1. Objectives for Lecture on Peptic Ulcer Disease
By the end of this class students will be able to:
List the causes of peptic ulcer disease from most common to least common
Identify the cause of peptic ulcer disease from history and diagnostic tests
Choose appropriate therapy based on the etiology of the condition
Describe the pharmacotherapies of peptic ulcer disease caused by H. pylori infection and NSAIDs and explain the rationale for these therapies
Explain the mechanism by which each drug cures or improves the symptoms of peptic ulcer disease

2. Gastric Ulcer

3. Peptic Ulcer Disease
Lesions of the gastric or duodenal mucosa 3 mm in diameter that extend through the muscularis mucosa
In North America, 90% occur in duodenum; in Asia, the great majority are in the gastric mucosa
Affects 11-14% of men and 8-11% of women at some time in their lives, 4.5 million people in the USA annually
Symptom: burning pain that
is felt anywhere from the navel to the sternum
lasts for a few minutes to many hours
is worse when the stomach is empty and is relieved temporarily by eating or by taking an antacid or acid-reducing medication
flares at night
comes and goes for a few days or weeks

4. Peptic Ulcer Disease - Etiology
Infection with Helicobacter pylori
60-65% of duodenal and gastric ulcers in North America today (90% of duodenal ulcers, 70% of gastric ulcers in the 1980s)
One out of 6 infected persons develops an ulcer
Thought to be spread by contaminated food and water and exchange of GI fluids
Declining due to improved sanitation and antibiotic therapy
Use of NSAIDs (~5%)
Tumors that cause hypersecretion of gastric acid (Zollinger-Ellison), other GI disorders (<1%)
Idiopathic
A growing contribution (30% in North America) as infection with H. pylori declines
Causes are unclear. Patients with an idiopathic ulcer tend to be older, sicker, and experience bleeding episodes more frequently. Many were “cured” of a previous ulcer caused by H. pylori or NSAID use. Probably related to fragile mucosa.

5. J. Robin Warren and Barry Marshall

6. Helicobacter pylori in the gastric mucosa

7. Helicobacter pylori A microaerophilic spiral-shaped Gram-negative rod
Named and associated with ulcers and chronic gastritis by Warren ( )
Cultured and sensitivity to bismuth demonstrated by Marshall (1982)
Patients treated successfully with bismuth + antibiotics by Marshall (1984)
H. pylori demonstrated to cause illness in humans by Marshall (1984)
Marshall/Warren theory accepted ( ), honors roll in (1994- )
Marshall/Warren awarded Nobel Prize in Medicine (2005)

8. Peptic Ulcer Disease and H. pylori - Diagnosis
Ulcer diagnosed from endoscopy and/or upper GI series
5% are malignant
H. pylori infection diagnosed by
Biopsy (demonstrate breakdown of urea by H. pylori urease in the sample). Most accurate test for diagnosis; seldom used for monitoring therapy.
Breath test (ingest 13C-urea, exhale 13C-CO2). Accurate for diagnosis and monitoring therapy, but expensive.
Serology (detect circulating antibody to H. pylori). Most cost effective test for diagnosis, but not as accurate as others. Not useful for monitoring therapy.
Stool antigen (detect H. pylori in feces with an antibody-based test). Useful for diagnosis and monitoring therapy. More cost effective than the breath test and more accurate than serology.

9. How Does H. pylori Cause Peptic Ulcer Disease?

10. Eradication of Helicobacter pylori
Optimal antibiotic therapy eradicates H. pylori and cures H. pylori-associated peptic ulcer disease in 85% of patients
Many H. pylori isolates are resistant to once-effective antibiotics and resistant strains emerge rapidly
At least two synergistic antibiotics must be used for maximal efficacy
Bismuth preparation may be added to improve efficacy, but it cannot substitute for a conventional antibiotic
Suppression of gastric acid secretion with a PPI speeds healing and improves the efficacy of amoxicillin. PPIs also have some toxicity toward H. pylori, but cannot substitute for a conventional antibiotic.

11. Triple Therapy – First-Line (where H
Triple Therapy – First-Line (where H. pylori resistance to metronidazole > to clarithromycin)
Amoxicillin
Cell wall inhibitor. Modest efficacy when used by itself.
Clarithromycin
Protein synthesis inhibitor. Normally a bacteriostatic drug, but amoxicillin damages the bacterial cell wall allowing a bactericidal concentration of clarithromycin to accumulate intracellularly.
PPI
Continue for 14 days
Note: Substitute metronidazole (source of intracellular free radicals in anaerobic and microaerophilic bacteria) for amoxicillin in patients with penicillin allergy.

