Continuing Education Activity

This activity focuses on nebivolol, a potent medication used to treat hypertension. A thorough discussion of nebivolol’s dual role as a vasodilator and cardioselective β-blocker underscores its versatility when managing cardiovascular conditions. As a selective β-blocker targeting β-1 adrenergic receptors, nebivolol’s mechanism of action allows modulation of cardiac function while sparing β-2 receptors in the lungs and smooth muscles. This cardioselective profile makes nebivolol crucial for managing hypertension and vascular disease. By understanding its pharmacological actions, indications, contraindications, pharmacokinetics, and adverse event profiles, healthcare professionals gain the necessary knowledge to administer this medication effectively.

Objectives:

• Identify the mechanism of action of nebivolol.

• Assess the adverse drug reactions of nebivolol.

• Determine the appropriate clinical monitoring of patients receiving nebivolol.

• Implement effective collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from nebivolol pharmacotherapy.

Indications

Nebivolol is an FDA-approved medication used to treat hypertension.[1] Beta-blockers are a class of agents used to treat multiple conditions, including hypertension, angina, arrhythmias, anxiety, hyperthyroidism, migraine prevention, and prevention of essential tremors.[2][3] The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines advise against using β-blockers as the first-line treatment for hypertension and to reserve them for patients with comorbidities such as ischemic heart disease.[4]

Beta-blockers fall into 2 categories based on whether they block β-1 receptors in cardiac muscles, β-2 receptors in the lungs and smooth muscles, or both. Beta-blockers are also classified as vasodilators or non-vasodilators based on their vasodilatory capabilities. The FDA has also approved a fixed-dose combination of nebivolol and valsartan for hypertension management.[5]

FDA-Approved Indications

Nebivolol is approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension. Clinicians should prioritize the use of medications such as β-blockers, ACE inhibitors, or ARBs for adults with a diagnosis of stable ischemic heart disease (SIHD) or hypertension and a history of myocardial infarction or stable angina. Additionally, individuals who have experienced a myocardial infarction or acute coronary syndrome are advised to continue guideline-directed medical therapy (including β-blockers) for at least 3 years as part of their long-term hypertension management.[4]

Off-Label Uses

The 2021 European Society of Cardiology (ESC) Guidelines for Heart Failure suggest nebivolol as a treatment option in combination with first-line therapies.[6] Nebivolol can also help manage microvascular angina.[7] There is potential for nebivolol in managing cancer therapy-related cardiac dysfunction (CTRCD), but further research is required.[8][9][10]

Mechanism of Action

Nebivolol is a β-1 adrenergic receptor antagonist that works by blocking beta-1 receptors, making it a cardioselective β-blocker. This drug 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 β-3 agonism, reducing systemic vascular resistance. Beta-blockers such as labetalol and carvedilol also have vasodilatory effects; however, their mechanism is via the blockade of α-adrenergic receptors. Patients with diabetes mellitus, erectile dysfunction, and vascular disease may have abnormal endothelial function, and nebivolol is more effective in these populations due to its NO-induced vasodilatory effect.[11][12][13] 

Nebivolol is chemically composed of a racemic mixture of L-nebivolol and D-nebivolol. This medication is classified as a third-generation β-1 adrenergic receptor antagonist and has the strongest β-receptor affinity of all β-blockers. This affinity explains its excellent tolerability in patients with lung disease. Nebivolol is also unique because of its β-1 vs. β-1 and β-2 selectivity. At low doses (≤10 mg) and in patients who are fast metabolizers, nebivolol is β-1 selective. However, nebivolol loses its selectivity and blocks β-1 and β-2 receptors at higher doses and in patients who are slower metabolizers.[14]

Pharmacokinetics

Absorption: Nebivolol reaches peak plasma concentration after 1.5 to 4 hours. Since food does not modify its pharmacokinetics, nebivolol tablets may be administered without regard to meals.

Distribution: Nebivolol is 98 % protein-bound and binds primarily to albumin.

Metabolism: Nebivolol is primarily metabolized in the liver via direct glucuronidation and secondarily through CYP2D6. The hydroxyl and glucuronide metabolites are pharmacologically active. Nebivolol is metabolized by CYP2D6. Pharmacogenetic variations of this enzyme can affect various pharmacokinetics parameters; the active isomer (D-nebivolol) has a half-life of about 12 hours in fast metabolizers of CYP2D6 and 19 hours in slow metabolizers of CYP2D6. However, these variations are only mildly relevant as the circulating hydroxyl and glucuronide metabolites also contribute to the β-blocking activity. The clinical efficacy and safety profiles of nebivolol are similar regardless of slow or fast metabolism status; no dose adjustment is necessary.

Elimination: Nebivolol is excreted via urine (35%) and feces (44%); patients who are slow metabolizers excrete 67% in urine and 13% in feces. Nebivolol is excreted as oxidative metabolites or glucuronide conjugates.[15]

Administration

Available Dosage Forms and Strengths

Nebivolol is administered orally and is not available in intravenous form. Oral tablets are available as nebivolol hydrochloride salt equivalent to 2.5, 5, 10, and 20 mg of nebivolol.

