Peptic ulcer treatment

pharmacotherapy of peptic ulcer , antiulcer drugs

1. Pharmacotherapy of Peptic ulcer

2. Objectives Regulation of Gastric acid secretion Classification of drugs used in peptic ulcer Mechanism of action, Uses & Adverse effects, drug interactions of H2 Blockers Proton pump inhibitors Antacids Ulcer protectives Drugs for eradication of H.pylori

3. Why Peptic ulcer occurs Imbalance primarily between Aggressive factors and Defensive factors Aggressive factors, e,g , acid, pepsin, bile , H.pylori . Defensive factors, e.g. mucus, HCO3, PG, NO

4. Formation of HCL

5. Regulation of gastric acid secretion

6. Classification of drugs used in peptic ulcer Drugs that inhibit gastric acid secretion Drugs that neutralize gastric acid (Antacids) Ulcer protectives Anti H. pylori drugs

7. Classification (Contd.) Drugs that inhibit gastric acid secretion H2 receptor blockers: Cimetidine, Ranitidine, Famotidine Proton pump inhibitors: Omeprazole, Pantoprazole , esomeprazole Anticholinergics : Pirenzepine Prostaglandin analogues: Misoprostol

8. Classification (Contd..) Drugs that neutralize gastric acid (Antacids) Systemic: Sodium bicarbonate, sodium citrate Non systemic: Magnesium hydroxide, Mag. Trisilicate , Aluminium hydroxide gel, Magaldrate

9. Classification (Contd..) Ulcer protectives Sucralfate Colloidal Bismuth Sulfate (CBS) Anti H. pylori drugs Amoxicillin, Clarithromycin , Metronidazole , Tinidazole , Tetracycline

10. H2 ANTAGONISTS

11. Mechanism of action Competitively block H2 receptors on parietal cell & inhibit gastric acid production Supress secretion of acid in all phases but mainly nocturnal acid secretion Also reduce acid secretion stimulated by Ach, gastrin , food, etc.

12. Pharmacokinetics Absorption is not interfered by food Can cross placental barrier and reaches milk, Poor CNS penetration The serum half-lives range from 1.1 to 4 hours; Cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction needed in moderate to severe renal insufficiency

13. 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 DOA (hrs) 6 8 12 8 Inhibition of 1 0.1 0 0 CYP 450 Dose mg ( bd ) 400 150 20 150 Cimetidine Ranitidine Famotidine Nizatidine Comparison of H 2 antagonists

14. H 2 antagonists - Uses Promote the healing of gastric and duodenal ulcers Duodenal ulcer – 70 to 90% at 8 weeks Gastric Ulcer – 50 to 75% NSAID ulcers induced ulcers Stress ulcer and gastritis GERD Zollinger -Ellison syndrome Prophylaxis of aspiration pneumonia

15. Adverse effects Headache, dizziness, bowel upset, dry mouth CNS: Confusion, restlessness Bolus IV – release histamine – bradycardia , arrhythmia, cardiac arrest Cimetidine has antiandrogenic actions

16. Drug interactions Cimetidine inhibits several CYP-450 isoenzymes and reduces hepatic blood flow, so inhibits metabolism of many drugs like theophylline , metronidazole , phenytoin , imipramine etc. Antacids reduce the absorption of all H2 blockers

17. Proton Pump Inhibitors Most effective drugs in antiulcer therapy Prodrugs requiring activation in acid environment Activated forms binds irreversibly to H+K+ATPase and inhibit it Omeprazole Pantoprazole Lansoprazole Esomeprazole

18. Mechanism of Action Prodrugs inactive at neutral pH At pH < 5 rearranges to two charged cationic forms ( sulfenamide + sulphenic acid) that bind covalently with SH groups of H⁺K⁺ ATPase and inactivate it irreversibly Also inhibits gastric mucosal carbonic anhydrase

19. Pharmacokinetics - PPI Available as enteric coated tablets They should be given 30 minutes to 1 hour before food intake half life is very short and only 1-2 Hrs Still the action persists for 24 Hrs to 48 hrs after a single dose Action lasts for 3-4days even after stoppage of the drug

20. PPI – contd. Therapeutic uses: Gastroesophageal reflux disease (GERD) Peptic Ulcer - Gastric and duodenal ulcers Bleeding peptic Ulcer Zollinger Ellison Syndrome Prevention of recurrence of nonsteroidal antiinflammatory drug (NSAID) - associated gastric ulcers in patients who continue NSAID use. Reducing the risk of duodenal ulcer recurrence associated with H. pylori infections Aspiration Pneumonia

21. Comparative success of therapy with PPI and H2 antagonist

22. Adverse Effects Nausea, loose stools, headache abdominal pain, constipation, Muscle & joint pain, dizziness, rashes Rare Gynaecomastia , erectile dysfunction Leucopenia and hepatic dysfunction Osteoporosis in elderly on prolonged use Hypergastrinemia

23. Drug interactions Omeprazole inhibits the metabolism of warfarin , phenytoin , diazepam, and cyclosporine. However, drug interactions are not a problem with the other PPIs.

24. PPI – Dosage schedule Omeprazole 20 mg o.d . Lansoprazole 30 mg o.d . Pantoprazole 40 mg o.d . Rabeprazole 20 mg o.d . Esomeprazole 20-40 mg o.d

25. Proton Pump Inhibitors Lansoprazole : Partly reversible, more potent, slightly more against H pylori, Higher BA, rapid onset. Pantoprazole : More acid stable, I.V, CYP450 less affinity Rabeprazole : claimed to most rapid Es-omeprazole Better intragastric pH , higher healing rates.

