Rofecoxib: a new selective COX-2 inhibitor.VD Rajadhyaksha, SA Dahanukar
Department of Pharmacology and Therapeutics, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai - 400 012, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 11590304
Source of Support: None, Conflict of Interest: None
Keywords: Anti-Inflammatory Agents, Non-Steroidal, therapeutic use,Arthritis, drug therapy,Cyclooxygenase Inhibitors, pharmacology,therapeutic use,Human, Lactones, pharmacology,therapeutic use,Randomized Controlled Trials,
Pain is one of the commonest symptoms in many patients. The common causes of pain include musculoskelet al conditions like osteoarthritis and rheumatoid arthritis. Nonsteroidal antiflammatory drugs (NSAIDS) are the first line drugs used in the treatment of such patients for alleviation pf pain.
The principal mechanism of action of NSAIDS is via the inhibition of cyclo-oxygenase enzyme (COX) involved in synthesis of prostaglandins. Decrease of prostaglandins can lead to decrease in pain and inflammation as they are one of the mediators involved in inflammation This enzyme exists in 2 isoforms - COX 1 and COX 2. The former is the constitutively expressed form of the enzyme, involved in prostaglandin synthesis in gastrointestinal, renal system and the platelets while the latter is induced by inflammation following inury. Recent studies confirm that inhibition of COX-2– the other isoform is responsible for antiinflammatory effects of NSAIDS. Rofecoxib is a newer COX-2 inhibitor that is developed for use in patients with osteoarthritis and/or acute pain and is now available in the Indian market.
Rofecoxib is a sulphur containing compound and also possesses multiple ketonic bonds and a terminal methyl group attached to a 3 phenyl ring structure.
Rofecoxib selectively inhibits COX - 2 activity in a dose dependent manner. There is no significant inhibition of COX-1 activity. In single oral doses ranging from 5 to 1000mg; rofecoxib inhibits COX-2 activity with decreased concentration of PGE. As compared to other conventional NSAIDS, these dosages do not inhibit any other isoform of COX enzyme or TBX2 and hence there is no effect on thromboxane production.
Rofecoxib has potent antipyretic activity similar to Ibuprofen. In doses of 12.5 - 25 mg, the drug possesses antipyretic actions. There is less propensity to develop peptic ulcer in patients receiving Rofecoxib as compared to other NSAIDS. It does not increase intestinal permeability nor does it affect local prostaglandin synthesis in the gastrointestinal system. In clinical studies, it has been found that there is less fecal blood loss seen with the use of Rofecoxib as compared to conventional NSAIDS.
The therapeutic effects of Rofecoxib are dose-proportional; however with doses more than 50 mg there is a decrease in dose - proportionality probably due to low solubility of Rofecoxib.
Rofecoxib has a good oral bioavailability upto 93%. It is highly protein bound and has a half life of 17 hours. The drug is initially hydroxylated to cis-dihydro and trans - dihydro derivatives in the liver and these derivatives then undergo glucuronidation. The drug is safe in mild hepatic failure; however should be used with caution in case of severe liver failure. Less than 1 % of the drug is recovered unchanged in the urine.
No data is currently available on its safety in pregnancy.
Rofecoxib can be used in a variety of conditions for its analgesic and anti-inflammatory actions. The most common indications for the use of rofecoxib are in the alleviation of pain in osteoarthritis and rheumatoid arthritis.
Osteoarthritis – Rofecoxib is equi-efficacious as diclofenac and ibuprofen in relieving pain and decreasing inflammation. In a dose of 5-50 mg, this drug is more safe than any other conventional NSAID when it is used in osteoarthritis as the sole NSAID. It can also be given for secondary failures ie patients not responding to standard NSAIDs and even in those conditions, it is much safer than other NSAIDs.
Post-operative dental pain – In various clinical trials, rofecoxib has been shown to alleviate post-operative dental pain. Its analgesic efficacy is comparable to that of nabumetone or naproxen in such cases. For this indication, a dose of 50 mg is more effective than 12.5 or 25 mg.
Primary dysmenorrhoea - Rofecoxib can slso be used as the sole agent in alleviating the pain caused due to primary dysmenorrhoea. There is a significant improvement in patients global evaluation, peak pain relief, time to remedication.
Rheumatoid arthritis – Rofecoxib is also known to be effective to alleviate pain associated with rhematoid arthritis. At present, it is being evaluated for the same in multicentric phase III trails and hence is not marketed for this indication at present.
The dose of rofecoxib in the various conditions mentioned above ranges from 12.5 - 50 mg. It is suggested that the initial dose can be 12.5 mg and further increments can be made on the basis of response of the patient.
The drug is generally well tolerated in patients. It is much safer than other NSAIDS. The most commonly reported adverse events are diarrhoea, headache, nausea and upper respiratory tract infection. The incidence of gastrointestinal adverse events are much less with rofecoxib as compared to ibuprofen and diclofenac. However, there are certain reports of mucosal ulceration and hyperracidity seen with rofecoxib. The drug does not appear to have any adverse effect on the kidney or on the platelets. But long term studies with Rofecoxib are needed to detect effects of prolonged inhibition of COX-2 in the brain, kidney and other organs.
Rofecoxib does not have any effect on cytochrome p450 3A or any of the other isoenzymes and therefore does not influence the hepatic metabolism of other drugs. It also does not have any effect on the pharmacodynamic and pharmacokinetic profile of steroids, antacids, H2 blockers, digoxin or ketoconazole. However, rofecoxib can reduce the excretion of methotrexate thereby plasma concentration of methotrexate. It also increases the plasma concentration of free warfarin by competing at the protein binding sites and causes increased incidence of bleeding.
Rifampicin, a potent hepatic microsomal enzyme inducer causes increased metabolism of rofecoxib associated with decreased efficacy.
Rofecoxib, a specific COX-2 inhibitor is approved for use in patients with osteoarthritis, post-operative dental pain and dysmenorhoea. It has similar analgesic efficacy as conventional NSAIDS and is much safer than them. Currently, it is also being evaluated as an analgesic and anti-inflammatory drug for rheumatoid arthritis.The selectiveness of its actions makes rofecoxib as the most promising NSAID to be used in the management of pain.
On the face of it, rofecoxib along with celecoxib seem to appear as the NSAIDs of the new millenium.