Nadolol

Nadolol is a non-selective Beta Adrenergic blocking agent belonging to the beta-blocker class.

Nadolol is approved to treat angina and Hypertension. Off-label, the indication includes atrial fibrillation, ventricular arrhythmias due to congenital long QT syndrome, Ventricular premature beat, catecholaminergic polymorphic ventricular tachycardia, supraventricular tachycardia, gastroesophageal variceal hemorrhage prophylaxis in a patient with liver cirrhosis and thyrotoxicosis.

Absorption of nadolol after oral dosing is variable, averaging about 30 %. Peak serum concentrations of nadolol usually occur three to four hours after oral administration, and the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol absorption. Approximately 30 % of the nadolol present in serum is reversibly bound to plasma protein. Unlike many other beta-adrenergic blocking agents, nadolol is not metabolized by the liver and is excreted unchanged, principally by the kidneys.

The common side effects associated with Nadolol include slower heart rate, diarrhea, weakness, tiredness, dizziness, anxiety, nausea, dry or burning eyes, headache, cold or flu symptoms, etc.

Nadolol is available in the form of Tablets.

The molecule is available in Sweden, Germany, Spain, the US, India.

Nadolol is a synthetic non-selective beta-adrenergic receptor blocker and an inverse agonist. It competitively blocks beta-1 receptors in the heart and vascular smooth muscles, thus inhibiting the effect of catecholamine on these receptors, without sympathomimetic or membrane-stabilizing properties, causing negative inotropic and negative chronotropic properties. This agent's inhibiting effect of beta-2 receptor in the juxtaglomerular apparatus results in inhibition of renin production and subsequent reduction of angiotensinogen, angiotensin II-dependent vasoconstriction, and aldosterone-dependent water retention.

The onset of action is within 3-4 hours of dosing, nadolol reaches its peak plasma concentrations, and after 6-9 days, steady-state levels are reached.

Nadolol peak plasma levels are achieved within Tmax of 2.7 hours and Cmax of 69 ± 15 ng/mL.

Nadolol is available in form of tablets.

Nadolol comes as a tablet. As directed by a physician, the regular tablet is often taken once or twice a day.

Nadolol is approved to treat angina and Hypertension. Off-label, indication includes atrial fibrillation, ventricular arrhythmias due to congenital long QT syndrome, Ventricular premature beat, catecholaminergic polymorphic ventricular tachycardia, supraventricular tachycardia, gastroesophageal variceal hemorrhage prophylaxis in a patient with liver cirrhosis and thyrotoxicosis.

It works by affecting response to nerve impulses in the certain parts of the body, like the heart. As a result, heart beats slower and decreases the blood pressure. When blood pressure is lowered, the amount of blood and oxygen is increased to the heart.

Nadolol is approved for use in the following clinical indications.

Angina

Nadolol has approval for long-term use in angina pectoris. Nadolol showed significant symptomatic improvement in exercise tolerance and exercise duration and was more effective than propranolol in slowing heart rate at rest and during exercise.

Hypertension

Nadolol is a second-line agent in the treatment of hypertension. Nadolol should not be used as the first line in treating hypertension in the absence of indications to start beta-blockers. Nadolol can reduce blood pressure significantly with minimal cardio depressant effect. Adding a diuretic can enhance the effectiveness of nadolol.

Off-label Indications of Nadolol

Atrial Fibrillation

Nadolol can be used to attain heart rate control in the acute management of atrial fibrillation. Oral beta-blockers, including nadolol, are also widely used as the primary therapy for chronic atrial fibrillation. Nadolol also decreases relapse in patients with paroxysmal atrial fibrillation.

Ventricular Arrhythmias due to Congenital Long QT Syndrome

The AHA recommends using nadolol in patients with ventricular arrhythmias due to congenital long QT syndrome to reduce adverse cardiac events, syncope, and the prevention of sudden cardiac death.

Ventricular Premature Beat

Nadolol is an option for the suppression of premature ventricular beats. This effect is due to bradycardia-induced prolongation of RR interval. It is more effective in patients with coronary artery disease than in patients without heart disease.

Catecholaminergic Polymorphic Ventricular Tachycardia

Nadolol effectively reduces the incidence and severity of ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Nadolol appears to reduce ventricular arrhythmia by reducing the catecholamine effect on the beta receptor. As a non-selective beta-blocker, nadolol prevents arrhythmia and cardiac arrest much more effectively than other beta-1 selective beta-blockers.

Supraventricular Tachycardia

Nadolol is effective in the termination of acute onset supraventricular tachycardia in those patients where the vagal maneuver is not an option or failed and did not respond to adenosine. Nadolol can potentially control the ventricular rate in patients with sustained response supraventricular tachycardia.

Gastroesophageal Variceal Hemorrhage Prophylaxis in Patients with Liver Cirrhosis

Clinicians use nadolol to prevent and manage gastroesophageal varices and variceal hemorrhage in patients with liver cirrhosis. Nadolol and other beta-blockers(e.g., propranolol) have been shown to significantly reduce variceal rebleeding, reduce deaths from variceal hemorrhage, and overall mortality. In combination with isosorbide dinitrate, nadolol is very effective as prophylaxis in a patient with liver cirrhosis. A multi-center trial proved that nadolol plus endoscopic variceal ligation (EVL) reduces the incidence of variceal rebleeding compared to EVL alone.