Adult Dosage

Hypertension: In a patient with hypertension, nebivolol dosing should be based on the patient's individual needs. The recommended starting dose for most patients is 5 mg once daily, which can be taken independently of meals. If further blood pressure reduction is necessary, the dose can be titrated up at 2 to 4-week intervals based on the clinical response. The maximum dose is 40 mg once daily. Nebivolol is a CYP2D6 substrate; drug-drug interactions should be considered before prescribing nebivolol. A recent review suggests that nebivolol is also effective in African-American patients with hypertension, who demonstrate decreased responsiveness to β-blockers compared to other ethnicities.[16]

Nebivolol should never be discontinued abruptly, and taper-off dosing is recommended if the patient needs to stop using nebivolol. Rebound hypertension, tachycardia, exacerbation of cardiac arrhythmia, and hospitalization are reported when β-blockers are stopped abruptly.[17]

Specific Patient Population

Hepatic impairment: Per product labeling, the initial recommended dose is 2.5 mg orally once daily, which is titrated slowly (if needed) for patients with moderate hepatic impairment. No data is available on nebivolol use for patients with severe hepatic impairment. 

Renal impairment: Per product labeling, the initial recommended dose for patients with severe renal impairment (CrCl <30 mL/min) is 2.5 mg orally once daily, titrated slowly if needed. There is no data available on nebivolol use for patients on dialysis.

Pregnancy considerations: Nebivolol is a former FDA pregnancy Category C medicine. If nebivolol is required for a pregnant woman with a history of hypertension, then fetal monitoring is indicated. The baby should be monitored for the first 48 hours post-delivery for possible hypoglycemia, bradycardia, and respiratory depression.[18][19] The American College of Gynecology & Obstetrics (ACOG) recommends treatment with labetalol for hypertensive disorders of pregnancy.[20]

Breastfeeding considerations: There is no information on using nebivolol for women who are breastfeeding. The risk of β-blockers causing bradycardia in breastfed infants should be considered, and an alternate drug with safer profiles should be administered.[19]

Pediatric patients: The safety and efficacy of nebivolol for pediatric patients have not been verified.

Older patients: The SENIORS study assessed nebivolol's effects in heart failure patients aged 70 or older, regardless of ejection fraction. Nebivolol reduced combined mortality and cardiovascular admissions compared to placebo, independent of age, gender, or ejection fraction. In conclusion, nebivolol was effective and well-tolerated in older patients with heart failure.[21]

Adverse Effects

Nebivolol's reported adverse effects typically involve the central nervous system (CNS). Headache is the most commonly reported adverse effect (6% to 9%).[22][23]

Other common adverse effects include:[24]

• Fatigue (Dose-dependent)
• Dizziness
• Rhinitis
• Insomnia
• Asthenia
• Hyperuricemia
• Paresthesias
• Weakness
• Some less observed adverse drug reactions are skin rash and gastrointestinal adverse effects such as diarrhea, nausea, and abdominal pain.

Less common adverse effects documented in case reports and post-marketing reports include:

• Acute pulmonary edema
• Acute kidney injury
• Second and third-degree atrioventricular (AV) block
• Bronchospasm
• Angioedema
• Hypersensitivity reaction
• Claudication
• Drug-induced liver injury: elevated serum ALT, AST, and serum bilirubin
• Thrombocytopenia
• Raynaud phenomenon
• Somnolence
• Syncope
• Erectile dysfunction (less common than for conventional β-blockers) [16][25]
• Psoriasis [26]

Drug-Drug Interactions

The CYP2D6 system metabolizes nebivolol. The dose may need to be reduced when giving nebivolol and CYP2D6 inhibitors. Nebivolol's potential drug-drug interactions include medication classes that are either substrate or inhibitors/inducers of CYP2D6.[16]

• CYP2D6 substrates: antiarrhythmics (class 1), 5-HT3 receptor antagonists, antidepressants, analgesics (opioids), protease inhibitors (ritonavir), antipsychotics, cholinesterase inhibitors
• CYP2D6 inhibitors: antiarrhythmics (class 3), antihistamines, antipsychotics, protease inhibitors (eg, ritonavir, tipranavir), antimalarials, H2 receptor antagonists
• CYP2D6 inducers: antiseizure medications
• When β-blockers are administered with non-dihydropyridine calcium channel blockers (eg, verapamil, diltiazem), they may cause significant negative inotropic and chronotropic effects. EKG and blood pressure monitoring are recommended when these agents are administered together.[27]
• Rivastigmine administered with β-blockers can cause bradycardia and possible syncope.[3]

Contraindications

Nebivolol should be used cautiously with a history of severe anaphylaxis to various allergens. Repeat challenges among patients taking β-blockers may cause increased sensitivity to severe anaphylaxis. Treating anaphylaxis in patients using β-blockers may not be effective and promote undesirable effects.[28][29][30]

Nebivolol is contraindicated in severe bradycardia, cardiogenic shock, decompensated heart failure, second or third-degree heart block, severe hepatic impairment, and sick sinus syndrome. However, it is still useful if a functioning pacemaker is present.[31]

