COX II Inhibitors

CLASS

• Selective COX-2 inhibitors

Types

• celecoxib
• parecoxib
• rofecoxib
• valdecoxib
• also known as coxibs

MECHANISM OF ACTION

• developed to try and inhibit prostacyclin synthesis by the COX-2 isoenzyme induced at sites of inflammation without affecting the action of the constitutively active COX-1 isoenzyme found in gastic mucosa, platelets & kidney.
• have fewer GI side effects
• no impact on platelet function
• COX-2 is constitutively active in kidneys -> still produce the renal toxicities

INDICATIONS

1. anti-inflammatory – OA, RA, familial adenomatous polyposis, gout, ankylosing spondylitis
2. anti-pyretic
3. analgesic – dysmenorrhoea, acute musculoskeletal pain, post op pain

ADVERSE EFFECTS

• no effect on platelet aggregation, bleeding time & post-op blood loss.
• bone healing attenuated
• interactions: aspirin -> increases GI haemorrhage, warfarin -> increases INR, K+ sparring diuretics -> increase K+
• ? increase in CVA & IHD events
• increase in incidence of CHF
• hypertension
• liver dysfunction can take place
• same renal risks as non-selective NSAIDs

PHARMACOKINETICS

• Absorption – highly lipophilic
• Distribution
• Metabolism – hepatic
• Elimination –

EVIDENCE

• -> COX 2 inhibitors and NSAIDS have similar effects on renal function
• -> COX 2 inhibitors don’t produce bronchospasm in aspirin induced respiratory disease
• -> COX 2 inhibitors -> no effect of platelet function
• -> COX 2 inhibitors -> same peptic ulcer rate as placebo (decreased compared to NSAIDS)
• -> COX 2 inhibitors -> don’t give in patients with lots of vascular risk factors
• -> parocoxib & valdecoxib DO NOT increase risk of cardiovascular disease after non-cardiac surgery
• -> COX 2 inhibitors and NSAIDS are associated with the same rates of adverse CVS effects (MI)
• -> short-term use of COX 2 inhibitors do not affect bone healing after spinal fusion
• -> VIGOR study looked @ rofecoxib vs naproxen and found significant increase in MI in rofecoxib group (patients on low-dose aspirin were excluded)

PROS AND CONS

Advantages

• less GI side-effects (dyspepsia, ulcers and GI bleeding) – although this point has been challenged
• NICE recommendation of COX 2 use in individuals with high risk of GIH (2000)
• opioid sparing actions

Disadvantages

• increase in vascular morbidity (CVA, MI, IHD) – rofecoxib (VIGOR study)
• more expensive
• same adverse effect on platelets
• contra-indicated in peri-operative patient with the following: previous MI or CVA, cardiac or vascular surgery, patient at high risk of vascular disease undergoing major surgery (MEDSAFE statement, 2005)
• Na+ and K+ retention (effect on renal PG synthesis)
• nephrotoxic
• increased risk of thrombosis (reduced platelet prostacyclin without change in thromboxane)
• hypertension
• pregnancy -> premature closure of ductus arteriosus -> intrauterine foetal death
• interacts with warfarin (increased risk of bleeding and increased INR)

References and Links