Treatment of gastric and duodenal ulcers

Question 1

What is the underlying pathology of peptic ulcers?

Answer 1

Helicobacter pylori: increase gastric acid formation; gastric metaplasia; decrease defence factors

Proton pump: H+ secretion - activated by increased Ca2+ and increased cAMP

Histamine released from epithelial cell layer cells act on H3 receptors - increased cAMP

Question 2

How does Helicobacter pylori cause peptic ulcers?

Answer 2

• Dissolves mucus layer on top of the epithelial cells: urease enzyme
• Causes epithelial cell death: exotoxins and inflammation
  Increased acidity –> peptic ulcer

Ulcer formation:

• Increased gastric acid formation = increased acidity – increased gastrin and decreased somatostatin
• Gastric metaplasia – cell transformation due to excessive acid exposure. Destroys epithelium
• Downregulation of defence factors - decrease in epidermal growth factor (responsible for the production of epithelial cells) and decrease in bicarbonate production (counteracts acidity)

Question 3

Describe the virulence of H pylori

Answer 3

Urease – catalyses urea into ammonium chloride and monochloramine –> Toxic –> damage epithelial cells

Urease – antigenic –> evokes immune response which also causes damage to the epithelial cells

Certain virulent strains produce CagA (antigenic) or VacA (cytotoxic) – more intense tissue inflammation. Increases virulence

Question 4

How do you treat peptic ulcers caused by H pylori?

Answer 4

Antibiotics (treat the underlying cause)- Amoxicillin and Clarithromycin/Metronidazole

Proton Pump Inhibitor (PPI) (treats the symptoms) – reduces acid production: Omeprazole (4-12 weeks)

Consider quinolone, tetracycline

Question 5

Describe proton pumps and how they lead to ulcer formation

Answer 5

H+K+ATPase (proton pump):
Expressed on secretory vesicles within parietal cells
increased [Ca2+]i –> increased cAMP –> translocation of secretory vesicles to parietal cell apical surface –> H+ secretion. So normally the proton pump is not on the apical membrane.

H+ is removed from the cell and K+ is taken into the cell.

Increased activity of proton pump – increased H+ secretion –> reduction gastric pH

Activated by increased Ca2+ and cAMP

Question 6

Describe gastric acid regulation

Answer 6

4 main types of receptors which play a role in acid production. REMEMBER: increased [Ca2+]i –> increased cAMP –> translocation of secretory vesicles to parietal cell apical surface –> H+ secretion.

• Acetylcholine (ACh) released from neurones (vagus / enteric) acts on muscarinic (M3) receptors - increased [Ca2+]i
• Prostaglandins (PGs) released from local cells act on EP3 receptors - increased cAMP
• Histamine released from enterochromaffin-like cells (ECL) act on H2 receptors - increased cAMP
• Gastrin released from blood stream acts on cholecystokinin B receptors - increased [Ca2+]i

Histamine activates H2 receptors which increase acid secretion.

Question 7

How would you treat peptic ulcers caused by NSAIDs?

Answer 7

NSAID: primarily asprin use
 - Directly cytotoxic
 - Reduces mucus production 
 - Increases likelihood of bleeding
Increased acidity --> peptic ulcer 

Treatment:

• Removal of NSAID
• Proton Pump Inhibitor or histamine H2 receptor antagonist (Ranitidine) – 4-8 weeks
• H2 receptor increases acid secretion

Question 8

Explain why combination treatment is the current best practice?

Answer 8

You are targeting multiple pathways

1) proton pumps = reduce acid secretion
2) target the underlying cause –> Antibiotics or H. pylori