Pharmacology 24 - Treatment of Gastric and Duodenal Ulcers Flashcards
What is H Pylori?
- Gram negative, motile, microaerophilic bacterium
- Resides in human GI tract, exclusively colonising gastric type epithelium
Describe H Pylori’s role in ulcer formation
- Dissolves the mucus layer in the gastric antrum
- Causes epithelial cell death
- Increases gastric acid formation via increased gastrin or decreased somatostatin
- Gastric metaplasia - cell transformation due to excessive acid exposure
- Downregulation of defence factors (decreased eidermal growth factor and bicarbonate production)
Describe the virulence of H pylori in ulcer formation
- Urease (catalyses urea conversion to ammonium chloride and monocloramine) which damages epithelial cells
- Urease (antigenic - produces various factors) evokes immune response
- Certain virulent strains produce CagA (antigenic, increases inflammatory response) or VacA (cytotoxic), causing more intense tissue inflammation)
How are H Pylori positive uncomplicated peptic ulcers treated?
- 2 antibiotics and 1 PPI (triple therapy)
- Antibiotics for H Pylori (amoxicillin and clarithromycin/ metronidazole)
- Proton pump inhibitor for 7 days
Describe pathophysiology of H Pylori in complicated (chronic) peptic ulcers
- Dissolves mucus layer via urease enzyme
- Causes epithelial cell death by exotoxins and inflammation
- Increased acidity resulting in peptic ulcer
- Increased activity of the proton pump
List treatments of H Pylori positive complex peptic ulcers
- Antibiotics for H Pylori (amoxicillin and clarithromycin/ metronidaxole)
- Quinolone/ tetracycline considered as second line treatment
- Bismuth therapy or sucralfate can be used (chelating agents, reduce acidity)
- Proton pump inhibitor (omeprazole) for 4-12 weeks
How are proton pumps involved in ulcer formation?
- Expressed on secretory vesicles within parietal cells
- Increased [Ca2+] intracellularly results in increased cAMP which results in translocation of secretory vesicles to parietal cell apical surface. H+ secretion occurs in exchange for potassium ions
- In the ulcer there is increased activity of proton pump, increased H+ and therefore reduced gastric pH
Describe pathway of NSAIDs causing ulcer formation
- Inhibition of COX1
- Directly cytotoxic
- Reduce mucus production and therefore increase acidity
- Increase likelihood of bleeding (blood thinners)
- Increased activity results in peptic ulcer formation
How are H Pylori negative NSAID induced ulcers treated?
- Removal of NSAID (not always an option)
- Proton pump inhibitor or histamine H2 receptor antagonist (ritanitidine OTC) for 4-8 weeks
- H2 receptor increases acid secretion
Describe gastric acid regulation
- Acetylcholine (ACh) released from neurones (vagus / enteric) acts on muscarinic (M3) receptors - increases intracellular calcium, therefore increases proton pump expression
- Prostaglandins (PGs) released from local cells act on EP3 receptors - decreases cAMP and therefore decreases proton pump expression (hence why NSAIDs increase likelihood of ulcer formation)
- Histamine released from enterochromaffin-like cells (ECL) act on H2 receptors - increases cAMP and therefore increase proton pump expression
- Gastrin (G cells) released from blood stream acts on cholecystokinin B (CCKB) receptors - increases intracellular calcium concentration to increase proton pump expression
Describe the process of gastric acid secretion
- Increased calcium intracellular
- Increased cAMP
- Both increase translocation of secretory vesicles to parietal cell apical surface, and therefore increased expression of proton pumps
- H+ secretion
- Somatostatin inhibits G cells, ECL cells and parietal cells.
Describe presentation of a gastric ulcer
- Epigastric pain
- Burning sensation after meals (acute H Pylori)/ all the time
Describe investigations and diagnosis of peptic ulcers
- Carbon-urea breath test (presence of H Pylori)
- Stool antigen test (for H Pylori)
Why is triple drug therapy best practice for gastric ulcer treatment (H Pylori)?
Eliminates bacterial infection while also decreasing the hydrogen produced from the parietal cells in the stomach
