NSAIDs & Their Complications

1. NSAIDs & Their Complications Dr Mohammad Taraz Clinical Pharmacist September 2016

2. HISTORY • Sodium salicylate • The first NSAID (1763) • GI toxicity (particularly dyspepsia) • Phenylbutazone • The first non-salicylate NSAID (1950) • Also induces uricosuria; useful in ankylosing spondylitis & gout • Bone marrow toxicity, particularly in women over the age of 60 • Indomethacin • As a substitute for phenylbutazone (1960) • There are now at least 20 different NSAIDs available for use in the USA.

3. MECHANISM OF ACTION • Prostaglandin-mediated effects • Nonprostaglandin-mediated effects • NSAIDs interfere with neutrophil-endothelial cell adherence by decreasing the expression of L-selectins • NSAIDs inhibit nuclear factor kappa B (NF-kB) dependent transcription in vitro, resulting in inhibition of inducible nitric oxide synthetase (iNOS). • The role of these non-prostaglandin mediated processes in clinical inflammation remains unclear.

6. Different NSAIDs have varying inhibitory potentials of the COX-1 & COX-2.

7. Variability of response in adults There is a clear individual variation in response to NSAIDs; some patients seem to respond better to one drug than to others. The risk of adverse events also seems to be variable among individual drugs & patients. At equipotent doses, the clinical efficacy of the various NSAIDs in patient populations is similar; in contrast, individual responses are highly variable.

8. The differences in the effects of the various NSAIDs have been ascribed to variations in one or more of the following: • Mechanism of action • Some NSAIDs are more potent inhibitors of PG synthesis, while others are more effective in altering other nonprostaglandin mediated biologic events. • Pharmacokinetics, pharmacodynamics, or metabolism

9. Observed variations in patient response may result in part from the pharmacodynamics of a particular drug. Thus, it is believed that, if a patient fails an NSAID of one class, the substitution of an NSAID of a different class is a reasonable therapeutic option. Each attempt to achieve a response should probably last for about 2 weeks. The NSAID dose should be at the maximal antiinflammatory range.

10. Unfortunately, the same approach is not necessarily applicable to patients who develop a toxic effect with one NSAID. Some toxicities are unique to particular classes of NSAIDs, while others are related to the general mode of action of inhibition of PG synthesis. One such example is ARFdue to renal vasoconstriction, which is mediated by decreased production of vasodilator PGs & may be similar across agents.

11. Adverse Effects Gastrointestinal effects Renal effects Cardiovascular effects Hepatic injury Hematologic effects Central nervous system Musculoskeletal effects Electrolyte complications

12. Gastrointestinal Effects Nonselective NSAIDs have potentially important gastrointestinal adverse effects, which include dyspepsia, peptic ulcer disease, & bleeding.

13. Systemic vs Topical Effects Aspirin & many other NSAIDs are carboxylic acid derivatives. As a result, they are not ionized at the acidic pH found in the gastric lumen & thus can be absorbed across the gastric mucosa. Once the drug moves from the acidic environment of the gastric lumen into the pH–neutral mucosa, the drug ionizes & is trapped temporarily in epithelial cells where it may damage these cells. However, this "topical" epithelial injury by many NSAIDs does not appear to be of prime importance in the pathogenesis of clinically important endpoints (symptomatic ulcers).

14. The pathogenesis of symptomatic PUD caused by exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of GI mucosal COX activity. Even IV or IM administration of aspirin or NSAIDs can cause gastric or duodenal ulcers in animals & human.

15. Risk Of Gastrointestinal Complications aCombinations of risk factors are additive.

16. The use of a nonselective NSAIDs is linked to a 3- to 4-foldin upper GI complications while there is a 2- to 3-fold  with partially & highly selective COX-2 inhibitors. • The risk for NSAID-induced ulcer & related complications is dose related, but ulcers can occur at any dosage, including low doses of OTC NSAIDs. • Upper GI events can occur at any time during treatment with an NSAID, as the risk for complications is similar throughout treatment.

17. Age is an independent risk factor for NSAID-induced ulcers, as risk  linearly with the age of the patient. The  incidence in older patients may be explained by age-related changes in gastric mucosal defense. • The relative risk of GI bleeding increases up to 20-foldwhen NSAIDs are taken concomitantly with anticoagulants(e.g., warfarin) & up to 6-fold with the concurrent use of SSRIs.

