1. HP98 /NK/1 06/10/2015

2. HP98 /NK/2 06/10/2015 Management of PU The aims of modern management are to: Relieve the symptoms Induce ulcer healing not only on the short term but also on the long term H. pylori eradication Prevent recurrence Prevent complications

3. HP98 /NK/3 06/10/2015 Drug Management of PU Cytoprotective drugs: Colloidal Bismuth –Has both antibacterial & cytoprotective activities –Less potent antibacterial activity on H. pylori compared to PPI –Forms adherent coat over an active ulcer pain –Enhances secretion of mucous & bicarbonate –Inhibits pepsin activity –Not readily absorbed after short term therapy (i.e. needs long term administration) –Common side effects: Indigestion, constipation and dry mouth, renal tubular injury, and rarely upon chronic use encephalopathy may occur –Used nowadays as an adjuvant therapy with triple therapy

4. HP98 /NK/4 06/10/2015 Management of PU Diet & Lifestyle It is now recognized that diet does not affect the course of peptic ulcer disease and it seems unfair to impose such "additional hardships and restrictions on patients. Modify the patient's reaction to stress Stopping smoking undoubtedly allows ulcers to heal more quickly Evidence concerning the effect of coffee on ulcers is less conclusive but since it stimulates acid secretion it is probably best only taken on a full stomach

5. HP98 /NK/5 06/10/2015 Drug Management of PU Cytoprotective drugs: Synthetic Prostaglandin –Approved for use in prevention of NSAIDs ulceration in patients who must take aspirin-like drugs –Main side effects: Abdominal pain, diarrhea and abortion –Pregnancy category X: causes miscarriage –Used nowadays in medical practice to induce labour and control post-partum bleeding –Misoprostol: Cytotec®

6. HP98 /NK/6 06/10/2015 Drug Management of PU Cytoprotective drugs: Alginate Alginate-containing antacids form a ‘raft’ that floats on the surface of the stomach contents to reduce reflux and protect the esophageal mucosa they are used in the management of mild symptoms of gastro- esophageal reflux disease Sucralfate It is aluminum hydroxide sulfated sucrose Has minimal GI absorption When exposed to gastric pH it becomes negatively charged and forms viscous ulcer adherent complex that inhibits back diffusion of H+ Side effects: constipation, secondary hypophosphataemia (as its Al binds to phosphorous), Drug interactions

7. HP98 /NK/7 06/10/2015 Drug Management of PUAntacids: Alkaline compounds that yield an acid-base reaction and cause only acid neutralization Have the fastest onset of action and the shortest duration of action Need highly repeat dosage regimen (may require taking medication up to once an hour No suppression of acid secretion Have many drug-drug & food-drug interactions as they have divalent & trivalent cations Used mainly as OTC drugs to relive dyspeptic & heartburn symptoms

8. HP98 /NK/8 06/10/2015 Drug Management of PU Antacids: Include: Aluminium & Mg hydroxide, Na bicarbonate and Ca carbonate Side Effects: –Al is known to cause constipation & Mg cause diarrhea –Excessive absorption of Mg in patients with renal failure lead to CNS toxicity –Aluminum causes a decrease in phosphate levels due to phosphate binding to the gut

9. HP98 /NK/9 06/10/2015 Drug Management of PU Antacids: Include: Aluminium & Mg hydroxide, Na bicarbonate and Ca carbonate Side Effects: –The produced CO 2 causes abdominal distension that leads to increased intra-abdominal pressure and discomfort or increased GERD or ulcer pain –Absorbed sodium causes blood pressure elevation especially in hypertensive patients (may also worsen CHF cases) –Absorbed HCO 3 may cause systemic alkalosis

10. HP98 /NK/10 06/10/2015 Drug Management of PU Antacids: Include: Aluminium & Mg hydroxide, Na bicarbonate and Ca carbonate Side Effects: –The produced CO 2 cause abdominal distension –Ca can cause rebound acidity (when absorbed to the blood taken by parietal cell stimulate Ca dependent pathways activate proton pump & stimulate acid secretion again. N.B. Early data implicated calcium carbonate as the only agent that caused “acid rebound effect”; however, it is now clear that most antacids may result in this effect

11. HP98 /NK/11 06/10/2015 Acid-Suppression Therapy (Antisecretory Therapy) Anticholinergics (Atropine/Pirenzepine) Muscarinic cholinergic antagonists can reduce basal secretion of gas­tric acid by 40% to 50%; stimulated secretion is inhibited to a lesser extent Selective antagonists of M1 receptors (e.g. Pirenzipine, telenzepine) are as effective as atropine or other nonselective muscarinic antagonists but are less likely to produce the adverse effects that are characteristic of cholinergic blockade (e.g., dry mouth, tachycardia) M1 antagonists also may inhibit the secretion of gastrin, mucus, and HC0 3 No full acid inhibition Side effects (dry mouth, blurred vision, constipation) may limit the utility of these drugs

