The FDA-labeled indications of Nadolol are:
Angina: Nadolol has approval for long-term use in angina pectoris. Nadolol showed significant symptomatic improvement in regards to exercise tolerance and duration of exercise and was more effective than propranolol in slowing heart rate at rest and during exercise.
Hypertension: Nadolol is indicated as the second line in the treatment of hypertension. Nadolol should not be used as the first line in the treatment of 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.
Nadolol can be used to attain heart rate control in the acute management of atrial fibrillation. Oral beta-blockers, including nadolol, is 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 the use of nadolol in patients with ventricular arrhythmias due to congenital long QT syndrome for the reduction of adverse cardiac events, syncope, and prevention of sudden cardiac death.
Ventricular premature beat:
Nadolol is an option for the suppression of ventricular premature 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 is effective in reducing the incidence and severity of ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Nadolol is believed to reduce the 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 compared to other beta-1 selective beta-blockers.
Nadolol is effective in the termination of acute onset supraventricular tachycardia, in those patients where 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: Nadolol is used for the prevention and management of gastroesophageal varices and variceal hemorrhage in patients with liver cirrhosis. Nadolol and other beta-blockers(e.g., propranolol) have shown to significantly reduce variceal rebleeding, reduce deaths from variceal hemorrhage and overall mortality. Nadolol, in combination with isosorbide dinitrate, 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.
Nadolol produces clinical improvement in patients with thyrotoxicosis, by reducing palpitations, nervousness, and tremor, among others. 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 a synthetic non-selective beta-adrenergic receptor blocker and an inverse agonist. It competitively blocks the beta1 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 effect on vascular smooth muscle causes a reduction in peripheral vascular resistance and thus decreases systolic and diastolic blood pressure at rest and during exercise. Its antiarrhythmic property is because it impairs the conduction through the AV node and suppress automaticity and thus decreases heart rate, cardiac output at rest and on exercise. This agent’s inhibiting effect of beta-2 receptor in juxtaglomerular apparatus results in inhibition of production of renin and subsequent reduction of angiotensinogen, angiotensin II-dependent vasoconstriction, and aldosterone dependent water retention.
Nadolol administration is primarily oral. It comes in 20 mg, 40 mg, 80 mg, 160 mg, 240 mg, and 320 mg tablet formulation. Various animal studies in dogs and rabbits (Lee 1975) have shown that pharmacological half-life is 12 to 24 hours. It’s the inherently longer duration of action allows once-daily dosing and is as effective as propranolol with its traditional four times daily dosing. Unlike other beta-blockers, nadolol gets renally excreted, and it undergoes its first-pass metabolism in the liver. But it has little to no effect on the CYP450 system, and hence rarely causes severe liver injury.
Also, nadolol reduces renal blood flow. Therefore, dosage intervals should require monitoring with creatinine clearance. Dosage requires no modification for CrCl over 50 ml/min. Extend the dosage interval to 24 to 36 hours, 24 to 48 hours and 40 to 60 hours for CrCl 31 to 49 ml/min/1.73 m2, 10 to 30ml/min/1.73 m2 and under 10 ml/min/1.73 m2 respectively.
In patients with angina pectoris and hypertension, according to the FDA, nadolol should be started as a 40 mg once daily oral formulation. It should be gradually increased in 40 to 80 mg increments to achieve the required therapeutic concentration and should be tailored based on the patient’s response. Maximum dosage for hypertension and angina are 320 mg and 240 mg, respectively.
In patients with atrial fibrillation, the American Heart Association recommends an oral dosage range of 10 mg to 240 mg, to be tailored based on the patient’s response. In patients with catecholaminergic polymorphic ventricular tachycardia, supraventricular tachycardia, and ventricular arrhythmia due to congenital long QT syndrome the American Heart Association recommends an oral dosage of 40 mg to 320 mg once a day. In patients with ventricular tachyarrhythmia, the American Heart Association recommends a dosage of 160 mg for long-term control.
For both primary and secondary prophylaxis in patients with gastroesophageal variceal hemorrhage, the initial dose is 40 mg per day. This dose can increase to up to 80 mg per day in patients with ascites and up to 160 mg per day in patients without ascites. In these patients, dosing should be gradually increased every 2 to 3 days to reach a maximum tolerated dose. Heart rate should be maintained at 55 to 60 bpm, and dosage should be stopped or decreased if the blood pressure drops below 90 mmHg.
In patients with thyrotoxicosis, American thyroid association recommends an oral dosage of 40 to 160 mg.
In patients with migraine, the American Academy of Neurology and American Headache Society recommends an oral dosage of 40 to 160 mg once a day for prophylaxis.
