Peptic ulcer disease

Peptic ulcer disease management

1. Pharmacotherapy of Peptic ulcer disease Dr. Irfan Ahmad Khan Senior Resident

2. Physiology of Gastric Acid Secretion Gastric cells: Chief cell: secrete pepsinogen Parietal cells: secrete HCl and intrinsic factor Mucus cells Enterochromaffin cells: histamine G cells: gastrin hormone Food is broken into macroparticles , acid causes hydrolysis, sterilizes the meal content & activates pepsinogen to pepsin Acid secretion: Basal: nocturnal Stimulated : cephalic, gastric and intestinal.

3. PHASES OF GASTRIC ACID SECRETION AND THEIR REGULATION 3

4. 4 PHYSIOLOGICAL REGULATION OF GASTRIC ACID SECRETION

5. ECL

6. PEPTIC ULCER DISEASE PEPTIC ULCER is defined as disruption of the mucosal integrity of the stomach and/or duodenum leading to a local defect or excavation due to active inflammation. Epidemiology Middle-age to older age . Peptic ulcers - first portion of the duodenum or in the stomach, in a ratio of about 4:1. Male/female ratio is 3:1

7. Abdominal pain, dyspepsia, vomiting, blood in vomit Complications: Gastric cancer, GIT bleeding, perforation

8. PATHOPHYSIOLOGY

9. PEPTIC ULCER DISEASE IMBALANCE FACTORS THAT PROTECT AGAINST ACIDITY FACTORS THAT INCREASE ACID SECRETION Acid Pepsin Bile acids NSAIDs H. pylori Alcohol Mucus Bicarbonate layer Blood flow Cell renewal Prostaglandins Tight junction b/w epithelium

10. DRUGS FOR PEPTIC ULCER 1. Drugs for reduction of acid secretion: Proton Pump Inhibitors : Omeprazole , Lansoprozole , Dexlansoprazole , Pantoprozole , Rabeprozole , Esomeprozole H 2 receptor antagonists : Ranitidine, Famotidine , Roxatidine Anticholinergics : Pirenzepine , Propantheline , Oxyphenonium Prostaglandin analogues : Misoprostol

11. 2. Drugs to neutralize gastric acid (antacids): Nonsystemic : Aluminium hydroxide, Mag. Hydroxide, Magaldrate , Mag.trisilicate , Calcium carbonate Systemic: Sodium bicarbonate , Sodium citrate MISCELLANEOUS ADJUVANTS- Simethicone

12. 3.Ulcer Protectives : Sucralfate , Colloidal Bismuth Subcitrate and Bismuth Subsalicylate Ranitidine bismuth citrate Newer cytoprotectives - Rebamipide , Ecabet 4.Antimicrobial drugs for H. pylori eradication : Amoxycillin Clarithromycin Metronidazole Tinidazole Tetracycline

13. 13 SITE OF DRUG ACTION

14. PROTON PUMP INHIBITORS Diminish daily acid production (basal and stimulated) by 80-95% Absorbed from small intestine at a pH of 6 PPIs are prodrugs - acidic environment needed for activation. MECHANISM OF ACTION After absorption prodrug gets activated to a tetracyclic sulfenamide cation . Activated form then binds covalently with sulfhydryl groups of cysteines in the H + , K + -ATPase, irreversibly inactivating the pump molecule.

15. Acid labile, so enteric coated tablets Maximum acid inhibitory effect between 2 and 6 hours after administration and duration of inhibition lasting up to 72–96 hours. Because the pumps need to be activated for these agents to be effective, their efficacy is maximized by giving them before meal. Food interferes with absorption, take empty stomach

16. Peptic ulcer disease: 90% healing of DU in 4wks & 85% healing of GU in 6-8 wks Along with long term NSAID therapy, prevent & also for treatment of NSAID induced ulcer

17. DOSAGE OF PPIs Omeprazole 20 mg OD Esomeprazole 20 - 40 mg OD Rabeprazole 20 mg OD Lansoprazole 30 mg OD Pantoprazole 40 mg OD

18. PPIs: ADRs Nausea, Diarrhea, Abdominal pain, Flatulence. Nosocomial pneumonia Hypergastrinemia , REBOUND hypersecretion of acid Arthralgia , headache, skin rashes. Drug interactions : Decreased acidity may decrease the absorption of Ketoconazole , Ampicillin esters, Iron salts, Digoxin CYP2C19 and CYP3A4 inhibition   metabolism of benzodiazepines, warfarin, phenytoin , theophylline etc

19. H 2 RECEPTOR ANTAGONISTS Inhibit acid production by reversibly competing with histamine for binding to H 2 receptors on the basolateral membrane of parietal cells. Suppress acid production by 70% Inhibit basal and stimulated acid secretion, which accounts for their efficacy in suppressing nocturnal acid secretion. Ranitidine, Famotidine , Roxatidine , Nizatidine .

20. Adverse Drug Reactions of H 2 antagonists Diarrhea , headache, drowsiness, fatigue, muscular pain . Confusion, delirium, hallucinations, slurred speech REBOUND hyperacidity Pancytopenia , neutropenia , anemia , and thrombocytopenia

21. Dose of H 2 antagonists   Ranitidine 300 mg hs   Famotidine 40 mg hs   Nizatidine 300 mg hs

22. PROSTGLANDIN ANALOGUES MISOPROSTOL- PGE 1 ANALOGUE MOA- Binds to EP 3 receptor on parietal cells and stimulate Gi pathway- thereby decreasing intracellular cAMP & gastric acid secretion. Cytoprotective effects Daily dose – The usual recommended dose for ulcer prophylaxis is 200 micrograms four times a day.