26. Muscarinic antagonists Block the M 1 class receptors Reduce acid production, Abolish gastrointestinal spasm Pirenzepine and Telenzepine Reduce meal stimulated HCl secretion by reversible blockade of muscarinic (M1) receptors on the cell bodies of the intramural cholinergic ganglia Unpopular as a first choice because of high incidence of anticholinergic side effects (dry mouth and blurred vision)

27. Prostaglandin analogues- Misoprostol Inhibit gastric acid secretion Enhance local production of mucus or bicarbonate Help to maintain mucosal blood Therapeutic use: Prevention of NSAID-induced mucosal injury (rarely used because it needs frequent administration – 4 times daily)

28. Misoprostol Doses: 200 mcg 4 times a day ADRs: Diarrhoea and abdominal cramps Uterine bleeding Abortion Exacerbation of inflammatory bowel disease and should be avoided in patients with this disorder Contraindications: Inflammatory bowel disease Pregnancy (may cause abortion)

29. Antacids Weak bases that neutralize acid Also inhibit formation of pepsin (As pepsinogen converted to pepsin at acidic pH) Acid Neutralizing Capacity: Potency of Antacids Expressed in terms of Number of mEq of 1N HCl that are brought down to pH 3.5 in 15 minutes by unit dose of a preparation (1 gm)

30. Systemic antacids Sodium Bicarbonate: Potent neutralizing capacity and acts instantly ANC: 1 gm = 12 mEq DEMERITS: Systemic alkalosis Distension, discomfort and belching – CO 2 Rebound acidity Sodium overload

31. Non systemic antacids Insoluble and poorly absorbed basic compounds React in stomach to form corresponding chloride salt The chloride salt again reacts with the intestinal HCO3 - so that HCO3 - is not spared for absorption

32. Non systemic Antacids Magnesium hydroxide (ANC 30 mEq ) Aqueos suspension is called Milk of magnesia Magnesium trisilicate (ANC 10 mEq ) Aluminium Hydroxide (ANC 1-2.5mEq/g) ( Magaldrate – hydrated hydroxy magnesium aluminate )

33. Non systemic antacids Duration of action : 30 min when taken in empty stomach and 2 hrs when taken after a meal Adverse effects: Aluminium antacids – constipation (As they relax gastric smooth muscle & delay gastric emptying) – also hypophosphatemia and osteomalcia Mg2+ antacids – Osmotic diarrhoea In renal failure Al3+ antacid – Aluminium toxicity & Encephalopathy

34. Miscellaneous drugs Simethicone : Decrease surface tension thereby reduce bubble formation - added to prevent reflux Alginates: Form a layer of foam on top of gastric contents & reduce reflux Oxethazaine: Surface anaesthetic

35. Chemical reactions of antacids with HCl in the stomach

36. Drug interactions By raising gastric pH & forming insoluble complexes ↓ absorption of many drugs Tetracyclines, iron salts, H2 Blockers, diazepam, phenytoin , isoniazid , ethambutol

37. Sucralfate – ulcer protective Aluminium salt of sulfated sucrose MOA: In acidic environment ( pH <4) it polymerises by cross linking molecules to form sticky viscous gel that adheres to ulcer crater - more on duodenal ulcer Astringent action and acts as physical barrier Dietary proteins get deposited on this layer forming another coat

38. Sucralfate – contd. Concurrent antacids avoided, (as it needs acid for activation) Uses: Prophylaxis of Stress ulcers Bile reflux gastritis Topically – burn, bedsore ulcers, excoriated skins Dose: 1 gm 1 Hr before 3 major meals and at bed time for 4-8 weeks ADRs: Constipation, hypophosphatemia Drug interactions : adsorbs many drugs and interferes with their absorption

39. Colloidal Bismuth Subcitrate (CBS) Mechanism of action CBS and mucous form glycoprotein bi complex which coats ulcer crater ↑ secretion of mucous and bicarbonate, through stimulation of mucosal PGE production Detaches H.pylori from surface of mucosa and directly kills them

40. Colloidal Bismuth subcitrate Dose: 120 mg 4 times a day Adverse effects blackening of tongue, stools, dentures Prolonged use may cause osteodystrophy and encephalopathy Diarrhoea, headache, dizziness

41. Eradication of H.pylori No acid No ulcer OLD TESTAMENT No HP No ulcer NEW TESTAMENT

42. H. pylori Gram (-) rod Associated with gastritis, gastric & duodenal ulcers, gastric adenocarcinoma Transmission route fecal-oral Secretes urease → convert urea to ammonia Produces alkaline environment enabling survival in stomach Higher prevalence in Low SES

43. Who are they ? Barry J Marshall J. Robin Warren Nobel Laureates of Medicine – 2005 Discovery of H. pylori & its role in peptic ulcer

44. Triple Therapy The BEST among all the Triple therapy regimen is: Omeprazole / Lansoprazole - 20 / 30 mg bd Clarithromycin - 500 mg bd Amoxycillin / Metronidazole - 1gm / 500 mg bd Given for 14 days followed by P.P.I for 4 – 6 weeks Short regimens for 7 – 10 days not very effective

45. Other 2 weeks regimen(mg) Amoxicillin 750/ + Tinidazole 500 +omeprazole 20 mg/ lansoprazole 30 mg BD clarithromycin 250 + Tinidazole 500/amoxicillin 1000 + lansoprazole 30 mg BD

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