1. Dyspepsia, Peptic Ulcer Disease and Helicobacter Pylori
Pharmacology & Therapeutics February 2007

2. Dyspepsia 40% of all adults 4% GP consultations
10% further investigations
10-20% NSAID users

3. Endoscopy findings 15% Duodenal or Gastric ulcer
15% Oesophagitis = GORD
30% Gastritis duodenitis or hiatus hernia
30% Normal = functional dyspepsia

4. Pathogenesis of Dyspepsia
Factor
Treatment approach
Infection with H. pylori
Eradication of H. pylori infection, e.g. triple tx
↑ gastric HCl secretion
↓ HCl secretion or neutralizing it, e.g. H2 antagonists, pirenzepine, antacids , PPIs
Inadequate mucosal defence against gastric HCl
Agents that protect gastric mucosa, e.g. sucralfate
Altered gastric motility
Prokinetic agents eg metoclopramide

5. Gastric acid secretion

6. Helicobacter Pylori

7. Symptomatic treatment

8. Antacids
Drug
Side effect
Magnesium
severe osmotic diarrhoea (therefore combined with AlOH)
↓ drug absorption
Aluminium
↓phosphate, ↓absorption of tetracycline, thyroxine & chlorpromazine, constipation
Calcium
↑Ca in blood & urine (high doses)
MOA: Weak bases that react with gastric acid to form H20+salt. ↓pepsin activity as pepsin inactive at pH>4
Symptom relief, liquids>tablets
E.g. Maalox = Mg(OH)2 + Al(OH)3

9. Mucosal Protective Agents
1) Sulcralfate
MOA: Binds to positively charged proteins present on damaged mucosa forming a protective coat
Useful in “stress ulceration”
As effective as H2-R antagonists/high dose antacids
SE: Constipation
↓absorption of cimetidine, digoxin, phenytoin & tetracycline
2) Bismuth
MOA: Antimicrobial action. Also inhibit pepsin activity, ↑mucus secretion & interact with proteins in necrotic mucosal tissue to coat & protect the ulcer crater

10. Additional agents Antifoaming agent
– Dimethicone to relieve flatulence (surfactant)
Alginates
- form a raft on surface of stomach contents to reduce reflux
Carbenoxolone
- liquorice derivative ? Alters mucin s/e H2O retention ↓K+

11. H2-receptor antagonists
Drug
Side effects
Cimetidine
-reversible impotence, gynaecomastia & ↓ sperm count (high doses) (nonsteroidal antiandrogen)
-mental status abnormalities-confusion, hallucinations (elderly/renal impairment)
-leukopenia & thrombocytopenia (rare)
-cytochrome P450 inhibitor (e.g. impairs metabolism of warfarin, theophylline & phenytoin)
Ranitidine,famotidine
-Impotence, gynaecomastia & confusion less frequently than cimetidine.
-Little interference with cytochrome P450
-Reversible drug-induced hepatitis with all H2-antagonists

12. Proton-pump Inhibitors (PPI)
MOA: block parietal cell H+/K+ ATPase enzyme system (proton pump) ↓ secretion of H+ ions into gastric lumen
More effective than H2-antagonists or antacids
Used in antimicrobial regimens to eradicate H. pylori
SE: n&v, diarrhoea, dizziness, headaches, gynaecomastia & impotence (rare), thrombocytopenia, rashes

13. Helicobacter Pylori 95% Duodenal ulcers 70% Gastric ulcers
10% Non-ulcer dyspepsia
Treatment benefits gastritis more than reflux symptoms

14. Diagnosing H. pylori Urea breath test 95% sensitive & specific
Stool antigen test 92% sensitive & specific
Serology 80% sensitive & specific
Endoscopy – CLO test 98% sensitive & specific
(urea and phenol red, a dye that turns pink in a pH of 6.0 or greater)
CLO = campylobacter like organisms
Breath test - Need to stop ppi 2/52/antibiotics4/52