23. Pharmacokinetics Inhibit acid sec. in 30 min., peaks at 60-90 min., lasts for 3 hrs . Adverse effects Diarrhea Exacerbations of IBD C/I in pregnancy as increases uterine motility Therapeutic Use - prophylaxis of NSAIDs induced ulcers

24. ANTICHOLINERGICS (rarely used now) -SELECTIVE M 1 BLOCKERS- PIRENZEPINE,TELENZEPINE -Suppress neural stimulation of acid production via actions on M 1 receptors of intramural ganglia. -The ACh receptor on the parietal cell is of the M 3 subtype. -Poor efficacy, significant and undesirable anticholinergic side effects, and risk of blood disorders ( pirenzepine )

25. ANTACIDS ALUMINIUM HYDROXIDE, MAGNESIUM HYDROXIDE, MAGNESIUM TRISILICATE, CALIUM CARBONATE, MAGALDRATE MOA- neutralizes HCl and form AlCl 3 and MgCl 2 & Carbonates More common use : combination of magnesium & aluminium salts; Advantages of combination: Magnesium is laxative, aluminium constipating Magnesium fast acting & aluminium slow acting so prompt & sustained effect

26. The magnesium-containing preparations : contraindicated in chronic renal failure patients because of possible hypermagnesemia . Aluminium causes chronic neurotoxicity. (Calcium Carbonate and Sodium Bicarbonate rarely used now a days. )

27. DRUG INTERACTIONS Aluminium and Magnesium ions form inert complexes- Tetracyclines , Fluoroquinlones , Itraconazole , Digoxin or Iron salts Aluminium group of antacids decrease the bioavailability of Phosphates, Iron salts and Digoxin By raising gastric pH and ionization, antacids decrease the absorption of acidic drugs- Barbiturates, Phenytoin , NSAIDS .

28. SIMETHICONE S ilicon polymer, reduces flatulence and hiccups Surfactant, antifoaming agent, cause proper dispersal of antacid over gastric surface, coats ulcer base.

29. ULCER PROTECTIVES SUCRALFATE - Complex sucrose salt - the hydroxyl groups substituted by aluminium hydroxide and sulfate . MOA: Enhances prostaglandin synthesis, At pH < 4 : polymerizes to a viscous, sticky gel adheres to ulcer crater precipitate the surface proteins and form a physical barrier preventing acid, pepsin contact Taken on empty stomach 1 hr. before meals Concurrent antacids, H 2 antagonist avoided, require acidic medium for action

30. Dose: 1 g four times daily (for active duodenal ulcer) 1 g twice daily (for maintenance therapy) SIDE EFFECTS Constipation Avoided in pts. with chronic renal insufficiency to prevent aluminium-induced neurotoxicity The "sticky" nature of the viscous gel - bezoars in some patients with underlying gastroparesis .

31. COLLOIDAL BISMUTH SUBCITRATE & BISMUTH SUBSALICYLATE In acidic media CBS- forms acid resistant protective coating over ulcer base Also stimulates mucosal PGE 2 synthesis & HCO 3 - secretion Dislodges H.PYLORI from gastric mucosa Dose: 120 mg qid Heals ulcer in 4 – 8 wks ADRs- blackening of stool, darkening of tongue Prolonged use– Neuropathy, osteodystrophy , encephalopathy.

32. Anti H.pylori drugs Helicobacter pylori: gram negative bacillus Attaches to gastric epithelium: gastritis, dyspepsia, peptic ulcer, gastric lymphoma, gastric carcinoma. No single agent is effective in eradicating the organism. Combination therapy for 14 days provides the greatest efficacy The agents used with the greatest frequency include amoxicillin, metronidazole , tetracycline, clarithromycin , and bismuth compounds.

33. TRIPLE THERAPY The BEST among all the Triple therapy regimens is Omeprazole / Lansoprazole - 20 / 30 mg BD Clarithromycin - 500 mg BD Amoxycillin - 1g BD Given for 14 days followed by P.P.I for 4 – 6 weeks

34. Some other Triple Therapy Regimens are Bismuth subsalicylate – 120 mg QID Metronidazole - 250 mg QID Tetracycline - 500 mg QID Ranitidine Bismuth citrate - 400 mg BD Tetracycline - 500 mg BD Clarithromycin / Metronidazole - 500 mg BD

35. QUADRUPLE THERAPY GIVEN WHEN TRIPLE THERAPY FAILS Omeprazole / lansoprazole - 20 / 30 mg OD Bismuth subsalycilate - 120 mg QID Metronidazole - 250 mg QID Tetracycline - 500 mg QID

36. SEQUENTIAL THERAPY (10 DAYS) For 1-5 days Omeprazole / lansoprazole -20 mg/30mg BD Amoxicillin -1 g BD Followed by 6-10 days Omeprazole / lansoprazole -20mg/30mg BD Clarithromycin -500 mg BD Tinidazole -500 mg BD

37. Treatment of patients infected with resistant strains of H.pylori Regimens considered for second-line therapy include: Combination of Pantoprazole , Amoxicillin, and Rifabutin for 10 days (86% cure rate) Levofloxacin -based triple therapy ( Levofloxacin , Amoxicillin, PPI) for 10 days . Furazolidone -based triple therapy ( Furazolidone , Amoxicillin, PPI) for 14 days.

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