Pharmacology: Pharmacodynamics: Mechanism of Action:
Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents that act more proximally in the renal tubule.
Aldosterone Antagonist Activity:
Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism.
Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis and nephrotic syndrome. By competing with aldosterone for receptor sites, spironolactone provides effective therapy for edema and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.
Spironolactone is effective in lowering the systolic and diastolic blood pressure in patients with primary hyperaldosteronism. It is also effective in most cases of essential hypertension, despite the fact that aldosterone secretion may be within normal limits in benign essential hypertension.
Spironolactone has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism.
Severe Heart Failure: RALES was a multinational, double-blind study in 1663 patients with an ejection fraction of ≤35%, a history of NYHA Class IV heart failure within 6 months, and Class III-IV heart failure at the time of randomization. All patients were required to be taking a loop diuretic and, if tolerated, an ACE inhibitor. Patients with a baseline serum creatinine of >2.5 mg/dL or a recent increase of 25% or with a baseline serum potassium of >5.0 mEq/L were excluded. Patients were randomized 1:1 to spironolactone 25 mg orally once daily or matching placebo. Patients who tolerated 25 mg once daily had their dose increased to 50 mg once daily as clinically indicated. Patients who did not tolerate 25 mg once daily had their dosage reduced to 25 mg every other day. The primary endpoint for RALES was time to all-cause mortality. RALES was terminated early, after a mean follow-up of 24 months, because of significant mortality benefit detected on a planned interim analysis. Spironolactone reduced the risk of death by 30% compared to placebo (p<0.001; 95% confidence interval 18%-40%). Spironolactone reduced the risk of cardiac death, primarily sudden death and death from progressive heart failure by 31% compared to placebo (p<0.001;95% confidence interval 18%-42%).
Spironolactone also reduced the risk of hospitalization for cardiac causes (defined as worsening heart failure, angina, ventricular arrhythmias or myocardial infarction) by 30% (p<0.001; 95% confidence interval 18%-41%). Changes in NYHA class were more favorable with spironolactone: in the spironolactone group, NYHA class at the end of the study improved in 41% of patients and worsened in 38% compared to improved in 33% and worsened in 48% in the placebo group (p<0.001).
Spironolactone is rapidly and extensively metabolized. Sulfur-containing products are the predominant metabolites and are thought to be primarily responsible, together with spironolactone, for the therapeutic effects of the drug. The following pharmacokinetic data were obtained from 12 healthy volunteers following the administration of 100 mg of spironolactone daily for 15 days. On the 15th day, spironolactone was given immediately after a low-fat breakfast and blood was drawn thereafter. (See Table 1).
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The pharmacological activity of spironolactone metabolites in man is not known. However, in adrenalectomized rats, the antimineralocorticoid activities of the metabolites canrenone (C), 7-α-(thiomethyl) spirolactone (TMS), and 6-β-hydroxy-7-α-(thiomethyl) spirolactone (HTMS), relative to spironolactone, were 1.10, 1.28, and 0.32, respectively. Relative to spironolactone, their binding affinities to the aldosterone receptors in rat kidney slices were 0.19, 0.86, and 0.06, respectively.
In humans the potencies of TMS and 7-α-thiospirolactone in reversing the effects of the synthetic mineralocorticoid, fludrocortisone, on urinary electrolyte composition were 0.33 and 0.26, respectively, relative to spironolactone. However, since the serum concentrations of these steroids were not determined, their incomplete absorption and/or first-pass metabolism could not be ruled out as a reason for their reduced in vivo
Spironolactone and its metabolites are >90% bound to plasma proteins. The metabolites are excreted primarily in the urine and secondarily in bile.
The effect of food on spironolactone absorption was assessed in a single-dose study of 9 healthy, drug-free volunteers. Food increased the bioavailability of unmetabolized spironolactone by almost 100%. The clinical importance of this finding is not known.
Toxicology: Preclinical Safety Data:
Carcinogenicity, Mutagenicity, Impairment of Fertility: Orally administered spironolactone has been shown to be a tumorigen in dietary administration studies performed in rats, with its proliferative effects manifested on endocrine organs and the liver. In an 18-month study using doses of about 50, 150 and 500 mg/kg/day, there were statistically significant increases in benign adenomas of the thyroid and testes and, in male rats, a dose-related increase in proliferative changes in the liver (including hepatocytomegaly and hyperplastic nodules). In a 24-month study in which the same strain of rat was administered doses of about 10, 30, 100 and 150 mg/kg/day of spironolactone, the range of proliferative effects included significant increases in hepatocellular adenomas and testicular interstitial cell tumors in males, and significant increases in thyroid follicular cell adenomas and carcinomas in both sexes. There was also a statistically significant, but not dose-related, increase in benign uterine endometrial stromal polyps in females.
A dose-related (above 20 mg/kg/day) incidence of myelocytic leukemia was observed in rats fed daily doses of potassium canrenoate (a compound chemically similar to spironolactone and whose primary metabolite, canrenone, is also a major product of spironolactone in man) for a period of 1 year. In 2-year studies in the rats, oral administration of potassium canrenoate was associated with myelocytic leukemia and hepatic, thyroid, testicular and mammary tumors.
Neither spironolactone nor potassium canrenoate produced mutagenic effects in tests using bacteria or yeast. In the absence of metabolic activation, neither spironolactone nor potassium canrenoate has been shown to be mutagenic in mammalian tests in vitro
. In the presence of metabolic activation, spironolactone has been reported to be negative in some mammalian mutagenicity tests and in conclusive (but slightly positive) for mutagenicity in other mammalian tests in vitro
. In the presence of metabolic activation, potassium canrenoate has been reported to test positive for mutagenicity in some mammalian tests in vitro
, inconclusive in others, and negative in still others.
In a three-litter reproduction study in which female rats received dietary doses of 15 and 50 mg/kg/day of spironolactone, there were no effects on mating and fertility, but there was a small increase in incidence of stillborn pups at 50 mg/kg/day. When injected into female rats (100 mg/kg/day for7 days, i.p.), spironolactone was found to increase the length of the estrous cycle by prolonging diestrus during treatment and inducing constant diestrus during a 2-week post-treatment observation period. These effects were associated with retarded ovarian follicle development and a reduction in circulating estrogen levels, which would be expected to impair mating, fertility and fecundity. Spironolactone (100 mg/kg/day), administered i.p. to female mice during a 2-week cohabitation period with untreated males, decreased the number of mated mice that conceived (effect shown to be caused by an inhibition of ovulation) and decreased the number of implanted embryos in those that became pregnant (effect shown to be caused by an inhibition of implantation), and at 200 mg/kg, also increased the latency period to mating.