1. Glucocorticoids Synthesis and release Adrenal steroids are synthesised and released as needed under the influence of ACTH, which is secreted from the anterior pituitary gland. ACTH secretion is regulated partly by CRF derived from the hypothalamus and partly by the level of glucocorticords in the blood. ADH, which may reach the pituitary through short portal vessels from the posterior pituitary, also stimulates ACTH release and may have a physiological role.

2. The release of CRF,in turn, is inhibited by the level of glucocorticords in the blood and is influenced by input from the CNS. The concentration of endogenous corticosteroids in the blood is high in the morning, at 8.am and low at midnight. Opioid peptides exercise a tonic inhibitory control on the secretion of CRF. Psychological factors can affect the release of CRF, as can stimuli such as excessive heat or cold, injury or infection; this is mechanism, by which the pituitary adrenal system is activated in response to threatenting environment.

3. The starting substance for the synthesis of glucocorticords is cholesterol. The first step, the conversion of cholesterol to pregnenolone is the rate – limiting step and is regulated by ACTH. Metyrapone prevents the β-hydroxylation at C11 and thus the formation of hydrocortisone and corticosterone. Synthesis is stopped at the 11 – deoxycorticosterioid stage and as these substances have no negative feedback effects on the hypothalamus and pituitary, there is a marked increase in ACTH in the blood.

4. Mechanism of Action For the most part, glucocorticord effects involve interactions between the steroids and intracellular receptors that belong to the superfamily of receptors that control gene transcription. This superfamily also includes the receptors for mineralocorticoids,the sex steroids, thyroid hormones, and vitamin D 3 retinoic acid. Its believed that there are 10 – 100 steroid- responsive genes in each cell. For the most part, glucocorticord effects involve interactions between the steroids and intracellular receptors that belong to the superfamily of receptors that control gene transcription.

5. The glucocorticoids, after entering the cells, bind to specific receptors (GRα and GRβ) in the cytoplasm. These receptors, which have a high affinity for glucocorticoids, are found in virtually all tissues – about 3000 to 10 000 per cell, the number varying in different tissues. GRα has been cloned and contain 777 amino acids residues. After interaction with the steroid, the receptor becomes ‘activated’, i.e. it undergoes a conformational changes that exposes a DNA – binding domain. The steroid – complexes forms a dimers (pair), then move to the nucleus and bind to steroid – response elements in the DNA.

6. The effect is either to repress ( prevent transcription of ) or induce (initiate transcription of) particular genes. Repression is brought about by inhibition of the action of various transcription factors such as AP-1 and NF- kB. These transcription factors normally switch on the genes for cyclooxygenase – 2, various cytokinin and adhesion factors, as well as the inducible isoform of nitric acid synthase. Basal and induced transcription of the genes for collagenase are modified and vitamin D3 induction of the ostecalcin gene in osteoblast is inhibited.

7. Induction involves the formation of specific mRNAs, which direct the synthesis of specific proteins. In addition to the enzymes involved in their metabolic action (e.g. cAMP – dependent kinase), glucocorticoids induce the formation of annexin-1 ( previously called lipocortin – 1).

8. Annexin – 1 is important in the negative feedback action of glucocorticoids on the hypothalamus and anterior pituitary and has anti-inflammatory actions ( possibly by inhibiting phospholipase A 2 ) As might be predicted, the anti-inflammatory effect of glucocorticoids take several hours to become evident since formation of annexin – 1 ( and other active proteins) is relatively slow. Action 1) General metabolic and systemic effects Metabolism of carbohydrate and protein. 2) Negative feedback effects on the anterior pituitary and hypothalamus. Negative feedback effect on the secretion of CRF and ACTH

9. 3) Anti – inflammatory and immunosuppressive effects. When given therapeutically, glucocorticords have powerful anti-inflammatory and immunosuppressive effects. They inhibit both the early and late manifestation of inflammation, i.e. not only the initial redness, heat, pain and swelling, but also the later stages of wound healing, and repair and proliferative reaction seen in chronic inflammation.

10. They affect all types of inflammatory reaction whether caused by invading pathogens, by chemical or physical stimuli or by inappropriately deployed immune responses such as are seen in hypersensitivity or autoimmune disease. When used clinically to suppress graft rejection, glucocorticords suppress the initiation and generation of a ‘new’ immune response more efficiently than a response that is already establish and in which clonal proliferation has already occurred.

11. Actions on inflammatory cells these include. Decrease egress of neutrophils from blood vessels and reduced activity of neutrophils and macrophages owing to decreased transcription of the genes for cell adhesion factors and relevant cytokinin Decrease action of T helper cells and reduced clonal proliferation of T cells, mainly through decreased transcription of genes for IL-2 and its receptors Decrease fibroblast function and, therefore, less production of collagen and glycosaminoglycans; the contribution of these events to chronic inflammation is reduced but so also is healing and repair

12. Action on the mediators of inflammatory and immune response these include: Decreased production of prostanoids owing to decreased expression of COX-2 Decrease generation of cytokinins – IL-1, to IL-8, TNF- y and cell adhesions factors and others. Reduction in the concentration of complements components in the plasma Decrease generation of induced nitric acid

13. Decrease histamine release from basophils Decrease IgG production.