Continuing Education Activity

Nadolol is a nonselective β-blocker and an inverse agonist, which is approved by the US Food and Drug Administration (FDA) for managing hypertension and angina. These 2 conditions are major risk factors associated with various cardiovascular diseases, including coronary artery disease, heart failure, and stroke. The drug's pivotal role in these conditions improves patient outcomes and helps mitigate the progression of cardiovascular disease. 

In addition to its FDA-approved indications, nadolol proves beneficial in various off-label uses, including the treatment of atrial fibrillation, ventricular arrhythmias linked to long QT syndrome, ventricular premature beats, catecholaminergic polymorphic ventricular tachycardia, supraventricular tachycardia, prophylaxis against gastroesophageal variceal hemorrhage in liver cirrhosis, thyrotoxicosis management, as well as migraine and vascular headache prophylaxis. This activity reviews indications for nadolol, elucidates its mechanism of action, explores adverse drug reactions and toxicity profiles, delineates management strategies and contraindications, and provides a comprehensive understanding of nadolol's multifaceted role in addressing hypertension, angina, and related conditions. This activity explores nadolol's pharmacological nuances and clinical applications, empowering interprofessional healthcare providers with the expertise to utilize its therapeutic potential effectively in diverse cardiovascular scenarios. 

Objectives:

• Identify the appropriate indications for nadolol in the management of cardiovascular conditions such as hypertension and angina.

• Implement appropriate dosing strategies and titration protocols for nadolol based on patient-specific factors and clinical guidelines.

• Apply knowledge of nadolol's mechanism of action to optimize its therapeutic benefits while minimizing risks.

• Collaborate with other healthcare professionals to ensure coordinated care and management of patients receiving nadolol in conjunction with other medications.

Indications

Nadolol is a nonselective β-blocker approved by the US Food and Drug Administration (FDA) for managing hypertension and angina. These 2 conditions are major risk factors associated with various cardiovascular diseases, including coronary artery disease, heart failure, and stroke. The drug's pivotal role in these conditions improves patient outcomes and helps mitigate the progression of cardiovascular disease. Nadolol was patented in 1970, and its medical use started in 1978.

FDA-Approved Indications

Angina: Nadolol is approved for long-term use in angina pectoris. Nadolol showed significant symptomatic improvement in exercise tolerance and duration 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 treating hypertension in the absence of indications to start β-blockers. Nadolol can reduce blood pressure significantly with minimal cardio-depressant effect.[2] Adding a diuretic can enhance the effectiveness of nadolol.[3]

Off-Label Uses

Atrial fibrillation: Nadolol can be used to attain heart rate control in the acute management of atrial fibrillation. Oral β-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.[4]

Ventricular arrhythmias due to congenital long QT syndrome: The American Heart Association (AHA) recommends using nadolol in patients with ventricular arrhythmias due to congenital long QT syndrome to reduce adverse cardiac events and syncope and the prevention of sudden cardiac death.[5]

Ventricular premature beat: Nadolol is an option for suppressing premature ventricular beats. This effect is due to bradycardia-induced prolongation of the RR interval.[6] Nadolol is more effective in patients with coronary artery disease than in patients without heart disease.[7]

Catecholaminergic polymorphic ventricular tachycardia: Nadolol effectively reduces the incidence and severity of ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia. Nadolol reduces ventricular arrhythmia by reducing the catecholamine effect on the β-receptor.[7] As a nonselective β-blocker, nadolol prevents arrhythmia and cardiac arrest much more effectively than other β-1 selective β-blockers.[8][9]

Supraventricular tachycardia: Nadolol is effective in terminating 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 control ventricular rate in patients with sustained response supraventricular tachycardia.[11]

