Drugs for peptic ulcer

PUD

1. GIT (GASTROINTESTINAL TRACT)

2. Peptic Ulcer Disease By Dr. BAHETI ASHISHKUMAR Department of Pharmacology MGIMS

3. No acid No ulcer OLD TESTAMENT

4. Learning objectives At the end of the lectures student should able to know- Definition of peptic ulcer Causes of peptic ulcer. Mechanism of secretion of gastric acid Goals of antiulcer drug Drugs for peptic ulcer disease pharmacology.

5. 1. Definition of Peptic Ulcer: A benign lesion of gastric or duodenal mucosa occurring at a site where the mucosal epithelium is exposed to acid and pepsin; 1) aggressive factors – HCl , H pylori 2) protective factors – mucus, bicarbonate

6. 2. Causes of peptic ulcer. 1. Helicobacter Pylori (H. pylori) Most ulcers are the result of infection with H. pylori Not all of those infected with H. pylori develop ulcers H. pylori MAY result in a weakening of the mucosal defense systems, allowing for development of ulcer subsequent to acid/pepsin aggression;

7. 2. NSAIDs Long term use of nonsteroidal anti-inflammatory drugs. NSAIDs block COX enzymes and decrease prostaglandins (PGs). 3. Gastrinoma ( Zollinger -Ellison Syndrome) Tumors of the duodenum or pancreas secrete abnormally high amounts of gastrin which stimulates gastric acid. 4. Stress ulcers Result of physical trauma (i.e., burn patients).

8. Helicobacter pylori Spiral shaped, flagellated, Gram negative bacterium

9. Diagnosis of Helicobacter pylori infection Invasive( through endoscopy) Gastric biopsy and staining culture of Bx specimen Tests using urease enzyme in Bx specimens Non-invasive: Urea breath test H.pylori antibodies Stool antigen Salivary antigen

10. 3. Mechanism of secretion of gastric acid Parietal cells in the stomach secrete roughly two liters of acid a day in the form of hydrochloric acid . Acid in the stomach functions to kill bacteria, and to aid digestion by solubilizing food. The acid is also important to establish the optimal pH (between 1.8-3.5) for the function of the digestive enzyme pepsin . A key protein for acid secretion is the H + /K + - ATPase (or proton pump ). This protein, which is expressed on the apical membrane of parietal cells, uses the energy derived from ATP hydrolysis to pump hydrogen ions into the lumen in exchange for potassium ions.

11. Stimulation of acid secretion involves the translocation of H + /K + - ATPases to the apical membrane of the parietal cell. When the cell is resting (not stimulated), H + /K + - ATPases are located in vesicles inside the cell. When the cell is stimulated, these vesicles fuse with the plasma membrane, thereby increasing the surface area of the plasma membrane and the number of proton pumps in the membrane

12. 4.Goals of antiulcer drug Relief from pain Promotion of ulcer healing Prevention of complication. Prevention of relapse.

13. 5.Drugs for peptic ulcer disease 1. Drugs which Reduce Gastric acid secretion 2. Drugs which neutralise gastric acid.-Antacids 3. Ulcer protective Drugs 4. Anti- Helicobactor pylori Drugs

14. 1. Drugs which Reduce Gastric acid secretion Anticholinergics – P irenzepine , T elenzepine H2 antagonist - cimetidine, ranitidine, famotidine, roxatidine , loxatidine . Proton Pump Inhibitor - omeprazole, lansoprazole , pantaprazole , rabeprazole , esmoprazole . Prostaglandin analogue - Misoprostol

15. 2. Drugs which neutralise gastric acid.-Antacids Systemic antacids – sodium bicarbonate Non systemic antacids - Al.hydroxide , Al.phosphate , Mg.tricilicate , M g.oxide , ca2+ carbonate. Misc – Alginates, Simelhi .

16. 3. Ulcer protective Drugs Sucralfate Collidal bismuth subcitrate Ulcer Healing Drugs Carbenoxolone

17. 4. Anti- Helicobactor pylori Drugs Amoxicillin Clarithromycin Tetracycline Metronidazole

18. 1. Drugs reduce gastric secretion 1) Anticholinergic drugs Pirenzepine and Telenzepine . Pharmacokinetics - These drugs reduce gastric acid secretion without raising pH unless there is food in stomach. They heal and prevent occurrence of duodenal ulcers. Pharmacodynamics – M1 receptor ( GqPCR ) ADR – dry mouth, diplopia , constipation and urinary retention.

19. 2) H2 antagonist Available as “over the counter” drugs.

20. Pharmacokinetic Cimetidine is prototype drug. A bsorption – oral, im , iv infusion. Bioavailability - 60-80% , Lipid soluble,non ionized form D istribution – widely distributed throuhout all the tissues.It can cross BBB and can cause headache,dizziness,somnolence . Volume of distribution 0.8L/kg M etabolism – liver . t1/2 - 2-3hrs E xcretion - urine.