Warning and Precautions

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

• Bronchospastic disease: β-blockers are not recommended in patients with bronchospastic disease.
• Diabetes: Nebivolol may enhance hypoglycemia and mask signs and symptoms (eg, tachycardia) of hypoglycemia.
• Hepatic impairment: Nebivolol is contraindicated in patients with Child-Pugh Class C hepatic impairment.
• Myasthenia gravis: Nebivolol should be used cautiously in patients with myasthenia gravis.
• Peripheral vascular disease (PVD) and Raynaud disease: Nebivolol can precipitate the symptoms of arterial insufficiency.
• Pheochromocytoma (not on treatment): The patient should be administered α-blockers before any β-blockers.
• Psoriasis: β-blockers can induce or exacerbate psoriasis, but the cause and effect remain unestablished. The proposed mechanism indicates that β-blockers cause intracellular changes in calcium, affecting keratinocyte and granulocyte function by reducing cyclic adenosine monophosphate (cAMP) levels.[26]
• Renal impairment: Dose adjustment is necessary with severe renal impairment (CrCl <30 mL/min).
• Thyroid disease: Nebivolol may mask signs and symptoms of hyperthyroidism (eg, 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; it is unclear if nebivolol gets excreted in breast milk; β-blockers can cause serious adverse effects in nursing infants (eg, bradycardia).
• Older population: Increased frequency of bradycardia in patients aged 65 or older; dose reduction should be considered.
• Surgery: Per ACC/AHA guidelines, patients with hypertension and a history of chronic β-blocker use who are preparing for major surgery should continue their β-blocker regimen. However, initiating β-blockers the day of surgery is not recommended for patients who have not previously used them.[4]

Monitoring

Parameters that should be monitored include:

• Blood pressure
• EKG for possible bradycardia
• Serum glucose in patients with diabetes mellitus [31]

Toxicity

Signs and Symptoms of Overdose

Clinical presentations of nebivolol overdose usually include bradycardia and hypotension. Further adverse effects linked to excessive nebivolol intake can cause vomiting, heart failure, bronchospasm, and AV block.

Management of Overdose

Glucagon is the first-line treatment for β-blocker overdose. Glucagon is only effective for a short time, and prolonged use can cause tachyphylaxis, rendering therapy ineffective. Glucagon is administered intravenously (IV) as a slow bolus followed by a continuous infusion. The initial bolus dose is typically 5 mg administered over 1 minute. Constant heart rate and blood pressure monitoring are required. If these measures do not increase after 15 minutes, administer another bolus. Glucagon starts working within 3 minutes, with a peak response at 5 to 7 minutes. If there is no notable effect within 10 minutes of the second bolus, then it is doubtful that an infusion would benefit the patient. If there is an increase in heart rate and blood pressure, an infusion will be beneficial. The infusion rate should be between 2 to 5 mg/h. The goal is a mean arterial pressure (MAP) of 60 mm Hg. If a MAP of 60 mm Hg cannot be achieved, the patient may require additional therapies.[32][33] 

Supportive care is required in overdose. Intravenous atropine administration may be required to manage bradycardia. Transthoracic or transvenous pacemaker placement may be necessary for heart block (second or third-degree). Intravenous fluids should be administered for hypotension, while inhaled β-2 agonists are indicated for bronchospasm. Intravenous glucose is advised for managing hypoglycemia. 

Treating anaphylaxis in the setting of β-blocker administration can be challenging. If epinephrine is ineffective, then glucagon should be administered as it can reverse refractory hypotension and bronchospasm during anaphylaxis in patients on β-blockers. Glucagon works by activating adenyl cyclase directly.[34]

Enhancing Healthcare Team Outcomes

Nebivolol is a medication that is FDA-approved to treat hypertension. All interprofessional healthcare team members must be aware of the current indications, interactions, adverse effects, and other pharmacodynamics and pharmacokinetic factors that can affect successful therapy implementation and improve patient outcomes.[12][35] Cardiologists treat refractory hypertension and complications associated with therapy. Pharmacists review the appropriateness of the selected drug and the dose, look for interactions or other contraindications, and consult the prescriber as necessary. They also counsel patients and their families about appropriate use and adverse effects. Nurses monitor vital signs, counsel the patient on dosing and administration, monitor for potential adverse effects, and report issues to the team for therapy adjustment. In an overdose of nebivolol, critical care input is crucial. A medical toxicologist should be consulted as the direct care provided by these specialists has been shown to reduce the length of stay and decrease healthcare utilization.[36]

If an overdose is intentional, a psychiatric consultation should be obtained. Nebivolol therapy has its best chance for therapeutic success with minimal adverse events if the interprofessional teamwork between MDs, DOs, PAs, NPs, and pharmacists is in place. The 2017 ACC/AHA guidelines for hypertension recommend interprofessional team-based care, which involves primary care providers, patients, cardiologists, physician assistants, nurses, pharmacists, dietitians, community health workers, and social workers. Randomized controlled trials and meta-analyses of interprofessional team-based hypertension care involving nurse or pharmacist-led lead intervention have demonstrated optimal blood pressure control compared to routine care.[37][38][39]