Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, ACE inhibitors, combinations. ATCvet code: QC09BA07.
Spironolactone and its active metabolites (including 7-α-thiomethyl-spironolactone and canrenone) act as specific antagonists of aldosterone by binding competitively to mineralocorticoid receptors located in the kidneys, heart and blood vessels. In the kidney, spironolactone inhibits the aldosterone-induced sodium retention leading to increase in sodium, and subsequently water excretion, and potassium retention. The resulting reduction in extracellular volume decreases the 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. Aldosterone promotes myocardial fibrosis, myocardial and vascular remodelling and endothelial dysfunction, although the precise mechanism of action is not yet clearly defined. 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.
Benazepril hydrochloride is a prodrug hydrolysed in vivo into its active metabolite, benazeprilat. Benazeprilat is a highly potent and selective inhibitor of angiotensin converting enzyme (ACE), thus preventing the conversion of inactive angiotensin I to active angiotensin II. Therefore, it blocks effects mediated by angiotensin II, including vasoconstriction of both arteries and veins, retention of sodium and water by the kidney.
The product causes a long-lasting inhibition of plasma ACE activity in dogs, with more than 95% inhibition at peak effect and significant activity (>80%) persisting 24 hours after dosing. The association of spironolactone and benazepril is beneficial as both act on the renin-angiotensinaldosterone system (RAAS) but at different levels along the cascade.
Benazepril, by preventing the formation of Angiotensin-II, inhibits the detrimental effects of vasoconstriction and stimulation of aldosterone release. However, aldosterone release is not fully controlled by ACE Inhibitors because Angiotensin-II is also produced by non-ACE pathways such as chymase (phenomenon known as “aldosterone breakthrough”). Secretion of aldosterone can also be stimulated by factors other than Angiotensin-II, notably K+ increase or ACTH. Therefore, to achieve a more complete inhibition of the deleterious effects of RAAS overactivity which occurs with heart failure, it is recommended to use aldosterone antagonists, such as spironolactone, concomitantly with ACE inhibitors to block specifically the activity of aldosterone (regardless of the source), through competitive antagonism on mineralocorticoid receptors. Clinical studies investigating the survival time demonstrated that the fixed combination increased the life expectancy in dogs with congestive heart failure with a 89% reduction in the relative risk of cardiac mortality assessed in dogs treated with spironolactone in combination with benazepril (as the hydrochloride) compared to dogs treated with benazepril (as hydrochloride) alone (mortality was classified as death or euthanasia due to heart failure). It also allowed a quicker improvement of cough and activity and a slower degradation of cough, heart sounds and appetite.
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.In a field study conducted in dogs with chronic degenerative valvular disease 85.9% of dogs showed good compliance with treatment (≥90% of prescribed tablets successfully administered) over a three month period.
The pharmacokinetics of spironolactone are based on its metabolites, as the parent compound is unstable at assay.
After oral administration of spironolactone to dogs, it was demonstrated that the three metabolites achieved levels of 32 to 49% of the administered dose. Food increases the bioavailability to 80 to 90%. Following oral administration of 2 to 4 mg/kg, absorption increases linearly over the range. After multiple oral doses of 2 mg spironolactone per kg (with 0.25 mg benazepril hydrochloride per kg) for 7 consecutive days, no accumulation is observed. At steady state, mean Cmax of 324 μg/l and 66 μg/l are achieved for the primary metabolites, 7-α-thiomethyl-spironolactone and canrenone, 2 and 4 hours post-dosing, respectively. Steady-state conditions are reached by day 2.
After oral administration of benazepril hydrochloride, peak levels of benazepril are attained rapidly and decline quickly as the drug is partially metabolized by liver enzymes to benazeprilat. Unchanged benazepril and hydrophilic metabolites account for the remainder. The systemic bioavailability of benazepril is incomplete due to incomplete absorption and first pass metabolism. There is no significant difference in the pharmacokinetics of benazeprilat when benazepril (as hydrochloride) is administered to fed or fasted dogs.
After multiple oral doses of 0.25 mg benazepril hydrochloride per kg (with 2 mg spironolactone per kg) for 7 consecutive days, a peak benazeprilat concentration (Cmax of 52.4 ng/ml) is achieved with a Tmax of 1.4 h.
The mean volumes of distribution of 7-α-thiomethyl-spironolactone and canrenone are approximately 153 litres and 177 litres respectively. The mean residence time of the metabolites ranges from 9 to 14 hours and they are preferentially distributed to the gastro-intestinal tract, kidney, liver and adrenal glands.
Benazepril and benazeprilat are rapidly distributed, mainly in liver and kidney.
Spironolactone is rapidly and completely metabolised by the liver into its active metabolites, 7-α-thiomethyl-spironolactone and canrenone, which are the primary metabolites in the dog. After coadministration of spironolactone (2 mg/kg bw) and benazepril hydrochloride (0.25 mg/kg bw) the terminal plasma half-lives (t½) were 7 hours and 6 hours for canrenone and 7-α-thiomethyl-spironolactone respectively.
Benazeprilat concentrations decline biphasically: the initial fast phase represents elimination of free drug, while the terminal phase reflects the release of benazeprilat that was bound to ACE, mainly in the tissues. After co-administration of spironolactone (2 mg/kg bw) and benazepril hydrochloride (0.25 mg/kg bw) the terminal plasma half-life of benazeprilat (t½) was 18 hours. Benazepril and benazeprilat are extensively bound to plasma proteins, and in tissues are found mainly in the liver and kidney.
Repeated administration of benazepril leads to slight bioaccumulation of benazeprilat, steady state being achieved within few days.
Spironolactone is mainly excreted via its metabolites. The plasma clearances of canrenone and 7-α-thiomethyl-spironolactone are 1.5 l/h/kg bw and 0.9 l/h/kg bw respectively. After the oral administration of radiolabelled spironolactone to the dog, 70% of the dose is recovered in faeces and 20% in the urine. Benazeprilat is excreted via the biliary and the urinary route in dogs. The clearance of benazeprilat is not affected in dogs with impaired renal function and therefore no adjustment of benazepril dose is required in cases of renal insufficiency