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Pharmacological particulars
Pharmacotherapeutic group: Aldosterone antagonist. ATCvet code: QC03DA01
Pharmacodynamic properties
Spironolactone and its active metabolites (including 7α-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone, and exert their effects by binding competitively to the mineralocorticoid receptor located in the kidneys, heart and blood vessels.
Spironolactone is a natriuretic drug (historically described as a soft diuretic). In the kidney, spironolactone inhibits the aldosterone-induced sodium retention leading to increase in sodium and subsequently water excretion, and potassium retention. The renal effects of spironolactone and its metabolites lead to a decrease in extracellular volume and consequently in a decrease of cardiac preload and left atrial pressure. The result is an improvement in heart function.
In the cardiovascular system, spironolactone prevents the detrimental effects of aldosterone. Although the precise mechanism of action is not yet clearly defined, aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction.
In experimental models in dogs, it was shown that long term therapy with an aldosterone antagonist prevents progressive left ventricle dysfunction and attenuates left ventricle remodelling in dogs with chronic heart failure.
When used in combination with ACE-inhibitors, spironolactone may counteract the effects of “aldosterone escape”.
A slight increase in aldosterone blood levels may be observed in animals on treatment. This is thought to be due to activation of feedback mechanisms without adverse clinical consequence. There may be a dose related hypertrophy of the adrenal zona glomerulosa at high dose rates.
Pharmacokinetic particulars
The pharmacokinetics of spironolactone are based on its metabolites, as the parent compound is rapidly metabolised.
In dogs, oral bioavailability of spironolactone as measured by canrenone AUCs was 83% relative to the iv route. It has been shown that feeding significantly increases the oral bioavailability of all measured metabolites resulting from dosing dogs with spironolactone. After multiple oral doses of 2 mg spironolactone per kg for 5 consecutive days, steady-state conditions are reached by day 3 and only a slight accumulation of canrenone is observed. After oral administration of spironolactone in dogs at 2 mg/kg, a mean Cmax of 41 ng/mL is achieved for the primary metabolites, canrenone, after 4 hours.
The mean apparent volume of distribution during elimination phase after oral dosing in dogs was 41 L/kg for canrenone.
The mean residence time of the metabolites ranges from 11 hours.
The protein binding is about 90%.
Spironolactone is rapidly and completely metabolised by the liver into its active metabolites, canrenone, 7α-thiomethyl-spironolactone and 6β-hydroxy-7α-thiomethyl-spironolactone, which are the primary metabolites in the dog.
Spironolactone is mainly excreted via its metabolites. Plasma clearance of canrenone is 3 L/h/kg for canrenone, in dogs. After oral administration of radiolabelled spironolactone to the dog, 66% of the dose is recovered in faeces and 12% in the urine. 74% of the dose is excreted within 48 hours.