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Nebivolol


Nebivolol

Article Author:
Shivani Priyadarshni
Article Editor:
Bryan Curry
Updated:
11/26/2020 12:52:02 PM
For CME on this topic:
Nebivolol CME
PubMed Link:
Nebivolol

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 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. 

Mechanism of Action

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.

Administration

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.

Adverse Effects

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, 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

Contraindications

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 before 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. Nebivolol's potential drug-drug interactions 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

Monitoring

Monitoring parameters include:

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

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 monitoring of the heart rate (HR) and blood pressure (BP) 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 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.[6]

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.[7][8] 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. With interprofessional teamwork in place, nebivolol therapy has its best chance for therapeutic success with minimal adverse events. [Level 5]


References

[1] Cicero AFG,Kuwabara M,Borghi C, A Critical Review of Nebivolol and its Fixed-Dose Combinations in the Treatment of Hypertension. Drugs. 2018 Nov     [PubMed PMID: 30426333]
[2] Ha H,Gonzalez A, Migraine Headache Prophylaxis. American family physician. 2019 Jan 1     [PubMed PMID: 30600979]
[3] Ong HT,Ong LM,Kow FP, Beta-blockers for heart failure: an evidence based review answering practical therapeutic questions. The Medical journal of Malaysia. 2012 Feb     [PubMed PMID: 22582541]
[4] Pessina AC, Metabolic effects and safety profile of nebivolol. Journal of cardiovascular pharmacology. 2001 Dec     [PubMed PMID: 11811391]
[5] [Heart and lung disease. Are beta blockers allowed in asthma?]. MMW Fortschritte der Medizin. 2001 May 24     [PubMed PMID: 11420835]
[6] Zaritsky AL,Horowitz M,Chernow B, Glucagon antagonism of calcium channel blocker-induced myocardial dysfunction. Critical care medicine. 1988 Mar     [PubMed PMID: 3277781]
[7] Ågesen FN,Weeke PE,Tfelt-Hansen P,Tfelt-Hansen J, Pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology. Pharmacology research & perspectives. 2019 Aug     [PubMed PMID: 31338197]
[8] Bouhanick B,Blacher J,Huyghe E,Colson MH,Boivin JM,Mounier-Vehier C,Denolle T,Fauvel JP, [Sexual dysfunction and antihypertensive treatment: Involvement of the different therapeutic classes and what to do about the treatment of hypertension]. Presse medicale (Paris, France : 1983). 2019 Nov     [PubMed PMID: 31303372]