Most of these drugs are well absorbed, and food does not substantially change their bioavailability. Most of the NSAIDs are highly metabolized, some by phase I followed by phase II mechanisms and others by direct glucuronidation (phase II) alone. NSAID metabolism proceeds, in large part, by way of the CYP3A or CYP2C families of P450 enzymes in the liver (see Chapter 4). While renal excretion is the most important route for final elimination, nearly all undergo varying degrees of biliary excretion and reabsorption (enterohepatic circulation). In fact, the degree of lower gastrointestinal (GI) tract irritation correlates with the amount of enterohepatic circulation. Most of the NSAIDs are highly protein-bound (~ 98%), usually to albumin. Most of the NSAIDs (eg, ibuprofen, ketoprofen) are racemic mixtures, while one, naproxen, is provided as a single enantiomer and a few have no chiral center (eg, diclofenac).
All NSAIDs can be found in synovial fluid after repeated dosing. Drugs with short half-lives remain in the joints longer than would be predicted from their half-lives, while drugs with longer half-lives disappear from the synovial fluid at a rate proportionate to their half-lives.
NSAID anti-inflammatory activity is mediated chiefly through inhibition of prostaglandin biosynthesis (Figure 36–2). Various NSAIDs have additional possible mechanisms of action, including inhibition of chemotaxis, down-regulation of IL-1 production, decreased production of free radicals and superoxide, and interference with calcium-mediated intracellular events. Aspirin irreversibly acetylates and blocks platelet COX, while the nonCOX-selective NSAIDs are reversible inhibitors.
FIGURE 36–1 Chemical structures of some NSAIDs.
Selectivity for COX-1 versus COX-2 is variable and incomplete for the older NSAIDs, but selective COX-2 inhibitors have been synthesized. The selective COX-2 inhibitors do not affect platelet function at their usual doses. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while GI safety may be improved. On the other hand, selective COX-2 inhibitors increase the incidence of edema, hypertension, and possibly, myocardial infarction. As of August 2011, celecoxib and the less selective meloxicam were the only COX-2 inhibitors marketed in the USA. Celecoxib has a
U.S Food and Drug Administration (FDA) “black box” warning concerning cardiovascular risks. It has been recommended that all NSAID product labels be revised to mention cardiovascular risks. In July 2015 the FDA strengthened the warning that NSAIDs can cause heart attacks or strokes. A study found that NSAID use was associated with increased risk of serious bleeding and cardiovascular events after myocardial infarction. The risk is higher among users of celecoxib and diclofenac, and lower among users of ibuprofen and naproxen.