COX-2 SELECTIVE INHIBITORS
COX-2 selective inhibitors, or coxibs, were developed in an attempt to inhibit prostaglandin synthesis by the COX-2 isozyme induced at sites of inflammation without affecting the action of the consti-tutively active “housekeeping” COX-1 isozyme found in the GI tract, kidneys, and platelets. Coxibs selectively bind to and block the active site of the COX-2 enzyme much more effectively than that of COX-1. COX-2 inhibitors have analgesic, antipyretic, and anti-in-flammatory effects similar to those of non-selective NSAIDs but with an approximate halving of GI adverse effects. Likewise, COX-2 inhibitors at usual doses have no impact on platelet aggregation, which is mediated by thromboxane produced by the COX-1 isozyme. In contrast, they do inhibit COX-2-mediated prostacyclin synthesis in the vascular endothelium. As a result, COX-2 inhibitors do not offer the cardioprotective effects of traditional nonselective NSAIDs, which has resulted in some patients taking low-dose aspirin in addition to a coxib regimen to maintain this effect. Unfortunately, because COX-2 is constitutively active within the kidney, recommended doses of COX-2 inhibitors cause renal toxici-ties similar to those associated with traditional NSAIDs. Clinical data have suggested a higher incidence of cardiovascular thrombotic events associated with COX-2 inhibitors such as rofecoxib and val-decoxib, resulting in their withdrawal from the market.
Celecoxib is a selective COX-2 inhibitor—about 10–20 times more selective for COX-2 than for COX-1. Pharmacokinetic and dosage considerations are given in Table 36–1.
Celecoxib is associated with fewer endoscopic ulcers than most other NSAIDs. Probably because it is a sulfonamide, celecoxib may cause rashes. It does not affect platelet aggregation at usual doses. It interacts occasionally with warfarin—as would be expected of a drug metabolized via CYP2C9. Adverse effects are the common toxicities listed above.
Meloxicam is an enolcarboxamide related to piroxicam that pref-erentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered “preferentially” selective rather than “highly” selective. It is associated with fewer clinical GI symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses, its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above).