NSAIDS NOTES and Tables

All material in this lecture is copyrighted© 2007 NSAIDs Aspirin and other salicylates (last lec.) Propionic acid derivatives Acetic acid derivatives Oxicam derivatives Fenamates Other agents (diclofenac, ketorolac, Tolmetin and nabumetone, diflunisal) All NSAIDs, including aspirin, are about equally efficacious with a few exceptions¾tolmetin seems not to be effective for gout, and aspirin is less effective than other NSAIDs (eg, indomethacin) for ankylosing spondylitis. Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin, tolmetin, and meclofenamate are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in this analysis. All material in this lecture is copyrighted© 2007

All material in this lecture is copyrighted© 2007

All material in this lecture is copyrighted© 2007 Pharmacokinetics NSAIDs: weak organic acids except nabumetone (ketone prodrug metabolized to acidic active drug). Most are well absorbed & food does not substantially change bioavaialbility. Renal excretion is the most important route for elimination, However, nearly all NSAIDs undergo enterohepatic circulation. The degree of lower GI irritation correlates with amount of enterohepatic circulation. All material in this lecture is copyrighted© 2007

Newer NSAIDS

Diclofenac lowers body temperature in animals with antigen-induced fever. Although the mechanism of antipyretic effect of NSAIDs is not known, it has been suggested that suppression of prostaglandin synthesis in the CNS (probably in the hypothalamus) may be involved. In rats, the antipyretic activity of diclofenac 0.5 mg/kg was similar to that of 1.2, 24, 35, 55, or 185 mg/kg of indomethacin, ibuprofen, phenylbutazone, naproxen, or aspirin, respectively.

Gastrointestinal Risk Different NSAIDs confer different gastrointestinal risk. Risk is high with some of the longer acting NSAIDs (e.g., piroxicam [57 hours], ketorolac [up to ten hours], and sustained-release formulations), perhaps due to longer mucosal exposure. Ibuprofen seems to have the lowest risk of gastrointestinal events. This might be because low doses are typically used, possibly owing to nonprescription availability, or because it has a short half-life (two hours)

GI Risk- summary In summary, the bulk of evidence suggests that ibuprofen and the agents with relatively more COX-2 selectivity have the lowest gastrointestinal risk, and piroxicam and ketorolac have the highest risk [Evidence level B; case-control and cohort studies].

A systematic review of observational studies revealed that risk of upper gastrointestinal bleeding or perforation was not increased by celecoxib. GI Risk was low with ibuprofen then diclofenac, meloxicam, indomethacin, ketoprofen, naproxen, piroxicam, and ketorolac.

A selective COX-2 inhibitor should provide pain relief with lower gastrointestinal risk. Among "traditional" NSAIDs, meloxicam, nabumetone, and etodolac have some COX-2 selectivity and seem to be less likely than less selective NSAIDs to cause gastrointestinal events. The selective COX-2 inhibitor celecoxib (Celebrex) is associated with about a 20% lower risk of bleeding compared to traditional NSAIDs. But this benefit is negated in patients who take aspirin concomitantly. Furthermore, celecoxib does not seem to be safer than non-selective NSAIDs past six months of use.

Cardiovascular risk In addition to the hypertension and heart failure concerns with all NSAIDs, NSAIDs seem to increase the risk of cardiovascular events (heart attack, stroke, death) to varying degrees, even in healthy people. Adverse cardiovascular events associated with NSAIDs are thought to be caused by NSAIDs upsetting the balance between vasoconstricting, platelet aggregating thromboxane A2 (produced by COX-1) and opposing vasodilating prostacyclin (produced by COX-2). This may lead to vasoconstriction, platelet aggregation, and thrombosis.

- NSAIDs that tend to be more COX-2 selective could therefore be assumed to have more cardiovascular risk. - In fact, the COX-2 selective agents rofecoxib (Vioxx), valdecoxib (Bextra), and lumiracoxib (Prexige, Canada only) were withdrawn from the market due to cardiovascular risk.

