Drug Insight: Cyclo-Oxygenase-2 Inhibitors--A Critical Appraisal

Burkhard Hinz; Bertold Renner; Kay Brune

Disclosures

Nat Clin Pract Rheumatol. 2007;3(10):552-560. 

In This Article

Summary and Introduction

Following the withdrawal of rofecoxib and valdecoxib, the discussion concerning selective cyclo-oxygenase (COX)-2 inhibitors was often characterized more by emotions than scientific evidence. In fact, the original rationale of these substances is still valid, in that selective COX2 inhibitors cause significantly fewer severe side effects in the gastrointestinal tract than traditional NSAIDs. Off-label long-term use of COX2 inhibitors in patients with a history of colorectal adenomas in well-designed, placebo-controlled trials showed that treatment with these agents is associated with an increased rate of cardiovascular adverse effects. Other studies have shown that both COX2 inhibitors and NSAIDs are associated with a similar cardiovascular risk, suggesting that there is presently no rationale for a further differentiation of these groups of drugs in terms of cardiovascular toxicity. Referring to the current debate, potential mechanisms underlying cardiovascular adverse effects associated with the long-term use of COX2 inhibitors and NSAIDs are discussed. Moreover, this Review summarizes the pharmacology of COX2 inhibitors with emphasis on their different pharmacokinetic characteristics.

In 1971, Vane showed that the analgesic action of traditional NSAIDs relies on inhibition of the cyclo-oxygenase (COX) enzyme, which in turn results in reduced synthesis of proalgesic prostaglandins.[1] Two decades later, COX was shown to exist as two distinct isoforms:[2,3] COX1, which is constitutively expressed as a 'housekeeping enzyme' in nearly all tissues, and mediates physiological responses (e.g., cytoprotection of the stomach, platelet aggregation); and COX2, which is responsible for the synthesis of prostanoids involved in pathological processes, such as acute and chronic inflammatory states. In fact, predominantly COX2-dependent prostaglandins sensitize peripheral nociceptors and act in the spinal cord to produce central hyperalgesia.[4] As will be discussed later, COX2 is also involved in many adaptive processes such as regulation of blood pressure, kidney function, and ulcer and wound healing.

Many of the adverse effects of NSAIDs (e.g., gastrointestinal ulceration and bleeding, platelet dysfunction) have been associated with a suppression of COX1-derived prostanoids, whereas inhibition of COX2-derived prostanoids mediates the anti-inflammatory, analgesic, and antipyretic effects of these compounds. In consequence, the hypothesis that selective inhibition of COX2 might have therapeutic actions similar to those of traditional NSAIDs, but cause fewer unwanted drug effects, was the rationale for the development of selective COX2 inhibitors. The development of these drugs has been reviewed previously.[5,6,7]

A substance is regarded as a selective COX2 inhibitor if it inhibits COX2 but causes no clinically relevant COX1 inhibition at therapeutic doses. Of the variety of available test systems, the ex vivo whole-blood assay has emerged as the best method to estimate COX2 selectivity in humans.[8] With the in vitro and ex vivo approaches of this assay, all NSAIDs were shown to inhibit both COX1 and COX2 at therapeutic doses, although some NSAIDs (diclofenac, aceclofenac, meloxicam) might confer a preferential inhibition of the COX2 enzyme.[9,10] X-ray crystallography of the three-dimensional structures of COX1 and COX2 explained how COX2 specificity is achieved: in the hydrophobic channel of the COX enzyme, a single amino acid difference in position 523 (isoleucine in COX1, valine in COX2) is critical for COX2 selectivity of several drugs. Accordingly, the smaller valine molecule in COX2 gives access to a side pocket that is the binding site of COX2-selective substances.[11]

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