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Peptic ulcer
- 2. Introduction • Sites • Types • Aetiology Defensive Aggressive
- 3. vagus ganglion M1 Ach histaminocyte M1 G Ach gastrin M1 G H Physiology of gastric acid secretion food
- 4. ACh PGE2 Histamine Gastrin Adenyl cyclase _ + ATP cAMP Protein Kinase (Activated) Ca++ + Ca++ Proton pump K K+ H+ Gastric acid Parietal cell Lumen of stomach Antacid Omeprazole Ranitidine H2M3 Misoprostol _ _ _ + PGE receptor + + Gastrin receptor+ + + Acknowledgement-slide from internet
- 5. Classification REDUCTION OF GASTRIC ACID SECRETION NEUTRALIZATION OF GASTRIC ACID ULCER PROTECTIVES ANTI-H.PYLORI DRUGS
- 6. REDUCTION OF GASTRIC ACID SECRETION 1.H2 blockers: • Cimetidine • Ranitidine Roxatidine Famotidine • Nizatidine Lafutidine
- 10. NEUTRALIZATION OF GASTRIC ACID • Systemic : Sodium bicarbonate, Sodium citrate • Nonsystemic : • Magnesium hydroxide • Magnesium trisilicate • Aluminium hydroxide gel • Magaldrate • Calcium carbonate
- 11. ULCER PROTECTIVES •Sucralfate •Colloidal bismuth subcitrate
- 12. ANTI-H.PYLORI DRUGS • Lansoprazole • Amoxicillin • Clarithromycin • Metronidazole • Tinidazole • Tetracycline
- 14. H 2 antagonists •Cimetidine-first –Black •Highly selective, No action on H1 or H3 receptors •Actions-blocks histamine –In stomach
- 15. Mechanism of action Reversible competitive blockade of the H 2 receptor on basolateral membrane of parietal cell
- 16. On gastric secretion Suppress all phases Basal Psychic Neurogenic Gastric Very effective in inhibiting nocturnal acid secretion Modest impact on meal stimulated acid secretion ↓ 60-70% of acid output
- 17. Pharmacokinetics Rapid oral absorption ↑ by food--↓ by antacids First pass metabolismcaution in Renal Failure t ½---2-3 h
- 18. Adverse effects • Dry mouth • Diarrhoea, Constipation • Restlessness, confusion • Hemolytic anemia, thrombocytopenia • Antiandrogenic effect of cimetidine
- 19. Decrease testosterone binding to receptor Inhibit CYP that hydroxylate estradiol Increase prolactin secretion
- 20. Drug interactions • ? –Theophylline –Warfarin –Sulfonylureas –Phenytoin –phenobarbitone • Antacids
- 21. Ranitidine 5 times more potent No antiandrogenic action Less CNS penetration Less drug interactions Less adverse effects Dose- 150 mg BD
- 22. Cimetidine Ranitidine Famotidine Nizatidine Bioavailability 80 50 40 >90 Relative Potency 1 5 -10 32 5 -10 Half life (hrs) 1.5 - 2.3 1.6 - 2.4 2.5 - 4 1.1 -1.6 Duration of 6 8 12 8 action (hrs) Inhibition of 1 0.1 0 0 CYP 450 Dose mg(bd) 400 150 20 150
- 23. Lafutidine H 2 blocker Increase NO production increase blood flow Increase mucin production increase somatostatin release
- 24. Therapeutic uses 1. Gastric ulcer 2. Duodenal ulcer 3. Stress ulcer and gastritis 4. Zollinger Ellison syndrome 5. GERD 6. Prophylaxis of aspiration pneumonia 7. Adjuvant to H 1 antihistamines
- 25. Proton Pump Inhibitors Most commonly used Most effective Most potent Safe? Irreversible inhibitor of H+ K+ ATPase
- 26. Reaches systemic circulation Accumulates in the canaliculiWeak bases pH- 0.8 Ionised
- 27. Omeprazole • Ionised ---- sulfenic acid and sulfenamide Covalent bond with SH of H-K ATPase Irreversible inactivation
- 28. Dose Omeprazole 20 mg o.d. Rabeprazole 20 mg o.d. Lansoprazole 30 mg o.d. Pantoprazole 40 mg o.d.
