The Pharmacology of Ulcers and Inflammation

What is a peptic ulcer?

Erosion of a small patch of stomach lining (gastric ulcer, GU) or duodenum (duodenum ulcer, DU). Tissue damage leads to inflammation and pain (presenting symptom). Erosion depends on depth of layers

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How is a peptic ulcer diagnosed?

Can be revealed using gastric endoscopy

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Which type of ulcer is more common?

DU more common than GU, incidence rises with age (2 & 0.5 cases per 1000 40-50 yr olds)

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What are the symptoms and pathology?

Gastric irritation, abdominal pain, vomiting, malaise, loss of appetite, poor sleep, inflammation of mucosa, submucosa and cellular infiltration, bleeding, perforation. (Most infections are asymptomatic)

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Describe the pathogenesis of gastric/duodenal (peptic) ulcers

Mucosal erosions, pain and bleeding. Mucosal defence is overwhelmed by acid plus other aggressive factors. H.pylori significant (thought that carriers of H.pylori less likely to be infected by other pathogens)

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What are the protective factors for gastric ulcers? (1)

Surface mucus layer (via goblet cells). Secretion of bicarbonate onto epithelial surface. Good mucosal blood flow (good perfusion of tissue). Cytoprotective PGs (PGE2, PGF 2 alpha). Epithelial regeneration (8 days)

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What are the protective factors for gastric ulcers? (2)

Epithelial tight junctions prevent acid diffusion into the underlying lamina propria

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Describe the protective factors of gastric ulcers which are present on the epithelial and parietal cells (1)

Basolateral membrane (left), luminal membrane (right), unstirred layer (mucus, bicarbonates secreted by epithelial cells), cell types (epithelial, parietal, endocrine), receptors expressed on cells. pH7 in mucus, pH2 in gastric lumen

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Describe the protective factors of gastric ulcers which are present on the epithelial and parietal cells (2)

PGE2 activates EP receptor on epithelial cell, promotes mucus/bicarbonate secretion. Parietal cell, 2 signalling pathways (Ca dependent with ACh mechanism and cAMP pathway), H-K ATPase (activated when there is an increase in Ca or cAMP)

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Describe the protective factors of gastric ulcers which are present on the epithelial and parietal cells (3)

PGE2 binds to EP on parietal cell, inhibits cAMP pathway (inhibits H-K ATPase). On parietal cell, ACh binds to muscarinic receptor. Tight junctions between cell types. H2 receptor present on parietal cell

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Which factors attack gastric and duodenal mucosae? (1)

Acid and pepsin, H.pylori, bile reflux and delayed gastric emptying, absence of protective PGs (NSAID side effect), microvascular vasoconstriction, failure of epithelial regeneration (e.g. anti cancer drugs)

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Which factors attack gastric and duodenal mucosae? (2)

Presence of stress/other risk factors (e.g. alcohol, smoking, aspirin)

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What are the acid stimulators on the epithelial, parietal and endocrine cells? (1)

Gastrin binds to G receptor on endocrine (ECL) cell, causes histamine release. Histamine (produced by ECL) binds to H2 receptor on parietal cell, results in activation of H-K ATPase/acid secretion

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What are the acid stimulators on the epithelial, parietal and endocrine cells? (2)

Cholinergic mechanism (muscarinic, vagus nerve, on parietal cell). G receptor also on parietal cell (activates Ca pathway). Gastrin enhances muscarinic activity (intracellular signalling).

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Describe features of acid stimulators (1)

Role of histamine, ACh and gastrin in acid secretion from parietal cell. Histamine is the final common mediator, but ACh and gastrin can both activate from parietal cell directly

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Describe features of acid stimulators (2)

Mediators act on parietal cell to activate ATP dependent proton pump (H-K). PGE2 can inhibit the same pump by reducing cAMP (histamine-induced) within the parietal cells

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What are the general treatment strategies?

