Nebivolol

Nebivolol is a cardio-selective beta-adrenergic blocking agent belonging to the beta-blocker class.

Nebivolol is approved for the treatment of hypertension. It is also used to treat chronic heart failure, atrial fibrillation, angina pectoris, and Myocardial infarction.

• The bioavailability of Nebivolol can range from 12-96% for extensive to poor CYP2D6 metabolizers. The d-nebivolol has an apparent volume of distribution of 10,290.81±3911.72L, and l-nebivolol has an apparent volume of distribution of 8,066.66±4,055.50L, and both enantiomers together have the volume of distribution of 10,423.42±6796.50L.
• Nebivolol is 98% bound to plasma proteins, mostly to the serum albumin. Nebivolol is metabolized mainly by glucuronidation and CYP2D6-mediated hydroxylation.
• In extensive CYP2D6 metabolizers, 38% is eliminated in urine and 44% in feces. In poor CYP2D6 metabolizers, 67% is eliminated in urine and 13% in the feces. <1% of a dose is excreted as the unmetabolized drug.
• It has mild vasodilating properties attributed to its interaction with the L-arginine/nitric oxide pathway, a property not shared by other β-blockers. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations.

The common side effects associated with Nebivolol are Bloating or swelling of the face, arms, hands, lower legs or feet, chest pain or discomfort, rapid weight gain, dizziness, slow or irregular heartbeat., etc.

Nebivolol is available in the dosage form as tablets.

Nebivolol is available in the US, Italy, Australia, Europe, and India.

• Nebivolol, belonging to the beta blocker, acts as a cardio-selective beta-1-adrenergic blocker. Nebivolol works by affecting the response to the nerve impulses in certain parts of the body, like the heart. As a result, the heart beats slower and decreases blood pressure. When blood pressure is lowered, the amount of blood and oxygen is increased in the heart.
• It works by blocking beta-1 adrenergic receptors by d-nebivolol which leads to decreased resting heart rate, exercises heart rate, myocardial contractility, systolic blood pressure, and diastolic blood pressure.
• The onset of action of Nebivolol occurs within 4 hours of its administration.
• The Duration of Action for Nebivolol can be detected 48 hours after its administration.
• The Tmax was found within 1.5-4 hours following the administration of nebivolol. Cmax was about 8.02±3.47ng/mL

Nebivolol is available in the form of tablets.

Tablets:

Tablets are to be swallowed whole with water. Nebivolol comes as a tablet to be taken by mouth. It is usually taken two times a day.

• Nebivolol is a cardio-selective beta-1-adrenergic blocker belonging to the beta-blocker class.
• Nebivolol is approved for the treatment of hypertension. It is also used to treat chronic heart failure, atrial fibrillation, angina pectoris, and Myocardial infarction.

Nebivolol is a highly selective beta-1 adrenergic receptor antagonist with weak beta-2 adrenergic receptor antagonist activity. Blocking beta-1 adrenergic receptors by d-nebivolol leads to decreased resting heart rate, exercise heart rate, myocardial contractility, systolic blood pressure, and diastolic blood pressure.

Nebivolol is approved for use in the following clinical indications:

• Hypertension:

Nebivolol is indicated for the treatment of hypertension, to lower blood pressure. Nebivolol may be used alone or in combination with other antihypertensive agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with nebivolol. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals.

Although not approved, there have been certain off-label uses documented for Nebivolol, These include:

• Chronic Heart failure:

Nebivolol is a new selective beta 1- receptor antagonist for treating chronic heart failure. Although the major trial with nebivolol was conducted in older people ( >70 years ), there is no evidence that nebivolol is more effective in any age group than other beta blockers used in heart failure.

• Other off-label indication includes atrial fibrillation, angina pectoris, and Myocardial infarction.

Nebivolol is available in the form of tablets

• Hypertension

In a patient with hypertension, a 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 the blood pressure is necessary, the dose can be titrated up at 2 to 4-week intervals based on 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.

It 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

Nebivolol can be administered orally before/ after meals. The dosage and the duration of treatment should be as per the clinical judgment of the treating physician.

Nebivolol is available in various dosage strengths as 2.5mg, 5mg, 10mg, 20mg

Nebivolol is available in the form of tablets.

Nebivolol is approved for the treatment of hypertension. It is also used to treat chronic heart failure, atrial fibrillation, angina pectoris, and Myocardial infarction.

• Hypertension: It has been observed that the low-salt Dietary Approaches to Stop Hypertension (DASH) diet lowers blood pressure. Sometimes after a few weeks, its effects on blood pressure become noticeable.
• Myocardial infarction: No more than 25 to 35 percent of your daily calories should come from total fat (including saturated fat). Less than 7 % of your daily calories should come from saturated fat. Avoid trans fats and Consume less than 200 milligrams a day of dietary cholesterol.
• Angina Pectoris: Avoid foods that are high in saturated fat and hydrogenated or partially hydrogenated fats. Reduce your intake of dairy products including cheese, cream, and eggs.
• Atrial Fibrillation: Some foods can negatively affect your heart health and have been shown to increase the risk of heart complications. Diets high in processed foods, such as fast food, and items high in added sugar, like soda and sugary baked goods, have been linked to increased heart disease risk. They can also lead to other negative health outcomes like weight gain, and diabetes, cognitive decline, and certain cancers.

The dietary restriction should be individualized as per the patient's requirements

Nebivolol may be contraindicated in the following

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.

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 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: It 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.

