Ask the Expert: Which NSAIDs are Most Selective for COX-1 and COX-2?
QUESTION: Which NSAIDs Are Most Selective For COX-1 and COX-2?
ANSWER: Non-steroidal anti-inflammatory drugs (NSAIDs) provide analgesic, anti-
inflammatory, and antipyretic effects and are used in the treatment of a variety of disorders. NSAIDs inhibit the rate-limiting enzyme cyclooxygenase (COX) in prostaglandin synthesis and two COX isoforms have been identified, COX-1 and COX-2. The COX-1 isoform produces cytoprotective prostaglandins and is present in most tissues, including the gastrointestinal mucosa, kidneys, and platelets.1 Alternatively, bacterial products and cytokines induce the expression of COX-2 and this isoform is primarily found in areas of inflammation.2 The rationale for developing selective COX-2 inhibitors is due to the concept that the therapeutic effects of traditional NSAIDs are related to inhibition of COX-2 while the adverse effects, such as gastrointestinal ulcers or uncontrolled bleeding, are caused by the concurrent inhibition of the COX-1 isoform.1,3 Most selective COX-2 inhibitor drugs possess a bulky side chain that is too large to appropriately orient into the binding site of the COX-1 isoform, but enables the molecule to align and bind to the COX-2 isoform.1
The COX-2 isoform appears to play a role in maintaining vascular integrity and adverse cardiovascular effects have been associated with selective COX-2 inhibitors. The inhibition of COX-2 leads to decreased production of vasodilator prostaglandins from endothelial cells, but platelet thromboxane is not concomitantly inhibited due to the lack of COX-2 present on mature platelets.1 This mechanism is thought to be a contributing factor to the increased risk of developing a myocardial infarction, stroke, congestive heart failure, pulmonary and systemic hypertension, and cardiac death.
Selecting an NSAID that is more selective to COX-2 may be a safer option in those patients at high risk for the gastrointestinal and bleeding adverse effects associated with traditional NSAIDs; however, it has been found that NSAIDs, regardless of selectivity, still pose some risk of these side effects.2 Moreover, NSAIDs that are more selective for the COX-2 isoform have been associated with an increased risk in cardiovascular adverse effects. Continuously weighing the benefits versus risks is pertinent when recommending or prescribing an NSAID for patients. All NSAIDs have been associated with some increased cardiovascular risks. If an NSAID is necessary in a patient at increased risk for cardiovascular events, the American Heart Association recommends using COX-1 selective NSAIDs first at the lowest dose and for the shortest duration.3 Table 1 summarizes the COX selectivity of NSAIDs.1,4-6