4. COX Enzyme Inhibitors

The use of non-steroidal anti-inflammatory drugs (NSAIDs) in anaesthetic practice is widespread, but side effects are common and there is continued interest in selective COX-2 inhibitors

it is now recognized that these exist in at least two isoforms: a ‘constitutive’ COX-1 enzyme that is present in all tissues and produces prostaglandins, and an ‘inducible’ COX-2 enzyme which is produced in high concentrations within cells at inflammatory sites. It is present in the brain, uterus, kidney and prostate, but is more or less undetectable elsewhere until induced by tissue damage.

COX enzymes catalyze the production of prostanoids, which comprise a family of lipid mediators with numerous diverse biological roles. The preferential substrate for COX enzymes is arachidonic acid. This is a 20-carbon unsaturated chain which is cleaved from the phospholipid of membranes by phospholipase A2 (PLA2). prostanoid biosynthesis is the conversion of arachidonic acid to prostaglandin PGG2 and thence to PGH2, which is the precursor to all the compounds in the series, including PGE2, PGD2, PGF2a, PGI2 (prostacyclin) and thromboxane (TXA2) COX enzymes are involved in two different biosynthetic reactions; in addition to catalyzing the production of prostaglandin PGG2, a secondary peroxidase reaction then converts PGG2 to PGH2

Tissue trauma or inflammation stimulate the release of inflammatory mediators and the enhanced production of prostaglandin PGE2. (There are four identified PGE2 receptors: EP1–EP4). PGE2 binds to end-plate receptors and decreases the threshold for neuronal depolarization. This in turn amplifies the afferent input from peripheral nociceptors to the dorsal horn of the spinal cord.

Non-steroidal anti-inflammatory drugs (NSAIDs): these include non-selective drugs in common use, such as diclofenac, ketoprofen, ibuprofen, aspirin and paracetamol, as well as the newer selective COX-2 inhibitors (the ‘-coxib’ class), for example, parecoxib and celecoxib of NSAIDs are mediated largely through COX-2 inhibition, whereas adverse effects are related to COX-1 inhibition

NSAIDs decrease production of the prostaglandins PGE2 and PGI2 that sensitize nociceptors to inflammatory mediators such as serotonin and bradykinin They also exert central effects at spinal cord level, with COX-2 mediating hyperalgesia secondary to increased neuronal excitability. COX-2 inhibition reduces the induction/up-regulation of the enzyme and has been described as ‘anti-hyperalgesic’ rather than ‘analgesic’, but the distinction is essentially academic.

: NSAIDs inhibit prostaglandin production in the hypothalamus. IL-1 release during an inflammatory response stimulates the hypothalamic production of prostaglandin PGEs, which effectively ‘reset’ the hypothalamic thermostat upwards. PGD2 in the brain is also involved in temperature homeostasis. COX-2 is induced centrally by pyrogens, with an increase in PGE2 production.

: the inflammatory response is complex, involving a large number of mediators (see under ‘Sepsis’ in Chapter 3). NSAIDs influence mainly those components in which the products of COX-2 reactions are important. These include vasodilatation, oedema formation and pain

NSAIDs reduce platelet aggregation by inhibiting thromboxane TXA2 synthesis. This is unaffected by COX-2 inhibitors, which have no antithrombotic effect.

the drugs affect only the main cyclo-oxygenation step and do not influence the peroxidase conversion stage of prostanoid synthesis. Non-selective drugs act mainly by competitive inhibition of the arachidonic acid binding site. This is reversible, except in the case of aspirin, which irreversibly acetylates hydroxyl groups on serine residues. The -coxib class are non-competitive, time-dependent COX-2 inhibitors, whereas the -oxicam class (meloxicam, tenoxicam) are competitiv

Gastrointestinal tract effects: gastrointestinal complications are common, with gastric damage present in around 20% of chronic users. Prostaglandins decrease gastric acid secretion, increase mucus production and improve the microcirculatory blood flow.

two prostaglandins are important in renal function. PGE2 has a role in water reabsorption and also mediates compensatory vasodilatation to offset the action of noradrenaline or angiotensin II. PGI2 also maintains renal dilatation and blood flow, but does so only under circumstances of physiological stress such as hypovolaemia. Concurrent administration of NSAIDs, therefore, can cause acute renal impairment. The situation is made more complex by the fact that COX-2 is constitutively expressed in the kidney. This explains why trials of high-dose COX-2 selective inhibitors have shown an association with hypertension and fluid retention.

Respiratory effects: bronchoconstriction can be triggered in about 10% of asthmatic subjects. This may be due partly to the inhibition of PGE2-mediated bronchodilatation

Cardiovascular effects: endothelial COX-1 releases PGI2 to mediate vasodilatation and inhibition of platelet aggregation. COX-2 can also be expressed in vascular smooth muscle with the release of PGI2 and PGE2. COX enzymes may therefore have a cardioprotective function. This may explain the findings of the large VIGOR unexplained increase in the incidence of myocardial infarction in the COX-2 (rofecoxib) group in comparison with the non-selective (naproxen) group

the inhibition of endothelial COX-1 blocks the production of thromboxane A2, thereby reducing platelet aggregation and prolonging bleeding time. COX-2 inhibitors have no such effect

the acute inflammatory response to trauma induces COX-2 in osteoblasts, and there is some suggestion that prostaglandin inhibition by NSAIDs compromises bone healing following fracture. The studies, however, are not robust enough to preclude their use, although many orthopaedic surgeons do prefer to avoid them.