Nadolol has been well-tolerated in most of the clinical studies with minimal side effects. The adverse effects of nadolol are mainly because of its effect on the beta-2 receptors. There are no known reports of major organ injury from using nadolol. However, there has been evidence of a mild to moderate increase in liver enzymes, especially aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in select patient populations; this is because of the first-pass metabolism of nadolol in the liver. These patients are usually asymptomatic, and the liver functions return to baseline with the continuation of therapy. There is no evidence of nadolol causing clinically apparent liver injury, but this adverse effect can get aggravated when used in combination with other hepatotoxic drugs. Nadolol is safe for use in patients with cirrhosis for primary or secondary prophylaxis of varices without affecting the liver function.
The most common adverse effect is drowsiness and insomnia. Some other common adverse effects of nadolol are as follows:
Central Nervous System:
Severe hypotension, bronchospasm, and allergic reactions are some of the rare but life-threatening adverse effects, often necessitating immediate emergency treatment. Nadolol should not be withdrawn abruptly [US BOX WARNING] as it can cause rebound tachycardia, hypotension and or ischemia. It should be stopped gradually to avoid these complications.
For managing hypertension during pregnancy, beta-blockers like labetalol is preferable to nadolol.
Heart rate should be maintained above 55 bpm in patients taking nadolol. The heart rate specifically requires monitoring while escalating the dose, where it can cause further bradycardia, and while withdrawing the medications, where it can cause rebound tachycardia.
The blood pressure should be maintained above 90 mmHg systolic, especially while escalating and withdrawing the medication.
Signs and symptoms of angina exacerbation: Abrupt withdrawal of nadolol can cause exacerbation or causing anginal symptoms as it can cause rebound tachycardia and cause reduced blood flow to the myocardial tissue. Abrupt withdrawal of nadolol can cause rebound tachycardia and reduced blood flow to the myocardial tissue. Hence it can increase the anginal symptoms in some patients.
Most of the nadolol poisonings occur via intentional consumption of the tablet. There are no reports of significant toxicity in the literature. Most cases of nadolol poisoning are mild. These patients can be observed in an emergency department for 4 hours and discharged if no signs of poisoning develop. If there is moderate to severe toxicity, early decontamination with activated charcoal can be used along with gastric lavage if significant ingestion is suspected. After stabilizing the patient for airway, breathing, and circulation, enhanced elimination with hemodialysis is possible considering the low volume of distribution and longer half-life of nadolol.
Signs and symptoms of moderate to severe poisoning include severe hypotension, bradycardia, bronchospasm, heart failure, hypoglycemia, seizure, and coma. First maintaining a patent airway is essential. Use suction if necessary, attempt to maintain oxygen saturation above 90% and resort to endotracheal intubation if necessary. Continuously monitor the patient for pulmonary edema or signs of shock. There is no specific antidote for nadolol toxicity. However, for the treatment of hypotension, glucagon, dopamine or sodium bicarbonate, followed by multiple IV boluses of epinephrine if former is not adequate, can be used. Glucagon increases cAMP via a non-catecholamine mechanism, and thus, it can produce both ionotropic and chronotropic effect. For bradycardia, atropine is the therapy of choice; if the heart rate remains low after that, then IV isoproterenol or cardiac pacing can be done. Treat heart failure with cardiac glycosides and diuretics. Treat bronchospasm with nebulized beta-agonists (albuterol). Please note that higher than normal or multiple doses may be necessary.  Treat beta-blocker induced anaphylaxis with a lower than usual dose of epinephrine as the unopposed alpha-receptor effect can cause coronary vasoconstriction and paradoxical hypertension.
While the drug is safe, its use still requires monitoring.
Healthcare workers, including physicians, nurses, and pharmacists, should be cautious while withdrawing or stopping the drug as it can cause life-threatening rebound hypotension, tachycardia, and signs and symptoms of angina. Nadolol should be used cautiously with diuretics as it can potentiate the effect of hypotension by nadolol . It is worth noting that nadolol can enhance and potentiate the effect of neuromuscular blocking agent tubocurarine chloride. Improved treatment outcome with nadolol is achievable with enhanced team performance, by ordering appropriate follow-up, monitoring for signs of inadequate dosage or signs of toxicity.
To improve outcomes and lower morbidity, the pharmacist should educate the patient on medication compliance and avoiding the use of other drugs/herbs without consulting with the physician. The pharmacist should also perform medication reconciliation to monitor for any potential interactions, and report these to the rest of the healthcare team. Nursing staff will have more frequent contact with patients and can gauge the success of treatment as well as observe for adverse effects. These factors must get communicated to the prescribing physician for dose and/or drug changes to the therapy regimen. Nadolol therapy requires an interprofessional healthcare team approach, including physicians, specialists, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]
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