NSAIDs and prostaglandin (PG)
synthesis inhibition
In 1971 Vane and coworkers made the landmark
observation that aspirin and some NSAIDs blocked prostaglandin (PG) generation. This is now considered to be the major mechanism of action of NSAIDs. Prostaglandins, prostacyclin (PG I,)
and thromboxane A, (TXA,) are produced from arachidonic acid by the enzyme cyclooxygenase (see
p. 198) which exists in a constitutive (COX-1) and an inducible (COX-2) isoforms; the former serves
physiological "house keeping functions, while the latter, normally present in minute quantities,
is induced by cytokines and other signal molecules at the site of inflammation. This leads to
generation of PGs locally which mediate many of the inflammatory changes. However, COX-2
is constitutively present at some sites in brain, in juxtaglomerular cells and in the foetus; it
may serve physiological role at these sites. Most NSAIDs inhibit COX-1 and COX-2 nonselectively,
but now some selective COX-2 inhibitors have been produced. Features of nonselective COX-1/
COX-2 inhibitors (traditional NSAIDs) and selective COX-2 inhibitors are compared .Aspirin inhibits COX irreversibly by acety- lating one of its serine residues; return of COX activity depends on synthesis of fresh enzyme.Other NSAIDs competitive reversible inhibitiors of COX; return of activity depends on their dissociation from the enzyme which in turn is governed by the pharmacokinetic
characteristics of the compound.
Analgesia PGs induce hyperalgesia (see p. 203) by affecting the transducng property of free nerve endings s0 that stimuli that normally do not elicit pain are able to do so. NSAIDs do not affect the tenderness induced by direct application of PGs, but block the pain sensitiz-ing mechanism induced by bradykinin, TNFa, interleukins (ILs) and other algesic substances primarily by inhibiting COX-2. This constitutes the peripheral component of the analgesic action of NSAIDs. They are, therefore, more effective against inflammation associated pain. Lately the central component of analgesic action of NSAIDs has also been shown to involve inhibition of PG synthesis in the spinal dorsal horn neurones as well as in brain, so that PG mediated amplification of pain impulses does not occur.
Antipyresis NSAIDs lower body temperature in fever, but do not cause hypothermia in norm thermic individuals. Fever during infection and tissue injury is produced through the generation of
pyrogens including, ILs, TNFa, interferons which induce PGE, production in hypothalamus-raise
its temperature set point. NSAIDs block the action of pyrogens but not that of PGE, injected
into the hypothalamus. The isoform dominant at this site appears to be COX-2 (possibly COX-3.a splice variant of COX-1 that is inhibited by paracetamol as well). However, fever can occur through non-PG mediated mechanisms as well.
Antiinflammatory The most important mecha-nism of antiinflammatory action of NSAIDs is
considered to be inhibition of COX-2 mediated enhanced PG synthesis at the site of injury. However, there is some evidence that inhibition of the constitutive COX-1 also contributes to suppression of inflammation, especially in the initial stages. The antiinflammatory potency or different compounds roughly corresponds with their potency to inhibit COX. However, nime-sulide is a potent antiinflammatory but relatively weak COX inhibitor. PGs are only one of the mediators of inflammation, and inhibition of COX does not depress the production of others mediatorslike LTs, PAF, cytokines, etc. Inflam-mation is the result of concerted participation of a large number of vasoactive, chemotactic and proliferative factors at different stages, and there are many targets for antiinflammatory action.
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