Towards developing new strategies to reduce the adverse side-effects of nonsteroidal anti-inflammatory drugs

The antipyretic and analgesic actions of nonsteroidal anti-inflammatory drugs (NSAIDs) are caused by the inhibition of prostaglandin E₂ (PGE₂), thromboxane A₂ and prostacyclin (PGI₂) production. Accumulating evidence suggests that the inhibition of PGE₂ production can cause adverse side-effects of NSAIDs on fluid and blood pressure regulation, such as hypertension and edema formation. Since both cyclooxygenase (COX)-1 and COX-2 isoforms contribute to the production of PGE₂, selective COX-2 inhibitors are not free of these adverse side-effects although they may be less severe. Four subtypes of PGE₂ receptors have been identified. The antipyretic action of blunted PGE₂ production is mediated predominantly by a reduced input to the prostaglandin E receptor 3 (EP₃) pathway, whereas the analgesic action is mediated predominantly by a reduced input to the EP₁ pathway and perhaps by contributions from the other EP receptors. Accordingly, some of the adverse side-effects might be moderated by combined use of NSAIDs with selective EP₂ or EP₄ agonists that do not block the antipyretic or analgesic actions of NSAIDs that are mediated by reduced activation of EP₁ or EP₃ receptors. Moreover, EP₂ receptor-deficient mice had salt-sensitive hypertension and EP₄ receptor blockade moderated salt and water excretion and both EP₂ and EP₄ agonists had renoprotective effects. This suggests that strategies to maintain activation of EP₂ and EP₄ receptors during NSAID administration may not only reduce adverse effects but might confer additional benefits. In conclusion, enhancing EP₂ and EP₄ receptor activity by administration of selective agonists during the administration of NSAIDs has the potential to permit treating fever, inflammation and pain but with marginal adverse effects on fluid or blood pressure regulation.