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.[12] Nadolol and other β-blockers, such as propranolol, have been shown to significantly reduce variceal rebleeding, reduce deaths from variceal hemorrhage, and overall mortality.[13] In combination with isosorbide dinitrate, nadolol is very effective as prophylaxis in a patient with liver cirrhosis.[14] A multicenter trial demonstrated that nadolol plus endoscopic variceal ligation reduces the incidence of variceal rebleeding compared to endoscopic variceal ligation alone.[15]

Thyrotoxicosis: Nadolol produces clinical improvement in patients with thyrotoxicosis by reducing palpitations, nervousness, and tremor. The drug achieves this effect by lowering the free thyroid hormone level in the bloodstream. Nadolol also reduces the triiodothyronine hormone (T3) levels and increases the reverse T3 levels.[16]

Migraine prophylaxis: Nadolol can be used as a second-line agent for migraine headache prophylaxis.[17]

Vascular headache prophylaxis: Nadolol can also be used off-label to help prevent vascular headaches.[18]

Mechanism of Action

Nadolol is a synthetic nonselective β-adrenergic receptor blocker and an inverse agonist.[19] Nadolol competitively blocks the β-1 receptors in the heart and vascular smooth muscles, 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 decreases systolic and diastolic blood pressure at rest and during exercise.[20] 

The drug's antiarrhythmic property impairs the conduction through the atrioventricular (AV) node and suppresses automaticity, decreasing heart rate and cardiac output at rest and during exercise. This inhibiting effect of the β-2 receptor in the juxtaglomerular apparatus results in the inhibition of renin production and reduction of angiotensinogen, angiotensin II–dependent vasoconstriction, and aldosterone-dependent water retention.

Pharmacokinetics

Absorption: Following oral dosing of nadolol, the drug is approximately 30% absorbed. Research showed that nadolol had a Tmax of 2.7 hours and a Cmax of 69±15 mg/mL following a 60 mg oral dose and 132±27 mg/mL after a 120 mg oral dose.[21]

Distribution: Nadolol's volume of distribution is between 147 and 157 L. The drug is approximately 30% protein-bound, binding to plasma α-1-acid glycoprotein.[21]

Metabolism: Following rapid first-pass metabolism in the liver, nadolol is not significantly hepatically metabolized, has little to no effect on the CYP450 system, and is unlikely to cause liver injury.[18] Nadolol's precise metabolic pathway is unclear. 

Elimination: Following intravenous (IV) dosing, 60% of a nadolol dose is eliminated in the urine and 15% in the feces 72 hours after administration. The drug's half-life is between 20 and 24 hours.[22] The inherently longer duration of action allows daily dosing and is as effective as propranolol with its traditional 4 times daily dosing.[23] Nadolol differs from other β-blockers in that it is excreted renally.

Administration

Available Dosage Forms and Strengths

Nadolol administration is primarily through the oral route. Tablet formulations are available in strengths of 20 mg, 40 mg, and 80 mg.

Adult Dosage

• According to the FDA, in patients with angina pectoris and hypertension, nadolol should be started as a 40 mg once-daily oral formulation and gradually increased in 40 to 80 mg increments to achieve the required therapeutic concentration and be tailored to the patient’s response.[24] The maximum dosages for hypertension and angina are 320 and 240 mg, respectively.

• The AHA recommends an oral dosage range of 10 to 240 mg in patients with atrial fibrillation 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 AHA recommends an oral dosage of 40 to 320 mg daily.[25][26]

• In patients with ventricular tachyarrhythmia, the AHA recommends a dosage of 160 mg for long-term control.[27]

• For primary and secondary prophylaxis in patients with gastroesophageal variceal hemorrhage, the initial dose is 40 mg/d. This dose can increase to 80 mg/d in patients with ascites and 160 mg/d in patients without ascites. Dosing should be gradually increased every 2 to 3 days to reach a maximum tolerated dose in these patients. 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 mm Hg.[28]The American Thyroid Association recommends an oral dosage of 40 to 160 mg in patients with thyrotoxicosis.[29]

• The American Academy of Neurology and American Headache Society recommends an oral dosage of 40 to 160 mg daily for prophylaxis in patients with migraines.[30] The dosage for vascular headache prophylaxis is 20 to 40 mg daily.

