Hypertension aldosterone antagonists

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. 

Patients with asymptomatic left ventricular systolic dysfunction and hypertension should be treated with P-blockers and ACE inhibitors. Those with heart failure secondary to left ventricular dysfunction and hypertension should be treated with drugs proven to also reduce the morbidity and mortality of heart failure, including P-blockers, ACE inhibitors, ARBs, aldosterone antagonists, and diuretics for symptom control as well as antihypertensive effect. In African-Americans with heart failure and left ventricular systolic dysfunction, combination therapy with nitrates and hydralazine not only affords a morbidity and mortality benefit, but may also be useful as antihypertensive therapy if needed.66 The dihydropyridine calcium channel blockers amlodipine or felodipine may also be used in patients with heart failure and left ventricular systolic dysfunction for uncontrolled blood pressure, although they have no effect on heart failure morbidity and mortality in these patients.49 For patients with heart failure and preserved ejection fraction, antihypertensive therapies that should be considered include P-blockers, ACE inhibitors, ARBs, calcium channel blockers (including nondihydropyridine agents), diuretics, and others as needed to control blood pressure.2,49... 

To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an EF of equal to or less than 40% and either heart failure symptoms or diagnosis of diabetes mellitus.3 Aldosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, hypertension, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone antagonists have been shown in experimental and human studies to attenuate these adverse effects.70 Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.71... 

Aldosterone (183) is one of the key steroid hormones involved in regulation of the body s mineral and fluid balance. Excess levels of this steroid quickly lead to marked retention of sodium chloride, water and, often as a consequence, hypertension. The aldosterone antagonist spironolactone (184) has proven of great clinical value in blocking the effects... 

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. 

The aldosterone antagonist, spironolactone> has been successfully used for the treatment of hypertension. Its natriuretic effect is associated with potassium retention. Specificity of spironolactone in certain types of hypertension had been suggested, but subsequently denied in well controlled studies(15,16). 

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. 

Gaddam, K.K., Pratt-Ubunana, M.N. and Calhoun, D.A. 2006. Aldosterone antagonists effective add-on therapy for the treatment of resistant hypertension. Expert Rev. Cardiovasc. Then 4, 353-359. 

Hollenberg NK, Williams GH, Anderson R, Akhras KS, Bittman RM, Krause SL. Symptoms and the distress they cause comparison of an aldosterone antagonist and a calcium channel blocking agent in patients with systohc hypertension. Arch Intern Med 2003 163(13) 1543-8. 

Cpierenone, U5P. Eplcrenone. 9,lla-epoxy-l7a-hy-droxy-3-oxopregn-4-enc-7a.2l-dicarboxylic acid, y-lac-tone. methyl ester (Inspra). is a new aldosterone antagonist that was approved by the FDA in 2002 for the treatment of hypertension. 

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

General. Noteworthy reports- and reviews pertaining to the pharma-cologicalj endocrinological > and clinical aspects of diuretics have appeared in the recent literature. The use of diuretics in the treatment of hypertension has been reviewed with especial emphasis on the hypotensive action of the aldosterone antagonist, spironolactone.° Fundamental studies on the mechanism of transport of electrolyte across the tubular epithelium have indicated that phospholipids may play a critical role. Phospholipase C and pancreatic lipase markedly reduced the rate of reabsorption of saline droplets infused into rat proximal tubules. Likewise, phospholipase C reduced the ability of extractable lipids to bind sodium and potassium ions in rat kidney homogenates whereas, phospholipase D and ribonuclease appear to enhance cation binding. ... 

Thiazides are the preferred type of diuretic for treating hypertension. In patients with adequate kidney function (estimated GER > 30 mL/min), thiazides are the most effective diuretics for lowering BR As kidney fnnction declines, a more potent diuretic is needed to counteract the associated increase in sodinm and water retention. In this case, a loop dinretic (e.g., furosemide dosed twice daily) should be considered. Dinretics ideally should be dosed in the morning if given once daily and in the morning and afternoon if dosed twice daily to minimize the risk of nocturnal diuresis. However, with chronic use, thiazides, potassium-sparing diuretics, and aldosterone antagonists rarely cause a pronounced diuresis. 

Overall, clinical trials have impressively demonstrated that aldosterone is a major contributor to cardiovascular morbidity and mortality in patients with arterial hypertension and heart failure. However, the currently available MR antagonists suffer from two substantial drawbacks that limit their benefit in clinical practice, i.e. lack of selectivity (in the case of spironolactone) and limited efficacy (in the case of eplerenone). Consequently a second race for new aldosterone antagonists has started, in search of a compound which ideally should combine the potency and efficacy of spironolactone with the selectivity of eplerenone. 

Increased water retention, hypertension and disturbed sodium and potassium balance aldosterone aldosterone antagonist)... 

It is generally assumed that the intracellular content of sodium in vascular smooth muscle is increased in essential hypertension. Although the major role of aldosterone in the regulation of blood pressure is a renal one, it may also be involved in some extrarenal effects responsible for the regulation of body fluid and blood pressure. Recent studies have suggested that vascular walls specifically bind to aldosterone and that aldosterone has a direct vasoconstrictive effect on vascular smooth muscle in vitro. Indeed, canrenoate potassium (Soldactone S), an aldosterone antagonist, reduces blood pressure (Figure 24). 

I Aldosterone antagonist, nesirltide I Consider multidisciplinary team I Revascularization, mitral-valve surgery I Cardiac resynchronization if bundle-branch block preseht Dietary Na restriction, diuretics, and dlgoxln I ACE Inhibitors and p blockers in all patients I ACE Inhibitors or AT blockers In all patients J3 blockers In selected patients Treat hypertension, diabetes, dyslipidemla ACE inhibitors or ATr blockers In some patients Risk-factor reduction, patient and family education... 

Spironolactone (aldactone) ("see Chapter 28) is an aldosterone antagonist that also is a weakAR antagonist and a weak inhibitor of testosterone synthesis, apparently inhibiting CYP17. When used to treat fluid retention or hypertension in men, gynecomastia is a common side effect. 

The mineralocorticoid-aldosterone essentially monitors the eleetrolyte balance in the body by enhaneing the excretion of and the retention of Na. Thus, aldosterone antagonists are usually employed for the effective treatment of edematous ailments and hypertension. 

Aldosterone antagonists have been advocated in the treatment of resistant hypertension, often as fourth-line agents. Their place in the hierarchy of treatment means that they are often used in combination with drugs that act on the renin-angiotensin... 

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... 

Li JS, Flynn JT, Portman R, Davis I, Ogawa M, Shi H, Pressler ML. The efficacy and safety of the novel aldosterone antagonist eplerenone in children with hypertension a randomized, double-blind, dose-response study. J Pediatr 2010 157(2) 282-7. 

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