Continuing Education Activity

Nebivolol is a medication used in the management and treatment of hypertension. It is in the beta-blocker class of drugs. This activity describes the indications, action, and contraindications for this medication as a valuable agent in managing hypertension and patients with vascular disease. 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. Nebivolol is a beta-1 adrenergic receptor antagonist that works via beta-1 receptor blockade; hence, it classifies as a cardioselective beta-blocker. Beta-blockers are also classified as vasodilators and non-vasodilators based on their vasodilatory capabilities. This activity will highlight the mechanism of action, adverse event profile, and other key factors (dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to healthcare team members in treating patients with hypertension and related conditions.

Objectives:

• Describe the mechanism of action of nebivolol.
• Summarize the adverse effects of nebivolol.
• Review the appropriate monitoring for nebivolol.
• Describe some interprofessional team strategies for improving care coordination and communication to advance nebivolol use and improve outcomes.

Indications

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 prevention, and prevent essential tremors.[2][3] 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 are also classified as vasodilators and non-vasodilators based on their vasodilatory capabilities. A fixed-dose combination of nebivolol and valsartan is also approved by the FDA for the treatment of hypertension.[4]

Mechanism of Action

Nebivolol is a beta-1 adrenergic receptor antagonist that works via beta-1 receptor blockade; hence, it classifies as a cardioselective beta-blocker. 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. Beta-blockers, such as labetalol and carvedilol, also have vasodilatory effects; however, their mechanism is via the blockade of alpha-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.[5][6][7] 

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, with the highest beta-receptor affinity among all beta-blockers explaining its excellent 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 with extensive metabolizers, nebivolol is beta-1 selective. However, nebivolol loses its selectivity and blocks beta-1 and beta-2 receptors at higher doses and in patients with poor metabolizers.[8]

Pharmacokinetics

• Absorption: Nebivolol reaches a peak plasma concentration after 1.5 to 4 hours. Food does not modify the pharmacokinetics of nebivolol. Therefore, 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. It is important to note that nebivolol is metabolized by CYP2D6; hence pharmacogenetic variations can affect the various pharmacokinetics parameters. The active isomer (d-nebivolol) has a half-life of about 12 hours in extensive metabolizers of CYP2D6 and 19 hours in poor metabolizers of CYP2D6. However, clinically it is less relevant as the predominant circulating hydroxyl and glucuronide metabolites also contribute to the beta-blocking activity. The clinical efficacy and safety profiles of nebivolol are similar regardless of poor or extensive metabolism status. Consequently, no dose adjustment of nebivolol is required.

• Elimination: Nebivolol is excreted 35 % through urine and 44 % via feces; patients who are poor metabolizers excrete 67 % of the nebivolol in urine and 13 % in feces. Nebivolol is excreted either as oxidative metabolites or glucuronide conjugates.[9]

Administration

Nebivolol is administered by the oral route, and no intravenous form is available. Oral tablets are available as nebivolol hydrochloride salt equivalent to 2.5, 5, 10, and 20 mg of nebivolol.

Hypertension

In a patient with hypertension, the dose of nebivolol should be recommended based on the patient's individual needs. The recommended starting dose for most patients is 5 mg once daily, and patients can take it without respect to food. If further reduction in blood pressure 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, and drug-drug interaction should be considered before prescribing nebivolol. A recent review suggests that nebivolol is also effective in African-American patients with hypertension, who have been identified as a population who respond less to beta-blockers than people of other ethnicities.[10]

Nebivolol should never be stopped abruptly, and taper-off medicine is recommended if the patient needs to stop using nebivolol. Rebound hypertension, tachycardia, exacerbation of cardiac arrhythmia, and hospitalization are reported when beta-blockers are stopped abruptly.[11]

Use in Specific Patient Population

• Pregnancy Considerations: Nebivolol is a former FDA pregnancy Category C medicine. If required to use in pregnant women with a history of hypertension, then fetal monitoring is needed. Right after the birth baby should be monitored for the first 48 hours for possible hypoglycemia, bradycardia, and respiratory depression.[12][13] American College of Gynecology & Obstetrics(ACOG) recommends treatment with labetalol for hypertensive disorders of pregnancy.[14]
• Breastfeeding Considerations: There is no information on using nebivolol while breastfeeding infants. The risk of beta-blockers causing bradycardia in breastfed infants should be considered, and an alternate drug with safer profiles should be used.[13]
• Patients with Hepatic Impairment: Per product labeling, the initial recommended dose is 2.5 mg orally once daily and titrated up slowly if needed in patients with moderate hepatic impairment. No data is available on nebivolol use in patients with severe hepatic impairment. 
• Patients with Renal Impairment: Per product labeling, in patients with severe renal impairment (CrCl less than 30 mL/min), the initial recommended dose is 2.5 mg orally once daily and titrated up slowly if needed. There is no data available on nebivolol use in patients on dialysis.