15. H. Pylori Eradication 1st line eradication tx for H. pylori
2nd line tx
Preferred tx= PPI PO + Clarithromycin 500mg BD PO + Amoxicillin 1 gm BD PO for 7 days
If Penicillin allergic= PPI + Clarithromycin 500mg BD PO + Metronidazole 400mg BD PO for 7 days
E.g. of PPI: Lansoprazole 30mg BD PO
PPI + Bismuth 120mg QDS PO + Metronidazole 500mg TDS PO + Tetracycline 500mg QDS PO for 7 days
Subsequent failures handled on individual basis with advice from gastro/micro

16. H. Pylori eradication
1 week triple-therapy regimens eradicate H. Pylori in >90% cases. Usually no need for continued antisecretory tx unless ulcer complicated by bleeding/perforation
2 week triple-therapy offer higher eradication rates cf 1 week but SE common & poor compliance
2-week dual-therapy with PPI & antibacterial produce low rates of H. pylori eradication & not recommended

17. H. pylori eradication Treatment failure may be due to
- Resistance to antibacterial drugs
- Poor compliance
Drug
Side effects
Bismuth
n&v, unpleasant taste, darkening of tongue & stools, caution in renal disease
Metronidazole
n&v, unpleasant taste, ↓effectiveness OCP, care with lithium/warfarin
Amoxicillin
& tetracycline
GI side effects, ↓ effectiveness OCP, pseudomenbranous colitis
Lansoprazole
↓ effectiveness OCP

18. Practical Management of dyspepsia

19. Who needs endoscopy? GI bleeding Unintentional weight loss Dysphagia
Persistent vomiting
Iron deficiency anaemia
Epigastric mass
>55 with unexplained persistent/recent onset dyspepsia

20. PUD on endoscopy Stop NSAIDs Start full dose PPI for 2 months
Eradication treatment if H Pylori positive
Repeat endoscopy for gastric ulcer 2% cancer risk

21. GORD on endoscopy Lifestyle advice Full dose PPI for 1-2 months
H Pylori Eradication may not benefit reflux symptoms
If recurrence - lowest dose PPI to control symptoms

22. GORD GORD = Symptoms of “heartburn” General advice includes AVOIDING
Drug Tx
Meals at night, lying down after meals
Elevate head of bed
Heavy lifting, tight clothing, bending
Being overweight
Smoking (nicotine relaxes lower oesophageal sphincter)
Aggravating substances (spicy foods, C2H5OH)
Drugs which encourage reflux (e.g. antimuscarinic, smooth muscle relaxants, theophylline)
antacids=+/-alginic acid
Pro-kinetic agent, e.g. metoclopramide
H2-antagonist
PPI
If severe sx when tx stopped, or bleed from oesophagitis or stricture maintenance tx with PPI or surgery may be necessary

23. NSAID Induced Dyspepsia
10-20% develop endoscopically visible PUD
1-5% perforation or major bleeding
Endogenous prostaglandins (PGE2 & I2) contribute to GI mucosa integrity by
- stimulation of mucus & bicarbonate secretion
- maintenance of blood flow (allows removal of luminal H-ions)
- prevent luminal H-ions from diffusing into the mucosa
- ↓ gastric acid secretion
- helping to repair damaged epithelium

24. NSAID Induced Dyspepsia
Elderly >65 years
History PUD
Other drugs – eg bisphosphonates, Steroids
PPI or misoprostol protection for at risk
Consider screening & eradicating H Pylori infection

25. Prostaglandin analogues
Misoprostol = synthetic prostaglandin E1 analogue
Prevents NSAID induced ulcers & heals chronic GU & DU
SE: Abdo pain, n&v, diarrhoea, abortifacient (produces uterine contractions)

26. Non ulcer dyspepsia Treat H pylori (no routine retesting)
Symptomatic treatment
PPI (proven benefit)
Prokinetic agent eg metoclopramide (probable benefit)

27. Dyspepsia without alarm symptoms
Lifestyle advice
Antacids and medication review
Empiric PPI
Test and treat for H Pylori

28. Shah, R.
BMJ 2007;334:41-43
Copyright ©2007
BMJ Publishing Group Ltd.