NSAIDs and prostaglandin (PG) synthesis inhibition

In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs

blocked PG generation. This is now considered to be the major mechanism of action of NSAIDs.

Prostaglandins, prostacyclin (PG I2) and  Thromboxane A2 (TXA2) are produced from arachidonic acid by the enzyme cyclooxygenase which exists in a 

• constitutive (COX-1 ) and  
• an inducible (COX-2) isoforms;

 the former [constitutive (COX-1 )] à serves physiological 'house keeping' functions, while

the latter [inducible (COX-2)]           ànormally present in minute quantities,

is induced by cytokines and other signal molecules at the site of inflammation à generation of

PGs locally which mediate many of the inflammatory changes. However, COX-2 is constitutively

present at some sites in brain and in juxtaglomerular cells: 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.

Aspirin inhibits COX irreversibly by acetylating one of its serine residues; return of COX

activity depends on synthesis of fresh enzyme.

Beneficial action due to PG synthesis Inhibition::-

• Analgesia: prevention of pain nerve ending sensitization

• Antipyresis

• Antiinflammatory

• Antithrombotic

• Closure of ductus arteriosus in newborn ' " ...

Other NSAIDs are competitive and reversible

inhibitors of COX, return of activity depends on

their dissociation from the enzyme which in turn

is governed by the pharmacokinetic characteristics of the compound.