Aldosterone receptors

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). 

Spironolactone antagonizes the effects of aldosterone by binding at the aldosterone receptor in the cytosol of the late distal tubules and renal collecting ducts. Side effects of spironolactone are gynecomastia, decreased Hbido, and impotency. 

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. 

Glucocorticoid Receptor GR GCR GRL Nuclear Receptor Subfamily 3, Group C, Member 1 (NR3C1) Glucocorticoid Receptor Type II Mineralocorticoid Receptor MR MCR MRL Nuclear Receptor Subfamily 3, Group C, Member 2 (NR3C2) Glucocorticoid Receptor Type I Aldosterone Receptor... 

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... 

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. 

Spironolactone - Spironolactone, a competitive inhibitor of aldosterone, binds to aldosterone receptors of the distal tubule and prevents the formation of a... 

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. 

An example of the importance of enzymatic modification of hormones for the tissue specificity of hormone action is the effect of the mineral corticoid aldosterone in the presence of a large excess of the glucocorticoid cortisol. Aldosterone regulates the Na -export and K -retention in the kidney by binding on the aldosterone receptor. 

Fig. 4.3. Example of a tissue-specific hormone inactivation. Cortisol is enzymatically converted to an keto compound at the Cll position. The modified cortisol compound can no longer bind and activate the aldosterone receptor. Aldosterone can not be turned over by 11-P-dehydroge-nase because the OH group at position 11 forms a half-acetal with the formyl group (C18).

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. 

Spironolactone Block aldosterone receptor in renal collecting tubule Increase Na and decrease excretion poorly understood reduction in heart failure mortality Aldosteronism, heart failure, hypertension ... 

Spironolactone Block cytoplasmic aldosterone receptors in collecting tubules of nephron possible membrane effect Increased salt and water excretion reduces remodeling reduces mortality Chronic heart failure aldosteronism (cirrhosis, adrenal tumor) hypertension Oral duration 24-72 h (slow onset and offset) Toxicity Hyperkalemia, antiandrogen actions... 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

Ion transport pathways across the luminal and basolateral membranes of collecting tubule and collecting duct cells. Inward diffusion of Na+ via the epithelial sodium channel (ENaC) leaves a lumen-negative potential, which drives reabsorption of and efflux of K+. (R, aldosterone receptor.)... 

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 Like spironolactone, more selective for aldosterone receptor ... 

Some of the effects of glucocorticoids can be attributed to their binding to aldosterone receptors (ARs). Indeed, ARs bind aldosterone and cortisol with similar affinity. A mineralocorticoid effect of cortisol is avoided in some tissues by expression of llE>-hydroxysteroid dehydrogenase type 2, the enzyme responsible for biotransformation to its 11-keto derivative (cortisone), which has minimal affinity for aldosterone receptors. 

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. 

It has also been suggested that certain diuretics such as spironolactone (Aldactone) might be especially helpful in heart failure.14,42 Spironolactone blocks aldosterone receptors in the kidneys and other tissues, thereby producing a diuretic effect as well as preventing adverse cardiovascular changes associated with excess aldosterone production. Future studies will help clarify whether spironolactone should be used preferentially in heart failure because of its ability to reduce fluid volume and protect against aldosterone-induced damage.53... 

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

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... 

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. 

---