4. COX Enzyme Inhibitors Flashcards
Use
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
COX enzymes:
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.
Mechanisms
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
Pain pathway
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.
Drugs Which Affect COX Enzymes
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
Analgesia:
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.
Antipyretic action
: 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.
Anti-inflammatory effects
: 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
Antithrombotic effect
NSAIDs reduce platelet aggregation by inhibiting thromboxane
TXA2 synthesis. This is unaffected by COX-2 inhibitors, which have no
antithrombotic effect.
Mechanisms of NSAID action:
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
Adverse Effects Gi
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.
Renal effects:
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
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
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
Effects on haemostasis:
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
