Biological effects of nonsteroidal anti-inflammatory drugs

Abstract

HROUGH THE FAILURE of any treatment regimen to significantly alter the course of the disease process in rheumatoid arthritis, there has been a tremendous proliferation in the number of nonsteroidal agents available to treat the condition. The precise mode of action of these drugs is still a point of contention, but in the following review we have attempted to present the evidence for the various mechanisms by which nonsteroidal anti-inflammatory drugs (NSAID) produce their effects. Relationships to Structure and to Physical Constants A great deal of work has been undertaken upon structure function relationships of the NSAID. Using the Hiickel theory, similarities have been documented between stereochemical structure and interatomic distances of NSAID, on the one hand, and of biologic amines (serotonin, histamine), on the other; it is suggested that this may be of relevance to the anti-inflammatory activity of these drugs.137-13g It has also been suggested that anti-inflammatory activity is related to pKa,2SS but this concept is contradicted by interesting recent work demonstrating that the corresponding alcohol derivatives of NSAID possess antiinflammatory activity.216 The relationship between lipid solubility and antiinflammatory activity has been studied, but with discrepant results,145 some strong NSAID possessing the same partition coefficients as drugs which would seem to have only weak anti-inflammatory effects. 216 Recently, the relationships between chelating power, measured by affinity constants for metallic ion binding have received interest, but there is insufficient evidence to assess any possible relevance of this to anti-inflammatory effect.2eg Eflects on Carbohydrate Metabolism Carbohydrate metabolism contributes both energy-rich molecules, such as glucose, and also basic structural subunits of macromolecules, such as Dgalactosamine or D-glucosamine to the organism; so any effect of drugs upon this system is of importance. The enzymatic conversion of glucosamine to