Nebivolol Hydrochloride

Nebivolol is a β adrenergic receptor blocking agent. It inhibits both β1 and β1 adrenergic receptors. At therapeutically relevant concentrations, nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity. At clinically relevant doses, it does not demonstrate β1-adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to the beta-blocking activity.

The mode of action of nebivolol involves decreased heart rate, decreased myocardia contractility, diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, suppression of renin activity, and vasodilation and decreased peripheral vascular resistance.

Pharmacokinetics

Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers. Exposure to d-nebivolol is substantially increased in poor metabolizers. This matters less than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to the b blocking activity.

Absorption and Distribution

Absorption of nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol, so it may be given without regard to meals. The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and it is independent of nebivolol concentrations.

Metabolism and Excretion

Nebivolol is mainly metabolized by direct glucuronidation of the parent drug, and to a lesser extent by N-dealkylation and oxidation via cytochrome P450 2D6. After a single oral dose of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs. For PMs, 67% was recovered in urine and 13% in feces.

Digoxin

Nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) were given together for 10 days to 14 healthy adults. There were no significant changes in the pharmacokinetics of digoxin or nebivolol.

Warfarin

Nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin after a single 10 mg dose of warfarin. In the same way, nebivolol has no significant effect on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers.

The starting dose should be reduced in patients with moderate hepatic impairment. No formal studies have been done in patients with severe hepatic impairment, and nebivolol should be contraindicated for these patients.