Current concepts of the mechanisms of side effects of nonsteroidal antiinflammatory drugs as a basis for establishing research priorities. An experimentalist's view.

Concepts of the mechanisms of side effects of NSAID implicate biochemical and cellular reactions of these drugs which are often, but not always, considered to underlie the therapeutic actions, e.g., inhibition of prostaglandin cyclooxygenase; effects on proteoglycan, energy (ATP) metabolism, cyclic nucleotide and possibly phosphoinositide metabolism; inhibition of platelet aggregation and lymphocyte functions. Additionally alterations with age as well as in disease or stress states of the pharmacokinetics and metabolism of these drugs may contribute profoundly to the propensity of the NSAID to effect these and other biochemical and cellular mechanisms underlying the development of side effects in specific organ systems. While the genetics relating to lymphocyte haplotype expression have been implicated in the mechanisms of slow acting drugs, genetic controls have not been explored in NSAID-associated side effects. Moreover, although certain biochemical changes have been observed in association with the development of certain side effects, little is known of the dose dependence and time sequence of changes in order to define precise mechanisms. Pharmacological or other agents can be employed to counter these effects, with some success, e.g., preventing gastrointestinal ulceration with H2-antagonists or sucralfate. These procedures give clues to the significance of certain biochemical changes, but further research is needed for elucidating more detailed aspects as well as applications of procedures to minimize the occurrence of side effects, especially in groups at risk.