12. HP98 /NK/12 06/10/2015 Acid-Suppression Therapy (Antisecretory Therapy) Anticholinergics ( Clidinium + chlordiazopoxide: Librax® ) Librax combines in a single capsule formulation the antianxiety action of Librium (chlordiazepoxide hydrochloride 5 mg) and the anticholinergic/spasmolytic effects of Quarzan (clidinium bromide 2.5 mg) FDA labeling: as adjunctive therapy in the treatment of peptic ulcer and in the treatment of the irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis In practice this drug mainly is prescribed in cases of stress ulcers (psychologic not physiologic) Anticholinergic side effects & sedation may occur

13. HP98 /NK/13 06/10/2015 Acid-Suppression Therapy (Antisecretory Therapy) H 2 -Antogonists or Blockers They provide reversible & competitive blockage for H 2 receptors on the parietal cell surface thus inhibit acid secretion that is caused by histamine Still there is acid secretion from the other pathways No full acid inhibition less potent than PPI They are selective, no anticholinergic effects appear Drug tolerance occurs: gradual loss of efficacy & thus there is a need to increase the dose to get the same effect The drugs have similar adverse reaction profile Cimetidine appears to have the greatest degree of antiandrogenic (e.g. sexual impotence, gynaecomastia) & CNS effects(e.g. mental confusion), inhibition of cytochrome P450 (drug-drug interactions)

14. HP98 /NK/14 06/10/2015 Acid-Suppression Therapy (Antisecretory Therapy) Proton Pump Inhibitors or PPIs All PPIs are substituted benzimidazoles which are protonatable weak bases PPIs concentrate in acidic environment (any space with a pH less than 4) This accounts for their high selective targeting in the secretory canaliculi of the parietal cells with a pH 0.8 - 3 as this region is the only physiological space with such low pH PPIs are unstable in acidic environment (they undergo conversion to active sulfenamide form by protonation)

15. HP98 /NK/15 06/10/2015 Gastric Gland Secreting Gastric Acid and Pepsin HCI and Pepsin Mucus Parietal Cells Chief Cells Lumen of Gland Epithelium Feldman M. In: Sleisenger & Fordtran’s Gastrointestinal and Liver Disease. 7th ed. 2002:715-732. Guyton AC, Hall HE. Textbook of Medical Physiology. 1996;815-851. Keet JD. The Pyloric Sphincteric Cylinder in Health and Disease. Available at: http://med.plig.org. Accessed July 15, 2003.

16. HP98 /NK/16 06/10/2015 HCI and Pepsin Mucus Parietal Cells Chief Cells Lumen of Gland Epithelium Parietal Cells in the Walls of the Gastric Gland

17. HP98 /NK/17 06/10/2015 Structure of the Active Parietal Cell Mitochondria TubulovesiclesCanalicular Membrane Basolateral Membrane Canaliculus

18. HP98 /NK/18 06/10/2015 The parietal Cells (Mechanism of HCl Secretion): - The Parietal Cells of the human stomach can secrete 2L of acidic gastric juice a day. - When maximally stimulated they can secrete HCl at concentrations that can produce pH of 0.8.

19. HP98 /NK/19 06/10/2015 - Parietal cells are stimulated to secrete HCl by the binding of either gastrin, acetylcholine or histamine (most significant role) to specific receptors on the surface of the parietal cell - Stimulation of these receptors activates the H + -K + ATPase system (the proton pump) located on the apical membrane and tubulovesicles bordering the secretory canaliculi of the parietal cells The parietal Cells (Mechanism of HCl Secretion):

20. HP98 /NK/20 06/10/2015 Stimulation of the Proton Pump ACh = acetylcholine; G = gastrin; H = histamine.

21. HP98 /NK/21 06/10/2015 1- Acetylcholine pathway:  (stimulated by sight, smell and taste of food). 2- Gastrin pathway: stimulated when food enters the stomach 3- Histamine pathway: stimulated when food enters the stomach Acid production by parietal cells

22. HP98 /NK/22 06/10/2015 Structure of the Proton Pump 12345678910 107 158 303 353 792833 853 945 963 1014 ATP α β ATP = adenosine triphosphate.

