Spironolactone, a competitive
aldosterone receptor antagonist (ARA), has traditionally been the treatment of first choice in idiopathic
hyperaldosteronism (IHA) and for preoperative management of
aldosterone producing
adenoma (APA).
Spironolactone is partially absorbed, is extensively metabolized mainly 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 controls blood pressure and
hypokalemia in the majority of cases. Endocrine side effect are often associated and mainly consist of
gynecomastia, decreased libido and
impotence in man and
menstrual irregularities in women.
Canrenone 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 trials. In
essential hypertension aldosterone can contribute to
hypertension and increases 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
left 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 vitro and in vivo evidences suggest that
aldosterone promotes myocardial
fibrosis. This effect reflects direct, extra-epithelial actions of
aldosterone via cardiac MR which are counteracted by ARAs in animal models. The RAAS is chronically activated in CHF. Non
potassium-sparing diuretics further stimulate the RAAS and cause
hypokalemia. Thus, use of ARAs in CHF was first proposed to correct
potassium and magnesium depletion. At present ARAs are indicated in the management of
primary hyperaldosteronism, in oedematous conditions in patients with CHF, in
cirrhosis of the liver accompanied by oedema and
ascites, in
essential hypertension and in hypokalemic states. Its indication as adjunctive
therapy of
heart failure is currently under investigation. In fact, it is well known that even high doses of
ACE inhibitors may not completely suppress the RAAS;
aldosterone 'escape' may occur through non
angiotensin II dependent mechanisms. Addition of
spironolactone to an
ACE inhibitor causes marked diuresis and symptomatic improvement. During the last few years, the
RALES study (Randomized
Aldactone Evaluation Study) was organized to explore the efficacy of combination
therapy with
spironolactone and
ACE inhibitor in patients with CHF, class III or IV NYHA. The study was stopped 18 months early because the results were so statistically and clinically significant that it would be unethical to continue the trial. It is reported a 30 percent decrease in mortality and hospitalisation for cardiac causes in
spironolactone-treated group vs placebo group.