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:
Important for homeostatic function.
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
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
Secondary to increased leukotriene synthesis due to increased arachidonic acid levels. Occurs in 20% of asthmatics with NSAID use.
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.
Occurs as a consequence of uninhibited afferent arteriolar constriction. Worse with concurrent hypovolaemia, renal artery stenosis, or concurrent ACE-I use.
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):
- Ibuprofen (<1.2g/day)
- COX-2 Inhibitors
- Transaminitis may occur following NSAID use
Comparison of COX Inhibitors
|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 unionised 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%.|
Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.