Special Patient Populations

Hepatic impairment: No information is available on the use of nadolol in patients with hepatic impairment.

Renal impairment: Nadolol reduces renal blood flow. Therefore, dosage intervals should require monitoring with creatinine clearance.[31] Dosage requires no modification for creatinine clearance (CrCl) over 50 mL/min. The dosage interval should be extended 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 30 mL/min/1.73 m², and less than 10 mL/min/1.73 m², respectively.

Pregnant considerations: Nadolol is considered an FDA pregnancy category C drug. Research shows that nadolol reduces birth weight in infants. Clinicians should weigh the risks versus benefits, particularly in the last 2 trimesters.

Breastfeeding considerations: Nadolol is relatively contraindicated postpartum due to its expression in breast milk; clinicians must carefully assess the risk/benefit ratio. The drug may induce hypotension and hypoglycemia in neonates and infants. No data exists regarding its effects on milk production.

Pediatric patients: Nadolol is occasionally utilized off-label in pediatric patients for ventricular arrhythmia at a dosage of 0.5 to 1 mg/kg per dose. The dose should be tapered over 1 to 2 weeks when discontinuing treatment.

Older patients: When starting older patients on nadolol, initiating therapy at half the standard adult dose may be beneficial before titrating upward.

Adverse Effects

Nadolol has been well-tolerated in most clinical studies with minimal adverse effects.[23] The adverse effects of nadolol are mainly because of its impact on the β-2 receptors. No known reports of major organ injury are from using nadolol. However, there is evidence of a mild-to-moderate increase in liver enzymes in certain patient populations, particularly aspartate aminotransferase (AST) and alanine aminotransferase (ALT), due to the first-pass metabolism of nadolol in the liver. Typically, these patients are asymptomatic, and liver functions return to baseline with continued therapy. No evidence of nadolol causing clinically apparent liver injury exists, 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 liver function.[32]

The most common adverse effects of the drug are drowsiness and insomnia. However, some other common adverse effects of nadolol are provided below.

• Cardiovascular: The adverse effects include AV block, bradycardia, hypotension, and Raynaud phenomenon.
• Central nervous system: The adverse effects include dizziness, depression, and memory loss.
• Gastrointestinal: The adverse effects include hepatotoxicity, weakness, and impotence.
• Respiratory: The adverse effects include cough and bronchospasm.

Severe hypotension, bronchospasm, and allergic reactions are rare but life-threatening adverse effects, often necessitating immediate emergency treatment. 

Contraindications

Warnings and Precautions

Asthma or chronic obstructive pulmonary disease: The effect of nadolol on the β-2 receptors of the bronchial lining prevents bronchodilation and increases airway resistance, exacerbating the effect in patients with a bronchospastic disease such as asthma, causing wheezing and shortness of breath.[33]

Sinus bradycardia: One known effect of nadolol is reducing the resting heart rate. In patients with low heart rates originating from sinus node (SA) dysfunction, nadolol can further reduce the rate unless a pacemaker is present.[34]

Greater than first-degree AV block: Nadolol reduces conduction through the AV node, potentially causing an AV block. Thus, nadolol can lead to severe bradyarrhythmia in patients with partial or complete AV block. The use of other drugs that might impair AV nodal conduction can exacerbate AV blockage.[33]

Cardiogenic shock: 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.[33]

Decompensated cardiac failure: β-blockers are a cornerstone in the long-term treatment of compensated chronic heart failure with reduced ejection fraction, reducing the detrimental effect of sympathetic drive on the heart. However, nadolol is contraindicated in patients with uncompensated heart failure. 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.[33]

Pregnancy and breastfeeding: For managing hypertension during pregnancy, β-blockers such as Labetalol are preferable to nadolol.[33]

Additionally, some patients may exhibit hypersensitivity to nadolol and myocardial depression due to anesthetic properties.

