Mineralocorticoid, 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... 

It was known for some time that even after the corticoids had been separated from crude extracts of the adrenal cortex, the remaining material, the so-called "amorphous fraction" still possessed considerable mineralocorticoid activity. Aldosterone (250), one of the last steroids to be isolated from this fraction, proved to be the active principle. This compound proved to be an extremely potent agent for the retention of salt, and thus water, in body fluids. An antagonist would be expected to act as a diuretic in those edematous states caused by excess sodium retention. Although aldosterone has been prepared by both total and partial synthesis, the complexity of the molecule discouraged attempts to prepare antagonists based directly on the parent compound. 

Fludrocortisone (Florinef) is a drug that has both glucocorticoid and mineralocorticoid activity and is the only currently available mineralocorticoid drug. 

Excess mineralocorticoid activity (renal H+ losses, hypokalemia-induced renal ammoniagenesis)... 

Potassium chloride replacement ° Excessive mineralocorticoid activity... 

Decrease dose or change corticosteroid to one with less mineralocorticoid activity (e.g., dexamethasone)... 

Monitor for adverse reactions from mineralocorticoid administration (e.g., hypertension, hypokalemia, fluid retention) and decrease the dose if these occur. Remember that hydrocortisone also possesses mineralocorticoid activity. 

Hydrocortisone given parenterally is the corticosteroid of choice because of its combined glucocorticoid and mineralocorticoid activity. The starting dose is 100 mg IV by rapid infusion, followed by a continuous infusion or intermittent bolus of 100 to 200 mg every 24 hours. IV administration is continued for 24 to 48 hours. If the patient is stable at that time, oral hydrocortisone can be started at a dose of 50 mg every 8 hours for another 48 hours. A hydrocortisone taper is then initiated until the dosage is 30 to 50 mg/day in divided doses. 

A is less potent as an anti-inflammatory B is available in the oral dosage form C has a longer duration of action D has more mineralocorticoid activity E is available for topical application... 

Triamcinolone is a corticosteroid that is more potent than hydrocortisone and has a longer duration of action. Triamcinolone has only slight mineralocorticoid activity, whereas hydrocortisone has high mineralocorticoid activity and therefore triamcinolone is unsuitable for disease suppression on a long-term basis. Triamcinolone is available as injection, dental paste, nasal spray and as cream or ointment preparations. Hydrocortisone is available as cream, tablets and injections. 

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. ... 

Fluorination at Cja-position increases the mineralocorticoid activity of both Cji-hydroxy (hydrocortisone) and C -deoxy (deoxycorticosterone) compounds. 

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

Dexamethasone Synthetic glucocorticoid, lacks mineralocorticoid activity Used to treat range of inflammatory diseases. Used to treat some forms of asthma, also cerebral oedema and congenital adrenal hyperplasia... 

Fludrocortisone acetate Synthetic corticosteroid with some glucocorticoid and potent mineralocorticoid activity Administered orally to treat primary adrenal insufficiency... 

Carbenoxolone is a derivative of glycyrrhizic acid and both carbenoxolone and liquorice have ulcer healing properties. However, carbenoxolone has considerable mineralocorticoid activity, frequently producing Na+ and fluid retention, hypertension and hypokalemia. It is therefore not generally recommended for routine use. 

Dexamethasone has a high potency and has minimal mineralocorticoid activity. It is rapidly absorbed after oral administration with peak effects within 1-2 hours. The duration of action is about 3 days after oral administration and up to weeks after injections of the sodium phosphate derivative. This long... 

The mechanism by which Na" is reabsorbed in coupled exchange with and K+ in the collecting duct has been discussed previously that is, Na+-driven K+ secretion is partially under mineralocorticoid control. Aldosterone and other compounds with mineralocorticoid activity bind to a specific mineralocorticoid receptor in the cytoplasm of late distal tubule cells and of principal cells of the collecting ducts. This hormone-receptor complex is transported to the cell nucleus, where it induces synthesis of multiple proteins that are collectively called aldosterone-induced proteins. The precise mechanisms by which these proteins enhance Na+ transport are incompletely understood. However, the net effect is to increase Na" entry across apical cell membranes and to increase basolateral membrane Na+-K+-ATPase activity and synthesis. 

The steroidal nature of adrenocortical hormones was established in 1937, when Reichstein synthesized desoxycorticosterone. Eventually it was clearly established that the adrenal cortex elaborated a number of hormones and that these compounds differed in their amount of inherent metabolic (glucocorticoid) and electrolyte regulating (mineralocorticoid) activity. The actions of these hormones extend to almost every cell in the body. In humans, hydrocortisone (cortisol) is the main carbohydrate-regulating steroid, and aldosterone is the main electrolyte-regulating steroid. 

D. Dexamethasone is a fluorinated glucocorticoid that is more potent and longer acting than cortisol. While devoid of salt-retaining activity in therapeutic doses, this glucocorticoid does possess most of the adverse effects observed with cortisol. Because it lacks mineralocorticoid activity, dexamethasone is not used in replacement therapy. 

A substitution (Me or OH) introduced at C-16 difluprednate excepted) which usually contributes to decrease the mineralocorticoid activity. The substituent can be a dexamethasone, paramethasone, flumetasone) (16a-Me) or p betamethasone, diflorasone) (16/ -Me) (Fig. 49). When a hydroxyl is present in... 

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 ... 

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. 

Other modifications of the molecule (e.g., introduction of a double bond or a substituent in position 1) have given rise to very powerful anti-inflammatory and anti-arthritic drugs that are used in dermatology (triamcinolone, betamethasone, dexa-methasone cf. Chapter 8) (Figure 4.5). These compounds have greatly reduced residual mineralocorticoid activity. 

The slight conformational modification of the A ring (revealed by X-ray diffraction), which probably comes from an interaction between the fluorine on C-9 and the axial OH on C-1, could contribute to the differences of affinity. However, X-ray structure of the cocrystallized form of fluorocortisol with the glucocorticoid receptor does not explain the impact of fluorine on the increase in affinity (cortisol = 0.67 pM versus 9a-fluorocortisol Xj = 0.027 The fluorine at C-9 can reduce the oxidative metabolism of hydroxyl-11. Oxidation of OH-11 into ketone is fast for the cortisol and is accompanied by the loss of biological activity. However, this hypothesis would imply metabolites to contribute to the mineralocorticoid activity. 

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). 

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