Abstract

The inflammatory process. Normally, small arterioles deliver blood to capillaries, which are then drained by venules. Vasoactive autacoids trigger the vascular phase, causing arterioles to dilate and endothelial cells to shrink, making capillaries and venules more permeable. Hyperemia produces the cardinal signs of redness and heat. Permeability allows extravasation of plasma leading to swelling and pain. Chemotactic autacoids target leukocytes (WBCs), which adhere to endothelium (margination), squeeze through the openings (diapedesis) and migrate out into the tissues (emigration). Nonsteroidal anti-inflammatory drugs (NSAIDS) inhibit the vascular phase, and the glucocorticoids inhibit both phases.

The hypothalamic-pituitary-adrenal (HPA) axis. ² In this figure, solid arrows represent stimulation and dashed arrows indicate inhibition. The hypothalamus secretes corticotropin-releasing factor (CRF), which stimulates the pituitary to secrete corticotropin (formerly called adrenocorticotropic hormone). Corticotropin stimulates the adrenal cortex to synthesize and secrete cortisol. Provided serum concentrations are adequate, cortisol performs vital physiological functions and inhibits further activity of the HPA axis. Serum cortisol levels peak at ∼8:00 am and gradually decline over 12–16 hours. As cortisol is consumed, its serum levels diminish and inhibition of the axis wanes. This allows production of cortisol to commence again. This pattern of function is called circadian or diurnal rhythm and occurs at a normal basal rate unless the axis is excited by other factors such as hypoglycemia, trauma, or stress. Glucocorticoids produce an impressive number of physiological effects. When supraphysiologic doses are administered, the subsequent pharmacological effects consist essentially of exaggerated physiologic effects. These doses will also impart a negative feedback on the axis that eventually leads to adrenal atrophy following sustained use.

Molecular structures of selected glucocorticoids. Prednisone is inactive as the parent drug and is converted to prednisolone following administration. Methylprednisolone differs only in a mere methyl substitution. Betamethasone and dexamethasone are optical isomers differing only in the orientation of the methyl group indicated by the asterisk. Triamcinolone is similar in structure and like other agents can be created for sustained activity as a repository formulation by adding slowly absorbed groupings such as acetates or the acetonide illustrated here by the shaded grouping.