Identifying and Treating Patients at Risk: The Inflammatory Response

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27 Jun 2010

The physiological reaction to injury, noxious agents, and autoimmune-triggered substances consists of an innate, non-immunologic response and an acquired, specific immune re-sponse. During this highly complex repertoire of responses, referred to as the inflammatory reaction (Figure 1), numerous mediators of inflammation (e.g., eicosanoids, histamine, platelet-activating factor [PAF], bradykinin, and cytokines) are synthesized or released. Of these, the eicosanoids (e.g., prostaglandins, prostacyclin [PGI2], thromboxane A2, and leukotrienes) are derived from arachidonate by either cy-clooxygenase (COX) or lipoxygenase and are considered among the most important mediators and modulators of the inflammatory reaction as well as key factors in the physiological regulation of vascular and renal homeostasis.

Cyclooxygenase has been found to exist as two distinct iso-forms, the constitutively expressed COX-1 (found in nearly all tissues) and the inducible enzyme COX-2 (found primarily in inflammatory cell types). COX-1 mediates the production of prostaglandins, which maintain the integrity of the gastric mucosa, mediate platelet function, and regulate renal blood flow, and thromboxane A2. COX-2 expression is increased by inflammatory stimuli (e.g, cytokines) and increases synthesis of prostanglandins that mediate inflammation, pain, and fever. canadian discount drugs

Figure 1 Prostaglandin biosynthesis pathway

Figure 1 Prostaglandin biosynthesis pathway. (Adapted from Rang HP, Dale MM, Ritter JM, Gardner P. Pharmacology, 4th ed. Edinburgh: Churchill Livingstone; 1999:198-228. Copyright 1999, with permission of Elsevier Science.)

COX-1 and COX-2 NSAIDs: Pharmacological Effects

Traditional NSAIDs are nonselective inhibitors of COX-1 and COX-2, albeit to differing degrees. Although it is difficult to assess selectivity, two groups of investigators have measured the extent to which traditional NSAIDs inhibit COX-1 and COX-2 in healthy volunteers. Vane and Botting found aspirin (Merck), sulindac (Clinoril®, Merck), and (Pfizer) to be relatively selective for COX-1, with ratios of COX-1 to COX-2 greater than 60. Acetaminophen were less selective for COX-1, with ratios of 15 and 7.5, respectively. Agents such as naproxen drug (with a ratio of 0.6) and (with a ratio of 0.7) were relatively equipotent against both isoforms of cyclooxygenase.

The pattern of COX selectivity may explain the differences observed between the various NSAIDs with respect to their relative risk (RR) of gastrointestinal mucosal injury. Agents more potent for COX-1 versus COX-2 inhibition are associated with higher relative risk for gastrointestinal mucosal damage. However, although the selective COX-2 inhibitors offer a decreased risk for serious gastrointestinal mucosal injury, compared with traditional COX-1/COX-2 agents, the effect on the more common gastric symptoms such as dyspepsia is less clear.

This difference in COX selectivity also offers a physiological explanation for the more recently noted potential difference in cardiovascular events that have been observed between the COX-1/COX-2 agents and the selective COX-2 NSAIDs. COX-1/COX-2 NSAIDs, including aspirin, alter the balance between thromboxane A2 (which promotes platelet aggregation) and PGI2 (which inhibits it). The overall result of these two opposing actions and this “balance shift” is an antiplatelet effect and a decrease in the number of cardiovascular events. In contrast, as a result of their selectivity, COX-2 NSAIDs have no effect on thromboxane A2 production and little to no effect on platelet function, but they do cause a decrease in PGI2 produc-tion. Therefore, patients receiving COX-2 inhibitors may not benefit from the vasodilatory and antiplatelet aggregatory effects of the COX-1/COX-2 agents. In addition, the decreased production of PGI2, and possibly of other prostaglandins, may tip the physiological balance toward thromboxane A2, thereby resulting in increased risk for thromboembolic events.

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