Nadolol - Drug Monograph

Introduction

Nadolol is a non-selective beta-adrenergic receptor blocking agent belonging to the class II antiarrhythmic drugs. It is a long-acting beta-blocker primarily used in the management of cardiovascular conditions including hypertension, angina pectoris, and certain arrhythmias. Nadolol is distinguished by its prolonged duration of action, allowing for once-daily dosing in most patients.

Mechanism of Action

Nadolol competitively blocks beta-1 and beta-2 adrenergic receptors, producing:

• Negative chronotropic effect (decreased heart rate)
• Negative inotropic effect (decreased myocardial contractility)
• Reduced blood pressure through decreased cardiac output
• Inhibition of renin release from the kidneys
• Decreased myocardial oxygen demand through reduced heart rate and contractility

Unlike some beta-blockers, nadolol lacks intrinsic sympathomimetic activity and membrane-stabilizing properties.

Indications

FDA-approved indications:

• Hypertension (alone or in combination with other antihypertensive agents)
• Angina pectoris management
• Prophylaxis of migraine headaches
• Supraventricular arrhythmias (including atrial fibrillation and flutter)

Off-label uses:

• Essential tremor
• Portal hypertension in cirrhosis
• Thyroid storm adjunctive therapy
• Long QT syndrome management

Dosage and Administration

• Initial dose: 40 mg orally once daily
• Maintenance dose: 40-80 mg daily (may increase to 120-160 mg daily if needed)
• Maximum dose: 320 mg daily

• Initial dose: 40 mg orally once daily
• Increase by 40-80 mg increments at 3-7 day intervals
• Usual maintenance: 40-80 mg once daily
• Maximum dose: 160-240 mg daily

• Renal impairment: Adjust based on creatinine clearance

- CrCl >50 mL/min: no adjustment needed - CrCl 31-50 mL/min: administer every 24-36 hours - CrCl 10-30 mL/min: administer every 24-48 hours - CrCl <10 mL/min: administer every 40-60 hours

• Hepatic impairment: Use with caution; no specific dosing recommendations
• Elderly: Initiate at lower end of dosing range
• Pediatric: Safety and effectiveness not established

Pharmacokinetics

• Oral bioavailability: approximately 30%
• Not significantly affected by food
• Peak plasma concentration: 3-4 hours post-dose

• Protein binding: approximately 30%
• Volume of distribution: 2.1 L/kg
• Crosses placenta and appears in breast milk

• Minimal hepatic metabolism
• Not significantly metabolized by cytochrome P450 system

• Primarily renal excretion unchanged
• Half-life: 20-24 hours (prolonged in renal impairment)
• Dialyzable: yes (hemodialysis)

Contraindications

• Bronchial asthma
• Cardiogenic shock
• Overt cardiac failure
• Second- or third-degree heart block
• Severe sinus bradycardia
• Hypersensitivity to nadolol or components
• Severe peripheral arterial disease

Warnings and Precautions

• Avoid abrupt discontinuation (may precipitate angina, MI, or ventricular arrhythmias)
• May precipitate congestive heart failure in susceptible patients
• Can mask signs of hypoglycemia in diabetics

• Can cause bronchospasm in patients with reactive airway disease
• Use with extreme caution in patients with COPD

• Can exacerbate symptoms of peripheral vascular disease

• Beta-blockade impairs ability of heart to respond to reflex stimuli
• Consider withdrawal 48 hours prior to elective surgery

• Masks tachycardia as sign of hypoglycemia
• Does not mask sweating or dizziness associated with hypoglycemia

• May mask clinical signs of developing or continuing hyperthyroidism

Drug Interactions

• Calcium channel blockers (verapamil, diltiazem): additive bradycardia and AV block
• Digoxin: additive bradycardia
• Insulin/oral hypoglycemics: enhanced hypoglycemic effect
• Clonidine: exaggerated rebound hypertension with concurrent withdrawal
• NSAIDs: may decrease antihypertensive effect
• CYP2D6 inhibitors: theoretical interaction (minimal metabolism)

• Other beta-blockers (additive effects)
• MAO inhibitors (risk of hypertension)

Adverse Effects

• Fatigue (≈15%)
• Bradycardia (≈10%)
• Dizziness (≈8%)
• Cold extremities (≈5%)
• Dyspnea (≈3%)
• Nausea (≈2%)

• Heart failure exacerbation
• Bronchospasm
• AV block
• Severe bradycardia
• Depression
• Raynaud's phenomenon
• Impotence
• Hypoglycemia
• Worsening of peripheral vascular disease

Monitoring Parameters

• Blood pressure and heart rate
• ECG (especially for conduction abnormalities)
• Renal function (BUN, creatinine, creatinine clearance)
• Hepatic function tests
• Blood glucose in diabetics

• Blood pressure at each visit
• Heart rate and rhythm
• Signs/symptoms of heart failure
• Respiratory status in patients with pulmonary disease
• Peripheral circulation
• Mental status changes
• Weight gain (possible heart failure)

• Diabetics: frequent blood glucose monitoring
• Elderly: fall risk assessment
• Renal impairment: more frequent renal function assessment

Patient Education

• Take at same time each day, with or without food
• Do not crush or chew tablets
• Do not stop abruptly unless directed by physician

• Rise slowly from sitting/lying position to prevent dizziness
• Avoid alcohol (may increase hypotensive effect)
• Monitor weight regularly and report sudden gains
• Exercise caution in hot weather (risk of heat prostration)

• Shortness of breath or wheezing
• Unusual weight gain or swelling
• Extreme fatigue or dizziness
• Very slow pulse rate (<50 bpm)
• Cold hands or feet
• Depression or mood changes

• Diabetics: regularly monitor blood sugar; be aware nadolol may mask fast heartbeat from low blood sugar
• Surgery: inform all healthcare providers about nadolol use

References

1. FDA Prescribing Information: Nadolol Tablets. Revised 2022. 2. Frishman WH. β-Adrenergic receptor blockers. Circulation. 2003;107(18):e117-e119. 3. Wiest D. Esmolol: a review of its therapeutic efficacy and pharmacokinetic characteristics. Clin Pharmacokinet. 1995;28(3):190-202. 4. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JNC 8 Guidelines. 2014. 5. American College of Cardiology/American Heart Association. Guideline for the Management of Patients With Atrial Fibrillation. 2019. 6. Micromedex® Healthcare Series. IBM Watson Health. 7. Lexicomp Online®. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.