Aldosterone receptor antagonists spironolactone

Potassium-Sparing Diuretics. Potassium-sparing diuretics act on the aldosterone-sensitive portion of cortical collecting tubules, and partially in the distal convoluted tubules of the nephron. The commonly used potassium-sparing diuretics are triamterene, amiloride, and spironolactone (Table 3). Spironolactone is a competitive aldosterone receptor antagonist, whereas triamterene and amiloride are not (44,45). 

Ascites. Patients with cirrhosis, especially fiver cirrhosis, very often develop ascites, ie, accumulation of fluid in the peritoneal cavity. This is the final event resulting from the hemodynamic disturbances in the systemic and splanchnic circulations that lead to sodium and water retention. When therapy with a low sodium diet fails, the dmg of choice for the treatment of ascites is furosemide, a high ceiling (loop) diuretic, or spironolactone, an aldosterone receptor antagonist/potassium-sparing diuretic. 

Spironolactone is poorly absorbed after oral administration and has a delayed onset of action it may take several days until a peak effect is produced. It has a somewhat slower onset of action than triamterene and amiloride (discussed later), but its natriuretic effect is modestly more pronounced, especially during long-term therapy. Spironolactone is rapidly and extensively metabolized, largely to the active metabohte canrenone. Canrenone and potassium canrenoate, its K+ salt, are available for clinical use in some countries outside the United States. Canrenone has a half-life of approximately 10 to 35 hours. The metabolites of spironolactone are excreted in both the urine and feces. New selective aldosterone receptor antagonists (SARA), such as eplerenone, have been developed but have not yet been introduced into clinical practice. Eplerenone and canrenone exhibit fewer steroidlike side effects (gynecomastia, hirsutism). 

When ascites and edema become severe, diuretic therapy can be very useful. However, cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels. In contrast, cirrhotic edema is unusually responsive to spironolactone and eplerenone. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. 

Eplerenone, another aldosterone antagonist, is approved for the treatment of hypertension (see Chapters 11 and 15). This aldosterone receptor antagonist is somewhat more selective than spironolactone and has no reported effects on androgen receptors. The standard dosage in hypertension is 50-100 mg/d. The most common toxicity is hyperkalemia but this is usually mild. 

Several mechanisms have been postulated to underlie the benefits of aldosterone receptor antagonists in heart failure (30). Aldosterone-induced cardiac fibrosis may reduce systolic function, impair diastolic function, and promote intracardiac conduction defects, with the potential for serious dysrhythmias. Aldosterone may also increase vulnerability to serious dysrhythmias by other mechanisms. The diuretic and hemodynamic effects of spironolactone in RALES and EPHESUS were subtle, and there were no significant changes in body weight, sodium retention, or systemic blood pressure. 

Spironolactone (aldosterone receptor antagonist) and amiloride and triamterene (Na+ channel blockers) prevent the above effects, leading to minor effects on Na+ reabsorption but major effects on the retention of K+ ions and protons. Thus, they cause small increases in urinary Na+ and marked decreases in urinary K+, resulting in hyperkalemia and acidosis. 

Carbonic anhydrase inhibitors are useful in glaucoma and altitude sickness. The answer is (A). Spironolactone is an aldosterone receptor antagonist, acts intracellularly in the cortical collecting tubule, and causes potassium retention. The answer is (E). 

A. Receptor Antagonists Spironolactone, an antagonist of aldosterone at its receptor, has been discussed in connection with the diuretics (see Chapter 15). Mifepristone (RU 486) is an inhibitor at glucocorticoid receptors as well as progesterone receptors (see Chapter 40) and has been used in the treatment of Cushing s syndrome. 

Urinary tract Acute renal insufficiency with hyperkalemia has been reported in a 76-year-old hypertensive woman taking both aliskiren and spironolactone [68 ]. Preexisting renal impairment and concomitant use of an aldosterone receptor antagonist were predisposing factors, and it is not surprising that the same pattern of adverse effects is seen in cases like this as have been seen with ACE inhibitors and angiotensin receptor blockers before. 

Triamterene is a pyrazine derivative that inhibits reabsorption of sodium ions without increasing excretion of potassium ions. It exhibits the same approximate effect as spironolactone however, it does not competitively bind with aldosterone receptors. Its action does not have an effect on secretion of aldosterone or its antagonists, which are a result of direct action on renal tubules. 

Figure 12.6 Mechanism of action of mineralocortjcoid receptor antagonists in the collecting tubule. Aldosterone enters the tubular cell by the basolateral surface and binds to a specific mineralocorticoid receptor (MNR) in the cytoplasm. The hormone receptor complex triggers the production of an aldosterone-induced protein (AlP) by the cell nucleus (NUC). The AIP acts on the sodium ion channel (ic) to augment the transport of Na+across the basolateral membrane and in to the cell. An increase in AIP activity leads to the recruitment of dormant sodium ion channels and Na pumps (P) in the cell membrane. AIP also leads to the synthesis of new channels and pumps within the cell. The increase in Na+conductance causes electrical changes in the luminal membrane that favour the excretion of intracellular cations, such as K+and H-h. Spironolactone competes with aldosterone for the binding site on the MNR and forms a complex which does not excite the production of AIP by the nucleus.

The mineralocorticoid antagonists used clinically include spironolactone (Aldactone) and eplerenone (Inspra). These drugs are competitive antagonists of the aldosterone receptor that is, they bind to the receptor but do not activate it. When bound to the... 

Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Its onset and duration of action are determined by the kinetics of the aldosterone response in the target tissue. Substantial inactivation of spironolactone occurs in the liver. Overall, spironolactone has a rather slow onset of action, requiring several days before full therapeutic effect is achieved. Eplerenone, a new spironolactone analog with greater selectivity for the aldosterone receptor, has recently been approved for the treatment of hypertension. 

Spironolactone is a competitive antagonist at aldosterone receptors. It acts through its active metabohte, canrenone. Canrenone itself has also been used as a potassium-sparing diuretic for intravenous use and its potassium salt has been used orally, in the hope of avoiding the hormonal adverse effects of spironolactone. 

Spironolactone is a competitive antagonist of aldosterone. It binds to the aldosterone receptor and prevents the induction of protein channels that exchange sodium for potassium in the urinary filtrate in the distal portion of the distal convoluted tubule and collecting ducts. Thus, sodium is excreted and potassium is retained. 

Prototypes and Mechanism of Action Spironolactone, a steroid derivative, is a pharmacologic antagonist of aldosterone in the collecting tubules. By combining with and blocking the intracellular aldosterone receptor, spironolactone reduces the expression of genes controlling... 

There is an increased risk of hyperkalaemia if angiotensin II receptor antagonists are given with potassium-sparing diuretics (such as amiloride and the aldosterone antagonists, epierenone and spironolactone), particularly if other risk factors are also present... 

Angiotensin II receptor antagonists reduce the levels of aldosterone, which results in the retention of potassium. This would be expected to be additive with the potassium-retaining effects of amiloride, triamterene, spironolactone and eplerenone, leading to hyperkalaemia, but usually only if other risk factors are present. 

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. 

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