Peptic ulcers

• Describe the cells that control gastric acid secretion

  G-cells secrete gastrin and nerve cell secrete acetylcholine, which stimulate parietal cells to secrete gastric acid. These cells can also stimulate enterochromaffin-like cells, which secrete histamine. Histamine binds to H2 receptors on parietal cells and further stimulates gastric acid secretion (major pathway). Increases in intracellular Ca2+ and cAMP lead to tubulovesicles becoming activated to form canaliculus, which increases surface area and increases the number of proton pumps.
• Describe the different types of ulcers

  Gastric ulcer forms in the stomach lining, whereas duodenal ulcers form in the duodenum following the pyloric sphincter. This leads to inflammation and tissue damage, which can be seen as a white region. They can also result in perforation where the gastric acid leaks into the peritoneum and damages neighbouring organs.
• What are H2 antagonists?

  These are identified by sharing structurally similar motifs with histamine. They target H2 receptors, which are only expressed in the stomach. Examples included cimetidine and ranitidine, which provide indigestion relief and are often co-administered with NSAIDs to provide pain relieved.
• Describe omeprazole

  This is a first generation PPI. It it lipid soluble, which allows it to be absorbed through the GI tract and into the circulation, and a weak base, meaning it will accumulate within acid compartments, such as the canaliculi. It is activated in low pH as it is chemically altered by protons to an active sulphenamide form. It has an IC50 of 50nM, making it very potent. It acts by forming irreversible disulphide bonds with H+ K+ ATPase and has been used to treat over a billion people. Encoated formulation prevents digestion in the stomach acid.
• Describe second generation PPIs

  Developed by purifying the S isomer of omeprazole, which typically contained both optical isomers. This was called esomeprazole and exhibited double the potency just from removing the R isomer.
• What are the main causes of ulcers?

  • Helicobacter pylori
  • NSAIDs
  • Smoking
  • Zollinger-Ellison syndrome
  • Anxiety
• How does helicobacter pylori cause ulcers?

  This is a gram negative bacteria that leads to inflammation of the stomach lining. Not everyone with infection (around 15%) develop ulcers and associated with stomach carcinoma. H. Pylori are able to tolerate low pH by metabolising urea, as well as penetrate the mucus and attach to epithelial cells. Inflammation in the antrum impairs somatostatin release, which increases gastrin and acid secretion.
• Describe the quadruple therapy for eradicating H. pylori

  • 2 Antibiotics- tetracycline, clarthromycin, amoxycillin and metronidazole
  • Proton pump inhibitors
  • Bismuth compounds

  Antibiotics only work on dividing bacteria so PPI raises pH and bismuth slows acidification of bacterial interior.
• How do NSAIDs increase risk of ulcers?

  NSAIDs inhibit COX1, which leads to a decrease in the production of PGE2 in the mucosa of stomach and duodenum. PGE2 decreases acid secretion and increases mucosal protection.
• Describe potassium-competitive acid blockers

  • These is a new class of proton pump inhibitor
  • Superior performance to PPIs as it is fast acting and long lasting
  • elevates pH more rapidly and for longer
  • Enhance antibiotic action, by reducing antibiotic resistance
  • E.g., vonoprazan