Primary effects mineralocorticoids

The most predominant primary effects of mineralocorticoids are adequately observed upon the cortical collecting tubule cells strategically positioned in the kidneys to enhance substantially sodium reabsorption vis-a-vis potassium secretion. This eventually leads to an elevated aldosterone titer values that actually governs, controls, and monitors effectively sodium retention and potassium depletion thereby giving rise to volume expansion and weight gain, metabolic alkalosis, and hypertension. 

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. 

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. 

Corticosteroids synthesized by the adrenal gland are mineralocorticoids and GC. Min-eralocorticoids regulate fluid and electrolyte balance by affecting ion transport in the kidney. Cortisol, the primary circulating GC in most species (including humans), has many activities, including resistance to stress, regulation of intermediary metabolism, and immunosuppressive and anti-inflammatory effects. GC synthesis and secretion is... 

See Table 15-6. Potassium-sparing diuretics are most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism), due either to primary hypersecretion (Conn s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume). Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response. 

Substitution therapy is used in cases of primary and secondary adrenocortical insufficiency the aim is to provide glucocorticoids and mineralocorticoids in physiological amounts, and the better the dosage regimen is adapted to the individual s needs, the less the chance of adverse effects (1). 

The two principal groups of adrenal steroids are the glucocorticoids and mineralocorticoids. These hormones are synthesized from cholesterol within cells of the adrenal cortex. The primary glucocorticoid produced in humans is cortisol (hydrocortisone), and the primary mineralocorticoid is aldosterone. Glucocorticoids exert a number of effects such as regulation of glucose metabolism, attenuation of the inflammatory response, and suppression of the immune system. Mineralocorticoids are involved primarily in the control of fluid and electrolyte balance. 

Several relatively common disorders result in aldosterone secretion abnormalities and aberrations of electrolyte status. In Addison s disease, the adrenal cortex is often destroyed through autoimmune processes. One of the effects is a lack of aldosterone secretion and decreased Na+ retention by the patient. In a typical Addison s disease patient, serum [Na+] and [CL] are 128 and 96 meq/L, respectively (see Table 16.2 for normal values). Potassium levels are elevated, 6 meq/L or higher, because the Na+ reabsorption system of the kidney, which is under aldosterone control, moves K+ into the urine just as it moves Na+ back into plasma. Thus, if more Na+ is excreted, more K+ is reabsorbed. Bicarbonate remains relatively normal. The opposite situation prevails in Cushing s disease, however, in which an overproduction of adrenocorticosteroids, especially cortisol, is present. Glucocorticoids have mild mineralocorticoid activities, but ACTH also increases aldosterone secretion. This may be caused by an oversecretion of ACTH by a tumor or by adrenal hyperplasia or tumors. Serum sodium in Cushing s disease is slightly elevated, [K+] is below normal (hypokalemia), and metabolic alkalosis is present. The patient is usually hypertensive. A more severe electrolyte abnormality is seen in Conn s syndrome or primary aldosteronism, usually caused by an adrenal tumor. Increased blood aldosterone levels result in the urinary loss of K+ and H+, retention of Na+ (hypernatremia), alkalosis, and profound hypertension. 

The adrenal cortex (AC) produces the glucocorticoid cortisol (hydrocortisone) in the zona fasciculata and the mineralocorticoid aldosterone in the zona glomerulosa. Both steroid hormones are vitally important in adaptation responses to stress situations, such as disease, trauma, or surgery. Cortisol secretion is stimulated by hypophyseal ACTH aldosterone secretion by angiotensin II in particular (p. 128). In AC failure (primary adrenocortical insuf ciency, Addison disease), both cortisol and aldosterone must be replaced when ACTH production is deficient (secondary adrenocortical insuf ciency), cortisol alone needs to be replaced. Cortisol is effective when given orally (30 mg/day, 2/3 a.m 1 /3 p.m.). In stress situations, the dose is raised 5- to 10-fold. Aldosterone is poorly effective via the oral route instead, the mineralocorticoid fludrocortisone (0.1 mg/day) is given. 

Spironolactone (see p. 534) is a competitive aldosterone antagonist which also blocks the mineralocorticoid effect of other steroids it is used in the treatment of primary hyperaldosteronism and as a diuretic, principally when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. 

Spironolactone antagonises the sodium-retaining effect of aldosterone and other mineralocorticoids. It is used to treat primary and secondary hyperaldosteronism (p. 538). 

In (hemid-l9.S()s. il was observed that progesterone inhibited the aniinalriurclic and kaliurelic effects of aldosterone, the primary mineralocorticoid in humans. An intensive effort was launched lo develop steroidal derivatives that pos-se.ssed only the antimincralocurticuid activity of progesterone. - " Spironolactone was. selected from a host of derivatives for further examination. ... 

The determination of plasma renin responsiveness, however, is not sufficient to diagnose primary aldosteronism because suppressed PRA also occurs in about 25% of patients with essential hypertension. Primary aldosteronism can be differentiated from other hypermineralocorticoid states on the basis of inappropriate secretion of aldosterone. The demonstration of an elevated concentration of aldosterone in blood or urine in a patient with an unequivocally suppressed PRA concentration (a plasma aldosterone/ plasma PRA ratio >50) is presumptive evidence of primary aldosteronism. Because hypokalemia has a suppressive effect on aldosterone secretion, the potassium deficit should be replaced before aldosterone measurements are done. To establish aldosterone autonomy, the clinician may attempt to suppress aldosterone production with rapid volume expansion (see Box 51-10), with a potent mineralocorticoid (see Box 51-11), or as mentioned with captopril. Failure... 

Some of the rare causes of metabolic alkalosis due to potassium depletion are those found in subjects with either Cushing s syndrome, primary aldosteronism, or Bartter s syndrome. In Cushing s syndrome, the potassium ions and alkalosis are related to increased mineralocorticoid activity resulting from an increase in adrenocorticotropic hormone (ACTH), cortisol, deoxycorticosterone, and corticosterone. In primary aldosteronism, the effects of increased aldosterone are manifest on the distal tubule of the kidney. In Bartter s syndrome, the basic abnormality appears to be a defect in the reabsorption of chloride in the ascending limb of loop of Henle, leading to loss of potassium (12). 

CARDIOVASCULAR SYSTEM The most striking cardiovascular effects of corticosteroids result from mineralocorticoid-induced changes in renal Na+ excretion, as is evident in primary aldosteronism. The resultant hypertension can lead to a diverse group of adverse effects on the cardiovascular system (see Chapter 32). Consistent with the known actions of mineralocorticoids in the kidney, restriction of dietary Na can lower the blood pressure considerably in mineralocorticoid excess. 

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