Nebivolol is an FDA approved medication used to treat hypertension.[1] Beta-blockers are a class of agents used to treat multiple conditions such as hypertension, angina, arrhythmias, anxiety, hyperthyroidism, migraine prophylaxis, and to prevent essential tremors.[2] Notably, the American College of Cardiology (ACC) /American Heart Association (AHA) guidelines does not recommend beta-blockers as initial antihypertensive therapy in most circumstances.

Beta-blockers fall into two categories based on whether they block beta-1 receptors in cardiac muscles, beta-2 receptors in the lungs and smooth muscles, or both. Beta-blockers also get classified as vasodilators and non-vasodilators based on their vasodilatory capabilities. 

Nebivolol is a beta-1 adrenergic receptor antagonist that works via beta-1 receptor blockade, and hence, it classifies as cardioselective. It also acts on the vascular endothelium by stimulating nitric oxide (NO) synthase, which induces NO-mediated vasodilation. Nebivolol stimulates NO synthase production from the endothelium via beta-3 agonism leading to a reduction in systemic vascular resistance. Other beta-blockers such as labetalol and carvedilol also have vasodilatory effects; however, their mechanism is via blockade of alpha-adrenergic receptors. Patients with diabetes mellitus, erectile dysfunction, vascular disease, and the African-American patient population may have an abnormal endothelial function, and nebivolol is more effective in these populations due to its NO-induced vasodilatory effect.[3][4][5] Nebivolol is chemically composed of a racemic mixture of L-nebivolol and D-nebivolol. It is classified as the third generation beta-1 adrenergic receptor antagonist, which has the highest β-receptor affinity among all beta-blockers, which explains its high tolerability in patients with lung disease. Nebivolol is unique in terms of its beta-1 vs. beta-1 and beta-2 selectiveness. At low doses of 10 mg or below and in patients who are extensive metabolizers, nebivolol is beta-1 selective. However, at higher doses and in patients who are poor metabolizers, nebivolol loses its selectivity and blocks both beta-1 and beta-2 receptors.

Nebivolol administration is via the oral route, and patients can take it without respect to food. There is no intravenous form available. The initial dose is 5 mg once daily, and the dose can titrate up at 2 to 4-week intervals based on the clinical response. The maximum dose is 40 mg once daily.

Central nervous system-related (CNS) side effects are the most common side effect with nebivolol. Headache is the most commonly reported side effect (6 to 9%).[1][2]

Other common side effects include:

• Fatigue: side-effect is dose-related
• Dizziness
• Insomnia
• Paresthesias
• Weakness
• Some less common side effects are dermatological side effects such as skin rash, hypercholesterolemia, decrease in HDL, increased triglycerides, and gastrointestinal side effects such as diarrhea, nausea, and abdominal pain.

Less common side effects reported in case reports and post-marketing reports were:

• Acute pulmonary edema
• Acute kidney injury
• Second and third-degree atrioventricular (AV) block
• Bronchospasm
• Angioedema
• Hypersensitivity reaction
• Claudication
• Hepatic insufficiency: increased serum ALT,  AST, serum bilirubin
• Thrombocytopenia

Nebivolol should be used cautiously with a history of severe anaphylaxis to a variety of allergens. Repeat challenges among patients taking beta-blockers expose patients to become more sensitive to severe anaphylaxis. Treatment of anaphylaxis in patients on beta-blockers may not be effective and promote undesirable effects.[3][4][5]

Beta-blockers are contraindicated in severe bradycardia, cardiogenic shock, decompensated heart failure, second-degree or higher heart block, and sick sinus syndrome. However, it is still useful if there is a functioning pacemaker present.

Other disease-related/age group-related relative contraindications include:

• Bronchospastic disease: beta-blockers s are not recommended in patients with bronchospastic disease
• Diabetes: may enhance hypoglycemia and mask signs and symptoms
• Hepatic impairment: contraindicated in patients with Child-Pugh class C hepatic impairment
• Myasthenia gravis: Use with caution
• Peripheral vascular disease (PVD) and Raynaud disease: can precipitate the symptoms of arterial insufficiency
• Pheochromocytoma (not on treatment): the patient should be on adequate alpha-blockade prior to using any beta-blockers
• Psoriasis: beta-blockers can induce or exacerbate psoriasis, but the cause and effect remain unestablished.
• Renal impairment: use with caution; dose adjustment is necessary with severe renal impairment (CrCl less than 30 mL/minute)
• Thyroid disease: may mask signs and symptoms of hyperthyroidism (e.g., tachycardia). If thyrotoxicosis is suspected, careful management and monitoring are required. Abrupt withdrawal may worsen symptoms of hyperthyroidism or precipitate thyroid storm               
• Pregnancy: Category C medication, unclear if nebivolol gets excreted in breast milk, however, beta-blockers can cause serious adverse reactions in nursing infants, e.g., bradycardia
• Elderly population: Increased frequency of bradycardia in patients with age 65 or above, used in reduced doses

Drug-drug interactions: the CYP 2D6 system metabolizes nebivolol, therefore reduce the dose when giving nebivolol along with CYP 2D6 inhibitors. Potential drug-drug interactions of Nebivolol include medication classes that are either substrate or inhibitors/inducer of CYP 2D6.

• Medications that are a substrate of CYP 2D6: antiarrhythmics (class 1), 5 HT3 receptor antagonists, antidepressants, analgesics (opioids), protease inhibitors (ritonavir), antipsychotics, cholinesterase inhibitors
• Medications that are inhibitors of CYP 2D6: antiarrhythmics (class3), antihistamines, antipsychotics, protease inhibitors (ritonavir, tipranavir), antimalarial, H2 receptor antagonists
• Medications that are inducers of CYP 2D6: antiseizure medications