Aldosterone receptor antagonists

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. 

Magni P, Motta M (2005) Aldosterone receptor antagonists biology and novel therapeutic applications. Curr Hypertens Rep 7 206-211... 

Aldosterone receptor antagonists, as antihypertensive agents, 5 154t, 159 Ale fermentations, 26 466 Aleprestic acid, 5 36t Alepric acid, 5 36t Aleprolic acid, 5 36t Aleprylic acid, 5 36t Alerting abstracts, in patent literature, 18 223... 

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). 

Mechanism of Action An aldosterone receptor antagonist that binds to the mineralo-corticoid receptors in the kidney, heart, bloodvessels, and brain, blocking the binding of aldosterone. Therapeutic Effect Reduces BP. 

Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effects of other diuretics. Aldosterone receptor antagonists in particular also have a favorable effect on cardiac function in people with heart failure. 

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. 

Khan NU, Movahed A. The role of aldosterone and aldosterone-receptor antagonists in heart failure. Rev Cardiovasc Med. 2004 5 71-81. 

Weinberger MH. Eplerenone a new selective aldosterone receptor antagonist. Drugs Today. 2004 40 481-485. 

Williams GH. Cardiovascular benefits of aldosterone receptor antagonists. Climacteric. 2003 6(suppl 3) 29-35. 

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. 

Although troublesome, these adverse effects are reversible and dose-related. The advent of selective aldosterone receptor antagonists, such as eplerenone, should reduce these adverse effects and thereby improve patient compliance. In EPHESUS there was no increase in the incidence of gynecomastia, breast pain, or impotence in men or menstrual irregularities in women who took eplerenone. 

Moore TD, Nawarskas JJ, Anderson JR. Epierenone a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis 2003 5(5) 354-63. 

Pitt B, Roniker B. Epierenone a novel selective aldosterone receptor antagonist (SARA) dose finding study in patients with heart failure. J Am CoU Cardiol 1999 33(Suppl A) A188-9. 

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. 

Barnes, B.J. and Howard, P.A. (2005) Eplerenone a selective aldosterone receptor antagonist for patients with heart failure. Ann Pharmacother, 39, 68-76. 

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). 

Aldosterone receptor antagonist K -sparing diuretic action in the collecting tubules used in aldosteronism, HTN, and female hirsutism. Tox h3 per-kalemia, gynecomastia. 

Epierenone (Inspra) [Anrihyperfensive/Seled ive Aldosterone Receptor Antagonist] Uses HTN HF following Ml Action Selective aldosterone antagonist Dose Adults. 50 rag PO daily-bid, doses >100 rag/d no benefit w/ T K" X to 25 rag PO daily if giving w/ CYP3A4 inhibitors (Table VI-8) Caution [B, +/-] monitor w/ ACE inhibitor, ARBs, NSAIDs, K -spai ing diiu etics grapefruit juice, St. John s wort Contra >5.5 mEq/L NIDDM w/... 

An increasing number of studies are being conducted to evaluate the effects of aldosterone receptor antagonists on the progression of cardiovascular and renal disease and in the treatment of hypertension. Aldosterone receptor antagonists are commonly... 

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