Abstract and Introductions

Abstract

The non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are commonly utilized agents for musculoskeletal conditions. The harmful cardiorenal effects of some nsNSAIDs are well described and thought to be related to inhibition of prostanoid synthesis. Since the non-specific inhibition of both cyclooxygenase enzymes was associated with a higher incidence of gastrointestinal side effects, the selective targeting of the COX-2 enzymes with the COX-2 inhibitors promised and delivered a lower incidence of gastrointestinal side effects. However, the COX-2 inhibitors have not been found to be bereft of cardiorenal side effects. Indeed, some of these agents lead to increased blood pressure, an excessive risk of congestive heart failure and pro-thrombotic effects, especially in high risk populations. These deletrious effects, however, may not be class-specific and possibly related to pharmacokinetics, enzyme specificity and endothelium effects. This article also reviews the body of literature linking the nsNSAIDs and COX-2 inhibitors with important adverse cardiorenal effects and their putative mechanisms.

Introduction

A comprehensive review of the extensive body of literature surrounding the adverse cardiorenal effects of non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and cyclooxygenase-2 (COX-2) selective agents is remarkable for several salient themes. First and foremost, it is apparent that all non-steroidal antiinflammatory drugs (nsAIDS), which include nsNSAIDs and COX-2 inhibitors, lead to variable degrees of fluid retention and blood pressure effects. Some agents possibly lead to de novo increases in blood pressure and others exacerbate blood pressure control in patients with diagnosed and controlled hypertension. The efficacy of some commonly utilized anti-hypertensive agents is also antagonized by some NSAIDs. By virtue of their effects on fluid retention, NSAIDs may also be associated with a risk of new or worsened heart failure. However, the impact of fluid retention and new or exacerbated heart failure on overall cardiovascular mortality and morbidity is unclear. Another issue on which most experts hold consensus is that not all traditional NSAIDs and COX-2 inhibitors lead to similar degrees of fluid retention and blood pressure changes. Significant and clinically important differences within the COX-2 and nsNSAID groups are also clearly evident from this literature review.

A favorable effect of blood pressure reduction on cardiovascular mortality has been borne out by several large randomized and epidemiological studies. Therefore, it is reasonable to hypothesize that even small increases in blood pressure can lead to relatively large numbers of adverse cardiovascular events including more deaths [Hansson et al. 1998; Staessen et al. 1997]. Besides the commonly attributable side effects, some NSAIDs may possess pro-thrombotic and pro-arrhythmic properties [Zhang et al. 2006]. The magnitude of the adverse cardiovascular effects associated with NSAIDs is also modulated by the underlying disease process such as rheumatoid arthritis, presence of traditional cardiovascular risk factors, concomitant drug therapy, and the dosage and duration of exposure.

Non-steroidal anti-inflammatory drugs are quite important from the public-health standpoint because the impact of musculoskeletal conditions on functional impairment outstrips that resulting from cardiovascular, respiratory, renal, gastrointestinal, psychiatric, and neurologic conditions in the United States [Sprangers et al. 2000]. It is conceivable that with the aging of the population and looming baby-boomer generation retirements, the burden of musculoskeletal disorders is only likely to increase. Non-specific NSAIDs and COX-2 inhibitors form an integral component of the treatment of these disorders in this population with extensive co-morbidities, necessitating the continued debate surrounding the safety of these agents in this population with a significantly higher likelihood of sustained nsNSAID/COX-2 inhibitor use and concomitant medication use. The continued pursuit of safe alternatives to NSAIDs is also required for all the reasons mentioned above.