Nebil Mechanism of Action

Beta-blocker.
Pharmacology: Mechanism of Action: Nebivolol is a racemic mixture of SRRR and RSSS in a β₁- selective adrenoceptor antagonist whose hemodynamic effects differ from those of classical β-adrenoceptor antagonist as a result of a vasodilating action. It has mild vasodilating properties attributed to its interaction with the L-arginine/nitric oxide pathway, a property not shared by other β-blockers. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, nebivolol does not demonstrate α₁-adrenergic receptor blockade activity.
Pharmacokinetics: Nebivolol is rapidly absorbed following oral administration. The absorption of nebivolol is not affected by food. It is extensively metabolized in the liver by alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; the hydroxy metabolites are reported to be active. The rate of aromatic hydroxylation by cytochrome P450 isoenzyme CYP206 is subject to genetic polymorphism and bioavailability, and half-life (t_½) vary widely. In fast metabolizers, the elimination t_½ of nebivolol is about 10 hrs and all the hydroxy metabolites is about 24 hrs. Peak plasma concentration of unchanged drug plus active metabolites are 1.3-1.4 times higher in slow metabolizers and the half-lives of nebivolol and its hydroxy metabolites are prolonged. Nebivolol is about 98% bound to plasma  proteins. It is excreted in the urine and feces, almost entirely as metabolites. The pharmacokinetics of nebivolol are not affected by age. One week after administration, 38% of the dose is excreted in the urine and 48% in the feces. Urinary excretion of unchanged nebivolol is <0.5% of the dose.
Special Populations: Renal Insufficiency: The apparent clearance of nebivolol is unchanged following a single dose of nebivolol 5 mg in patients with mild renal insufficiency (CrCl 50-80 mL/min) and it is reduced negligibly in patients with moderate renal insufficiency (CrCl 30-50 mL/min). However, it is reduced by 53% in patients with severe renal insufficiency (CrCl <30 mL/min). The dose of nebivolol should be adjusted in patients with severe renal insufficiency.
Hepatic Insufficiency: Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic insufficiency (Child-Pugh Class B). The starting dose should be reduced in patients with moderate hepatic insufficiency.