Thyrotoxicosis

Nadolol produces clinical improvement in patients with thyrotoxicosis by reducing palpitations, nervousness, and tremor. It produces this effect by reducing the level of free thyroid hormone in the bloodstream. It also reduces the T3 levels and increases the reverse T3 levels.

Nadolol is available in the form of tablets.

High Blood Pressure: Nadolol is administered only orally as 5 or 10 mg tablets once daily. Nadolol has low lipophilicity, so it does not cross the blood-brain barrier with a high amount. Nadolol has a long half-life that extends from 9 to 12 hours. It also has high bioavailability, reaching 80 % compared to most beta-blockers with lower bioavailability since they have high first-pass metabolism in the liver.

Nadolol are available with dosage strength of 20 mg, 40 mg, 80 mg, 120 mg, 160 mg.

Nadolol is available in the form of tablet.

Nadolol should be used in the treatment of high blood pressure, angina pectoris, atrial fibrillation, and acute myocardial infarction along with appropriate dietary restrictions.

• High Blood Pressure: 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.
• 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, like Atrial fibrillation as well as heart disease. 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.
• Gastroesophageal Variceal Hemorrhage Prophylaxis: Patients are suggested to have a soft diet—naturally soft foods that include ripe bananas, eggs, and cooked food—in order to prevent veins from rupturing.

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.

The dietary restriction should be individualized as per patient requirements

Sympathetic stimulation is an important component supporting circulatory function in the setting of congestive heart failure, and beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure, it may be necessary to utilize them. In such a situation, they must be used cautiously.

• In Patients Without a History of Cardiac Failure:

Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At first signs or symptoms of heart failure, discontinuation of Nadolol should be considered. In some cases, beta-blocker therapy can be continued while the heart failure is treated with the other drugs.

• Abrupt Cessation of Therapy :

Exacerbation of angina pectoris and, in some instances, myocardial infarction or ventricular arrhythmia have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against the interruption or discontinuation of therapy without the physician's advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with Nadolol over approximately one week with the patient under careful observation. If withdrawal symptoms occur, Nadolol therapy should be reinstituted, at least temporarily.

• Peripheral Vascular Disease :

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

• Bronchospastic Disease:

Patients with bronchospastic disease should, in general, not receive beta-blockers. Because of its relative beta 1-selectivity, however, nadolol may be used with caution in patients with bronchospastic disease who do not respond to or who cannot tolerate other antihypertensive treatments. Since beta 1-selectivity is not absolute, the lowest possible dose of Nadolol should be used, with the therapy starting at 2.5 mg. A beta2 agonist (bronchodilator) should be made available.

• Anesthesia and Major Surgery:

If Nadolol treatment is to be continued perioperatively, particular care should be taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.

• Diabetes and Hypoglycemia:

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta 1-selectivity, this is less likely with NADOLOL. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, must be cautioned about these possibilities, and nadolol fumarate should be used with caution.

• Thyrotoxicosis:

Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abruptly the withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

This drug has a black box warning. This is the most serious warning from Food and Drug Administration (FDA). A black box warning alerts doctors and patients about drug effects that may be dangerous.

Suddenly stopping treatment with nadolol can cause a heart attack, stroke, irregular heartbeat, or severe high blood pressure.

PRECAUTION:

• Applies only to hypertension or angina pectoris:

Nadolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

• Applies only to chronic heart failure:

There is no therapeutic experience of nadolol in treating heart failure in patients with the following diseases and conditions:

• Insulin-dependent diabetes mellitus (type I)
• Severely impaired renal function
• Severely impaired hepatic function
• Restrictive cardiomyopathy
• Congenital heart disease
• Hemodynamically significant organic valvular disease
• Myocardial infarction within three months.

Alcohol lowers the blood pressure. Drinking alcohol while taking nadolol may lower the blood pressure to dangerously low levels.

The intake of Nadolol with alcohol can increase the feeling of dizziness or faintness.

Category C: In animal reproduction studies with the nadolol, evidence of embryo- and fetotoxicity was found in rabbits, but not in rats or hamsters, at doses, 5 to 10 times greater (on an mg/kg basis) than the maximum indicated human dose. No teratogenic potential was observed in any of these species.

There are no adequate and well-controlled studies on pregnant women. Nadolol should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates whose mothers are receiving nadolol at parturition have exhibited bradycardia, hypoglycemia, and associated symptoms.

The food warning while consuming Nadolol that should be taken in concentrations while consumption:

• Green Tea: Green tea with nadolol will reduce the absorption of the drug in the bloodstream and reduce the effect of the drug.
• Potassium-Rich Foods: Potassium-rich foods when taken along with beta blockers like nadolol may result in high blood potassium levels.
• Pleurisy Root: Pleurisy roots are not recommended with most heart medications due to the cardiac glycoside content of the root.

