Steroids
Steroids are 21-carbon, 4-ring molecules, with biologically active steroids have a double covalent bond between carbon atoms 4 and 5, and a ketone group at C3. The body endogenously produces steroids which are essential for life; they regulate a variety of functions under normal physiological conditions and have important roles in response to stress. These steroids are produced in the adrenal cortex and are therefore known as "corticosteroids". The corticosteroids can be further divided to mineralocorticoids and glucocorticoids which are synthesised in different areas of the cortex. mineralocorticoids (such as aldosterone) are produced in the zona glomerulosa; glucocorticoids include cortisol (from the zona fasiculata) and corticosterone (from the zona reticularis). Corticosteroids are synthesised from plasma cholesterol which is stored in the adrenal gland and assimilated to corticosteroids as they are required. Endogenous glucocorticoid levels are regulated by the hypothalamus-pituitary adrenal axis, whereas the renin angiotensin aldosterone system controls mineralocorticoid levels.
Mechanism of Action
Steroids cross the cell membrane by diffusion and bind to a steroid-specific cytoplasmic receptor. The receptor-steroid complex then translocates to the nucleus and acts to up- or down-regulate expression of certain genes by increasing or decreasing the transcription of their mRNAs. Sometimes this action is linked to interaction of the complex with transcription activator protein, an enhancer of gene transcription.
Examples of genes which are induced by steroids are angiotensins convertins enzyme and the Beta2-adrenoceptor. Those inhibited include cytokines, cyclo-oxygenase and collagenase.
Actions
Metabolic Effects
Systemic Effects
Anti-Inflammatory Effects
Immuno-Suppressive Effects
Pharmacokinetic Considerations
Corticosteroids are highly plasma protein bound (around 90%). Binding may be both "generic" (to albumin) and "specific". Specific binding occurs to corticotrophin binding globulin (CBG), which has a high affinity but low capacity and hence binds endogenous corticosteroids only. Albumin binds both endogenous and synthetic steroids.
Corticosteroids have a short half-life, with that of cortisol being only 90 minutes. The drugs are metabolised in the liver, where the C4-5 double bind is reduced and conjugation with sulphate or glucuronic acid occurs. They are then excreted in the urine. Cortisone and prednisone are inactive prodrugs; upon liver metabolism they are converted to hydrocortisone and prednisolone respectively.