12. Quadruple Therapy – Backup (first-line where H
Quadruple Therapy – Backup (first-line where H. pylori resistance to clarithromycin > to metronidazole)
Tetracycline
Protein synthesis inhibitor
Metronidazole
Source of intracellular free radicals
Bismuth subsalicylate (Pepto-Bismol) or bismuth citrate
Toxic to H. pylori and protects stomach lining from acid
PPI
Continue for 14 days

13. H. pylori-Associated Tumors
Gastric carcinoma
H. pylori infection leads to chronic gastritis, epithelial cell hyperplasia, increased risk of malignant transformation
Increases risk 3 to 5-fold
MALT (mucosa-associated lymphoid tissue) lymphoma
Low-grade type of B cell non-Hodgkin’s lymphoma (extranodal marginal zone B cell lymphoma)
Lymphoid tissue normally absent from the stomach
Inflammation of gastric mucosa causes development of MALT-type lymphoid tissue
B lymphocytes stimulated to replicate by constant presence of bacteria
In some people, lymphoid cells undergo malignant transformation. Transformation to a more aggressive form in <10% of cases.
Eradication of H. pylori induces tumor regression in 50-70% of cases.

14. Oxyntic (Acid-Producing) Gland

15. Secretory Products of Oxyntic Glands
Parietal cells
HCl
Solubilizes food, extracts metals from food
Converts pepsinogen to pepsin
Disinfects
Intrinsic factor
Absorption of vitamin B12
Mucous cells
Mucus and bicarbonate
Protect the gastric mucosa from chemical/mechanical damage
Chief cells
Pepsinogen
Enterochromaffin-like (ECL) cells
Histamine
G cells (Pyloric glands)
Gastrin

16. Regulation of Gastric Acid Secretion
PPI

17. Proton Pump Inhibitors (PPIs)

18. Proton Pump Inhibitors (PPIs) Mechanism of Action
Irreversible inhibitors of H+/K+-ATPase (proton pump). 95% suppression of acid production.
Complex mechanism
Enter parietal cell from the circulation
Accumulate in the acidic secretory canaliculi because they are weak bases
Activated by proton-catalyzed process to thiophilic sulfenamide or sulfenic acid
Activated form binds irreversibly to cysteine residues from the extracellular domain of the pump
Conversion to active form ceases when pH rises to 4-5
Because they are destroyed by acid, PPIs are formulated in enteric-coated capsules. Absorption is entirely from the small intestine.

19. Proton Pump Inhibitors (PPIs)

20. Proton Pump Inhibitors (PPIs) Clinical Uses
Because they reduce gastric acid secretion more effectively than any other class of drugs, they have become the mainstays of therapy to
Promote healing of gastric and duodenal ulcers
Treat gastroesophageal reflux disease (GERD)
Treat Zollinger-Ellison syndrome

21. Proton Pump Inhibitors (PPIs) Adverse Effects
Remarkably safe when used for a short time, as in triple and quadruple therapy for peptic ulcer disease
Increasing reports of adverse effects when used chronically
Infection of stomach with E. coli, Clostridium difficile, and other lower-GI bacteria
Nosocomial pneumonia
Increased incidence of fractures related to hypocalcemia

22. H2 Blockers

23. H2 Blockers
H2 Blockers

24. H2 Blockers
Competitive antagonists at the H2 histamine receptor on parietal cell. Blocks stimulation of acid production by histamine.
Less effective than PPIs; reduce acid secretion by 60%
Most prominent effect is on basal acid secretion. Reduces nocturnal acid secretion effectively if taken during the evening.
Used today to suppress less serious symptoms of peptic ulcer disease and GERD and when PPI is undesirable; generally second-line

25. Sucralfate Sucrose octasulfate + Al(OH)3
Polymerizes at pH <4 into viscous sticky gel that adheres to mucosa and especially to ulcer crater
Protects mucosa from acid and pepsin
As effective in promoting ulcer healing as H2 blockers

26. Antacids

27. NSAID-Induced Ulcers
Diagnosed mainly in persons who use large doses to treat arthritis and other chronic inflammatory conditions, but less frequently even in persons who use aspirin for thrombotic prophylaxis
3-4.5% of chronic NSAID users have clinically-significant upper GI events

28. How Do NSAIDs Cause Ulcers?

29. Prevention/Healing of NSAID-Induced Ulcers
Use the lowest effective dose. Minimize/avoid aspirin if possible (except for thrombotic prophylaxis)
Combine with PPI (80-90% success)
Combine with misoprostol (analog of prostaglandin E1) (60-75% success)
Inhibition of acid secretion
Stimulation of mucus and bicarbonate secretion
Increased mucosal blood flow
Diarrhea, uterine contraction possibly leading to abortion
Use celecoxib (COX-2 inhibitor)
Cardiovascular risk

30. Misoprostol