 The adverse reaction related to nadolol can be categorized as :

Most adverse effects have been mild and transient.

• Allergic: Fever, combined with an aching and sore throat, laryngospasm, and respiratory distress.
• Common Adverse effects: Reversible mental depression progressing to catatonia; an acute reversible syndrome characterized by the disorientation of time and place; short-term memory loss; emotional lability with slightly clouded sensorium; and decreased performance on neuropsychometrist.
• Infrequent adverse effects: Mesenteric arterial thrombosis, ischemic colitis.
• Rare adverse effect: Erythematous rash.
• Miscellaneous: There have been reports of skin rashes and dry eyes associated with the use of beta-adrenergic blocking drugs.

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, the physician may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of these medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

The common side effects of Nadolol include headache, feeling tired, insomnia, joint pain, swelling, or cold symptoms such as stuffy nose, runny nose, cough, and sore throat.

Other side effects include: shortness of breath, slow heart rate, eye pain, vision problems, etc.

Pharmacodynamics

• Nadolol is a beta-adrenergic receptor blocking agent with prolonged activity, permitting once-daily dosage in angina, hypertension, cardiac arrhythmias, the prophylaxis of migraine, and the relief of hyperthyroid symptoms.
• Nadolol is not metabolized. It has no membrane stabilizing or intrinsic sympathomimetic activity, and its only effect on the autonomic nervous system is the beta-adrenergic blockade. Nadolol is nonselective.
• Receptor blockade by nadolol results in the protection from excessive inappropriate sympathetic activity. Nadolol reduces the number and severity of the attacks of angina pectoris by blocking response to catecholamine stimulation and thus lowers the oxygen requirement of the heart at any given level of effort.
• Nadolol reduces both supine and erect blood pressure. Like other beta-blockers, nadolol exerts an antiarrhythmic action. Nadolol has been shown to reduce rapid ventricular response which accompanies the atrial fibrillation/flutter by slowing conduction through the A-V node. Beta-blockade is of particular value in arrhythmias caused by increased levels of, or sensitivity of the heart to, circulating catecholamines, e.g. arrhythmias associated with pheochromocytoma, thyrotoxicosis, or exercise. Nadolol is effective in reducing ventricular premature beats in selected patients.
• Nadolol exerts an effect on prophylaxis of the migraine by a mechanism that may involve the prevention of vasoconstriction in the area served by the internal carotid artery and prevention of excessive adrenergic vasodilation in the external carotid artery.
• Nadolol alleviates the symptoms of thyrotoxicosis and provides symptomatic control before and during thyroid surgery.
• Beta-blocking agents have been shown in large-scale studies to reduce mortality by preventing reinfarction and sudden death in patients surviving their first myocardial infarction.

Pharmacokinetics

• Absorption:

About 30 percent of an oral dose of Nadolol is absorbed. The presence of food in the gastrointestinal tract does not affect the rate or extent of Nadolol absorption.

• Distribution:

Peak serum concentrations usually occur in 3 to 4 hours after drug administration. Approximately 30 percent of the Nadolol present in serum is reversibly bound to plasma protein.

• Metabolism:

Nadolol is not metabolized.

• Elimination:

Unlike most available beta-blocking agents, Nadolol is not metabolized and is excreted unchanged principally by the kidneys. The serum half-life of a therapeutic dose of Nadolol is relatively long, ranging from 20 to 24 hours (permitting a once-daily dosage).

1. Merkel C, Marin R, et.al. A placebo-controlled clinical trial of nadolol in the prophylaxis of growth of small esophageal varices in cirrhosis. Gastroenterology. 2004 Aug 1;127(2):476-84. DOI: https://doi.org/10.1053/j.gastro.2004.05.004
2. Merkel C, Marin R, et.al. C. Long‐term results of a clinical trial of nadolol with or without isosorbide mononitrate for primary prophylaxis of variceal bleeding in cirrhosis. Hepatology. 2000 Feb;31(2):324-9. DOI: https://doi.org/10.1002/hep.510310210
3. Hanania NA, Singh S, et.al. The safety and effects of beta-blocker, nadolol, in mild asthma: an open-label pilot study. Pulmonary pharmacology & therapeutics. 2008 Feb 1;21(1):134-41. DOI:https://doi.org/10.1016/j.pupt.2007.07.002

1. 1.https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018063s060lbl.pdf
2. 2.https://reference.medscape.com/drug/corgard-nadolol-342361
3. 3.Schäfer-Korting M, Bach N, et.al,.Pharmacokinetics of nadolol in healthy subjects. European journal of clinical pharmacology. 1984 Jan;26(1):125-7.
4. 4.Mehta AV, Chidambaram B, Rice PJ. Pharmacokinetics of nadolol in children with supraventricular tachycardia. The Journal of Clinical Pharmacology. 1992 Nov;32(11):1023-7.DOI:https://doi.org/10.1002/j.15524604.1992.tb03805.https://link.springer.com/article/10.1007/s00246-016-1544-y