Aldosterone Hyperaldosteronism

Hyperaldosteronism is accompanied by elevation of blood pressure (115), and can be treated with an aldosterone antagonist, eg, spironolactone (117) which... 

Hyperaldosteronism is a syndrome caused by excessive secretion of aldosterone. It is characterized by renal loss of potassium. Sodium reabsorption in the kidney is increased and accompanied by an increase in extracellular fluid. Clinically, an increased blood pressure (hypertension) is observed. Primary hyperaldosteronism is caused by aldosterone-producing, benign adrenal tumors (Conn s syndrome). Secondary hyperaldosteronism is caused by activation of the renin-angiotensin-aldosterone system. Various dtugs, in particular diuretics, cause or exaggerate secondary peadosteronism. 

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 major mineralocorticoid, aldosterone, is secreted by cells of the zona glomerulosa. Primary hyperaldosteronism (Conn s syndrome) is associated with potassium depletion which is, in mm, responsible for the observed neuromuscular abnormalities seen in the disorder. These are similar to those seen in hypokalemic periodic paralysis (PP), with episodic and severe exacerbations of fixed muscle weakness. Muscle biopsy shows occasional muscle necrosis and vacuoles often these feamres are accompanied by mbular aggregates as in hypokalemic PP. All these changes can be attributed to the hypokalemia and not to excess aldosterone production per se. 

Potassium-sparing diuretics are often coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. In this way, edema fluid is lost to the urine while K+ ion balance is better maintained. The aldosterone antagonists are particularly useful in the treatment of primary hyperaldosteronism. 

Uses Hyperaldosteronism, ascites from CHF or cirrhosis Action Aldosterone... 

Aldosterone stimulates the rates of Na+ reabsorption and K+ secretion. This is relevant to the action of spironolactone, a diuretic that is a competitive inhibitor of aldosterone (discussed later). It is also pertinent because administration of diuretics can cause secondary hyperaldosteronism, which may exaggerate the potassium wasting that is a consequence of the increased delivery of Na+ and enhanced flow through distal convoluted tubules and collecting ducts. 

Aldosterone is a mineralocorticoid hormone of the adrenal gland that stimulates retention of salt and water by the epithelium of the late DCT and CD (Figure 12.6). Aldosterone also increases the permeability of the tight junctions between tubular cells to H20 molecules. Hyperaldosteronism is characterised by hypernatraemia, hypokalaemia, alkalosis and fluid retention. 

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. 

Mineralocorticoid disorders can have high or low aldosterone production. Even in hyperaldosteronism disorders, circulating aldosterone and aldosterone metabolite excretion can be in the upper normal range. For this reason it is important to determine the aldosteroneirenin ratio. 

Lefebvre H, Cartier D, Duparc C, et al. Effect of serotonin4 (5-HT4) receptor agonists on aldosterone secretion in idiopathic hyperaldosteronism. Endocr Res 2000 26 583-587. 

Secondary hyperaldosteronism Fluid retention is also promoted by elevated levels of circulating aldosterone. This secondary hyperaldosteronism results from the decreased ability of the liver to inactivate the steroid hormone and leads to increased Na+ and water reabsorption, increased vascular volume, and exacerbation of fluid accumulation (see Figure 23.3). 

Mineralocorticoids help control the body s water volume and concentration of electrolytes, especially sodium and potassium. Aldosterone acts on kidney tubule cells, causing a reabsorption of sodium, bicarbonate, and water. Conversely, aldosterone decreases reabsorption of potassium, which is then lost in the urine. [Note Elevated aldosterone levels may cause alkalosis and hypokalemia, whereas retention of sodium and water leads to an increase in blood volume and blood pressure (see p. 180). Hyperaldosteronism is treated with spironolactone (see p. 232).]... 

Spironolactone competes for the mineralocorticoid receptor and thus inhibits sodium reabsorption in the kidney (see p. 232). It can also antagonize aldosterone and testosterone synthesis. It is effective against hyperaldosteronism. The drug is also useful in the treatment of hirsutism in women, probably due to interference at the androgen receptor of the hair follicle. 

Spironolactone, an aldosterone antagonist, is the drug of choice since secondary hyperaldosteronism often coexists in patients with hepatic ascites. Aldosterone is usually metabolised by the liver and is highly protein bound, therefore the free aldosterone levels are raised in cirrhosis. Spironolactone competes with aldosterone for receptor sites in the distal tubule, resulting in potassium retention and sodium and water loss. The initial dose of spironolactone is 100-200 mg and can be slowly increased according to response. There is a lag of 3-5 days between the beginning of spironolactone treatment and the onset of the natriuretic effect. 

Metoclopramide has been shown to significantly reduce spironolactone-induced diuresis in cirrhotic patients with ascites. When administered to patients with secondary hyperaldosteronism, metoclopramide significantly reduced urinary sodium excretion, with a corresponding increase in urinary potassium excretion and a significant increase in plasma aldosterone. This effect was not seen with domperidone. From this study it is recommended that metoclopramide is avoided during diuretic therapy in cirrhotic patients with ascites [15]. 

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). 

Alkalosis and hypokalaemia (possibly caused by secondary hyperaldosteronism or use of diuretics) shift the dissociation constant towards free, toxic NH3. By contrast, ammonia is considered - in a process resembling a vicious circle - to be a secondary stimulus for aldosterone production. Thiazide diuretics in particular put an overload on the detoxification capacity of the scavenger cells. This is because of an insufficient supply of bicarbonate for carbamoyl phosphate synthetase reaction due to diuretic-induced inhibition of the mitochondrial carboanhydrase. 

In humans, spironolactone is absorbed readily and is metabolized in the liver to active compounds called canrenones. It is these metabolites that compete with aldosterone for its cytosolic receptor therefore, the maximal natriuretic effect is not observed until 24-48 h after treatment has been initiated. Spironolactone is indicated for the treatment of primary hyperaldosteronism but is also used in refractory edema and in secondary hyperaldosteronism consequent to use of loop or thiazide-type diuretics (Martinez-Maldonado Cordova 1990, Rose 1989, 1991, Wilcox 1991). In one study, the administration of spironolactone via nasogastric tube (1 and 2mg/kg) to ponies more than doubled the urinary excretion of sodium and reduced the urinary excretion of potassium for a period of 72 h, although there was no difference in the volume of urine produced (Alexander 1982). This suggests that spironolactone is a potassium-sparing agent in horses however, to date, no pharmacokinetic studies have been published. 

Indications Hyperaldosteronism, hirsutism, hypertension Category Aldosterone antagonist Diuretic Half-life 78-84 minutes... 

The presence of excess TBW and hypernatremia indicates a net gain of water and Na, with Na gain in excess of water (see Figure 46-3). This condition is commonly observed in hospital patients receiving hypertonic saline or sodium bicarbonate. Other causes of hypervolemic hypernatremia include hyperaldosteronism and Cushing s syndrome (see Chapters 24 and 51). Excess aldosterone and cortisol (which also act as ligands for the distal tubule aldosterone receptor) results in excess Na and water retention. Corticosteroid therapy can have similar effects as weh. 

Most patients with autonomous aldosterone overproduction are hypokalemic, but most patients with hypokalemia do not have primary aldosteronism. In hyperaldosteronism, urinary potassium excretion is inappropriately high, and a random urine potassium >30mraol/L is usually indicative of primary aldosteronism or some type of mineralocorticoid excess condition. If hypokalemia can be shown to he due to nonrenal potassium loss, the diagnosis of aldosteronism does not need to be considered further. ... 

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