate to toxic levels, e.g.
theophylline, phenytoin, carbamazepine, phenobarbitone, sulfonylureas, metronidazole,
warfarin, imipramine, lidocaine, nifedipine, quinidine.
• Uses
Duodenal Ulcer, Gastric Ulcer, Stress Ulcer
Zollinger-Ellison syndrome
Gastroesophageal reflux disease (GERD)

19. Proton Pump Inhibitors
• Proton pump inhibitors (PPIs) reduce the
production of acid by blocking the enzyme in
the wall of the stomach that produces acid.
• Mechanism of Action
Proton pump inhibitors (PPIs) effectively block
gastric acid secretion by irreversibly binding to
and inhibiting the hydrogen-potassium ATPase
pump that resides on the luminal surface of
the parietal cell membrane.

20. `

21. PPIs
Absorb in small intestine
Blood
Diffuse into parietal cells
Canaliculi of the cell (acidic pH)
Converted to sulfenamide (active form)
Binds covalently with SH group of the proton
pump
Irreversibly inactivates proton pump

22. • Inhibit both fasting and stimulating acid secretion.
Pharmacokinetics
All PPIs are administered orally in enteric coated (e.c.) form to protect them from
molecular transformation in the acidic gastric juice.
Oral bioavailability of omeprazole is ~50% due to acid lability
Bioavailability of all PPIs is reduced by food; they should be taken in empty stomach,
followed 1 hour later by a meal to activate the H+K+ ATPase.
Omeprazole is highly plasma protein bound, rapidly metabolized in liver and excreted
in urine.
Uses
Peptic ulcer, Stress Ulcer, Gastroesophageal reflux disease (GERD), Zollinger-
Ellison syndrome
Adverse Effects
Nausea, loose stools, headache, abdominal pain, muscle and joint pain,
dizziness, atrophic gastritis (occasionally)

23. ANTICHOLINERGICS
• Pirenzepine- It is a selective M1
anticholinergic that has been used in Europe
for peptic ulcer. Gastric secretion is reduced
by 40–50% without producing intolerable side
effects, but side effects do occur with slight
excess. It has not been used in India and USA.
• They are not commonly used because of their
low efficacy and anticholinergic side effects.

24. PROSTAGLANDIN ANALOGUE
• PGE2 and PGI2 are produced in the gastric mucosa
and appear to serve a protective role by inhibiting
acid secretion and promoting mucus as well as HCO¯
secretion and also have cytoprotective effect.
• Misoprostol a synthetic PG analogue is effective
orally for prevention and treatment of NSAIDs
induced gastric and duodenal ulcers.
• Side effects- diarrhea, abdominal cramps
• Contraindicated in pregnancy as it causes uterine
contraction.

25. ULCER PROTECTIVE
Sucralfate
It is a complex of aluminium hydroxide and sulphated sucrose.
Sucralfate is given orally on an empty stomach at least 1 hour before meals.
Contraindication
It reduces the absorption of drugs, such as digoxin, tetracyclines,
ketoconazole and fluoroquinolones.
Since it requires pH 4 for activation, concurrent administration of antacids,
H2-blockers or PPIs should be avoided.
Adverse Effects
Constipation is a common side effect. Nausea may occur.
Aluminium toxicity can occur in patients with renal failure.
Uses
Sucralfate is effective for prevention of bleeding from stress ulcers and to
reduce the risk of aspiration pneumonia. It is also useful in GERD with
esophagitis, as it is a mucosal protector. Other uses are oral mucositis,
radiation proctitis, rectal ulcer, burns, bed sores, etc.

26. • MOA
In the acidic environment of stomach (pH & 4),
sucralfate undergoes polymerization to form a
sticky polymer that adheres to the ulcer base
and protects it. It also precipitates proteins at
the ulcer base – forms a barrier against acid–
pepsin. It also increases mucus and bicarbonate
secretion – enhances mucosal defence and
repair.
It stimulates the release of PGs and epidermal
growth factor locally, thus produces
cytoprotective effect.

27. ANTACID
• Antacids are weak bases that neutralize gastric
acid and raise the gastric pH. They do not
affect acid production. Acid neutralizing
capacity reflects the potency of an antacid.

28. Anti-H. pylori Agents
• H. pylori, Gram-negative, rod-shaped bacterium, is associated
with gastritis, duodenal ulcer, gastric ulcer and gastric
carcinoma.
• The objectives of combination therapy are as follows:
1. To prevent or delay the development of resistant organism.
2. To prevent relapse.
3. To promote rapid ulcer healing. 4.
4. To eradicate H. pylori infection.
The duration of treatment could be 1 week or 2 weeks, of which
14-day therapy is more effective. The antimicrobials used in H.
pylori infection are amoxicillin, tetracycline, clarithromycin,
metronidazole and tinidazole.

29. • Tetracyclines
Mechanism of Action
Tetracyclines
Actively taken up by susceptible bacteria
Bind reversibly to 3OS ribosomal subunit
Prevent binding of aminoacyl tRNA to mRNA–ribosome complex
Prevent the addition of amino acid to the growing peptide chain
Inhibit bacterial protein synthesis (bacteriostatic)

30. • Amoxicillin
β-Lactam antibiotics produce bactericidal effect by inhibiting cell
wall synthesis in susceptible bacteria.
Bacterial cell wall is composed of peptidoglycan which contains
amino sugars. The enzyme, transpeptidase , removes terminal
alanine of one strand resulting in its linkage with glycine of
adjacent strand. Cross-linking makes the cell wall rigid and stable
β-Lactam, the structural analogues of d-alanine, inhibit
transpeptidase, thus inhibiting cross-linking of peptidoglycans
and cell wall synthesis. Cell wall–deficient forms are produced
which undergo lysis (bactericidal action). β-Lactams exert their
cidal effect when the bacteria are actively multiplying and
synthesizing cell wall.

31. Surgical Treatment
• < 20% of patients with ulcers need surgical
intervention
• Indications for surgical interventions
Intractability
History of hemorrhage, ↑ risk of bleeding
Prepyloric or pyloric ulcers
Multiple ulcer sites
Drug-induced ulcers
Possible existence of a malignant ulcer
Obstruction

32. Surgical procedures
 Gastroduodenostomy
 Gastrojejunostomy
 Vagotomy
 Pyloroplasty