Aldosterone antagonists in hypertension and heart failure

Spironolactone, a competitive aldosterone receptor antagonist (ARA), has tr aditionally been the treatment of first choice in idiopathic hyperaldostero nism (IHA) and for preoperative management of aldosterone producing adenoma (APA). Spironolactone is partially absorbed, is extensively metabolized ma inly by the liver and its therapeutic properties are attributable to active metabolite canrenone. At therapeutic doses of 25 to 400 mg per day, spironolactone effectively co ntrols blood pressure and hypokalemia in the majority of cases. Endocrine s ide effect are often associated and mainly consist of gynecomastia, decreas ed libido and impotence in man and menstrual irregularities in women. Canre none and the K+ salt of canrenoate are also in clinical use: they avoid the formation of intermediate products with anti-androgenic and progestational actions, resulting in a decreased incidence of side effects. Furthermore, a relatively new selective ARA compound (eplerenone) with reduced affinity for androgen and progesterone receptors, is currently undergoing clinical t rials. In essential hypertension aldosterone can contribute to hypertension and in creases the incidence of myocardial hypertrophy and cardiovascular events. On the other hand, inhibition of Renin-Angiotensin-Aldosterone System (RAAS ) is associated with a decrease in blood pressure, with a regression of lef t ventricular hypertrophy and a reduction of target organ damage. Thus, ARA have been proposed as complementary treatment associated to ACE inhibitors and angiotensin receptor antagonists, Aldosterone is also known to play an important role in pathophysiolgy of congestive heart failure (CHF). In vit ro and in vivo evidences suggest that aldosterone promotes myocardial fibro sis. This effect reflects direct, extra-epithelial actions of aldosterone v ia cardiac MR which are counteracted by ARAs in animal models. The RAAS is chronically activated in CHF. Non potassium-sparing diuretics f urther stimulate the RAAS and cause hypokalemia. Thus, use of ARAs in CHF w as first proposed to correct potassium and magnesium depletion. At present ARAs are indicated in the management of primary hyperaldosteronism, in oede matous conditions in patients with CHF, in cirrhosis of the liver accompani ed by oedema and ascites, in essential hypertension and in hypokalemic stat es. Its indication as adjunctive therapy of heart failure is currently unde r investigation. In fact, it is well known that even high doses of ACE inhi bitors may not completely suppress the RAAS; aldosterone 'escape' may occur through non angiotensin ii dependent mechanisms. Addition of spironolacton e to an ACE inhibitor causes marked diuresis and symptomatic improvement. D uring the last few years, the RALES study (Randomized Aldactone Evaluation Study) was organized to explore the efficacy of combination therapy with sp ironolactone and ACE inhibitor in patients with CHF, class III or IV NYHA. The study was stopped 18 months early because the results were so statistic ally and clinically significant that it would be unethical to continue the trial, it is reported a 30 percent decrease in mortality and hospitalisatio n for cardiac causes in spironolactone-treated group vs placebo group.