بسم الله الرحمن الرحیم

1. بسم الله الرحمن الرحیم

2. NSAIDs GI Toxicity Dr. N. Aletaha MD

3. NSAIDs • NSAIDs are popular because : • Analgesic • Antipyretic • Anti-inflammatory (at higher doses) • Aspirin is also used as an anti-thrombotic agent.

4. Epidemiology • The spectrum of NSAID-induced morbidity ranges from nausea and dyspepsia (prevalence reported as high as 50–60%) to a serious GI complication such as peptic ulceration (15–30% of individuals taking NSAIDs regularly) complicated by bleeding or perforation in as many as 1.5% of users per year.

5. Epidemiology • It is estimated that NSAID-induced GI bleeding accounts for 60,000 to 120,000 hospital admissions per year, and deaths related to NSAID-induced toxicity may be as high as 16,000 per year in the United States.

6. Epidemiology • Approximately 4–5% of patients develop symptomatic ulcers within 1 year. Unfortunately, dyspeptic symptoms do not correlate with NSAID-induced pathology. Over 80% of patients with serious NSAID-related complications did not have preceding dyspepsia.

7. Epidemiology • Even 75 mg/d of aspirin may lead to serious GI ulceration; thus, no dose of NSAID is completely safe.

8. Riskfactors • Established risk factorsinclude • advanced age • history of ulcer • concomitant use of glucocorticoids • high-dose NSAIDs • multiple NSAIDs • concomitant use of anticoagulants, clopidogrel • and serious or multisystem disease.

9. Risk factors • Possible risk factors include • concomitant infection with H. pylori, • cigarette smoking, • and alcohol consumption.

10. Risk of gastrointestinal toxicity • The risk increased by the presence of one or more of the following: • Prior history of a gastrointestinal event (ulcer, hemorrhage) • Age>60 • High dosage of a NSAID • Concurrent use of glucocorticoids

11. Risk of gastrointestinal toxicity • Concurrent use of anticoagulants. • Chronic as opposed to short-term (less than one week) use • Untreated Helicobacter pylori infection • Use of selective serotonin reuptake inhibitors (SSRI)

12. PHARMACOLOGY • Nonsteroidalantiinflammatory drugs (NSAIDs) are competitive inhibitors of the enzyme cyclooxygenase (COX) • NSAIDs prevent COX-mediated production of prostaglandins and thromboxanes, but not leukotrienes and other eicosanoids.

13. PHARMACOLOGY

14. OVERVIEW  •  Many of the toxic effects of the NSAIDs are related to their main mode of action, the inhibition of prostaglandin synthesis.

15. PATHOGENESIS • TOPICAL EFFECTS • Aspirin and many other NSAIDs are not ionized at the acidic pH in the gastric lumen absorbed across the gastric mucosa. • The drug ionizes and is trapped temporarily in epithelial cells damage these cells

16. PATHOGENESIS • Aspirin and many NSAIDs are weak acids that remain in a nonionized lipophilic form when found within the acid environment of the stomach. Under these conditions, NSAIDs migrate across lipid membranes of epithelial cells, leading to cell injury once trapped intracellularly in an ionized form.

17. PATHOGENESIS • Topical NSAIDs can also alter the surface mucous layer, permitting back diffusion of H+ and pepsin, leading to further epithelial cell damage. • Moreover, enteric-coated or buffered preparations are also associated with risk of peptic ulceration.

18. PATHOGENESIS • This "topical" epithelial injury by many NSAIDs does not appear to be importance

19. PATHOGENESIS • SYSTEMIC EFFECTS • The pathogenesis of symptomatic peptic ulcer disease caused by exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of GI mucosal cyclooxygenase (COX) activity.

20. PATHOGENESIS • Even intravenous or intramuscular administration of NSAIDs can cause gastric or duodenal ulcers in animals and humans

21. PATHOGENESIS • There are at least two forms of COX in the body, COX-1 and COX-2 • Cyclooxygenase-1 (COX-1) and COX-2 are the enzymes responsible for the synthesis of prostaglandins.

22. PATHOGENESIS • The healthy gastric and duodenal mucosa constitutively use COX-1 to produce its mucosal-protective PGs • Conventional NSAIDs such as ibuprofen inhibit the COX-1 and the COX-2 enzymes.

23. PATHOGENESIS • COX-1 is an enzyme in most cells of the body. • COX-2 is expressed in many cells only in inflammatoryproccess. • COX-3 in the brain may be one target of acetaminophen (paracetamol)

24. PATHOGENESIS • Drugs that more selectively inhibit COX-2 than COX-1 have less suppressive effects on gastric PG synthesis Examples include celecoxib .

25. PATHOGENESIS • However, COX-2 selective inhibitors may still block COX-1 at clinically recommended doses and thus have the potential to also block COX-1 in the stomach and duodenum and cause damage.

