The Clinical Pharmacology of Past, Present, and Future Glucocorticoids

Abstract

Because glucocorticoids (GCs) have powerful anti-inflammatory and immunomodulatory actions, they are widely used to treat several diseases, including acute and chronic inflammatory conditions, severe allergic reactions, and autoimmune diseases. During the past century, research yielded more potent GCs with longer half-lives and virtually no mineral corticoid effects (e.g., betamethasone and dexamethasone) compared with endogenous GCs (cortisol) and the first GC (prednisolone). GC molecules that have entered the clinic in the past 20 years are GC analogues that decrease the risk-to-benefit ratio during long-term topical treatments of some diseases. These molecules have particular pharmacokinetic properties that increase the wanted effects in peripheral tissues and decrease the unwanted systemic effects. Because most metabolic effects of GCs depend on gene upregulation and most anti-inflammatory effects of GCs depend on decreased production of proinflammatory cytokines, some researchers have hypothesized that glucocorticoid-responsive element–dependent transactivation is responsible for the adverse effects of GCs, whereas transcription factor heterodimerization is the basis of their anti-inflammatory activity. Although this hypothesis does not consider the GC anti-inflammatory effects caused by transactivation, new drugs called selective GC receptor agonists (SEGRA), which favor GC receptor heterodimerization but not homodimerization, have been synthesized and are under clinical development.