For patients with cardiovascular disease or risk factors for ischemic heart disease: acetaminophen, aspirin, tramadol, opioids, or nonacetylated salicylates (e.g., diflunisal; choline magnesium trisalicylate [U.S. only]) are recommended before moving to an NSAID. Keep in mind that aspirin and diflunisal seem to have moderate gastrointestinal risk, although diflunisal has been included in only a few studies.

ACG Recommendations Recommendation GI Risk CV Risk choose an NSAID with the least GI risk at the lowest effective dose when appropriate (e.g., ibuprofen). Low use celecoxib or add a PPI or misoprostol to a less COX-2 selective NSAID Moderate avoid NSAIDs if possible. Alternatively, use celecoxib with a proton pump inhibitor or misoprostol High [Evidence level B; lower quality RCT].

For patients with low or moderate gastrointestinal risk but high cardiovascular risk (e.g., history of cardiovascular event, diabetes, hypertension, hyperlipidemia, obesity) taking aspirin, choose naproxen. These patients will also require a proton pump inhibitor or misoprostol. Patients with high risk of both gastrointestinal and cardiovascular risk should not receive an NSAID (including celecoxib). [Evidence level A; high-quality meta-analyses].

Etoricoxib (Arcoxia®). Selective COX-2 inhibitor Etoricoxib (Arcoxia®). Selective COX-2 inhibitor. Available as 60, 90 and 120 mg tablets. Given once to twice daily. Similar cardiovascular risk to cox-2 selective agents. Not FDA approved. etoricoxib: significantly fewer upper GI uncomplicated clinical events with etoricoxib than with diclofenac, but no decrease in more serious complicated events etoricoxib is currently sold in 63 countries but received an FDA non-approval (further data necessary to demonstrate a favorable risk-to-benefit ratio)

Renal Risk NSAIDs induce abrupt decreases in GFR in at-risk patient populations, specifically those with CHF, liver disease, the elderly, or dehydrated patients. Indomethacin is associated with the highest risk of NSAIDs-induced renal ischemia, where as aspirin appears to have the lowest risk. Naproxen, ibuprofen, piroxicam and diclofenac are considered intermediate in their relative capacities to acutely compromise renal perfusion. Sulindac may offer a “renal sparing” effect. Sulindac is a prodrug that is converted to its active sulfide metabolite by the liver and then becomes reversibly oxidized back to its parent compound in the kidney; renal prostaglandin synthesis is essentially unaltered by sulindac. Cases of sulindac-induced renal dysfunction have been reported when the drug was administered to patients with cirrhosis and ascites.

Many patients taking bisphosphonates, such as alendronate, ibandronate, and risedronate, for osteoporosis may also be taking various nonsteroidal antiinflammatory drugs (NSAIDs) for arthritis or other disorders. Whereas both of these drug classes can separately cause gastrointestinal (GI) toxicity, it is important to determine if the combination can have additive negative effects on the GI tract.

In a recent report of rheumatoid arthritis patients receiving NSAIDs for at least 3 months with or without concurrent therapy with bisphosphonates, GI ulcers occurred in 17% of patients on NSAIDs without concurrent bisphosphonates, and in 31% of patients receiving bisphosphonates with NSAIDs. Conversely, some other studies looking at upper GI bleeding or other GI adverse effects did not find an increase in GI toxicity when bisphosphonates were combined with NSAIDs, compared with NSAIDs alone. Explain !!! Explain: patients in this study were taking PPIs

Recommendations Patients taking bisphosphonates should be advised not to take OTC NSAIDs for minor problems such as colds and minor aches and pains. Acetaminophen might be preferable in such cases. It is not known if using less than daily administration of bisphosphonates reduces the risk of additive GI toxicity when combined with NSAIDs, but theoretically it might. In patients taking bisphosphonates who require long-term therapy with NSAIDs, preliminary evidence suggests that PPIs may reduce the risk of ulcers. Nonetheless, there is not enough evidence to recommend that these patients be routinely given prophylactic PPIs.