Selective COX 2 Inhibitors

Selective COX-2 inhibitors (coxibs) block cyclo-oxygenase-2 at therapeutic doses while sparing COX-1 to a large degree. They give anti-inflammatory analgesia with fewer gastrointestinal complications and no meaningful platelet inhibition, at the cost of persistent renal, hypertensive and thrombotic risk, which has restricted the class.

Mechanism. COX-2 inhibition lowers prostaglandin E2 at inflamed sites but also lowers endothelial prostacyclin without reducing platelet thromboxane A2, which tilts the balance toward thrombosis and raises blood pressure. Renal COX-2 inhibition reduces sodium excretion and renal blood flow.

Pharmacokinetics. Celecoxib: peak 2 to 3 hours, half-life 11 hours, metabolised by CYP2C9. Etoricoxib: half-life about 22 hours, hepatic CYP3A4. Parecoxib is a prodrug converted to valdecoxib. Both are cleared mostly as metabolites in urine.

Celecoxib. Osteoarthritis 200 mg daily or 100 mg twice daily; rheumatoid arthritis 100 to 200 mg twice daily; acute pain 400 mg first dose then 200 mg as needed; maximum 400 mg daily. Contains a sulphonamide group (avoid after sulphonamide anaphylaxis). Halve the dose in CYP2C9 poor metabolisers, moderate hepatic impairment (Child-Pugh B) and with fluconazole; contraindicated in severe hepatic impairment.

Etoricoxib. Osteoarthritis 30 to 60 mg daily; rheumatoid arthritis and ankylosing spondylitis 90 mg daily; acute gout 120 mg daily for no more than 8 days; maximum 120 mg daily. Raises blood pressure more than celecoxib; not licensed in some countries. Hepatic impairment: maximum 60 mg daily if mild, 60 mg on alternate days if moderate; contraindicated in severe.

Parecoxib. 40 mg intravenously or intramuscularly, then 20 to 40 mg every 6 to 12 hours; maximum 80 mg daily and 3 days of treatment. Used perioperatively when oral dosing is not possible; contraindicated after coronary bypass surgery. Not licensed in some countries.

Meloxicam and nimesulide. Meloxicam is COX-2 preferential at 7.5 mg and loses selectivity at 15 mg. Nimesulide has restricted licensing because of hepatotoxicity.

• First-line. Not routinely first-line; used when an NSAID is needed in a patient at high gastric risk with low cardiovascular and renal risk.
• Alternative. Perioperative analgesia where platelet function and surgical bleeding matter, such as orthopaedic and plastic surgery; acute gout when other NSAIDs are unsuitable; ankylosing spondylitis.
• Specialist. Parecoxib in selected perioperative multimodal regimens.
• Emergency. No distinct emergency role.

Selection rules. Use the lowest dose for the shortest time. In patients at high gastric risk who need long-term NSAID, add a proton pump inhibitor to a coxib. Confirm blood pressure control and renal function first.

Contraindications. Established ischaemic heart disease, stroke, peripheral arterial disease; moderate to severe heart failure; active gastrointestinal bleeding; eGFR under 30 mL/min; sulphonamide anaphylaxis (celecoxib); third trimester; perioperative coronary bypass; severe hepatic impairment.

Serious adverse effects. Myocardial infarction and stroke (boxed-warning-level risk); hypertension and fluid retention; acute kidney injury; gastrointestinal events (less than with nonselective NSAIDs but not abolished, especially with aspirin co-prescription); severe skin reactions; hepatotoxicity.

Major interactions.

• Aspirin: erodes the gastric advantage.
• Anticoagulants: bleeding.
• ACE inhibitors, ARBs and diuretics: kidney injury.
• Fluconazole and other CYP2C9 inhibitors: raise celecoxib.
• Lithium and ciclosporin.
• Rifampicin lowers etoricoxib exposure.

Common prescribing errors.

• Treating coxibs as cardiovascularly safe.
• Prescribing to patients with established vascular disease.
• Omitting blood pressure checks.
• Full-dose celecoxib with fluconazole.
• Parecoxib beyond 3 days.

Special groups.

• Pregnancy: avoid from 20 weeks and contraindicated in the third trimester.
• Breastfeeding: avoid etoricoxib; celecoxib is used when necessary.
• Children: not licensed for routine use.
• Older adults: start at the lowest dose.
• Kidney: avoid at eGFR under 30 mL/min.
• Liver: celecoxib halved in Child-Pugh B; etoricoxib capped at 60 mg daily (mild) or 60 mg on alternate days (moderate); both contraindicated in severe impairment.
• East Africa: availability of coxibs varies and cost may limit use; a nonselective NSAID with a proton pump inhibitor is often the practical alternative.

Monitoring. Blood pressure at start, at 2 weeks and every 3 to 6 months; creatinine and potassium in those at renal risk; liver enzymes if prolonged; review need every 3 months.

Referral and escalation. New chest pain, neurological deficit, uncontrolled hypertension, acute kidney injury or gastrointestinal bleeding.

Comparison with alternative classes. Coxibs cause less gastric injury than nonselective NSAIDs and spare platelets, but are not safer for the heart or kidney. Paracetamol, topical NSAIDs or naproxen with a proton pump inhibitor are often better if cardiovascular risk is raised.