- 29. Proton Pump Inhibitors – Kinetics Given as enteric coated tablets Pantoprazole ,Rabeprazole, Omeprazole-- intravenously Half life – 1.5 hrs Given ½ -1 hr before meals Other acid suppressing agents not co- administered
- 30. Now answer this question It is given in the previous slides that the half life of proton pump inhibitors is 1.5 hours only and these drugs are generally given once daily. How this can be justified ? Answer : P.P.I - Irreversible inhibitors of H+K+ATPase (Hit and run drugs)
- 31. Inhibition of secretion Starts -1 hr Maximum - 2 hrs ½ maximum -24 h Lasts for- 3days Resumes- 5 days
- 32. Uses Peptic ulcer Bleeding peptic ulcer Stress ulcer GERD ZE syndrome Systemic mastocytosis Aspiration pneumonia
- 33. Adverse effects
- 34. CLARITHROMYCIN OMEPRAZOLE OMEPRAZOLE ITRACONAZOLE OMEPRAZOLE CLOPOIDOGREL Metabolism Absorption Activation Interaction
- 35. • Esomeprazole –↑ bioavailability –long t ½ –High healing in erosive gastritis • Lansoprazole –Potent –Long t ½ • Pantoprazole –More acid stable –Given iv –Bleeding ulcers • Rabeprazole –Fastest acid suppression –Aid mucin secretion
- 37. Prostaglandin analogues Inhibit acid secretion Increase mucosal blood flow Promote mucus and HCO3 secretion CYTOPROTECTIVE Adverse effects- diarrhoea, abortion
- 39. Non systemic antacids Insoluble , Poor absorption React with HCl No acid base disturbance Inhibit formation of pepsin OTC drug
- 40. Mg salts MgOH-quick long acting efficacious laxative Mg trisilicate- low solubility and reactivity • Silicate-gelatinous-adsorb and inactivate pepsin, protect ulcer base Magaldrate • Hydroxy magnesium aluminate • Prompt sustained action
- 41. AlOH Polymerize into less reactive form delay gastric emptying at pH> 3 adsorb pepsin, toxin, gas & bacteria Bind phosphate -used in hyperphosphatemia and phosphate stones Al toxicity-encephalopathy, osteodystrophy
- 42. CaCO3 Milk alkali syndrome-headache, anorexia weakness, abdominal discomfort, abnormal Ca deposits and renal stones Can cause constipation/loose motion Directly stimulate parietal cell -acid rebound Potent and rapid action
- 43. Antacids Duration of action 30 min when taken in empty stomach 2 hrs when taken after a meal Side effects Al3+ antacids – constipation Al3+ antacid – Al toxicity, Encephalopathy in RF Mg2+ antacids – Osmotic diarrhoea
- 44. Antacid - Interactions Adsorb drugs and form insoluble complexes that are not absorbed Clinical importance : Interactions can be avoided by taking antacids 2 hrs before or after ingestion of other drugs .
- 45. Now answer this question Is it rational to combine Aluminium hydroxide and Magnesium hydroxide in antacid preparations ?
- 46. Answer Combination provides a relatively fast and sustained neutralising capacity (Magnesium Hydroxide – Rapidly acting Aluminium Hydroxide - Slowly acting ) Combination preserves normal bowel function. (Aluminium Hydroxide – constipation Magnesium hydroxide – diarrhoea ) Gastric emptying least affected Dose Reduction
- 47. Use 1. Intercurrent pain relief and acidity 2. Non ulcer dyspepsia 3. Mild heartburns Limitations 1. Large frequent dose 2. Acid rebound---↑ gastrin 3. Belching ,fullness, nausea can occur
- 48. Systemic antacids • Soluble instant short duration • But cause systemic alkalosis • So other uses – Metabolic acidosis – Alkalinisation of urine – Antipruritic lotion,eye wash,mouth wash
- 49. Ulcer protectives Augment mucosal PG synthesis Acts as physical barrier Precipitate surface protein Sticky gel and hence adheres Cause cross linking Polymerisation at pH<4 Basic Al salt of sulfated sucrose
- 50. • No antacids with sucralfate? • Adverse effects-constipation, hypophosphatemia • Other uses –Bile reflux Gastritis Stomatitis –Prophylaxis of stress ulcers
- 51. Colloidal Bismuth Subcitrate Water soluble, precipitate at pH<5 Increase mucus,HCO3, PGE2 Precipitate mucous glycoproteins and coat Detaches and kills H. pylori Use-gastritis ,non ulcer peptic dyspepsia Adverse effects- osteodystrophy, encephalopathy, black tongue, dentures, stool
- 52. H.pylori
- 54. Can you identify these people ? Nobel prize Medicine – 2005 Barry J Marshall J. Robin Warren Discovery of H.pylori & its role in ulcer
- 56. Strategy • All positive patients • All failed conventional treatment • Relapses • Drugs Amoxicillin Clarithromycin Tetracycline Metronidazole Tinidazole
- 57. Triple Therapy Given for 7 days followed by P.P.I for 4 – 6 weeks 1000mg 500 mg
- 58. US FDA Approved Regimen • Lansoprazole 30mg • Amoxicillin 1000mg • Clarithromycin 500mg Twice daily Two weeks
- 59. Regimen popular in India •Metronidazole 400mg TDS •Amoxicillin 500 mg TDS •Omeprazole 20 mg BD For 1 week
- 60. Quadruple Therapy Given when Triple Therapy fails CBS - 120 mg qid Omeprazole / Lansoprazole - 20 / 30 mg bd Metronidazole - 400 mg TDS Tetracycline - 500 mg qid
- 61. Now you have learnt about drugs used for treating peptic ulcer ? Are there any drugs that can cause peptic ulcer ? Non Steroidal Anti Inflammatory Drugs (NSAIDs) Glucocorticoids Cytotoxic agents
- 62. Stress induced ulceration after head trauma Cushing’s ulcer Stress induced ulceration after severe burns Curling’s ulcer
- 63. Re-Cap 1. Anticholinergics used for peptic ulcer 2. Prostaglandin analogues for peptic ulcer 3. Drugs used in NSAID induced ulcer 4. H+-K+ inhibitors inhibitors 5. Two drug which decrease acid secretion and are enzyme inhibitors
- 64. a .Cimetidine and Warfarin b. Sucralfate and Antacid c. Omeprazole and Itraconazole d. Aluminium hydroxide and Magnesium Hydroxide 2. Short notes a. Proton pump inhibitors b. Triple drug Regimen What is the drug interaction between