Relieve pain (e.g. antacids). Allow healing (e.g. antisecretory agents, mucosal strengtheners) - collectively acid modifying. Prevent relapse (e.g. maintenance therapy/avoidance of risk factors, changes of lifestyle. Surgery - obsolete

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What are the main treatments of peptic ulcers? (1)

Avoid risk factors, stress, smoking, alcohol, aspirin etc. Neutralise acid (antacids) or reduce its secretion (Mg carbonate, Al(OH)3, NaHCO3 in indigestion remedies)

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What are the main treatments of peptic ulcers? (2)

Encourage healing with H2 antagonists or eliminate H.pylori (after positive urease test) antibiotics. Improve mucosal defence with sucralfate (Al-sugar complex, protects ulcer area) or bismuth chelate

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What are the main treatments of peptic ulcers? (3)

(De-Noltab, coats ulcer area but also stains tongue/stools black). Try to prevent relapse (70-80% do at 2 yrs unless HP is eliminated - maintenance therapy, lifestyle changes)

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Describe features of antacids (acid neutralisers) (1)

OTC liquid medicines provided when pain is expected (between meals) or to relieve acute pain e.g. Mucogel. Rapid relief as acid is neutralised chemically. Short but variable action - as pH rises, more acid secreted (can lead to acid rebound)

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Describe features of antacids (acid neutralisers) (2)

Don't use for >4 weeks. Caution should be non-absorbable (Mg2+ is a laxative while Al3+ may be constipating). Al hydroxide, Mg trisilicate, mixtures with NaHCO3 (Gaviscon - also used for heartburn/reflux oesophagitis and simple indigestion/dyspepsia)

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What are the types of acid-modifying drugs?

Antihistamines (H2 antagonists), PPIs, PGs (analogue - antisecretory and protective effects), antimuscarinics (discontinue)

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Describe features of acid-modifying drugs (1)

Reduce acid secretion by blocking histamine effects (H2 antagonists - ranitidine, famotidine, cimetidine, nizatidine). Reduce acid secretion with PPIs (omeprazole, lanzoprazole, esomaprazole/isomer of omeprazole)

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Describe features of acid-modifying drugs (2)

Triple therapy (if HP+) - omeprazole, clarithromycin (eradicate H. pylori), metronidazole (eradicates anaerobic bacteria like H. pylori), tinidazole (occasional alternative to metronidazole). Resistance can develop (clar/met) during treatment

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Describe features of acid-modifying drugs (3)

Omeprazole plus amoxicillin - but recently shown to produce low rates of HP eradication - no longer recommended

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What are the drug targets for the following acid modifying drugs - ranitidine, amoxicillin/clarithromycin/metronidazole, omeprazole, sucralfate, (aspirin)? (1)

Ranitidine (H2 antagonist on H2 receptor on parietal cell, reduces cAMP levels, inhibits H-K ATPase, inhibit acid secretion). Antibiotic (target H.pylori directly). Omeprazole (directly inhibits H-K ATPase to inhibit acid secretion)

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What are the drug targets for the following acid modifying drugs - ranitidine, amoxicillin/clarithromycin/metronidazole, omeprazole, sucralfate, (aspirin)? (2)

Sucralfate (strengthens mucosal layer). (Aspirin - inhibits COX enzyme, prevents conversion of arachidonic acid to PGE2, removal of protective factor)

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Describe features of H2 antagonists (1)

Reduce acid secretion under fasting, meal-induced and nocturnal conditions. Effective - healing DU (>90% in 4 weeks) and GU (70% in 4 weeks) but relapse common (up to 80% 1 yr, 70-70% 2 yrs). Very safe (few side effects, cimetidine), active by mouth

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Describe features of H2 antagonists (2)

Taper therapy - use single bed time dose to prevent relapse

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Give examples of H2 antagonists

Cimetidine (some CYP450 side effects), ranitidine, famotidine, nizatidine

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Describe features of proton pump inhibitors

Powerful long-lasting suppression of acid, needs only single dose of 20 mg enteric coated capsule (Prolonged acidity?)

