Since the introduction of glucocorticoids in the treatment of rheumatoid arthritis in 1949, intense efforts have been made by science and industry to maximize the beneficial and to minimize the side effects of glucocorticoids. Thus, many synthetic compounds with glucocorticoid activity were manufactured and tested. The pharmacologic differences among these chemicals result from structural alterations of their basic steroid nucleus and its side groups. These changes may affect the bioavailability of these compounds - including their gastrointestinal or parenteral absorption, plasma half-life, and metabolism in the liver, fat, or target tissues - and their abilities to interact with the glucocorticoid receptor and to modulate the transcription of glucocorticoid - responsive genes (9). In addition, structural modifications diminish the natural cross-reactivity of glucocorticoids with the mineralocorticoid receptor, eliminating their undesirable salt-retaining activity. Other modifications increase glucocorticoids' water solubility for parenteral administration or decrease their water solubility to enhance topical potency (2, 10-14).

Thus, prednisolone has the structure of cortisol with an additional double bond between C-1 and C-2, which increases its glucocorticoid and decreases its mineralocorticoid activity. Introduction of an alpha-fluoro group at C-9, on the other hand, enhances both glucocorticoid and mineralocorticoid activity, whereas addition of a hydroxyl or methyl group at C-16 practically eliminates mineralocorticoid activity. Dexamethasone, a potent synthetic glucocorticoid that has a double bond at C-1 and C-2, a fluoro group at C-9, and an alpha-methyl group at C-16, has 25 to 50 times the glucocorticoid potency of cortisol and a minimal mineralocorticoid effect. A double bond between C-2 and C-3 and methylation at the C-2 or C-16 positions significantly prolong the plasma half-life of a compound. A keto group at C-11 is normally reduced by liver enzymes to an 11-hydroxyl group, which is necessary for glucocorticoid activity. In contrast, a C-11 hydroxyl group is oxidized to a keto group in the kidney, minimizing the access of the compound to the mineralocorticoid receptor, and thus its salt retaining effect (10, 14).

Most synthetic glucocorticoids (eg, methylprednisolone and dexamethasone) are minimally bound to cortisol-binding globulin (transcortin) and circulate mostly bound to albumin, or in the free form. The percentage of such glucocorticoids bound to plasma proteins is relatively constant, and because this binding is concentration-independent, the metabolic clearance rate of glucocorticoids remains constant regardless of dose. Table 1 shows the relative glucocorticoid and mineralocorticoid potencies of different commonly used systemic glucocorticoids and their approximate plasma and biologic effect half-lives (2). Glucocorticoid activity has been mostly defined in rat bioassays and may not always pertain to human responses, especially the growth-suppressing properties of synthetic glucocorticoids, which have been markedly underestimated. The biologic effect half-life of glucocorticoids divides them into short-, intermediate-, or long-acting, based on the duration of corticotropin suppression after a single dose of the compound (2, 13).