21. Pharmacodynamics Mechanism of action - H2 blockers blocks H2 receptor (GPCR) present on parietal cells  blocks the action of histamine released through vagal or gastrin stimmulation .

22. Adverse drug reaction (ADR) CNS effects – Headache, dizziness, restlessness, convulsion, coma sp. in large doses. Bolus i.v. dose  can release histamine  bradycardia , arrythmia , cardiac arrest. Antiandrogenic action- increases plasma prolactin. High dose gynaecomastia in male, loss of libido, impotence, decrese sperm count.

23. Drug interaction Antacids redues absorption of all H2 blockers. So atleast 2 hour gap shoud be kept between two drugs. H2 blockers (C.R.F) reduce absorption of ketoconazole. Cimetidine is potent inhibitor of cyt.P 450.

24. Now answer this question Your friend wants to take a H 2 antagonist before he takes alcohol to avoid gastric irritation .He consults you .Which H 2 antagonist will you ask him to take ?

25. Answer : Famotidine Explanation : All H 2 antagonist except famotidine inhibit gastric first pass metabolism of ethanol and increase its bioavailability .

26. 3) Proton pump inhibitors All PPIs are prodrug as their active entity is sufanelamide cations that formed within parietal cells. MOA PPIs bind with H+/k+ ATPase enzyme and block proton pump and shutting off acid secretion. They inhibit gastric mucosal carbonic anhydrase and reduce bicarbonate secretio

27. Clinical uses Duodenal and gastric ulcer. GERD NSAID induced ulceration. Prevention of ulcer recurrence. Zollinger –Ellison syndrome. H.pylori associated dis. Stress induced mucosal bleeding. ( i.v.pantoprazole ) Prophylaxis of acid aspiration during gen. anesthesia.

28. Adverse drug reaction Diarrhoea , abd . pain, headache rarely. Inhibit Vit B12 on prolong use but not show deficiency(6-8wks). Muscle and joint pain-2-5% pt. On prolong use  atropic gastritis

29. 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)

30. 4) Prostaglandin analogue They inhibit acid secretion by inhibiting cAMP and gastrin release from antral cell. Also enhances mucosal blood flow and stimulates the secretion of mucous and bicarbonates. Dose- Misoprostol 200ug four times a day used and approved for healing of peptic ulcer in pt using NSAIDs and person who are chronic smokers.

31. Adverse effect- diarrhoea ,colic pain bcoz it increases water and electrolyte secretion in intestine. GIT- N,V, flatulence. C/I Pregnant lady

32. Now Answer this Question A patient comes to your clinic at midnight complaining of heart burn. You want to relieve his pain immediately. What drug will you choose?

33. Answer : Antacids Explanation : Antacids neutralise the already secreted acid in the stomach. All other drugs act by stopping acid secretion and so may not relieve symptoms atleast for 45 min.

34. 2. Drugs which neutralise gastric acid.-Antacids Systemic antacids – sodium bicarbonate Oral antacids - Al.hydroxide , Al.phosphate , Mg.tricilicate , M g. hydroxide , ca2+ carbonate. Misc – Alginates, Simethicone .

35. These are basic substances which neutralize gastric acid and raise pH of gastric contents. They do not decrease acid production; rather raise the antral pH >4.  gastric release  more acid is secreted, specially in pt. with hyperacidity and duodenal ulcer.

36. A ) Systemic antacids-Sodium bicarbonate (NaHCO3) Water soluble. Acts rapidly, has short duration of action. 1g  12meq HC pH raises above 7.

37. Disadvantages Absorb systemically large doses will induce alkalosis. On neutralisation of gastric HCl,it forms CO2 in stomach  discomfirt , distention, belching and risk of ulcer perforation. Sudden rise of pH and release of CO2 promotes gastrin release which causes rebound acidity. Increase Na+ load may worsen odema and CHF.

38. Now answer this question Is it rational to combine aluminium hydroxide and magnesium hydroxide in antacid preparations ?

39. 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 )

40. 3. Ulcer protective Drugs Sucralfate Collidal bismuth subcitrate Ulcer Healing Drugs Carbenoxolone

41. 3. Ulcer protective drugs Sucralfate Ammonium salt of sufated sucrose. MOA It acts a acid resistant physical barrier by forming sticky like gel over ulcer crater. It also binds to epithelial as well as fibroblast growth factor which promotes mucosal repair. It promotes ulcer healing, though it has no acid neutraling action and delays gastric emptying.

42. Cont.. S/E - It binds phosphate ions in intestine  hypophosphataemia . Drug interaction Sucuralfate should not given with tetracycline, fluroquinolones , H2 blockers, phenytoin bcoz it adsorbs these drug and decreses there absorption. Other uses Stomatitis Gel is used for burn dressing and bed sore High dos used to prevent phosphate stone in kidney

43. Collidal Bismuth Subcitrate Used for dyspepsia and travellers diarrhoea A/E blackening of stool Darkening of tongue Bismuth