Cox-2 Inhibitors - Non-Steroidal Anti-Inflammatory Drug(NSAID)

Cox-2 Inhibitors

The cyclo-oxygenase-2 (COX-2) inhibitors decrease the synthesis of prostaglandins through the selective inhibition of COX-2, with little or no inhibition of COX-1, resulting in anti-inflammatory and analgesic properties. Although similar to traditional non-steroidal anti-inflammatory drugs (NSAIDs), selective inhibition of COX-2 is claimed to result in fewer adverse effects traditionally associated with NSAIDs.

Examples

Celecoxib, parecoxib rofecoxib, valdecoxib and etoricoxib. As of September 30, 2004, Merck voluntarily withdrew.

As of September 30, 2004, Merck voluntarily withdrew  rofecoxib from the market after drug safety monitoring of a long-term study indicated that the drug may increase the risk of serious cardiovascular events, including myocardial infarctions and strokes among patients receiving rofecoxib, as compared to patients receiving placebo. Although the risk appeared small among individual users, the overall risk of a heart attack was twice the risk, as compared to placebo-treated patients. The Acting Commissioner of the FDA, reported that other drugs in this class would be closely monitored for similar side effects (FDA, 2004).

Several Indian doctors are also of the opinion that Cox-2 inhibitors must be restricted in use. The role of fatty acids in modifying the cardiovascular hazards of Cox-2 inhibitors is being investigated. Possible future (safer) alternatives to these drugs include nitric oxide (NO) NSAIDs, which have a nitric oxide moiety linked to a conventional NSAID, and show promise of a high safety profile.

Uses

Treatment of osteoarthritis and rheumatoid arthritis, manage-ment of acute pain in adults, and for treatment of primary dysmenorrhoea. 

Mode of Action

The cyclo -oxygenase enzyme (prostaglandin synthase H) consists of 2 isoforms, COX-1 and COX-2. The cyclo-oxyge-nase-2 (COX-2) inhibitors decrease the synthesis of prosta-glandin H2 through the selective inhibition of COX-2, with little or no inhibition of COX-1, resulting in anti-inflammatory and analgesic properties. Although similar to traditional non-steroidal anti-inflammatory drugs (NSAIDs), selective inhibi-tion of COX-2 may result in fewer gastrointestinal adverse effects traditionally associated with NSAIDs.

Clinical Features

·      In various controlled trials, COX-2 inhibitors have been associated with a decreased incidence of gastrointestinal side effects and increased GI tolerability compared to traditional non-steroidal anti-inflammatory drugs. However, the COX-2 inhibitors are not without gastric side effects, and the amount of safety afforded by selective inhibition of COX-2 has been questioned. Several authors have reported cases of acute renal failure with therapeutic dosing of COX-2 inhibitors. In fact the COX-2 inhibitors are said to be as nephrotoxic as conventional NSAIDs.

·      Celecoxib is contraindicated in patients with a hypersen-sitivity to sulfonamides. The relative reporting rate of sulfonamide-type adverse drug reactions with celecoxib was 80% higher than with rofecoxib.

·              Overdose information with COX-2 inhibitors is limited. Significant poisonings may be expected to result in symp-toms similar to those observed with typical non-steroidal anti-inflammatory agents, such as gastrointestinal upset or lethargy. Significant poisoning may result in rare effects of hypertension, acute renal failure, respiratory depression and coma.

·      In a large, randomised study of patients receiving long-term, daily treatment for rheumatoid arthritis with either rofecoxib 50 mg/day, or naproxen 1000 mg/day (Vioxx Gastrointestinal Outcomes Research Study (VIGOR); aspirin not permitted), patients receiving rofecoxib had a relative risk of 2.38 (95% confidence interval, 1.39 to 4.0; p less than 0.001) for developing serious, thrombotic, cardiovascular adverse events (MI, ischaemic stroke, unstable angina, cardiac thrombus, sudden or unexplained death, transient ischaemic attack, resuscitated cardiac arrest) compared with patients treated with naproxen. These results may be due to prothrombotic effects of rofecoxib or antithrombotic effects of naproxen.

Treatment

·      Monitor serum electrolytes, renal function and urinalysis after significant overdose.

·      Management consists of controlling possible gastrointes-tinal bleeding and providing supportive care.

·      No data are available regarding the utility of extracorporeal elimination techniques to remove celecoxib or other COX-2 inhibitors from the body. However, based upon celecoxib’s high degree of protein binding (97%) and large volume of distribution (400 L), dialysis is unlikely to be clinically useful.