18. When clopidogrel is taken in combination with ASA, an NSAID, or an anticoagulant, the risk of GI bleeding is increased compared with when these agents are taken alone. • Even when prescribed as monotherapy, clopidogrel increases the risk of rebleeding for patients with history of a bleeding ulcer. • Corticosteroids do not  the ulcer risk when used alone, but the risk is  2foldin corticosteroid users who are also taking concurrent NSAIDs.

19. High risk • History of complicated peptic ulcer disease • Multiple (>2) risk factors (see below) • Moderate risk (1 to 2 risk factors) • Age >65 years • High dose NSAID therapy • A previous history of an uncomplicated ulcer • Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants • Low risk • No risk factors

20. Nonselective NSAIDs • The following conclusions were reached in a meta-analysis of controlled trials involving some of the most commonly prescribed NSAIDs: • The risk of GI complications was highest with indomethacin followed by naproxen, diclofenac , tolmetin, piroxicam, ibuprofen, & meloxicam. • Ketorolacis also associated with a high risk of GI toxicity, particularly when used in higher doses, in older patients, & for > 5 days. • One study found that ketorolac was 5.5 times more likely to cause GI toxicity than other NSAIDs.

21. Aspirin & GI ulcer Enteric-coated ASA may protect against the topical mucosal damage in the stomach & minimize dyspepsia, but does not prevent an ulcer from forming. Taking food, milk, or an antacid with ASA or NSAIDs may minimize dyspepsia but does not prevent an ulcer. Even low-dose ASA (e.g., 81 mg/day) remains capable of causing an ulcer, especially when used in conjunction with a NSAID.

22. Selective COX-2 inhibitors Data suggest that COX-2 inhibitors are associated a reduced risk of GI bleeding compared with nonselective NSAIDs but the risk is increased compared with placebo. Thus, COX-2 inhibitors may be safer than conventional NSAIDs for reduction in the risk of GI bleeding but are still associated with an increased risk.

23. Celecoxib with low dose aspirin Any potential gastroduodenal sparing effect with selective COX-2 inhibitors may be abrogated when they are used concurrently with low dose aspirin therapy for primary or secondary prevention of CVD. Thus, patients receiving both aspirin & a selective COX-2 inhibitor may require prophylactic antiulcer therapy if they are at increased risk for gastroduodenal toxicity.

24. Primary Prevention • Strategies to  the risk of NSAID ulcers & upper GI complications in a patient taking a nonselective NSAID include: • Cotherapy with a PPI or misoprostolor • Use of a selective COX-2 inhibitor in place of the nonselective NSAID • Strategies aimed at reducing the topical irritant effects of nonselective NSAIDs, e.g., prodrugs, slow-release formulations, & enteric-coated products, do not prevent ulcers or GI complications.

25. PPI Cotherapy • PPI cotherapy reduces NSAID-related gastric & duodenal ulcer risk & is better tolerated than misoprostol. • Misoprostol Cotherapy • Misoprostol  the risk of NSAID-induced gastric & duodenal ulcers. • Initially, the recommended dosage was 200 mcg QID, but diarrhea & abdominal cramping limited its use. A dosage of 200 mcg TID is comparable in efficacy & should be used in patients unable to tolerate the higher dose.

26. H2-Receptor Antagonist Cotherapy • Standard H2RA dosages (e.g., famotidine 40 mg/day) are effective in  NSAID-related DU but not GU. • Higher dosages (e.g., famotidine 40 mg BID, ranitidine 300 mg BID) may reduce the risk of GU & DU. • The H2RAs are not recommended as prophylactic cotherapybecause it is likely that they are not as effective as the PPIs or misoprostol in preventing NSAID-induced GU & related GI complications. • An H2RA, however, may be used to relieve NSAID-related dyspepsia.

27. The approved doses of drugs in patients taking nonselective NSAIDs include : • Misoprostol (200 µg QID) • Lansoprazole (15 or 30 mg daily) • Esomeprazole (20 or 40 mg daily) • Although not all PPIs have received FDA approval, they probably all have similar effectiveness.

28. Secondary Prevention With continued NSAID therapy Considered together studies suggest that patients with gastroduodenal ulcers or numerous erosions who must continue NSAID therapy should be treated with a PPI for as long as the NSAID or aspirin is used. Omeprazole was found to be superior to ranitidine & misoprostol in maintaining remission. Combination therapy with omeprazole & misoprostoldid not appear to be more effective than omeprazole alone. However, in this study, a low, possibly suboptimal dose of misoprostol was used.