Box Warning

Clinicians should not abruptly withdraw nadolol, as it can cause rebound tachycardia, hypertension, or ischemia. Treatment should be titrated gradually to avoid these complications.[33]

Monitoring

The clinical team should maintain the patient's heart rate above 55 bpm in patients under nadolol therapy. The heart rate specifically requires monitoring while escalating the dose, which can cause further bradycardia. Abruptly withdrawing the medications can cause rebound tachycardia, hence the need for downward titration for discontinuation.[34] The patient's blood pressure should be maintained above 90 mm Hg systolic, especially while escalating and withdrawing the medication.[33] Abrupt withdrawal of nadolol can cause rebound tachycardia and reduced blood flow to the myocardial tissue, generating anginal symptoms or worsening angina.[33]

Toxicity

Most nadolol poisonings occur via the intentional consumption of the tablet. No reports of significant toxicity are apparent in the literature.[23] 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 moderate-to-severe toxicity persists, 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 nadolol's low distribution volume and longer half-life.[33]

Signs and symptoms of moderate-to-severe poisoning include severe hypotension, bradycardia, bronchospasm, heart failure, hypoglycemia, seizure, and coma. First and foremost, maintaining a patent airway is essential. If necessary, suction should be utilized, efforts should be made to sustain oxygen saturation above 90%, and consideration should be given to endotracheal intubation. Continuous monitoring of the patient for pulmonary edema or signs of shock is imperative. Notably, no specific antidote for nadolol toxicity has been identified. However, for the treatment of hypotension, glucagon, dopamine, or sodium bicarbonate, followed by multiple IV boluses of epinephrine if the former is not adequate, can be used.[35] Glucagon elevates cAMP through a non-catecholamine mechanism, enabling it to induce both ionotropic and chronotropic effects. In cases of bradycardia, atropine is the preferred therapy. If the heart rate persists low, IV isoproterenol or cardiac pacing.[33] 

Heart failure is typically managed with cardiac glycosides and diuretics.[33] Bronchospasm is treated with nebulized β-agonists, with consideration that higher than usual or multiple doses may be required.[33] In cases of β-blocker–induced anaphylaxis, a lower-than-usual dose of epinephrine is administered, as the unopposed α-receptor effect can lead to coronary vasoconstriction and paradoxical hypertension.

Enhancing Healthcare Team Outcomes

The primary use of nadolol is in the treatment of angina and hypertension.[36][2] Despite its safety profile, careful monitoring is necessary during its use. Members of the interprofessional healthcare team, such as physicians, advanced practice practitioners, specialists, nursing staff, and pharmacists, should exercise caution when discontinuing nadolol, as it may lead to life-threatening rebound hypertension, tachycardia, and signs of angina. Additionally, nadolol should be cautiously used alongside diuretics, as these agents can enhance the hypotensive effects of nadolol.[3] 

Notably, nadolol can enhance and potentiate the effect of the neuromuscular blocking agent tubocurarine chloride. Improved treatment outcomes with nadolol can be achieved through improved team performance, including ordering appropriate follow-up and monitoring for signs of inadequate dosage or symptoms of toxicity.

To enhance outcomes and reduce morbidity, pharmacists should educate patients on medication compliance and advise against using other drugs or herbs without consulting the prescribing clinician. Additionally, pharmacists should conduct medication reconciliation to monitor potential interactions and communicate any findings to the rest of the healthcare team. Nursing staff with frequent patient contact should assess treatment efficacy and monitor for adverse effects. These observations must be relayed to the prescribing clinicians for any necessary adjustments to the therapy regimen. Nadolol therapy necessitates a coordinated effort from an interprofessional healthcare team collaborating across disciplines to attain optimal patient outcomes and mitigate adverse events.