10.02.3.3 Selective COX-2 Inhibitors

Rofecoxib is the most selective COX-2 inhibitor marketed to date. Clinical trials showed that rofecoxib was very effective against the pain and inflammation of chronic conditions such as osteoarthritis and rheumatoid arthritis. Rofecoxib was very popular with patients, many of whom considered rofecoxib a wonder drug, as it gave them more relieve from pain and inflammation than NSAIDs. As predicted, from the COX-2 selectivity, there was less gastrointestinal toxicity with rofecoxib than with non-selective NSAIDs. However, eventually, rofecoxib was withdrawn for causing a slight increase in cardiovascular toxicity, mainly myocardial infarction (heart attacks). This was an unexpected finding, and the reason for it is still being worked out.

Celecoxib (Celebrex) is not as COX-2 selective as rofecoxib. Unfortunately, this meant that it celecoxib is still able to inhibit enough COX-1 to induce some gastrointestinal toxicity. Indeed, clinical trials have failed to establish less gastrointestinal toxicity with celecoxib than with the non-selective NSAIDs. With regard to COX-2 inhibitory effects, cardiotoxicity is borderline and/or disputed with celecoxib. Celecoxib has not been withdrawn, but comes with a warning not to be used in subjects with cardiovascular or cerebrovascular disease i.e. subjects with increased cardiovascular risk. Celecoxib is active after oral administration, lipophilic and widely distributed, with a t_1/2 of elimination of 11 hours. Celecoxib is commonly used for the relief of inflammation in osteoarthritis and rheumatoid arthritis. Celecoxib is also used to give relief from post-extraction dental pain.

Although it has been around for many years, only recently has diclofenac (Voltaren) been shown to be a selective inhibitor of COX-2. Diclofenac has a similar selectivity for COX-2 to celecoxib. Thus, the gastrointestinal toxicity and cardiotoxicity of diclofenac is similar to that of celecoxib. Diclofenac has rapid absorption, with a short t_1/2 (1-2 hours). It is effective as an analgesic, antipyretic, and anti-inflammatory agent. Diclofenac is used long term in osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis (a form of arthritis that affects the spine). Diclofenac is also used short term use in acute musculoskeletal pain, postoperative pain, and dysmenorrhoea.

The quest for a selective COX-2 inhibitor is presently stalled, as although rofecoxib had less gastrointestinal toxicity than NSAIDs, it induced cardiotoxicity. Celecoxib and diclofenac do not have the cardiotoxicity, but do not have acceptable levels of gastrointestinal tolerability. Another approach to prevent gastrointestinal toxicity is to use celecoxib and diclofenac with gastrointestinal protective medicines. Diclofenac is available in combination with misoprostol. Misoprostol stimulates EP receptors to provide gastric cytoprotection, as discussed in the next section. The combination of diclofenac and misoprostol has decreased gastrointestinal toxicity, compared to diclofenac alone. The proton pump inhibitors (PPIs) can also be used to give gastrointestinal protection. Omeprazole is the prototype PPI. There are other –prazoles, which are all proton pump inhibitors e.g. esomeprazole. In addition to being used alone in the treatment of peptic ulcer, gastric reflux etc, the PPIs are also used for the prevention and/or treatment of gastrointestinal adverse effects of NSAIDs.