Chapter 27 Upper GI

1. Chapter 27 Upper GI John Noviasky

2. Upper GI • Includes dyspepsia • Peptic ulcer disease • Zollingers-Ellison, ZE • GERD • Stress ulcer prophylaxis

3. Dyspepsia • Persistent or recurrent pain or discomfort (fullness, bloating, nausea) in upper abdomen • 25-55% will experience • (fig. 27-1)

4. PUD • Up to 10% will develop once during lifetime • 3 main risk factors: Helicobacter pylori (H Py), NSAID, and smoking • in those not exposed to NSAID, H Py is common cause (90%) for PUD • Fig. 27-2

5. GERD • Heartburn > or = 2 times per week • backflow (reflux or regurgitation) of GI contents into esophagus • heartburn - pain in center of chest, “burping up” stomach contents into mouth

6. GERD continued • If persistent heartburn - more likely to get esophageal adenocarcinoma • Most common cause - inappropriate lower esophageal sphincter (LES) relaxation • some drugs (eg. Verapamil, theophylline)cause decreased LES tone

7. GERD - disease • Heartburn - symptom • Esophagitis - endoscopic finding

8. Peptic Ulcer Disease (PUD) • Lesions in stomach/duodenum as result of acid/pepsin • Zollinger Ellison Syndrome (ZES) - rare, hypersecretion d/t gastrin secreting tumor

9. PUD continued • Incidence of PUD peaked in 50’s and has decreased since that time - more effective drugs, change in hospital coding practice. • Duodenal ulcers incidence is decreasing • gastric ulcers about the same –may be due to NSAID use

10. PUD continued • In Japan - gastric 5-10 times more common than duodenal • in US - duodenal 2 times more common than gastric • M~F for gastric ulcers

11. PUD continued • Gastric ulcers rare before 40 yo, peak 55-65 yo • Duodenal ulcer incidence increase with age until 60 yo • < 2% have serious complication (bleed, perforation, obstruction)

12. Physiology of GIT • Fig. 27-3 • cardia, body and antrum • Body - 80-90% of stomach • contains parietal cells - secrete acid and intrinsic factor (required for B12 absorption) • chief cells secrete pepsinogen

13. Physiology of GIT cont. • Antrum • 10-20% of stomach • contains G cells - secrete gastrin

14. Physiology cont. • Stimuli: trigger secretion of acid • figure 27-4 • stimulus - cholinergic pathway - parietal cell and G cell - release acetylicholine (A) eventually gastrin (G) released • histamine (H) also released • A,G, + H - activates K-H+ - ATPase in parietal cell which secretes H+ (acid)

15. Physiology cont. • negative feedback - cholecystokinin, glucagon, and vasoactive intestinal peptide (VIP) - inhibit gastrin secretion

16. Physiology cont. • Protective mechanisms - (protects against pepsin and acid) • prostaglandin E and somatostatin - decrease gastric acid secretion and maintain mucosal blood flow and stimulate mucus and bicarb. • Gastric mucus - viscous gel - lubricant, traps microorganism, barrier to H+

17. PUD continued • Protective Mechanisms (cont.) • mucosal blood flow -transports O2 to mucosa and removes damaging acids • rapid and continual renewal of gastric epithelial cells • when injured - healing requires formation of fibrin cap (aka restitution) • balance needs to be maintained for healthy GIT

18. Pathogenesis • ZE syndrome - increase parietal cells - increase acid secretion • duodenal ulcers - normal acid secretion • Gastric ulcers - normal or low acid

19. Pathogenesis continued • Acid in not only mechanism for ulcer production • decreased mucosal defenses as well (eg. NSAIDs) and PG inhibition • Helicobacter Pylori (H Py) - gram (-) spiral bacterium • found in 90% of duodenal ulcers and 70% of gastric ulcers • not everyone w/H py gets an ulcer • Increases ammonia which may disrupt gastric mucosa

20. Risk Factors (pg. 27-6) • Disruption of mucosal resistance (eg. H py) • NSAID use (especially gastric ulcers) • Cigarette smoking - stimulates gastric ulcer secretion and bile salt reflux, alters mucos blood flow, and decreases PG production

21. Risk Factors continued • Foods- caffeine, milk, spicy food - increase H+ and cause dyspepsia BUT no data says they increase ulcers • alcohol - damages mucosa and causes lesions and GI bleeding - BUT not proven to cause PUD • genetics - 20-50% of duodenal ulcers have + family history • Stressful life event may cause PUD

22. Clinical Presentation • Pain relieved by food and antacids • Definitive diagnosis requires endoscopy • Epigastric pain - may be only symptom not well localized “annoying”, “burning”, “gnawing”, “aching” • Duodenal ulcer pain - episodic, occurs when stomach empty (during night, between meals relieved by food and antacids)

23. Clinical Presentation continued • Gastric ulcer pain may be similar to duodenal ulcer pain but occurs at any time of day. • However patients with ulcer may not have pain and patients with pain may not have ulcer (eg. Elderly pt. on analgesic may have ulcer and no pain)

24. Treatment Goals • Relief of symptoms (esp. dypepsia) • Ulcer healing • Prevention of recurrence • Eliminate HPy if present • Decrease acidity • Increase mucosal defenses • DRUGS - tables 27-1 and 27-2

