Spire Mechanism of Action

Pharmacotherapeutic group: Potassium-sparing agents. ATC code: C03DA01.
Pharmacology: Pharmacodynamics: Mechanism of action: Spironolactone, as a competitive aldosterone antagonist, increases sodium excretion whilst reducing potassium loss at the distal renal tubule. It has a gradual and prolonged action, maximum response being usually attained after 2 to 3 days treatment. Combination of Spironolactone with a conventional, more proximally acting diuretic usually enhances diuresis without excessive potassium loss.
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).
Paediatric population: There is a lack of substantive information from clinical studies on spironolactone in children. This is a result of several factors: the few trials that have been performed in the paediatric population, the use of spironolactone in combination with other agents, the small numbers of patients evaluated in each trial and the different indications studied. The dosage recommendations for paediatrics are based upon clinical experience and case studies documented in the scientific literature.
Pharmacokinetics: Spironolactone is well absorbed from the gastrointestinal tract, with a bioavailability of about 90%. It is about 90% bound to plasma proteins. Spironolactone is metabolized extensively to a number of metabolites including canrenone and 7α-thiomethylspironolactone, both of which are pharmacologically active. The major metabolite may be 7α-thiomethylspironolactone, although it is uncertain to what extent the actions of spironolactone are dependent on the parent compound or its metabolites.
Spironolactone is excreted mainly in the urine and also in the feces, in the form of metabolites. Spironolactone or its metabolites may cross the placental barrier and canrenone is distributed into breast milk.