GIS15 Aggressive Factors And Ulcer Healing Drugs Flashcards
Peptic ulcer
- break in mucosa of stomach (gastric ulcer)
- break in mucosa of duodenum (1st part) (duodenal ulcer)
Causes: - imbalance between aggressive and defensive factors (aggressive > defensive) - aggressive factors: —> H. pylori —> acid —> pepsin —> NSAIDs —> stress —> alcohol —> smoking
- defensive factors: —> mucus —> HCO3 —> blood flow —> ***prostaglandins —> nitric oxide —> growth factors
Peptic ulcer treatment goal
- Remove risk factors (alcohol, cigarette, stress)
- Decrease acid secretion / neutralise acid
- Promote mucosal defence
- Eradicate H. pylori
***Mechanism of gastric acid secretion
G-cells —(gastrin)—>
- G(CCK) receptor on ECL cells —(histamine)—> H2 receptor on parietal cells —> ***↑cAMP —> protein kinase —> H/K ATPase (proton pump)
- G(CCK) receptor on Parietal cells —> *** ↑Ca —> protein kinase —> H/K ATPase (proton pump)
Enteric NS —(ACh)—>
- **M1 receptor on ECL cells —(histamine)—> H2 receptor on parietal cells —> **↑cAMP —> protein kinase —> H/K ATPase (proton pump)
- **M3 receptor on Parietal cells —> **↑Ca —> protein kinase —> H/K ATPase (proton pump)
Agents that decrease gastric acid secretion
- H2 antagonist
- Muscarinic antagonist e.g. Pirenzepine, Dicyclmine (very rarely used now)
—> not as effective as H2 antagonist and PPI
—> many SE: dry mouth, blurred vision, urinary retention, arrhythmia - PPI
H2 antagonist
- Cimetidine (lowest potency and duration of action)
- Ranitidine
- Nizatidine
- Famotidine (highest potency and duration of action)
SE:
- well-tolerated
- GI disturbance (constipation, diarrhoea)
- headache, dizziness
- ***inhibit binding of dihydrotestosterone to androgen receptor —> impotence and gynecomastia (for Cimetidine only)
Drug interactions:
- ***inhibit CYP450 enzymes in liver (Cimetidine to greater extent: consider other H2 antagonist)
—> decrease metabolism of other drugs (phenytoin, theophylline, warfarin)
—> increase blood level
—> drug toxicity
Proton pump inhibitor
all similar in potency and pharmacokinetics:
- Omeprazole
- Esomeprazole
- Lansoprazole
- Pantoprazole
- Rabeprazole
SE:
- well-tolerated
- headache, dizziness, GI disturbance
Agents that neutralise acid
Antacids
- NaHCO3
- CaCO3
- Mg(OH)2 / Al(OH)3 (most commonly used)
SE:
- belching (wind)
- Na: exacerbate fluid retention in patients with heart failure, hypertension, renal insufficiency
- CaCO3: belching, hypercalcaemia, renal calculi (Ca intake), constipation
- Mg(OH)2: diarrhoea; Al(OH)3: constipation —> administered together
- Hypermagnesaemia very rare because Mg poorly absorbed
Agents that promote mucosal defence
- Sucralfate
- Bismuth
- Misoprostol
Sucralfate
- complex of Sucrose sulphate + Al(OH)3
MOA:
- in the presence of acid, aluminium is released
—> acquired **strong Negative charge
—> bind to Positively charged groups in **glycoprotein in mucus
—> form a ***viscous gel which adhere to the epithelial cells of the stomach, including areas of ulceration
—> gel protects the stomach luminal surface, including areas of ulceration, from being degraded by acids and pepsin
SE:
- not absorbed —> virtually no systemic adverse effects
- constipation occurs in 2% (∵ aluminium)
Drug interactions:
- requires ***acidic environment for activation, Antacid given concurrently or prior to its administration will reduce its efficiency
- take on ***empty stomach (sucralfate may bind to food, reducing its efficacy)
- may bind to several drugs e.g. quinolones, phenytoin, warfarin, limiting their absorption
Bismuth
MOA:
1. Combines with mucus glycoprotein to form a **barrier
—> protect the ulcerated area from acid and pepsin damage
2. Stimulates secretion of **mucus, **HCO3 and **prostaglandin
3. Direct ***antimicrobial activity against H. pylori
SE:
- ***darkening of teeth and tongue
- darkening of stool (may confused with GI bleeding)
- take on ***empty stomach (bismuth may bind to food, reducing its efficacy)
- in patient with renal failure, prolonged use of bismuth cause toxicity, resulting in encephalopathy (ataxia, headache, confusion, seizures)
Misoprostol
- ***Prostaglandin analogue
Prostaglandin:
- ***↓ Acid secretion (bind to PGE1 receptor —> ↓ cAMP —> ↓ H/K ATPase)
- ***↑ Mucus, HCO3 secretion by mucus cells
- ***↑ Blood flow
SE:
- GI discomfort (diarrhoea, abdominal cramps)
- ***stimulates uterine contraction (not to be used during pregnancy) (PGF2α —> Contraction of uterine smooth muscle)
Eradication of H pylori
- Amoxicillin
MOA:
- inhibits ***transpeptidase
- interfere with bacterial cell wall synthesis
SE:
- hypersensitivity (rash, fever, anaphylactic shock)
- GI disturbance (diarrhoea since alter bacterial flora)
2. Clarithromycin MOA: - binds to ***50s ribosomal subunit - inhibits translocation process during protein synthesis SE: - hypersensitivity reactions - GI disturbance
3. Tetracycline MOA: - binds to ***30s - blocks attachment of tRNA to A site of ribosome SE: - N/V - ***tooth discolouration - enamel dysplasia - ***reduced bone growth (children <8) - ***photosensitivity
- Metronidazole
MOA:
- Nitro group of metronidazole is chemically reduced by redox enzyme pyruvate-ferredoxin oxidoreductase (PFOR)
- product **disrupts the DNA helical structure —> inhibit DNA synthesis
- metronidazole is selectively toxic for anaerobic organism (and H. pylori) (PFOR is expressed in anaerobic but not in mammalian system)
SE:
- GI disturbance
- **metallic taste
- occasional sensory neuropathy
Regimens for treating H pylori-associated peptic ulcer
Triple therapy:
- PPI + Amoxicillin / Metronidazole + Clarithromycin
Quadruple therapy:
- PPI + Metronidazole + Tetracycline + Bismuth
