FRCA Notes

Specific COX-2 Inhibitors

  • Specific COX-2 inhibitors ('coxibs') were designed with the intent of creating NSAIDs with a reduced GI side-effect profile
  • However, the improved profile was not as good as hoped for and they carry risk of major vascular events e.g. Rofecoxib and Valdecoxib have been withdrawn from the market

  • As such, the Committee on Safety of Medicines advise that COX-2 inhibitors are contraindicated in:
    • Ischaemic heart disease
    • Peripheral vascular disease
    • Cerebrovascular disease
    • Heart failure
  • Careful consideration should be given before using them in patients with cardiovascular risk factors
  • CLASS (2000) and PRECISION (2016) trials:
    • Gastrointestinal side-effect rate similar or better than other NSAIDs
    • Similar incidence of MI and stroke

Presentation

  • Presents as 100mg tablets for use in chronic pain secondary to OA/RA (up to 200mg BD)

Pharmacokinetics

  • Peak plasma concentration after 2-3hrs
  • 97% plasma protein bound
  • High volume of distribution: 5.7 L/kg
  • Elimination half-life 8-12hrs
  • Metabolised by hepatic CYP2C9 to inactive metabolites
    • CYP2C9 subject to pharmacogenetic variation
    • Plasma concentration of celecoxib increased by CYP2C9 inhibitors (omeprazole)
    • Plasma concentration reduced by CYP2C9 inducers (carbamazepine)
  • Contains a sulphonamide group and therefore contra-indicated in sulphonamide allergy

  • Valdecoxib has been withdrawn due to significant dermatological side-effects, causing hypersensitivity reactions in those with sulphonamide allergy:
    • Exfoliative dermatitis
    • Stevens-Johnson syndrome
    • Toxic dermal necrolysis
    • Angioedema

Parecoxib

  • Parecoxib is a pro-drug converted to the active drug valdecoxib
    • Parecoxib has a plasma half-life of 20mins and has no intrinsic activity
    • It remains in use as it is not associated with these side-effects
    • NB parecoxib has a non-aromatic sulphonamide group (similar to furosemide) and is not contra-indicated in those with sulphonamide sensitivity
  • Parecoxib is a selective COX-2 inhibitor with a COX-1 to COX-2 inhibitory ratio of 1:61

  • Requires reconstitution in saline to form a parenteral solution
  • Dose 40mg, then 20-40mg 6-12hrly (max 80mg/day)

  • Pharmacokinetics:
Parecoxib metabolic pathway
  • Reduced dose required if co-administered with CYP2C9 inhibitors (e.g. fluconazole)
  • As valdecoxib itself inhibits CYP2C19/CYP2D6 it may increase the concentrations of drugs dependent on these enzymes for their metabolism
  • Elimination half-life of valdecoxib is 8hrs

  • A methyl-sulphone which is highly selective for COX-2
  • COX-1 to COX-2 inhibitory ratio of 1:344

Pharmacokinetics

  • >95% oral bioavailability
  • 90% protein bound
  • Volume of distribution 1.5 L/kg
  • Metabolism is hepatic via CYP3A4 among others
  • Elimination half life 22hrs (and increased in hepatic failure)
  • Is a weak inhibitor of CYP2C9, CYP2D6 and CYP3A

Pharmacodynamics

  • Reduced gastric side effects compared to COX-1 inhibitors for the first 9-12 months, then similar
  • Similar major vascular event profile as diclofenac

  • A phenylacetic acid derivative structurally similar to diclofenac and therefore different from the other 'coxibs' in this manner
  • Highly COX-2 selective with a COX-1 to COX-2 inhibitory ratio of 1:700
  • Owing to its structural difference it has a lower volume of distribution compared to the other COX-2 inhibitors
  • Contraindicated in patients with liver disease or a history of drug-induced transaminase elevation owing to risk of serious hepatotoxicity
  • Must monitor LFTs during treatment
  • Short elimination half life (5hrs)