COX Inhibitors

Cyclo-oxygenase inhibitors are typically used to treat mild to moderate pain. Oral COX inhibitors typically have:

  • Rapid absorption
  • High protein binding
  • Low VD

Mechanism of Action

There are two(ish) isoenzymes of COX:

  • COX-1
    Important for homeostatic function.
  • COX-2
    Induced with tissue damage and contributes to inflammation. COX-2:
    • Exists in the vascular endothelium where it synthesises prostacyclin (which opposes the action of thromboxanes)
    • Inhibition may result in a relative abundance of thromboxane, causing platelet aggregation and vasoconstriction
  • COX-3
    Variant of COX-1 which exists centrally and mediates the analgesic and antipyretic effects of paracetamol.

Effects occur due to:

  • Decrease in endoperoxidases
    Inhibited by COX.
  • Increase in other arachidonic-acid derived factors
    Due to the diversion of arichdonic acid down other pathways.

COX inhibition has different effects in different tissues:

  • Prevents subsequent conversion of prostaglandins to thromboxane A2 and PGI2
  • Peripherally, inhibition of prostaglandin synthesis is anti-inflammatory
  • Centrally, it is anti-pyretic
  • In the stomach, it decreases mucous production and leads to mucosal ulceration
  • Aspirin (a non-specific COX inhibitor), prevents production of both thromboxane A2 and PGI2
    • As platelets have no nucleus, the COX inhibition remains for the entirety of the platelet lifespan
    • Endothelial cells will produce new COX within hours, and so its anti-inflammatory effects are temporary

Adverse Effects

  • Asthma/Bronchospasm
    Secondary to increased leukotriene synthesis due to increased arachidonic acid levels. Occurs in 20% of asthmatics with NSAID use.

  • Platelet dysfunction
    A consequence of COX-1 inhibiton only, and may result in increased perioperative bleeding risk (though decreased AMI and CVA risk).

  • Thrombotic events, including MI and CVA
    Risk is greater with COX-2 inhibitors, due to selective inhibition of prostacyclin. with NNH for non-fatal MI being 500 patient-years, and NNH for fatal MI being 1000 patient-years.

  • Impaired GFR
    Occurs as a consequence of uninhibited afferent arteriolar constriction. Worse with concurrent hypovolaemia, renal artery stenosis, or concurrent ACE-I use.

  • Gastric erosion
    A consequence of impaired mucosal secretion through COX-1 inhibition. This can result in pain, anaemia, or fatal bleed. In general, risk of gastric erosion is (from highest to lowest risk):

    • Ketorolac
    • Diclofenac/naproxen
    • Ibuprofen (<1.2g/day)
    • COX-2 Inhibitors
  • Transaminitis may occur following NSAID use

Comparison of COX Inhibitors

Characteristic Aspirin Diclofenac Ketorolac Ibuprofen Celecoxib Parecoxib
Mechanism of Action Irreversible inhibition of platelet thromboxane production. As platelets are anucleic, they are unable to regenerate thromboxane. Non-selective COX inhibitor Non-selective COX inhibition Non-selective COX-inhibition COX-2 inhibitor (30:1 in favour of COX-2) COX-2 inhibitor (61:1 in favour of COX-2)
Uses Prevention of arterial thromboembolism, MI, CVA, migraine, analgesia, others (e.g. Still's disease) Mild-to-moderate pain Potent anti-analgesic, minimal anti-inflammatory properties Mild-to-moderate pain Analgesia, particular chronic arthritic pain Acute inflammatory pain
Distribution 85% protein bound. Weak acid with a pKa of 3, unionised in the stomach and ionised at physiological pH 97% protein bound
Absorption Gastric absorption (pKa 3) leads to rapid onset.
Metabolism Hepatic metabolism to salicyluric acid and glucuronides. May have zero-order eliminiation in overdose. CYP to inactive metabolites CYP2C9 to inactive metabolites CYP2C9 to inactive metabolites
Elimination Renal. Elimination may be increased with urinary alkalinisation.
Dose Low-dose (100mg daily) selectively inhibits platelet COX, whilst preserving endothelial COX, resulting in decreased platlet aggregation whilst maintaining vasodilation. 300-900mg for analgesia/migraine. 50mg BD/TDS 15-30mg IM/IV Q6H 400-800mg TDS, or 10mg/kg 100-200mg BD 20-40mg BD
Route PO PO/PR/IM/IV IM/IV (off-label in Aus) PO/PR PO IV
Respiratory Aspirin uncouples oxidative phosphorylation, increasing O2 consumption and CO2 production. It also may stimulate, and (at higher doses) depress the respiratory centre. In overdose, these are significant, and may result in a mixed respiratory and metabolic acidosis.
CVS MI and CVA risk reduction. Increased bleeding. Risk of MI similar to COX-2 inhibitors. Local thrombus with IV injection. Lower dose not associated with prothrombotic events. Unclear effect on CVA and MI, but recommended to avoid use in IHD/CVD Unclear effect on CVA and MI, but recommended to avoid use in IHD/CVD
Metabolic Reye's syndrome is mitochondrial damage, hepatic failure, and cerebral oedema (and encephalopathy) in children <12. Mortality 40%.

References

Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.

Last updated 2018-03-03

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