Systemic glucocorticoids are potent immunosuppressive and antiinflammatory agents that are frequently used for severe dermatologic diseases.
Complications are increased with fluorinated compounds, higher doses, longer duration of therapy, and more frequent administration.
Intralesional, IM, IV, topical, and oral routes of administration can be used.
Careful monitoring of systemic and cutaneous side effects is an essential component of therapy.
Glucocorticoid-induced osteoporosis begins early in treatment and should be aggressively managed in all patients on long-term therapy.
Glucocorticoids are a mainstay of dermatologic therapy because of their potent immunosuppressive and antiinflammatory properties. By understanding the properties and mechanisms of action of glucocorticoids, one can maximize their efficacy and safety as therapeutic agents.
PHARMACOLOGY AND MECHANISM OF ACTION
The major naturally occurring glucocorticoid is cortisol (hydrocortisone). It is synthesized from cholesterol by the adrenal cortex. Normally, less than 5% of circulating cortisol is unbound; this free cortisol is the active therapeutic molecule. The remainder is inactive because it is bound to cortisol-binding globulin (also called transcortin) or to albumin. Daily cortisol production is 5 to 7 mg/m2, with a diurnal peak around 8:00 AM.1 Cortisol has a plasma half-life of 90 minutes. It is metabolized primarily by the liver, although it exerts hormonal effects on virtually every tissue in the body. The metabolites are excreted by the kidney and the liver.
The mechanism of glucocorticoid action involves passive diffusion of the glucocorticoids through the cell membrane, followed by binding to soluble receptor proteins in the cytoplasm.2 This hormone-receptor complex then moves to the nucleus and regulates the transcription of a limited number of target genes. There are 3 main mechanisms of glucocorticoid action. The first is direct effects on gene expression by the binding of glucocorticoid receptors to glucocorticoid-responsive elements, leading to the induction of proteins like annexin I and MAPK (mitogen-activated protein kinase) phosphatase 1. Annexins reduce phospholipase A2 activity, which reduces the release of arachidonic acid from membrane phospholipids, limiting the formation of prostaglandins and leukotrienes.3-5 The second mechanism is indirect effects on gene expression through the interactions of glucocorticoid receptors with other transcription factors. For example, inhibitory effects on AP-1 and nuclear factor κB, coupled with increased inhibitor of nuclear factor κB (IκB), decreases the synthesis of a number of proinflammatory molecules, including cytokines, interleukins, adhesion molecules, and proteases.6 The third is glucocorticoid receptor–mediated effects on second messenger cascades through nongenomic pathways such as the phosphatidylinositol 3′-kinase (PI3K)-Akt-endothelial nitric oxide synthase (eNOS) pathway.7,8
There is usually a delay in the onset of pharmacologic activity of glucocorticoids relative to their peak blood concentrations, which is probably consequent to altering the transcription of genes,7 although some actions appear to be independent of transcription. Some effects of glucocorticoids are too rapid to be mediated by genomic glucocorticoid action,9 which might explain the ...