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Mechanism of Action of Nonsteroidal Anti-inflammatory Drugs

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Abstract

Salicylic acid and salicylates, obtained from natural sources, have long been used as medicaments. Salicylic acid was chemically synthesized in 1860 and was used as an antiseptic, an antipyretic, and an antirheumatic. Almost 40 years later, aspirin was developed as a more palatable form of salicylate. Soon after, other drugs having similar actions to aspirin were discovered, and the group was termed the “aspirin-like drugs” (also now termed the nonsteroidal anti-inflammatory drugs [NSAIDs]). Twenty-five years ago, it was proposed that the mechanism of action of NSAIDs was through their inhibition of prostaglandin biosynthesis. Since then, there has been general acceptance of the concept that these drugs work by inhibition of the enzyme cyclo-oxygenase (COX), which we now know to have at least two distinct isoforms: the constitutive isoform, COX-1, and the inducible isoform, COX-2. COX-1 has clear physiologic functions. Its activation leads, for instance, to the production of prostacyclin, which when released by the endothelium is antithrombogenic and when released by the gastric mucosa is cytoprotective. COX-2, discovered 6 years ago, is induced by inflammatory stimuli and cytokines in migratory and other cells. It is therefore attractive to suggest that the anti-inflammatory actions of NSAIDs are due to inhibition of COX-2, whereas the unwanted side-effects, such as irritation of the stomach lining, are due to inhibition of COX-1. Drugs that have the highest COX-2 activity and a more favorable COX-2 : COX-1 activity ratio will have a potent anti-inflammatory activity with fewer side-effects than drugs with a less favorable COX-2 : COX-1 activity ratio. The identification of selective inhibitors of COX-2 will therefore lead to advances in therapy.

Section snippets

Early Explanations for the Mechanism of Action of NSAIDs

Before 1971, little was known about the mechanism of action of NSAIDs, except that they produced an anti-inflammatory effect that was qualitatively and quantitatively different from the more potent anti-inflammatory glucocorticosteroids. Many of the biochemical effects of NSAIDs had been documented,4, 5, 6, 7but the theories based on these effects had been abandoned. Perhaps the most reasonable hypothesis at that time was based on the observation that the salicylates could inhibit several

NSAIDs and the Prostaglandin System

It was against the above background that investigation into the mechanism of action of aspirin was taken over by prostaglandin researchers. Piper and Vane employed he technique of continuous bioassay using the cascade bioassay system that had been developed by Vane[11]in the mid-1960s for use with blood or an artificial salt solution. The method involved perfusing guinea pig isolated lungs with Krebs’ solution and using the effluent to successively superfuse strips of vascular or

COX-1 and COX-2

A homogeneous, enzymatically active cyclo-oxygenase (COX) or prostaglandin endoperoxide synthase was isolated in 1976.[17]This membrane-bound hemo- and glycoprotein had a molecular mass of 71 kiloDaltons (kDa) and was found in greatest amounts in the endoplasmic reticulum of prostanoid-forming cells.[18]The glycoprotein was shown to exhibit COX activity—both cyclized arachidonic acid and added the 15-hydroperoxy group to form prostaglandin G2. The hydroperoxy group of prostaglandin G2 is known

Functions of COX-1 and COX-2

The constitutive isoform of COX, COX-1, has clear physiologic functions. Its activation leads, for instance, to the production of prostacyclin, which, when released by the gastric mucosa, is cytoprotective.[23]

The inducible isoform, COX-2, was discovered 6 years ago and is induced in a number of cells by pro-inflammatory stimuli.[24]Its existence was first suspected when Needleman and his group reported that bacterial lipopolysaccharide increased the synthesis of prostaglandins in human

Pathophysiology of COX-1 and COX-2

Several papers on COX-1 and COX-2 gene-deficient mice have been published.36, 37, 38At first sight, some of the results are surprising, until it is remembered that in both physiology and pathology the body uses several parallel pathways to reinforce a common result. For example, it might have been expected that without the ability to generate prostacyclin, the gastric mucosa of COX-1 gene-deficient (−/−; knockout) mice would show the kind of erosions that are produced by NSAIDs. However, COX-1

Selective Inhibition of COX-2

The importance of the discovery of the inducible COX-2 is highlighted by the differences in pharmacology between the two enzymes.[42]Aspirin, indomethacin, and ibuprofen are much less active against COX-2 than against COX-1.[43]Indeed, the most potent inhibitors of COX-1, such as aspirin, indomethacin, and piroxicam, are the NSAIDs that cause the most damage to the stomach.[44]The spectrum of activities of 10 standard NSAIDs against the two enzymes was shown to range from a high selectivity

Conclusions

All the results published to date (and many yet to be published) support the hypothesis that the unwanted side-effects of NSAIDs are due to their ability to inhibit COX-1, while their anti-inflammatory (therapeutic) effects are due to inhibition of COX-2. The identification of selective inhibitors of COX-2 will not only provide an opportunity to test the new hypothesis, but will also lead to advances in the treatment of inflammation. New uses will also be found for selective COX-2 inhibitors

Acknowledgements

The William Harvey Research Institute is supported by grants from the Ono Pharmaceutical Company, Schwarz Pharma Limited, and the Servier International Research Institute.

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