Indications
Nebivolol is primarily indicated for the management of hypertension. Through its action as a beta-blocker, it contributes to the reduction of blood pressure, thereby decreasing the risk of cardiovascular events associated with high blood pressure.
Pharmacodynamics
As a selective beta-1 adrenergic receptor antagonist, nebivolol reduces vascular resistance and enhances stroke volume and cardiac output without compromising left ventricular function. Its effects are long-lasting, observable up to 48 hours after cessation, and it possesses a broad therapeutic window, typically administered in daily doses ranging from 5 to 40 mg. It's crucial to avoid abrupt discontinuation of nebivolol, as this can worsen coronary artery disease. Diabetic patients should closely monitor blood glucose levels because beta blockers can obscure the symptoms of hypoglycemia.
Absorption
The absorption of nebivolol remains unaffected by food intake. The time to reach maximum plasma concentration (Tmax) ranges from 1.5 to 4 hours. Its bioavailability varies significantly based on CYP2D6 metabolic activity, ranging from 12% in extensive metabolizers to 96% in poor metabolizers. For a 20 mg dose, the maximum concentrations (Cmax) of its enantiomers and glucuronides are diverse, with d-nebivolol at 2.75 ng/mL, l-nebivolol at 5.29 ng/mL, both enantiomers together at 8.02 ng/mL, and nebivolol glucuronides at 68.34 ng/mL. The area under the curve (AUC) metrics for these compounds exhibit similar variability.
Metabolism
Nebivolol undergoes extensive metabolism primarily through glucuronidation and CYP2D6-mediated hydroxylation. The metabolic pathways include n-dealkylation, hydroxylation, oxidation, and glucuronidation. Among its metabolites, the aromatic hydroxyl and acyclic oxide forms are pharmacologically active, whereas the n-dealkylated and glucuronide forms are inactive.
Mechanism of Action
Nebivolol is a highly selective antagonist of beta-1 adrenergic receptors, with minimal activity against beta-2 adrenergic receptors. Its action on beta-1 receptors primarily results in a reduction in resting and exercise-induced heart rates, myocardial contractility, and both systolic and diastolic blood pressures. The specificity of nebivolol for beta-1 receptors minimizes the adverse effects typically associated with beta blockers, particularly in respiratory function and insulin sensitivity. Additionally, nebivolol inhibits aldosterone production and reduces renin release from the juxtaglomerular apparatus. This dual action leads to a decrease in blood volume and vasoconstriction. The stereoisomer l-nebivolol contributes by acting as an agonist at the beta-3 adrenergic receptors, stimulating endothelial nitric oxide synthase. This increases the production of nitric oxide, promoting vasodilation and lowering peripheral vascular resistance, which enhances stroke volume, ejection fraction, and overall cardiac output. The combination of vasodilation, decreased oxidative stress, and reduced platelet aggregation provided by nebivolol offers potential therapeutic benefits for patients with heart failure.