29. When COX-2 inhibitors were first introduced, these agents appeared to hold promise as an alternative to traditional NSAIDs in preventing recurrent PUD in individuals who required ongoing antiinflammatory therapy. However, the relative risk reduction in GI bleeding associated with these agents appears to be modest at best. Replacing a COX-2 inhibitor for the nonselective NSAID in patients with NSAID-related ulcer disease should not be chosen over PPI maintenance therapy.

30. With continued low-dose aspirin Patients with low-dose aspirin(75 to 325 mg/day) have an increased risk of GI bleeding, which must be weighed against a possible increase in mortality. Patients who have had a bleeding ulcer while taking low-dose aspirin therapy should be treated with a PPI (rather than an H2-blocker), along with H. pylori eradication if they test positive for H. pylori. There are no compelling data that suggest that any of the available PPIs are more effective than another.

31. Treatment If a patient develops an ulcer while on a NSAID or low-dose aspirin, the NSAID or low-dose aspirin should be stopped if at all possible & traditional ulcer therapy with a PPI or an H2 antagonist started. PPIs are generally preferred because they are associated with more rapid ulcer healing. For patients who must remain on low-dose aspirin or NSAID therapy, randomized trials have shown that ulcer healing occurs more rapidly with a PPI than an H2 antagonist, misoprostol, or sucralfate.

32. Treatment with a PPI is generally continued for 4 to 8 weeks, depending on the ulcer location (duodenal or gastric), the original ulcer size & the severity of the initial clinical presentation. Maintenance therapy is indicated in patients who remain on or resume NSAID treatment.

33. RENAL EFFECTS • NSAID can induce two different forms of AKI: • Hemodynamically-mediated • Acute interstitial nephritis, Nephrotic syndrome • The former & perhaps the latter are directly related to the reduction in PG synthesis induced by the NSAID.

34. Hemodynamically-mediated AKI Acute kidney injury can occur with any NSAID. The selective COX-2 inhibitors also may precipitate AKI in certain patients. There has been concern that ketorolac might have greater nephrotoxic potential than other NSAIDs. There is suggestive evidence that some nonselective NSAIDs have a lower nephrotoxic potential than others. Low-dose aspirin (studied at approximately 40 mg per day), low-dose OTC ibuprofen, & perhaps sulindac appear to be safer; one proposed mechanism is relative sparing of renal PG synthesis.

35. Acute Interstitial Nephritis & Nephrotic Syndrome Affected patients typically present with hematuria, pyuria, white cell casts, proteinuria, & an acute rise in the SrCr. The full picture of an allergic reaction — fever, rash, eosinophilia, & eosinophiluria— is typically absent but one or more of these findings may be present. Spontaneous recovery generally occurs within weeks to a few months after therapy is discontinued.

36. All NSAIDS should be terminated in patients suspected of having NSAID-induced acute interstitial nephritis. Since topically administered NSAIDs can be systemically absorbed, such therapy should also be terminated. There is no definitive evidence that corticosteroid therapy is beneficial in this setting. However, a course of prednisone may be considered in patients whose renal failure persists > 1 to 2 weeks after the NSAID has been discontinued. Such patients should avoid the subsequent administration of NSAIDs. Relapse may occur with rechallenge.

37. CARDIOVASCULAR EFFECTS • NSAIDs have a variety of effects on the cardiovascular system. • Interference with the beneficial antiplatelet activity of aspirin • An increase in cardiovascular events • Exacerbation of heart failure

38. Interference with Aspirin The beneficial antiplatelet effects of aspirin for secondary or primary prevention of CVD result from irreversible acetylation of the active site of COX in platelets; these effects may be attenuated by prior or ongoing administration of some nonselective NSAIDs, including ibuprofen & naproxen. Thus, regular NSAID use should be avoided, if possible, in patients taking low-dose aspirin for cardiovascular protection. In patients who require NSAIDs on an occasional short-term basis, we suggest that aspirin be taken at least 2 h before the NSAID, although the data are limited.

39. Effect On Cardiovascular Risk The effect of NSAID therapy on cardiovascular risk has been evaluated with both the nonselective & COX-2 selective NSAIDs; medications within both NSAID classes appear to increase such risk. The degree of COX-2 selectivity, even among nonselective NSAIDs, may be related to the level of risk.

40. Naproxen appears to be the safest with respect to such risk, although an increased risk of MI or stroke with naproxen use has also been reported. Several COX-2 selective inhibitors (eg, rofecoxib) have been withdrawn from the market because of an increased risk of ischemic cardiovascular events.