• 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 a thyroid storm.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

• Abrupt Cessation of Therapy

Do not abruptly discontinue Nebivolol therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of angina pectoris. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of Nebivolol is planned, carefully observe and advise patients to minimize physical activity. Taper Nebivolol over 1 to 2 weeks when possible. If angina worsens or acute coronary insufficiency develops, re-start Nebivolol promptly, at least temporarily.

• Angina and Acute Myocardial Infarction

Nebivolol was not studied in patients with angina pectoris or who had a recent MI.

• Bronchospastic Diseases

In general, patients with bronchospastic diseases should not receive β-blockers.

• Anesthesia and Major Surgery

Because beta-blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta-blockers should generally continue treatment throughout the perioperative period. If Nebivolol is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. The β-blocking effects of nebivolol can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers.

• Diabetes and Hypoglycemia

β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective βblockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities.

• Thyrotoxicosis

β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

• Peripheral Vascular Disease

β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

• Non-dihydropyridine Calcium Channel Blockers

Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor the ECG and blood pressure in patients treated concomitantly with these agents.

• Use with CYP2D6 Inhibitors

Nebivolol exposure increases with inhibition of CYP2D6. The dose of Nebivolol may need to be reduced.

• Impaired Renal Function

Renal clearance of nebivolol is decreased in patients with severe renal impairment. Nebivolol has not been studied in patients receiving dialysis.

• Impaired Hepatic Function

Metabolism of nebivolol is reduced in patients with moderate hepatic impairment. NebivoloL has not been studied in patients with severe hepatic impairment.

• Risk of Anaphylactic Reactions

While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenges. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

• Pheochromocytoma

In patients with known or suspected pheochromocytoma, initiate an α-blocker prior to the use of any βblocker.

Drinking alcohol while taking Nebivolol can increase drowsiness and dizziness, which in turn increases the risk of accidental injury.

Nebivolol use in breastfeeding patients is not recommended.

Teratogenic Effects: Category C. Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats when exposed during the perinatal period (late gestation, parturition, and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia, and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size, and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the decreased fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight, or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

The Adverse reactions related to the molecule Nebivolol can be categorized as

• Common Adverse effects:

Fatigue: side-effect is dose-related, Dizziness, Rhinitis, Insomnia, Asthenia, Hyperuricemia, Paresthesias, Weakness

• Less Common adverse effects:

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, Myocardial infarction, Pruritus, Psoriasis, Raynaud's phenomenon, Somnolence, Syncope

• Rare adverse effects:

Heart failure, tachyarrhythmia, bronchospasm, depression, decreased exercise tolerance, Raynaud's phenomenon, etc.

The clinically relevant drug interactions of Nebivolol are briefly summarized here

• CYP2D6 Inhibitors

Use caution when Nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.)

• Hypotensive Agents

Do not use Nebivolol with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of Nebivolol may produce an excessive reduction of sympathetic activity. In patients who are receiving Nebivolol and clonidine, discontinue Nebivolol for several days before the gradual tapering of clonidine.

• Digitalis Glycosides

Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

• Calcium Channel Blockers

Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylethylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.

The common side of Nebivolol includes the following

Fatigue, dizziness, vertigo, headaches, depression, Hyperuricemia, depression, dizziness, nausea, etc.

The use of Nebivolol should be prudent in the following group of special populations:

• Pregnancy Teratogenic Effects:

Category C.

Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition, and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia, and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size, and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight, or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

• Labor and Delivery

Nebivolol caused prolonged gestation and dystocia at doses ≥ 5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups and decreased birth weight, live litter size, and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition, and lactation). No studies of nebivolol were conducted in pregnant women. Use Nebivolol during pregnancy only if the potential benefit justifies the potential risk to the fetus.

• Nursing Mothers

Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk. Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, Nebivolol is not recommended during nursing.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility.

• Geriatric Use

Of the 2800 patients in the U.S. sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.

• Heart Failure

• In clinical trials and worldwide postmarketing experience, there were reports of Nebivolol overdose. The most common signs and symptoms associated with Nebivolol overdosage are bradycardia and hypotension. Other important adverse reactions reported with nebivolol overdose include cardiac failure, dizziness, hypoglycemia, fatigue, and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block.
• The largest known ingestion of nebivolol worldwide involved a patient who ingested up to 500 mg of Nebivolol along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure, and vomiting. The patient recovered.
• Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance.
• If an overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping Nebivolol, when clinically warranted.
• Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.
• Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.
• Heart Block (second or third degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.
• Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consider the use of inotropic and vasodilating agents.
• Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline.
• Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is 12-19 hours.

Pharmacodynamics:

Nebivolol is a racemic mixture of s-enantiomer and r-enantiomer in a β1- selective adrenoceptor antagonist whose hemodynamic effects differ from those of classical β-adrenoceptor antagonists as a result of a vasodilating action. It has mild vasodilating properties attributed to its interaction with the L-arginine/nitric oxide pathway, a property not shared by other β-blockers. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, nebivolol does not demonstrate α1-adrenergic receptor blockade activity.

Pharmacokinetics:

• Absorption:

Absorption of Nebivolol is similar to an oral solution. The absolute bioavailability has not been determined. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Under fed conditions, nebivolol glucuronides are slightly reduced. Nebivolol may be administered without regard to meals.

• Distribution:

The in vitro human plasma protein binding of Nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

• Metabolism:

Nebivolol is predominantly metabolized via direct glucuronidation of the parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. Its stereospecific metabolites contribute to pharmacologic activity.

• Elimination:

After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine, and 13% in feces for PMs. Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates

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