Adverse Effects

Central nervous system-related (CNS) side effects are nebivolol's most common adverse effect. Headache is the most commonly reported side effect (6 to 9%).[15][16]

Other common side effects exist.[17] These include:

• Fatigue: side-effect is dose-related
• Dizziness
• Rhinitis
• Insomnia
• Asthenia
• Hyperuricemia
• Paresthesias
• Weakness
• Some less common side effects are dermatological side effects such as skin rash, hypercholesterolemia, decreased 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
• Erectile dysfunction (less common than conventional beta-blockers)[10]
• Raynaud's phenomenon
• Somnolence
• Syncope
• Psoriasis[18]

Contraindications

Nebivolol should be used cautiously with a history of severe anaphylaxis to various allergens. Repeat challenges among patients taking beta-blockers expose patients to becoming more sensitive to severe anaphylaxis. Treating anaphylaxis in patients on beta-blockers may not be effective and promote undesirable effects.[19][20][21]

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.[22]

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

• Bronchospastic disease: Beta-blockers are not recommended in patients with bronchospastic disease.
• Diabetes: Nebivolol may enhance hypoglycemia and mask signs and symptoms (e.g., tachycardia) of hypoglycemia.
• Hepatic impairment: Nebivolol is contraindicated in patients with Child-Pugh class C hepatic impairment.
• Myasthenia gravis: Use nebivolol with caution 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 on adequate alpha-blockers before using any beta-blockers.
• Psoriasis: Beta-blockers can induce or exacerbate psoriasis, but the cause and effect remain unestablished. The proposed mechanism indicates that beta-blockers cause intracellular changes in calcium, involving both keratinocyte and granulocyte function by reduced cyclic adenosine monophosphate (cAMP) levels[18]
• Renal impairment: Use 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, consider reducing the dose when giving nebivolol along with CYP 2D6 inhibitors. Nebivolol's potential drug-drug interactions include medication classes that are either substrate or inhibitors/inducers of CYP2D6.[10]

• Medications that are a substrate of CYP2D6: antiarrhythmics (class 1), 5 HT3 receptor antagonists, antidepressants, analgesics (opioids), protease inhibitors (ritonavir), antipsychotics, cholinesterase inhibitors
• Medications that are inhibitors of CYP2D6: antiarrhythmics (class3), antihistamines, antipsychotics, protease inhibitors (ritonavir, tipranavir), antimalarial, H2 receptor antagonists
• Medications that are inducers of CYP2D6: antiseizure medications
• When beta-blockers are administered with non-dihydropyridine calcium channel blockers (verapamil, diltiazem), they may cause significant negative inotropic and chronotropic effects. Close monitoring of the EKG and blood pressure is recommended when these agents are administered concomitantly.[23]
• Rivastigmine administered with beta-blockers can lead to bradycardia and possible syncope.[3]

Monitoring

Monitoring parameters include:

• Blood pressure
• EKG for possible bradycardia
• Serum glucose in patients with diabetes mellitus[22]

Toxicity

Glucagon is the first-line treatment for beta-blocker overdose. Glucagon is only effective initially for a short time. Prolonged use of glucagon can cause tachyphylaxis, and therapy can be ineffective. Glucagon is administered intravenously (IV) as a slow bolus followed by a continuous infusion. Initial bolus doses include a 5 mg IV dose administered over one minute. Constant heart rate (HR) and blood pressure (BP) monitoring is required. If HR and BP do not increase after 10 to 15 minutes, administer another bolus. Glucagon starts working within 1 to 3 minutes, with a peak response at 5 to 7 minutes. If there is no notable effect in 10 minutes, followed by a second bolus, then it is doubtful that an infusion would benefit the patient. If there is an increase in HR and BP, an infusion can start. The rate of the infusion is between 2 to 5 mg/hour. The goal is a mean arterial pressure (MAP) of 60 mm of Hg. If unable to achieve a MAP of 60 mmHg, the patient might require additional therapies such as calcium salts.[24][25] 

Treatment of anaphylaxis in the settings of beta-blocker administration is challenging. If epinephrine is ineffective, then glucagon should be administered as glucagon can reverse refractory hypotension and bronchospasm during anaphylaxis in patients on beta-blockers by activating adenyl cyclase directly.[26]

Enhancing Healthcare Team Outcomes

Nebivolol is an FDA-approved medication for hypertension. All interprofessional healthcare team members must be aware and up to date on the indications, interactions, adverse effects, and other pharmacodynamics and pharmacokinetic factors that can affect successful therapy implementation and lead to improved patient outcomes.[6][27] Clinicians prescribe nebivolol for hypertension. Cardiologists are important in treating refractory hypertension and complications associated with the therapy. Pharmacists review the appropriateness of drug selection and the dose, looking for interactions or other contraindications, and consulting the prescriber as necessary. They also counsel patients and their families about appropriate use and side 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 direct care provided by the medical toxicologist has been shown to reduce the length of stay and decrease healthcare utilization.[28] 

If an overdose is intentional, a psychiatrist consultation should be obtained. If the interprofessional teamwork of MDs, DOs, PAs, NPs, and pharmacists is in place, nebivolol therapy has its best chance for therapeutic success with minimal adverse events. Study finding suggests that direct care provided by medical toxicologists has been shown to reduce the length of stay and decrease healthcare utilization in drug-related overdose.[28] The 2017 ACC/AHA guidelines for hypertension recommend interprofessional team-based care, including the primary care provider, 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 lead intervention have demonstrated optimal blood pressure control compared to routine care.[29][30][31] [Level 1]