Selective COX2 Inhibitors (Coxibs)

SELECTIVE COX2 INHIBITORS (COXIBS)

Because of the theoretical advantage of inhibiting COX2 without affecting COX1 function, some highly selective COX2 inhibitors have been introduced over the past decade. They cause little gastric mucosal damage; occurrence of peptic ulcer and ulcer bleeds is clearly lower than with traditional NSAIDs. They do not depress TXA₂ production by platelets (COXI dependent); do not inhibit platelet aggregation or prolong bleeding time, but reduce PGI₂ production by vascular endothelium.

Currently, 3 selective COX2 inhibitors (also called coxibs) Celecoxib, Etoricoxib and Parecoxib are available in India; Lumiracoxib is marketed in Europe, while Rofecoxib and Valdecoxib have been withdrawn for increasing cardiovascular (CV) risk.Selective COX2 inhibitors    cardiovascular risk

COX2 inhibitors reduce endothelial PGI₂ production without affecting platelet TXA₂ synthesis. This appears to exert prothrombotic influence and enhance CV risk.

VIGOR (VIOXX gastrointestinal outcomes research) study in over 8000 patients found 4fold higher incidence of myocardial infarction (MI) in rofecoxib (VIOXX) recipients compared to those on naproxen.

APPROVE (adenomatous polyp prevention on VIOXX) a placebo controlled trial among subjects with history of colorectal adenomas was stopped prematurely at 3 years because it confirmed higher risk of heart attack and stroke: rofecoxib was withdrawn globally in 2004.

A metaanalysis of 18 trials with rofecoxib for musculoskeletal disorders has also inferred that it increases incidence of MI.

Valdecoxib increased occurrence of MI in patients undergoing coronary bypass surgery. There were reports of severe skin reactions as well. It was withdrawn in 2005.

Though CLASS (celecoxib longterm safety study) did not find any increase in CV events, the APC (adenoma prevention with celecoxib) trial has been terminated prematurely due to 2.5 fold higher risk of the same.

There is no clear evidence as yet that etoricoxib and lumiracoxib also increase CV risk.

A joint committee in USA (2005) has concluded that enough evidence to withdraw all selective COX2 inhibitors is lacking, but that their labelling should include a warning of CV risk.

It has been concluded that selective COX2 inhibitors should be used only in patients at high risk of peptic ulcer, perforation or bleeds. If selected, they should be administered in the lowest dose for the shortest period of time. Moreover, they should be avoided in patients with history of ischaemic heart disease/hypertension/cardiac failure/cerebrovascular disease, who are predisposed to CV events.

Concerns, other than cardiovascular, have also been expressed about selective COX2 inhibitors.Other concerns with selective COX2 inhibitors

COX1 generated PGs may also play a role in inflammation: COX2 inhibitors may not have as broad range of efficacy as traditional NSAIDs.

Ulcer injury and H. pylori induce COX2 in gastric mucosa, which may contribute to gastroprotective PG synthesis; COX2 inhibition may delay ulcer healing.

Juxtaglomerular COX2 is constitutive; its inhibition can cause salt and water retention; pedal edema, precipitation of CHF and rise in BP can occur with all coxibs.

Celecoxib

The COX2 selectivity of celecoxib is modest (6–20 fold). It exerts anti-inflammatory, analgesic and antipyretic actions with low ulcerogenic potential. Comparative trials in rheumatoid arthritis have found it to be as effective as naproxen or diclofenac, without affecting COX1 activity in gastroduodenal mucosa. Platelet aggregation in response to collagen exposure remained intact in celecoxib recipients and serum TXB₂ levels were not reduced. Though tolerability of celecoxib is better than traditional NSAIDs, still abdominal pain, dyspepsia and mild diarrhoea are the common side effects. Rashes, edema and a small rise in BP have also been noted.

Celecoxib is slowly absorbed, 97% plasma protein bound and metabolized primarily by CYP2C9 with a t½ of ~10 hours. It is approved for use in osteo and rheumatoid arthritis in a dose of 100–200 mg BD.

CELACT, REVIBRA, COLCIBRA 100, 200 mg caps.

Etoricoxib

This newer COX2 inhibitor has the highest COX2 selectivity. It is suitable for once-a-day treatment of osteo/rheumatoid/acute gouty arthritis, dysmenorrhoea, acute dental surgery pain and similar conditions, without affecting platelet function or damaging gastric mucosa. The t½ is ~ 24 hours. Side effects are dry mouth, aphthous ulcers, taste disturbance and paresthesias.

Dose: 60–120 mg OD; ETODY, TOROCOXIA, ETOXIB, NUCOXIA 60, 90, 120 mg tabs.

Parecoxib

It is a prodrug of valdecoxib suitable for injection, and to be used in postoperative or similar shortterm pain, with efficacy similar to ketorolac.

Dose: 40 mg oral/i.m./i.v., repeated after 6–12 hours.

REVALDO, VALTOP 40 mg/vial inj, PAROXIB 40 mg tab.