41. Exacerbation Of Heart Disease Use of NSAIDs may cause worsening of HF & an increased risk of new events, including MI, in patients with established heart disease. If NSAIDs are required, they should be used at the lowest effective dose & for the shortest duration necessary for the given indication. We suggest naproxenfor patients with known CVD or increased CV risk who require treatment with a nonselective NSAID, when an equivalent therapeutic intervention is not available.

42. Elevation In Blood Pressure All NSAIDs in doses adequate to reduce inflammation & pain can increase BP in both normotensive & hypertensive individuals. The average rise in BP is 3/2 mmHg but varies considerably. These effects may contribute to the increase in cardiovascular risk associated with the selective COX-2 inhibitors.

43. Consensus Statements & Guidelines • High GI/high CV risk: should not receive NSAIDs, including COX-2 inhibitors • High GI/low CV risk: should receive a COX-2 inhibitor PLUS a PPI or misoprostol • Moderate GI/low CV risk: should receive a COX-2 inhibitor alone or a conventional NSAID PLUS a PPI or misoprostol. • Moderate GI/high CV risk: should receive naproxen PLUS a PPI or misoprostol • Low GI/high CV risk: should receive naproxen PLUS a PPI or misoprostol • Low GI/low CV risk: can receive a conventional NSAID alone, although the "least ulcerogenic NSAID at the lowest effective dose" is recommended. • All patients regardless of risk who are about to start long-term traditional NSAID therapy should be considered for testing for H. pylori & treated if positive.

44. HEPATIC INJURY Elevations of serum aminotransferasesare commonly associated with NSAID use; however, liver failure is quite rare. Sulindac was the only NSAID with a substantially greater risk than that of the overall NSAID group; However, the liver injury associated with sulindac & the other NSAIDs was generally mild & reversible. Diclofenac has been reported to cause clinical hepatitis. Introduction of another class of NSAID in many of these patients appeared to be safe.

45. Hepatotoxicity is rare, & the cost-effectiveness of monitoring serum transaminase levels is uncertain. However, if the aminotransferases are noted to rise to > 3 times the upper limit of normal, if there is a fall in serum albumin (suggestive of a synthetic defect induced by the drug), or if the INR is prolonged, NSAID toxicity should be suspected, & the potentially offending agent should be discontinued.

46. HEMATOLOGIC EFFECTS Some of the early NSAIDs (eg, phenylbutazone and, to a lesser degree, indomethacin) have been associated with an increased risk for bone marrow failure (ie, aplastic anemia). Although phenylbutazone is rarely used, neutropenia & antiplatelet effects can be induced by any of the NSAIDs.

47. For most NSAIDs, platelet function normalizes within 3 days of discontinuation, suggesting that NSAIDs should generally be discontinued at least 3 days before surgery. • In healthy individuals receiving ibuprofen for one week, platelet function appears to return to normal within 24 h after the last dose; thus, ibuprofen can be stopped 24 h prior to surgery.

48. Aspirin irreversibly inhibits platelet COX, & platelets lack the machinery to produce new COX. Thus, if aspirin is discontinued preoperatively, patients should stop aspirin for at least 1 week prior to a planned surgical procedure to allow the body to generate new platelets that have not been exposed to aspirin. Highly selective inhibitors of the COX-2 have little or no effect on the platelet, since COX-2 activity has not been found in platelets.

49. CENTRAL NERVOUS SYSTEM • Psychosis & cognitive impairment: • Are more prevalent in older patients, particularly with the use of indomethacin. Thus, indomethacin should be prescribed judiciously in geriatric patients, with close attention to mental status changes. • Tinnitus: • Is a common problem in patients who are prescribed high doses of salicylates. Although it can occur with all of the available NSAIDs, it is less commonly seen among non-salicylate NSAIDs. Tinnitus is typically reversible upon cessation of drug therapy & is a good warning sign to identify those patients who are developing high blood levels of the drug.

50. MUSCULOSKELETAL EFFECTS Possible effect on fracture healing A causal relationship has not been proven, & the effect of these drugs on fracture healing in humans is uncertain. Possible effect on tendon injury Animal studies suggest a theoretical adverse impact of some NSAIDs (both nonselective & COX-2 selective) on healing from tendon & ligament injuries for which NSAIDs are often used. However, there are no published human data demonstrating such effects.