Pharmacology Notes

Nonsteroidal anti-inflammatory drugs (NSAIDs) have their primary role in relief of nociceptive pain associated with tissue damage or inflammation. For a discussion of the physiological basis of nociceptive pain, see Physiology and pathophysiology of pain. NSAIDs exert their main effect by inhibition of cyclo-oxygenase (COX), with consequent reduction in the synthesis of pro-inflammatory prostaglandins from arachidonic acid. This occurs at both peripheral sites in the body and in the central nervous system.

NSAIDs may differentially inhibit the COX-1 and COX-2 isoforms of COX. COX-1 plays a major role in normal functioning of the gastrointestinal tract, platelets and kidneys. Inhibition of COX-1 reduces thromboxane A2 synthesis, effectively inhibits platelet aggregation, and is associated with gastrointestinal toxicity. COX-2 is constitutively expressed in the kidney and probably contributes to the production of prostaglandins, which regulate renal blood flow. COX-2 is induced by inflammatory stimuli and cytokines. Inhibition of COX-2 reduces pain associated with inflammation, and is the basis for the use of NSAIDs in inflammatory states. Prostacyclin, a vascular patency factor, is produced in blood vessels via COX-2. All NSAIDs inhibit COX-2 and, as a class, their use has been associated with an increased risk of serious cardiovascular events. As COX-2 inhibition has no effect on production of thromboxane A2 by platelets, which occurs through COX-1, this risk may be especially problematic with COX-2–selective inhibitors.

The nonselective inhibitors of COX are NSAIDs that inhibit both COX-1 and COX-2 (eg ibuprofen). Some NSAIDs preferentially (eg celecoxib, diclofenac, meloxicam) or selectively (eg parecoxib) inhibit COX-2. They have analgesic effectiveness equivalent to that of nonselective COX inhibitors. COX specificity may depend on the concentration of the drug at the receptor sites. Since both COX-1 and COX-2 inhibition are associated with significant health risks, no NSAID should be considered ‘safe’.