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Pharmacological particulars
Pharmacotherapeutic group: ACE inhibitors, combinations.
ATCvet code: QC09BX90
Pharmacodynamic properties
Benazepril hydrochloride is a prodrug which is hydrolysed in vivo to its active metabolite, benazeprilat. Benazeprilat is a highly potent and selective inhibitor of ACE, thus preventing the conversion of inactive angiotensin I to active angiotensin II and thereby also reducing the synthesis of aldosterone. Therefore, benazepril blocks effects mediated by angiotensin II and aldosterone, including the vasoconstriction of arteries and veins, the retention of sodium and water by the kidney, and remodelling effects (including pathological cardiac hypertrophy and degenerative renal changes).
In dogs with congestive heart failure benazepril hydrochloride reduces the blood pressure and volume load on the heart. Benazepril increased the time to worsening of heart failure, and the time to death, improved clinical condition, reduced cough and improved exercise tolerance in dogs with symptomatic congestive heart failure caused by valvular disease or dilated cardiomyopathy.
Pimobendan, a benzimidazole-pyridazinone derivative, is a non-sympathomimetic, non-glycoside inotropic substance with potent vasodilating properties. It increases the calcium sensitivity of cardiac myofilaments and inhibits phosphodiesterase (type III). It also exhibits a vasodilatory action through the inhibition of phosphodiesterase type III activity.
Pharmacokinetic properties
Following oral administration of pimobendan alone the absolute bioavailability of the active ingredient is 60–63%. Since this bioavailability is considerably reduced when pimobendan is administered with food or shortly thereafter, it is recommended to treat animals approximately 1 hour before feeding.
After oral administration of benazepril hydrochloride alone, the systemic bioavailability is incomplete (~13%) in dogs due to incomplete absorption (38%) and first pass metabolism. Levels of benazepril decline quickly as the drug is partially metabolised by liver enzymes to benazeprilat. There is no significant difference in the pharmacokinetics of benazeprilat when benazepril hydrochloride is administered to fed or fasted dogs.
After the oral administration of FORTEKOR PLUS tablets at twice the recommended dose to dogs, peak levels of both compounds are attained rapidly (Tmax 0.5 h for benazepril hydrochloride and 0.85 h for pimobendan) with peak concentrations (Cmax) for benazepril hydrochloride of 35.1 ng/ml and 16.5 ng/ml for pimobendan. Peak benazeprilat levels are seen after 1.9 h with peak concentrations (Cmax) of 43.4 ng/ml.
The volume of distribution at steady state is 2.6 l/kg after intravenous administration of pimobendan alone, indicating that pimobendan is distributed readily into the tissues. The mean plasma protein binding in vitro is 93%.
Benazeprilat concentrations decline biphasically: the initial fast phase (t1/2 = 1.7 h) represents elimination of the free drug, while the terminal phase (t1/2 = 19 h) reflects the release of benazeprilat that was bound to ACE, mainly in the tissues. Benazepril and benazeprilat are extensively bound to plasma proteins (85–90%), and in the tissues they are found mainly in the lung, liver and kidney.
Repeated administration of benazepril hydrochloride leads to slight bioaccumulation of benazeprilat (R = 1.47), steady state being achieved within a few days (4 days).
Pimobendan is oxidatively demethylated to its major active metabolite, O-desmethyl pimobendan. Further metabolic pathways are phase II, glucuronides and sulfates.
Benazepril hydrochloride is partially metabolised by liver enzymes to the active metabolite benazeprilat.
The plasma elimination half-life of pimobendan when dosed with FORTEKOR PLUS tablets is 0.5 h, consistent with the high clearance of the compound. The main active metabolite of pimobendan is eliminated with a plasma elimination half-life of 2.6 h. Pimobendan is excreted principally in the faeces and to a lesser extent in the urine.
The plasma elimination half-life of benazepril hydrochloride and benazeprilat, when dosed with FORTEKOR PLUS tablets is 0.36 h and 8.36 h, respectively. Benazeprilat is excreted via the biliary (54%) and urinary (46%) routes in dogs. The clearance of benazeprilat is not affected in dogs with impaired renal function; therefore no adjustment of the FORTEKOR PLUS dose is required in dogs with renal insufficiency.