25. Pharmacokinetics (table 27-3) of H2 • Well absorbed - oral and IV doses similar • Peak 1-3 hours • Hepatic metabolism mainly (cimetidine and ranitidine) • Renal elimination mainly - famotidine and nizatadine • All need dose adjustment in renal disease

26. Adverse effects of H2 • Most common- diarrhea, constipation, CNS (mental confusion, headaches, dizziness) • Cimetidine- • anticholinergic effects • gynecomastia • impotence • Hepatoxicity - rare

27. Adverse Effects of H2 continued • Especially at risk - elderly, high doses, renal disease

28. Drug Interactions (table 27-4) • Most prominent with cimetidine -CYP 450 interaction, reduces clearance of other drugs by about 20-30% • most critical with narrow therapeutic rages (eg. Phenytoin, warfarin, theophylline)

29. Drug interactions continued • Ramitidine, famotindine and nizatadine have less chance for interaction than cimetidine • decreased absorption of ketoconazole d/t increased Ph • cimetidine, ranitidine and nizatadine increase absorption of ethanol by decreasing gastric alcohol dehydrogenase

30. Dosing • Night-time dosing similar efficacy to multiple daily dosing

31. PPI mofA • Bind to K+ - H+ - ATPase (transports acid across parietal cell) • inhibit gastric acid secretion

32. PPI efficacy • Inhibit > 90% of gastric acid secretion w/in 24 hours • Heals more quickly than H2 antagonists (2-4 wks compared to 4-8 wks) • absolute healing rates similar after usual therapy course • Useful for erosive reflux disease, ZE

33. PPI PK • PPI are unstable in acid media so they are enteric coated • rapidly absorbed and peak 2-4 hours • bioavailability 50-80% • eliminated hepatically and plasma T1/2 ~ 1-2 hours, antisecretory effect is 1 1/2 to 3 days

34. PPI PK continued • PPI dosage adjustment not needed for renal dysfunction • Should be considered with hepatic disease

35. PPI adverse effects • Infrequent - GI (nausea, diarrhea), CNS (dizziness, headache) skin rash, gynecomastia, increase liver enzymes. • In theory - increase gastrin could lead to carcinoid tumors - no evidence to support this

36. PPI Drug interaction (DI) • Omeprazole (increase BDZ, phenytoin, warfarin) • pantoprazole has fewer DI than omeprazole

37. Sucralfate • M of A - at low ph (2-2.5) binds to damaged and ulcerated tissue and forms barrier, no systemic effects • efficacy - similar to H2 antagonists • dosing QID but 2 gram BID is as effective

38. Sucralfate continued • ADV effects - constipation, dry mouth, nausea, rashes • difficult to swallow • Drug interactions- many drugs absorption is decreased (eg. Digoxin, FQ, ketoconazole, levothyroxine)

39. Antacids • Mof A - neutralize gastric acid, provide cytoprotective effect (stimulate prostaglandins) • Efficacy - heals duodenal ulcers in 50-90% of pts after 4 wks compared to 25-50% on PCB • effective with in 5-15 minutes and duration ~ 2 hours

40. Antacids continued • Dosing - multiple times per day (1 and 3 hours p meals and HS)

41. Antacids • Adverse Effects • sodium bicarb - systemic alkalosis • aluminum Hydroxide - constipation, aluminum absorption • avoid in renal insufficiency • magnesium Hydroxide - diarrhea, Mg absorption, avoid in renal insufficiency (< 20 ml/min) • Adverse effects -sedation, nausea, vomiting

42. Antacids continued • Calcium carbonate - high doses (4 to 8g/day) can stimulate gastric acid production and cause milk - alkali syndrome (hypercalcemic nephropathy with alkalosis)

43. Antacids continued • Drug interactions increased ph - alters absorption of ketoconazole digoxin, phenytoin, INH (Acid required for absorption) • Binding cipro and tetracycline absorption decreased by > 50% give cipro 2 hrs before antacid

44. H Py eradication • Most patients with ulcer are colonized with HPy • Higher ulcer recurrence when HPy positive • combination therapy preferred (table 27-5)

45. Question 2 • What should MB be tested for if PUD is suspected? • When is endoscopy indicated in pts with PUD? • Is a positive HPy diagnostic of ulcer?

46. Question 3 • Which type of testing for HPy is now commonly done because of its simplicity and low cost?

47. Question 7 • What is limit of H Py testing by serology? • In what situations is serology testing most useful? • If JL had tested negative for H Py antibodies, what should the clinician have suspected?

48. Question 11 • What is the prevalence of endoscopically confirmed GI ulcers in NSAIDS users?

49. Question 12 • What is the % of patients that develop symptomatic ulcers after 6 months and 1 year of NSAID therapy? • Why doesn’t pain correlate well with associated ulcers?

50. Question 13 • How do NSAIDs produce gastric damage? • When aspirin consumption exceeds ____tablets, the occurrence of ulcers is increased. • Does the potential for ulceration still exist with enteric coated aspirin? • Which NSAIDs affect COX-2 to a greater degree than COX 1?