23. HP98 /NK/23 06/10/2015 Proton Pump in the Canalicular Membrane CanalicularM embrane ` Canalicular Lumen HCI Cl - H+H+ K+ Inside of Parietal Cell

24. HP98 /NK/24 06/10/2015 K+ Canaliculus Interstitial Fluid

25. HP98 /NK/25 06/10/2015 PPIs Mechanism of Action PPIs undergo activation to the active sulfenamide form by protonation depending upon some factors This active form binds with cysteine (-SH) on the surface of H +, K + ATPase molecule by a covalent bond blocking its activity This active form binds with cysteine (-SH) on the surface of H +, K + ATPase molecule by a covalent bond blocking its activity Thus the PPIs effect is largely irreversible Thus the PPIs effect is largely irreversible Reverse inhibition thus requires the synthesis of a new H +, K + ATPase molecule As the half-life of the proton pump is 50 hours, 96 hours are required for full restoration

26. HP98 /NK/26 06/10/2015 PPIs Mechanism of Action The plasma half-life of PPIs is 60 - 90 min Since only the stimulated cells are inhibited during presentation of the drug, the acid secretory capacity of resting cells during that time is not inhibited Since only the stimulated cells are inhibited during presentation of the drug, the acid secretory capacity of resting cells during that time is not inhibited Intragastric pH restores rapidly after the first dose due to subsequent stimulation of these resting cells and 3 days are required for steady state inhibition Intragastric pH restores rapidly after the first dose due to subsequent stimulation of these resting cells and 3 days are required for steady state inhibition

27. HP98 /NK/27 06/10/2015 Proton Pump Inhibition: The Final Common Pathway ACh = acetylcholine; G = gastrin; H = histamine. proton pump, blocking its action Receptors are Receptors are still active, but cannot stimulate acid production, as the pump is blocked ACh H G

28. HP98 /NK/28 06/10/2015 Management of PU Surgical Treatment –vagotomy/gastric resection –Not used nowadays Antimicrobial Agents –Used for eradication of H pylori –High resistance to metronidazole –Triple therapy: most commonly used (reserved for resistant or frequently relapsing duodenal ulcer) –Old regime: colloidal bismuth for one month with simultaneous metronidazole (3 x 400 mg) & amoxicillin (4 x 250 mg) during the first week –Current regimen: zantac + Amoxicillin + Klacid –Long-term maintenance: Zantac

29. HP98 /NK/29 06/10/2015 Management of H. pylori Infection Through H. pylori eradication Two-week triple-therapy regimens offer the possibility of higher eradication rates compared to one-week regimens, but there is higher possibility for adverse effects and less compliance Resistance to clarithromycin or to metronidazole is much more common than to amoxicillin and can develop during treatment A regimen containing amoxicillin and clarithromycin is therefore recommended for initial therapy and one containing amoxicillin and metronidazole for eradication failure Other regimens, including those combining clarithromycin and metronidazole are best used in specialist settings Treatment failure usually indicates antibacterial resistance or poor compliance

30. HP98 /NK/30 06/10/2015 Management of H. pylori Infection A two-week regimen using tripotassium dicitratobismuthate plus a proton pump inhibitor plus two antibacterials may have a role in the treatment of resistant cases after confirmation of the presence of H. pylori Metronidazole 400 mg can be substituted with Tinidazole 500 mg Tetracycline 500 mg 4 times daily can be also used in combination with metronidazole, PPI & bismuth Dual treatments combining a proton pump inhibitor with either amoxicillin or clarithromycin were popular a few years ago as they were easy to explain and well tolerated. They have now been abandoned because they were not very effective. Note: –Clarithromycin should not be given for patients with renal failure –Metronidazole should not be given for patients taking alcohol –Amoxicillin should not be given for patients who have penicillin hypersensitivity

31. HP98 /NK/31 06/10/2015 Recommended Regimens for Management of H. pylori Infection Acid Suppressant Antibacterial Agent AmoxicillinClarithomycinMetronidazole Omeprazole20 mg twice daily 1 g twice daily 500 mg twice daily ____ 500 mg 3 times daily ___ 400 mg 3 times daily ___ 500 mg twice daily 400 mg twice daily

32. HP98 /NK/32 06/10/2015 Recommended Regimens for Management of H. pylori Infection Acid Suppressant Antibacterial Agent AmoxicillinClarithomycinMetronidazole Lansoprazole30 mg twice daily 1 g twice daily 500 mg twice daily ____ 1 g twice daily ___ 400 mg twice daily ___ 500 mg twice daily 400 mg twice daily

33. HP98 /NK/33 06/10/2015 Recommended Regimens for Management of H. pylori Infection Acid Suppressant Antibacterial Agent AmoxicillinClarithomycinMetronidazole Ranitidine bismuth citrate400 mg twice daily 1 g twice daily 500 mg twice daily ____ 1 g twice daily ___ 400 mg twice daily ___ 500 mg twice daily 400 mg twice daily

34. HP98 /NK/34 06/10/2015 Recommended Regimens for Management of H. pylori Infection Acid Suppressant Antibacterial Agent AmoxicillinClarithomycinMetronidazole Esomeprazole20 mg twice daily 1 g twice daily 500 mg twice daily ____ ____ 400 mg twice daily

35. HP98 /NK/35 06/10/2015 Peptic ulcer is typically recurrent disease 80% of ulcer healed with medical relapse “major problem” Reduced rate of relapse provides effective treatment of recurrence Long term maintenance ( One year or more) for : 1- In whom recurrence is likely 2- In whom recurrence is potentially very serious

36. HP98 /NK/36 06/10/2015