Cooh

Flurbiprofen

Ibuprofen

Naproxen

Fenoprofen Ketoprofen Suprofen

Figure 24.19 • Aryl- and heteroarylpropionic acids.

Oxaprozin

Fenoprofen Ketoprofen Suprofen

Figure 24.19 • Aryl- and heteroarylpropionic acids.

Oxaprozin acute gouty inflammation, and in primary dysmenorrhea. It shows good analgesic activity (i.e., 400 mg is comparable to 75-150 mg of oral meperidine and superior to 65 mg of propoxyphene and 325 mg of aspirin plus 30 mg of codeine). It is also available OTC as 200-mg tablets (Aleve).

Fenoprofen

Fenoprofen (Nalfon), is rapidly absorbed orally, reaches peak plasma levels within 2 hours, and has a short plasma half-life (3 hours). It is highly protein bound, just like the other NSAIDs, thus caution is needed when it is used concurrently with other medications including hydantoins, sul-fonamides, and sulfonylureas. It is recommended for RA and OA, at an oral dose of 300 to 600 mg for 3 or 4 times per day, but not exceeding 3 g/d to avoid any serious side effects. It should be noted that in a comparison study of all NSAIDs, fenoprofen is the one that has been most closely associated with a rare acute interstitial nephritis.188 For mild to moderate pain relief, the recommended dosage is 200 mg given every 4 to 6 hours, as needed.

Ketoprofen and Suprofen

Ketoprofen (Orudis, Rhodis) and suprofen (Profenal) are closely related to fenoprofen in their structures, properties, and indications. Even though ketoprofen has been approved for OTC use (Orudis KT, Actron), its GI side effects are similar to indomethacin (Table 24.1), and therefore its use should be closely monitored, especially in patients with GI or renal problems.

Flurbiprofen

Flurbiprofen (Ansaid, Ocufen, Froben), is another drug in this class indicated for both acute and long-term management of RA and OA but with a more complex mechanism of action. Unlike the other drugs in this class, it does not undergo chiral inversion (i.e., the conversion of the "inactive" [R]-enantiomer to the active, [S]-enantiomer). Similar to aspirin and other salicylates, both flurbiprofen enantiomers block COX-2 induction as well as inhibiting the nuclear factor-^B-mediated polymorphonuclear leukocyte apoptosis signaling189; therefore, both enantiomers are believed to contribute equally to its overall anti-inflammatory action.

(R)-flurbiprofen is actually a strong clinical candidate for the treatment of Alzheimer disease, because it has been shown to reduce A^42 production by human cells.190

Oxaprozin

Oxaprozin, 4,5-diphenyl-2-oxazolepropionic acid (Daypro), differs from the other members of this group in being an arylpropionic acid derivative. It shares the same properties and side effects of other members in this group. It is indicated for the short- and long-term management of OA and RA, administered as a once-daily dose of 600- to 1,200-mg dose because of its long duration of action.191

W-ARYLANTHRANILIC ACIDS (FENAMATES) AND STRUCTURALLY RELATED ANALOGS

This class of NSAIDs shares one common structural feature that is not present in the other classes discussed earlier. Unlike other classes discussed earlier, the second aromatic ring in this class is connected to the main aromatic car-boxylic acid containing ring through a secondary amine linkage (rather than carbonyl group or other nonbasic linker) and at the ortho position rather than at the meta or para position (see their structures in Fig. 24.20). As a result of this structural feature, this class of NSAIDs appears to have a lower risk of causing GI irritation. Recent crystallo-graphic evidence suggests that diclofenac binds to COX isozymes in an inverted conformation with its carboxylate group hydrogen-bonded to Tyr-385 and Ser-530.192 This finding provides a reason why diclofenac and especially its related analog, lumicoxib, have much greater selectivity toward COX-2 isozymes.

Mefenamic Acid

Mefenamic acid (Ponstel, Ponstan) is one of the oldest NSAIDs, introduced into the market in 1967 for mild to moderate pain and for primary dysmenorrhea. It is rapidly

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