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.[1]

Hypertension: Nadolol is a second-line agent 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.[2] Adding a diuretic can enhance the effectiveness of nadolol.[3]

Non-FDA approved:

Atrial fibrillation:

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.[4]

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.[5]

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.[6] It is more effective in patients with coronary artery disease than in patients without heart disease.[7]

Catecholaminergic polymorphic ventricular tachycardia:

Nadolol is effective in reducing the incidence and severity of ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Nadolol appears to reduce the ventricular arrhythmia by reducing the catecholamine effect on the beta receptor.[7] As a non-selective beta-blocker, nadolol prevents arrhythmia and cardiac arrest much more effectively compared to other beta-1 selective beta-blockers.[8][9]

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.[10] Nadolol can potentially control the ventricular rate in patients with sustained response supraventricular tachycardia.[11]

Gastroesophageal variceal hemorrhage prophylaxis in patients with liver cirrhosis: Clinicians use nadolol for the prevention and management of gastroesophageal varices and variceal hemorrhage in patients with liver cirrhosis.[12] Nadolol and other beta-blockers(e.g., propranolol) have shown to significantly reduce variceal rebleeding, reduce deaths from variceal hemorrhage and overall mortality.[13] Nadolol, in combination with isosorbide dinitrate, is very effective as prophylaxis in a patient with liver cirrhosis.[14] A multi-center trial proved that nadolol plus endoscopic variceal ligation (EVL) reduces the incidence of variceal rebleeding compared to EVL alone.[15]

Thyrotoxicosis:

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.[16]

Nadolol is a synthetic non-selective beta-adrenergic receptor blocker and an inverse agonist.[17] 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.[18] 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 that allows once-daily dosing and is as effective as propranolol with its traditional four times daily dosing.[19] 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.[20] 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 m^2, 10 to 30 ml/min/1.73 m^2 and under 10 ml/min/1.73 m^2 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.[21] The 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.[4] 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.[22][23] In patients with ventricular tachyarrhythmia, the American Heart Association recommends a dosage of 160 mg for long-term control.[24]

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 the dosage should be stopped or decreased if the blood pressure drops below 90 mmHg.[25]

In patients with thyrotoxicosis, the American Thyroid Association recommends an oral dosage of 40 to 160 mg.[26]

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.[27]

Nadolol has been well-tolerated in most of the clinical studies with minimal side effects.[19] 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.[28]

The most common adverse effect is drowsiness and insomnia. Some other common adverse effects of nadolol are as follows:

Cardiovascular:

• AV block
• Bradycardia
• Hypotension
• Raynaud phenomenon

Central Nervous System:

• Dizziness
• Depression
• Memory loss

Gastrointestinal:

• Hepatotoxicity
• Weakness
• Impotence

 Respiratory:

• Cough
• Bronchospasm

Severe hypotension, bronchospasm, and allergic reactions are some of the rare but life-threatening adverse effects, often necessitating immediate emergency treatment. Clinicians should not withdraw nadolol abruptly [US BOX WARNING] as it can cause rebound tachycardia, hypotension, and or ischemia. It should be stopped gradually to avoid these complications.[29]

1. Asthma/COPD: The effect of nadolol on the beta-2 receptors of bronchial lining prevents bronchodilation and increases airway resistance, which exacerbates the effect in patients with a bronchospastic disease like asthma, and thus causing wheezing and shortness of breath.[29]
2. Sinus bradycardia: One of the known effects of nadolol is reducing the resting heart rate. In patients with low heart rate originating from sinus node dysfunction, nadolol can lead to further reduction of the rate unless a pacemaker is present.[30]
3. Greater than first degree AV block: Nadolol reduces conduction through AV node, potentially causing an AV block. Thus, nadolol can lead to serious bradyarrhythmia in patients with partial or complete AV block. Use with other drugs that might impair AV nodal conduction can exacerbate AV blockage.[29]
4. Cardiogenic shock: The combined effect of lowering the resting heart rate and increasing the AV nodal conduction delay can potentially aggravate the already reduced cardiac output in patients with cardiogenic shock.[29]
5. Decompensated cardiac failure: Beta-blockers are a cornerstone in the long-term treatment of compensated chronic heart failure with reduced ejection fraction, as it reduces the detrimental effect of sympathetic drive on the heart. But nadolol is contraindicated in patients with uncompensated heart failure as these patients rely on catecholamines for sustaining their heart rate, and cardiac output and nadolol in these patients can exacerbate the symptoms of heart failure.[29]
6. Hypersensitivity to nadolol.
7. Anesthetic agents that can cause myocardial depression
8. Nadolol is considered a pregnancy category C drug. Research has shown it to reduce birth weight in infants. It is also contraindicated postpartum as it is expressed in breast milk and has proved to induce hypotension and hypoglycemia in neonates and infants.

For managing hypertension during pregnancy, beta-blockers like labetalol is preferable to nadolol.[29]