The primary property of this class of drugs is the inhibition of COX.^11–13 There are 2 major COX isoenzymes: COX-1 is expressed constitutively (constantly) in most tissues, whereas COX-2 is induced in inflammation. Both COX-1 and COX-2 use arachidonic acid to generate the same product, prostaglandin H₂. A number of enzymes further modify this product to generate bioactive lipids (prostanoids) such as prostacyclin, thromboxane A₂, and prostaglandins D₂, E₂, and F₂. These prostanoids influence immune, cardiovascular, gastrointestinal (GI), renovascular, pulmonary, central nervous system, and reproductive function.¹² Of note, it is now recognized that COX-2 is expressed in normal endothelial cells in response to shear stress and that inhibition of COX-2 is associated with suppression of prostacyclin synthesis.¹⁴ On the basis of experiments in animals and observations from clinical trials and registries, it has been proposed that major cardiovascular consequences of COX-2 inhibition include a shift in the prothrombotic/antithrombotic balance on endothelial surfaces toward thrombosis; an increase in sodium and water retention, leading to edema, as well as exacerbations of heart failure and hypertension; and loss of the protective effects of COX-2 upregulation in the setting of myocardial ischemia and infarction, which leads to a larger infarct size, greater thinning of the left ventricular wall in the infarct zone, and an increased tendency to myocardial rupture.^12,13,15,16

A variety of NSAIDs can block the enzymatic activity of COX; they vary in their chemical structure and relative ability to block the COX-1 versus the COX-2 isoenzymes (Figure 4). The COX-2 inhibitors also vary in their selectivity for the COX-2 versus the COX-1 enzyme (for medications currently or formerly on the market in the United States, rofecoxib > valdecoxib > parecoxib > celecoxib). Other COX-2 inhibitors are under development and may be introduced into the US market in the future. The differences in the biological effects of COX inhibitors are a consequence of the degree of selectivity for COX-2 versus COX-1 and tissue-specific variations in the distribution of COX and related enzymes that convert prostaglandin H₂ into specific prostanoids.

For example, several prostanoids, including prostaglandin E₂ and prostacyclin, are both hyperalgesic (elicit an increased sense of pain) and gastroprotective. Thus, nonselective COX inhibition with agents such as aspirin, ibuprofen, indomethacin, and naproxen, which inhibit both COX-1 and COX-2 enzymes, provides effective pain relief for inflammatory conditions but carries with it a risk for erosive gastritis and GI bleeding. Selective COX-2 inhibitors (valdecoxib, rofecoxib, celecoxib, and others yet in development) were developed to minimize GI toxicity because of the relative paucity of COX-2 expression in the GI tract and the relative abundance of COX-2 expression in inflamed and painful tissues.

In the cardiovascular system, the products of COX regulate complex interactions between platelets and the vessel wall. Prostacyclin is the dominant prostanoid produced by endothelial cells.^17,18 In addition to producing local smooth muscle cell relaxation and vasodilation, prostacyclin can interact with platelet IP receptors, thereby antagonizing aggregation. Platelets contain only COX-1, which converts arachidonic acid to the potent proaggregatory, vasoconstrictive eicosanoid thromboxane A₂ (TXA₂), the major COX product formed by platelets. Nonselective COX inhibition with aspirin is effective for arterial thrombosis because of its ability to reduce COX-1–dependent production of platelet TXA₂; however, selective inhibition of COX-2 could produce a relative reduction in endothelial production of prostacyclin, while leaving the platelet production of TXA₂ intact. It has been speculated that this imbalance of hemostatic prostanoids might increase the risk for thrombotic cardiovascular events^19,20 (Figure 5). COX-2 inhibitors, like NSAIDs, also raise blood pressure and increase the incidence of heart failure significantly compared with placebo.^21,22 By elevating blood pressure, NSAIDS, particularly coxibs, attenuate the benefit of previously prescribed antihypertensive therapy and may also move certain patients not previously diagnosed as hypertensive over the threshold for initiation of treatment for hypertension.^23,24

FOR THE HIGHEST RISK GROUP, those with prior MI, the excess mortality risk was approximately 6 persons per 100 per year of treatment with a COX-2 inhibitor.  {The authors of one large report estimated that in patients with a prior myocardial infarction, the excess risk of mortality is 6 deaths per 100 person-years of treatment with a COX-2 inhibitor compared with no NSAID treatment.⁴  In these patients, prudence dictates extra caution in the use of COX-2 inhibitors}

Disclaimer:  The information, facts, and opinions provided here is not a substitute for professional advice.  It only indicates what JK believes, does, or would do.  Always consult your primary care physician for any medical advice, diagnosis, and treatment.