Mechanism Of Action

Glucocorticoids diffuse into the cell but access to the receptor may be prevented, for example in kidney, by the enzyme 11-beta hydroxysteroid dehydrogenase, which converts active Cortisol into inactive cortisone. When activated, the receptors translocate to the nucleus where they can upregu-late gene transcription by dimerising on specific DNA response elements and recruiting co-activator proteins, but can also oppose other transcription factor function, for example NFkB and AP-1, by protein-protein interaction. The anti-inflammatory actions of glucocorticoids are mediated mainly by this latter mechanism, suggesting that one day drugs may be found which have the beneficial

1 The mere introduction of a double bond transforms hydrocortisone to prednisolone, a big biological change: see Table 34.1 for relative potencies 1.0:1.0 to 4:0.8.

effects of steroids with less of the undesired properties.

Glucocorticoids inhibit pathways that normally lead to production of prostaglandins, leukotrienes and platelet activating factor. These mediators would normally contribute to increased vascular permeability and subsequent changes including oedema, leucocyte migration, fibrin deposition.

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