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Give examples of proton pump inhibitors

Omeprazole (20 mg enteric coating, pro-drug, active at pH7, metabolite blocks pump at pH<3), lansoprazole, pantoprazole, esomeprazole, rabeprazole

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Describe features of antimuscarinics

No longer used. E.g. pirenzepine (now obsolete). Side effects include dry mouth, blurred vision, difficulty in micturition. Also reduced gastric motility as well as reducing acid, may have aided the anti-ulcer effect

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Describe features of prostaglandin analogues (1)

Misoprostol - synthetic stable PGE1 analogue. Mimics effects of PGE 1/2 on EP receptors. Anti-secretory and cytoprotective, promoting healing of gastric and duodenal ulcers. Can prevent NSAID associated ulcers.

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Describe features of prostaglandin analogues (2)

Can be used prophylactically (e.g. frail/elderly from whom NSAIDs cannot be withdrawn)

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Describe features of prostaglandin analogues (3)

Misoprostol targets EP receptors on epithelial cells (promote secretion of bicarbonate ions and mucus) and parietal cells (inhibit cAMP, inhibit H-K ATPase, inhibit acid secretion)

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Describe features of mucosal strengtheners (1)

Bismuth chelates (tripotassium dicitratobismuthate) - forms coat over ulcer, may stain tongue/black stools, after healing relapse rate is lower, can be used in combination with clarithromycin and another antimicrobial (if required)

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Describe features of mucosal strengtheners (2)

Sucralfate (Al(OH)3-sulphated sucrose complex) - protects ulcer area and enhances gastric mucus secretion (also true for carbenoxolone, based around liquorice component)

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Describe features of multiple therapies (1)

Prime targets in DU/GU are acid and H.pylori. Combined treatment of PPI and antimicrobial. E.g. omeprazole and clarithromycin, now improved eradication rates with triple or quadruple therapy (if initial eradication failed)

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Describe features of multiple therapies (2)

Omeprazole, clarithromycin, metronidazole or amoxicillin plus DeNoltab. 90% of ulcers can be cured in 2 months. Particularly for patients who test positive for H.pylori (13-C urea breath test)

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Summarise features of acid-modifying drugs (1)

Modern drugs have completely altered the clinical picture for patients with gastric/duodenal ulcers. Healing is faster, cheaper and more certain than before. Suffering is greatly reduced. Drug earners (SKB, Glaxo, Pfizer, saving for NHS)

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Who discovered the H2 antagonist cimetidine?

James Black

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Describe features of inflammatory bowel disease (1)

Effective management requires drug therapy, attention to nutrition and in severe or chronic active disease - surgery. Chronic inflammatory diseases, multiple likely causes e.g. elevated levels of tumour necrosis factor (TNF alpha) and INF gamma

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Describe features of inflammatory bowel disease (2)

Ulcerative Colitis - large bowel. Crohn's Disease - mainly SI (INF gamma implicated). Both - episodic with remissions and treatment aims to reduced number of episodes and prolong remission time

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Describe features of inflammatory bowel disease (3)

Anti-inflammatories e.g. corticosteroids, aminosalicylates. Anti-cytokine agents e.g. infliximab

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What are the treatment options for inflammatory bowel disease? (1)

Corticosteroids - enema or systemic depending on severity e.g. prednisolone, hydrocortisone, budesonide (beclometazone - adjunct to aminosalicylates), inhibit phospholipase A2 activity and AA-PG cascasde (no protective factor)

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What are the treatment options for inflammatory bowel disease? (2)

Immunosuppressants - e.g. ciclosporin, if refractory to steroids (unlicensed medication), reduce T cell number/signalling

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What are the treatment options for inflammatory bowel disease? (3)

Monoclonal TNF alpha antibodies - e.g. infliximab, inhibits actions of TNF alpha (also used in RA), treats severe/active CD. Adalimumab licensed for severe CD in patients intolerant to steroids, also for maintenance therapy in CD, cytokine inhibitors

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What are the treatment options for inflammatory bowel disease? (4)

Aminosalicylates (maintain remission of UC), 5-aminosalicylate (5-ASA also known as mesalazine), comes from prodrug, sulfalazine (sulphapyridine and 5-ASA), taken PO (for diffuse IBD) or rectally

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What are the treatment options for inflammatory bowel disease? (5)

(for acute mild to moderate disease of recto-sigmoid region) and bacterial degradation release 5-ASA. Olsalazine - 2 molecules of 5-ASA given PO

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The Pharmacology of Ulcers and Inflammation

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