The Mineralocorticoids

Aldosterone, the most potent of the mineralocorticoids (Figure 25.43), is involved in the regulation of sodium and potassium balances in tissues. Aldosterone increases the kidney s capacity to absorb Na, Cl, and HgO from the glomerular filtrate in the kidney tubules. 

The main endogenous mineralocorticoid is aldosterone, which is mainly produced by the outer layer of the adrenal medulla, the zonaglomerulosa. Aldostorone, like other steroids, binds to a specific intracellular (nuclear) receptor, the mineralocorticoid receptor (MR). Its main action is to increase sodium reabsotption by an action on the distal tubules in the kidney, which is accompanied by an increased excretion of potassium and hydrogen ions. 

The renin-angiotensin-aldosterone system (RAAS) generates the peptide hormone angiotensin II and subsequently the mineralocorticoid aldosterone, which both exert considerable impact on blood pressure ( blood pressure control) and fluid homeostasis, and... 

ACE inhibitors do not completely block aldosterone synthesis. Since this steroid hormone is a potent inducer of fibrosis in the heart, specific antagonists, such as spironolactone and eplerenone, have recently been very successfully used in clinical trials in addition to ACE inhibitors to treat congestive heart failure [5]. Formerly, these drugs have only been applied as potassium-saving diuretics in oedematous diseases, hypertension, and hypokalemia as well as in primary hyperaldosteronism. Possible side effects of aldosterone antagonists include hyperkalemia and, in case of spironolactone, which is less specific for the mineralocorticoid receptor than eplerenone, also antiandrogenic and progestational actions. 

The adrenal gland lies on the superior surface of each kidney. It is a double organ composed of an outer cortex and an inner medulla In response to ACTH secreted by the anterior pituitary, the adrenal cortex secretes several hormones (the glucocorticoids, the mineralocorticoids, and small amounts of sex hormones). 

The mineralocorticoids consist of aldosterone and des-oxycorticosterone and play an important role in conserving sodium and increasing die excretion of potassium. Because of diese activities, die mineralocorticoids are important in controlling salt and water balance Aldosterone is die more potent of these two hormones. Deficiencies of the mineralocorticoids result in a loss of sodium and water and a retention of potassium. 

Cortisol synthesis requires three hydroxylases located in the fasciculata and reticularis zones of the adrenal cortex that act sequentially on the Cjy, C21, and Cjj positions. The first two reactions are rapid, while Cu hydroxylation is relatively slow. If the C, position is hydroxylated first, the action of 17a-hydroxylase is impeded and the mineralocorticoid pathway is followed (forming corti-... 

The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and excretion of potassium. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system. 

The answer is c. (Hardmanr pp 706-708.) Spironolactone is an aldosterone antagonist that acts on the mineralocorticoid receptor It is a Kksparing diuretic. It can also function as an androgen antagonist, which could explain the gynecomastia and erectile dysfunction. Women with hirsutism are sometimes treated with spironolactone. 

Spironolactone and eplerenone block the mineralocorticoid receptor, the target site for aldosterone. In the kidney, aldosterone antagonists inhibit sodium reabsorption and potassium excretion. However, diuretic effects are minimal, suggesting that their therapeutic benefits result from other... 

An important drug in the present context is the mineralocorticoid receptor antagonist spironolactone (7.74, Fig. 7.12). Among its many metabolic reactions, spironolactone is readily hydrolyzed at the thioester bond (Fig. 7.12, Reaction a) to form deacetyl-spironolactone (7.75, Fig. 7.12), a metabolite found in a variety of tissues [155 -157]. This thiol compound, which is also a potent mineralocorticoid antagonist, promotes the mechanism-based inactivation of hepatic, adrenal, and testicular cytochrome P450 isozymes. There is now good evidence to indicate that this behavior is the result of microsomal 5-oxidation (see Chapt. 7 in [7]). When spironolactone was incubated with liver microsomes from rats pretreated with dexamethasone (an inducer of CYP3A), the sulfinic and sulfonic acid derivatives were characterized [158]. Perhaps the importance of the 5-deacetylation of spironolactone... 

Finally, we have the mineralocorticoids. Aldosterone is a good example ... 

Addison s disease), both cortisol and aldosterone must be replaced when ACTH production is deficient (secondary AC insufficiency), cortisol alone needs to be replaced. Cortisol is effective when given orally (30 mg/d, 2/3 a.m., 1/3 p.m.). In stress situations, the dose is raised by 5- to 10-fold. Aldosterone is poorly effective via the oral route instead, the mineralocorticoid fludrocortisone (0.1 mg/d) is given. 

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

The glucocorticoids induce a number of biological effects (Table 1.14), but their principal actions relate to modulation of glucose metabolism. The mineralocorticoids regulate water and... 

GC exert their regulatory effects on the HPA system via two types of corticosteroid receptors the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR) (Reul and De Kloet 1985). GRs occur everywhere in the brain but are most abundant in hypothalamic CRH neurons and pituitary corticotropes. MRs, in contrast, are highly expressed in the hippocampus and, at lower expression levels, in hypothalamic sites involved in the regulation of salt appetite and autonomic outflow. The MR binds GC with a tenfold higher affinity than does the GR (Reul and De Kloet 1985). These findings on corticosteroid receptor diversity led to the working hypothesis that the tonic influences of corticosterone... 

Although patients may require varying amounts of replacement steroid, 20 to 30 mg/day of cortisol supplemented with the mineralocorticoid 9-a-fluorocortisol (0.1 mg/day) is generally adequate. A doubling of the cortisol dose may be required during minor stresses or infections. In patients who require high-dose supplementation, prednisone can be substituted for cortisol to avoid fluid retention. 

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... 

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