Pharmacology of Ulcers and Inflammation Treatments

Histamine

Histamine binds to H₂ receptors on parietal cells, activating adenylyl cyclase via G-proteins. This increases intracellular cAMP, which activates protein kinase A, ultimately stimulating the H⁺/K⁺-ATPase (proton pump) to secrete H⁺ ions into the gastric lumen.

Acetylcholine (ACh)

ACh released from vagal nerve endings binds to muscarinic (M₃) receptors on parietal cells. This activates the phospholipase C pathway, increasing intracellular Ca²⁺ levels.

Gastrin

Gastrin is released from G cells in response to proteins in the stomach. It binds to CCK₂ receptors (gastrin receptors) on enterochromaffin-like (ECL) cells, stimulating histamine release.

H⁺/K⁺-ATPase

The H⁺/K⁺-ATPase (proton pump) is the final common pathway for acid secretion. It uses energy from ATP hydrolysis to transport H⁺ ions into the gastric lumen in exchange for K⁺ ions.

Prostaglandin E₂ (PGE₂)

PGE₂, produced by the gastric mucosa, has an inhibitory effect on acid secretion. It binds to EP₃ receptors on parietal cells, inhibiting adenylyl cyclase activity and reducing cAMP levels.

Peptic ulcer

Erosion of a small patch of the lining of the stomach (gastric ulcer, GU) or duodenum (duodenal ulcer, DU).Tissue damage leads to inflammation and pain, which is the presenting symptom

Common symptoms of peptic ulcers

Gastric irritation, abdominal pain, vomiting, malaise, loss of appetite, poor sleep, inflammation of mucosa and submucosa, cellular infiltration, bleeding, and in severe cases, perforation.

Duodenal ulcers

Duodenal ulcers (DU) are more common than gastric ulcers (GU). Incidence rises with age (e.g., 2 DU cases and 0.5 GU cases per 1000 people aged 40-50 years).

Protective factors for mucosal integrity

1) Surface mucus layer (via goblet cells), 2) Secretion of HCO₃⁻ onto epithelial surface, 3) Good mucosal blood flow, 4) Cytoprotective prostaglandins (PGE₂ and PGF₂α), 5) Epithelial regeneration and tight junctions.

Factors attacking gastric and duodenal mucosae

1) Acid and pepsin, 2) Helicobacter pylori, 3) Bile reflux and delayed gastric emptying, 4) Absence of protective prostaglandins (NSAID side-effect), 5) Microvascular vasoconstriction, 6) Failure of epithelial regeneration, 7) Stress and risk factors like alcohol, smoking, and aspirin.

Role of H. pylori in ulcer formation

H. pylori is a key factor in ulcer pathogenesis. It damages the mucosal defense system and increases inflammation, making the mucosa more susceptible to acid damage.

Main stimulators of gastric acid secretion

Histamine (the 'final common mediator'), acetylcholine (ACh), and gastrin. All three can activate the parietal cell to secrete acid.

How antacids work

Antacids chemically neutralize stomach acid, providing rapid pain relief. Examples include aluminum hydroxide, magnesium trisilicate, and sodium bicarbonate.

Limitations of antacid therapy

Antacids have short but variable action, and as pH rises, more acid may be secreted (acid rebound). They should not be used for more than 4 weeks. Also, some cations have side effects (Mg²⁺ is laxative, Al³⁺ may be constipating).

H₂ antagonists

H₂ antagonists (e.g., cimetidine, ranitidine, famotidine, nizatidine) block histamine's effects on the H₂ receptors on parietal cells, reducing acid secretion under fasting, meal-induced, and nocturnal conditions.

Proton pump inhibitors

Proton pump inhibitors (e.g., omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole) are powerful, long-lasting suppressors of acid secretion. They are pro-drugs that become active at low pH and block the H⁺/K⁺ ATPase pump in parietal cells.

Misoprostol

Misoprostol is a synthetic stable PGE₁ analogue that mimics the effects of PGE₁ and PGE₂ on EP receptors. It has both antisecretory and cytoprotective properties, promoting healing of gastric and duodenal ulcers and preventing NSAID-associated ulcers.

Antimuscarinic drugs

Antimuscarinics like pirenzepine worked by blocking muscarinic (M₁ and M₃) receptors, which inhibited acetylcholine-stimulated acid secretion. They also reduced gastric motility, which may have aided their anti-ulcer effect. They are now obsolete due to their side effects (dry mouth, blurred vision, difficulty in urination) and the availability of more effective treatments.

Treatment strategies for peptic ulcers

1) Relieve pain (e.g., antacids), 2) Allow healing (e.g., antisecretory agents, mucosal strengtheners), 3) Prevent relapse (maintenance therapy, avoiding risk factors, lifestyle changes), 4) Surgery (now obsolete).

Triple Therapy for H. pylori eradication

Triple Therapy typically includes: 1) A proton pump inhibitor (e.g., omeprazole), 2) Clarithromycin (antibiotic), and 3) Metronidazole or amoxicillin (to eradicate H. pylori and other anaerobic bacteria).

Mucosal strengtheners

Mucosal strengtheners include bismuth chelates (forms a coat over the ulcer) and sucralfate (an Al(OH)₃-sulphated sucrose complex that protects the ulcer area and enhances gastric mucus secretion).

H. pylori eradication

H. pylori eradication has completely altered the clinical picture for patients with gastric/duodenal ulcers. With eradication therapy, healing is faster, cheaper, and more certain, with a significant reduction in relapse rates (without eradication, relapse rates can be 70-80% at 2 years).

Inflammatory bowel disease types

Ulcerative colitis (UC) - affecting the large bowel, and Crohn's disease (CD) - mainly affecting the small intestine.

Classes of drugs for inflammatory bowel disease

1) Anti-inflammatories (corticosteroids, aminosalicylates), 2) Immunosuppressives (e.g., ciclosporin), 3) Anti-cytokine agents (e.g., Infliximab, Adalimumab), and 4) Aminosalicylates (5-ASA/mesalazine).

Corticosteroids in IBD treatment

Corticosteroids (e.g., prednisolone, hydrocortisone, budesonide) inhibit phospholipase A₂ activity and the arachidonic acid-prostaglandin cascade, reducing inflammation. They can be administered as an enema or systemically depending on disease severity.

Mechanism of action of anti-TNFα antibodies

Monoclonal TNFα antibodies (e.g., Infliximab, Adalimumab) inhibit the actions of tumor necrosis factor alpha (TNFα), which is elevated in IBD and contributes to inflammation. They are used in severe/active Crohn's disease, especially in patients intolerant to steroids.

Aminosalicylates in IBD management

Aminosalicylates like 5-aminosalicylate (5-ASA/mesalazine) help maintain remission of ulcerative colitis. They can be delivered via prodrugs like sulfasalazine (sulphapyridine + 5-ASA) and olsalazine (2 molecules of 5-ASA). They can be administered orally for diffuse IBD or rectally for localized disease.