Glucocorticoid activity

Methylated Glucocorticoids. The preparation of 2a-methyl-9a- uorocortisol has been reported (76). This compound shows enhanced glucocorticoid activity and greatiy enhanced mineralocorticoid activity, so much that it surpasses aldosterone (19) ia sodium-retaining and potassium-excreting potency. Attention was then turned to the preparation of 6-methylated corticoids... 

Fludrocortisone is used for replacement therapy for primary and secondary adrenocortical deficiency. Even though this drug lias both mineralocorticoid and glucocorticoid activity, it is used only for its mineralocorticoid effects. 

Braughler, J.M., Chase, R.L., NefF, G.L., Yonkers, P.A., Day, J.S., HaU, E.D., Sethy, V.H. and Lahti, R.A. (1988). A new 21-amino steroid antioxidant lacking glucocorticoid activity stimulates ACTH secretion and blocks arachidonic acid release from mouse pituitary tumor (ArT-20) cells. J. Pharmacol. Exp. Ther, 244, 423-427. 

Non-prescription and herbal products with glucocorticoid activity (e.g., non-prescription anti-itch products with hydrocortisone, herbal products with magnolia bark or those claiming to contain adrenal cortex extracts or other by-products)... 

Other drugs with glucocorticoid activity (e.g., megestrol acetate, medroxyprogesterone)... 

The answer is e. (Katzung, p 672. Hardman, pp 1477—1978.) Fludrocortisone is a synthetic steroid compound that exhibits profound mineralo-corticoid activity and some glucocorticoid activity Electrolyte and water metabolisms are affected by the administration of this compound. Fludrocortisone promotes the reabsorption of Na and the urinary excretion of K and hydrogen ions in the collecting duct of the nephron. The drug is indicated for mineralocorticoid replacement therapy in primary" adrenal insufficiency... 

Davani B, Khan A, Hult M, et al. Type 1 1 lbeta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem 2000 275(45) 34841-34844. 

The introduction of a 9a-fluoro substituent increases anti-inflammatory activity, but it increases mineralocor-ticoid activity even more (300x). Fludrocortisone acetate is of little value as an anti-inflammatory, but it is employed as a mineralocorticoid. On the other hand, additional modifications may be employed. Introduction of a 1,2-double bond increases glucocorticoid activity over mineralocorticoid activity, and a 16-methyl group reduces mineralocorticoid activity without affecting glucocorticoid activity. A combination of these three structural modifications gives valuable anti-inflammatory drugs, e.g. betamethasone, with hardly any mineralocorticoid activity. ... 

In particular, it should be noted that since 11-deoxycorticosterone does not exhibit glucocorticoid activity yet, it is a powerful mineralocorticoid and has only two potentially reactive substituents capable of reacting with a receptor, and the interaction should occur by way of a Cj-keto and/or a Ci7j3-C0-CH20H groups. The necessity of either a simultaneous presence of acidic functions at Cu and or the necessity of simultaneous absence of acidic functions at and C17 in the structure of the pregnane system is also apparent. 

Various synthetic corticosteroids have also been developed. Some display greater potency than the native steroids, while others exhibit glucocorticoid activity with little associated mineralocorticoid effects, or vice versa. The major glucocorticoids used clinically are synthetic. They are usually employed as ... 

Betamethasone Synthetic corticosteroid, displays glucocorticoid activity, lacks mineralocorticoid activity Use mainly as anti-inflammatory and immunosuppressive effect... 

The naturally occurring mineralocorticosteroid is aldosterone. Its release is not ACTH dependent but is stimulated under control of the renin-angiotensin system. Aldosteron is not in clinical use because of its short halflife (20 min). Fludrocortisone is a synthetic analogue with considerably more potent mineralocorticoid than glucocorticoid activity. It is used as substitution therapy in adrenocorticoid insufficiency and in low-renin hypoaldosteronism. It is well absorbed orally and its effects last 1-2 days. 

Within the basic structure of the steroid molecule (Fig. 60.4), a 4,5 double bond and a 3-ketone group are needed for typical steroid activity. A hydroxyl group on Cll is needed for glucocorticoid activity (corticosterone) but is not required for sodium-retaining activity (desoxycorticosterone). The addition of a hydroxyl group on C17, which converts corticosterone to cortisol, also increases glucocorticoid activity. 

The ultimate aim in altering the steroid molecule is to decrease sodium-retaining activity and to increase antiinflammatory glucocorticoid activity. 

As soon as corticosteroids, such as cortisone, were used in the treatment of rheumatoid arthritis (glucocorticoid activity), important undesirable side effects appeared (sodium retention). In view of lowering the sodium retention, while increasing the anti-inflammatory activity. Fried performed various chemical modifications. Thus, he could observe that introducing a fluorine atom at the 9a position of the hydrocortisone acetate highly enhanced (11 times) the glucocorticoid activity, while the undesired sodium retention was lowered [130]. 

The reason of effects of fluorine atoms at C-6 and C-9 positions on the pharmacological profile (in particular on the enhancement of the glucocorticoid activity and its dissociation from the mineralocorticoid activity) is not always very clear. Three hypothesis coexist ... 

The enhancement of the acidity of the 11)S hydroxyl can increase the affinity of the molecule for the receptor which is responsible for the glucocorticoid activity ... 

Corticosterone. A natural corticoid with moderate glucocorticoid activity and some mineralocorticoid activity, possessing life-maintaining properties in adrenalectomized animals and several other activities peculiar to the adrenal cortex. Its actions closely resemble those of cortisol, except that it is not anti-inflammatory. 

Fluorination of corticosteroids at C-9 or/and C-6 increases glucocorticoid activity, while mineralocorticoid activity, responsible for sodium retention (the main adverse effect of corticoids), is decreased (cf. Chapter 4). Fluorocorticoster-oids were the first fluorinated compounds to be used clinically. They are still major drugs against many inflammatory disorders rheumatoid polyarthritis, ORL (asthma, rhinitis), brain edema, dermatological, allergies, anaphylactic shock, Quincke s edema). 

Cortisone is a natural corticosteroid secreted by the adrenal cortex along with many steroidal hormones. It has mainly glucocorticoidal activity and some degree of mineralo-corticoid activity. 

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