26. Cytoprotective mechanisms of PGs • Inhibit gastric acid secretion • Stimulation of glycoprotein (mucin) • Stimulation of bicarbonate secretion • Stimulation of phospholipid secretion

27. Cytoprotective mechanisms of PGs • Local vasodilation mucosal blood flow and oxygen delivery to epithelial cells • Increased epithelial cell migration towards the luminal surface • Epithelial cell proliferation

28. PATHOGENESIS • COX-1 inhibition reduces prostaglandin synthesis • Reductionin mucosal blood flow • Hypoxia • Reduction in mucosal defense.

29. PATHOGENESIS • Other mechanism of NSAIDs damage • One such mechanism is increased leukotriene production that occurs because arachidonic acid metabolism shifts to the alternative 5-lipooxygenase pathway when the COX-1 pathway is inhibited

30. PATHOGENESIS

32. GASTROINTESTINAL Side EFFECTS • Dyspepsia • Peptic ulcer disease • Bleeding • Ulcers, perforations, bleeding, obstruction, strictures enteropathy

33. Spectrum of NSAID-InducedGI Mucosal Injury Upper GI • GERD • Subepithelialpetechial hemorrhages • Erosions • Ulcers – Stomach > duodenum • Bleeding – Stomach » duodenum • Perforations/obstruction Small Intestine • Ulcers • Strictures • Diaphragms •Enteropathy

34. Spectrum of NSAID-InducedGI Mucosal Injury • Colon • • Colitis • • Ulcers • • Strictures • • Diverticular bleed or perforation • • Collagenous colitis • • Relapse of IBD

35. adverse effects of high-dose aspirin use • nausea • vomiting • diarrhea or constipation • dyspepsia (impaired digestion) • epigastric pain • bleeding, and ulceration (primarily gastric).

36. Therapy of NSAID-Related Gastric or Duodenal Injury

37. Patients requiring antiplatelet therapy • Those with a history of ulcer complications or a history of ulcer disease (non-bleeding) undergo testing for H. pylori and treatment if positive.

38. Patients requiring antiplatelet therapy • Those with a history of ulcer complications or a history of ulcer disease (non-bleeding), a history of upper gastrointestinal bleeding, those receiving dual antiplatelet therapy or concomitant anticoagulants be treated with a PPI.

39. patients requiring antiplatelet therapy • Patients without the above risk factors but who have other risk factors for gastrointestinal complications (including age 60 or more, use of corticosteroids, dyspepsia or GERD symptoms) should also be treated with a PPI.

40. Risk of gastrointestinal toxicity • ACG guidelines (2009) : • High risk • History of complicated peptic ulcer disease • Multiple (>2) risk factors (see below) • Moderate risk (1 to 2 risk factors) • Low risk • No risk factors

41. Risk of gastrointestinal toxicity • Risk: • Age >65 years • High dose NSAID therapy • A previous history of an uncomplicated ulcer • Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants

42. Risk of gastrointestinal toxicity • COX-2 inhibitors may be safer than conventional NSAIDs for reduction in the risk of gastrointestinal bleeding but are still associated with an increased risk.

43. combined GI and CV risk profile: • Patients who are at high GI/high CV risk should not receive NSAIDs, including COX-2 inhibitors. • Patients at high GI/low CV risk should receive a COX-2 inhibitor in combination with either a PPI or misoprostol.

44. Patients requiring antiplatelet therapy • Patients at moderate GI/low CV risk should receive a COX-2 inhibitor alone or a conventional NSAID + either a PPI or misoprostol.

45. patients requiring antiplatelet therapy • Patients at moderate GI/high CV risk should receive naproxen (due to its putative cardioprotective properties) and either a PPI or misoprostol. • This same strategy is endorsed for patients at low GI/high CV risk.

46. Patients requiring antiplatelet therapy • Patients at low GI/low CV risk can receive a conventional NSAID alone, although the "least ulcerogenic NSAID at the lowest effective dose" is recommended

47. Patients requiring antiplatelet therapy • All patients regardless of risk who are about to start long-term traditional NSAID therapy should be considered for testing for H. pylori and treated if positive.

48. primary prevention • primary preventionincluded • avoiding the agent • using NSAIDs that are theoretically less injurious • and/or the use of concomitant medical therapy to prevent NSAID-induced injury.

49. primary prevention • Several nonselective NSAIDs that are associated with a lower likelihood of GI toxicity include diclofenac, aceclofenac, and ibuprofen, although the beneficial effect may be eliminated if higher dosages of the agents are used.

50. prevention of NSAID-induced GI damage • Primary prevention of NSAID-induced ulceration can be accomplished by misoprostol (200 g qid) or a PPI. High-dose H2 blockers (famotidine, 40 mg bid) have also shown some promise in preventing endoscopically documented ulcers, although PPIs are superior.