Propranolol - Drug Monograph

Introduction

Propranolol is a non-selective beta-adrenergic receptor antagonist that was first developed in the 1960s. As the prototypical beta-blocker, it has served as a foundational cardiovascular medication for decades. Propranolol is unique among beta-blockers for its ability to cross the blood-brain barrier, making it valuable for both cardiovascular and certain central nervous system indications. It remains widely used despite the development of newer beta-blockers due to its established efficacy profile and diverse therapeutic applications.

Mechanism of Action

Propranolol competitively blocks both β1- and β2-adrenergic receptors. Its therapeutic effects are primarily achieved through:

• Reduction of heart rate and cardiac output via β1-receptor blockade in the heart
• Decreased renin secretion from renal juxtaglomerular cells
• Inhibition of lipolysis via β3-receptor blockade
• Central nervous system effects including reduced sympathetic outflow and anxiolytic properties
• Prevention of migraine through cerebral vasoconstriction and reduced neuronal excitability

The drug has no intrinsic sympathomimetic activity and possesses mild membrane-stabilizing properties at high concentrations.

Indications

• Hypertension
• Angina pectoris
• Cardiac arrhythmias (supraventricular tachycardia, ventricular tachycardias)
• Hypertrophic subaortic stenosis
• Pheochromocytoma (in combination with alpha-blockers)
• Migraine prophylaxis
• Essential tremor

• Performance anxiety and situational anxiety
• Portal hypertension in cirrhosis
• Thyroid storm adjunctive therapy
• Post-traumatic stress disorder symptoms
• Akathisia induced by antipsychotic medications

Dosage and Administration

• Initial: 40 mg twice daily
• Maintenance: 120-240 mg daily in divided doses
• Maximum: 640 mg daily

• Initial: 80 mg daily in divided doses
• Maintenance: 160-240 mg daily

• 10-30 mg three to four times daily

• Initial: 80 mg daily in divided doses
• Maintenance: 160-240 mg daily

• Initial: 40 mg twice daily
• Maintenance: 120-320 mg daily

• Hepatic impairment: Reduce dose by 50-75%
• Renal impairment: No significant adjustment needed
• Geriatric: Start with lower initial doses
• Pediatric: 0.5-1 mg/kg/day in divided doses (for specific indications)

• Oral administration with food to reduce bioavailability variability
• Should not be abruptly discontinued (taper over 1-2 weeks)
• Immediate-release and long-acting formulations available

Pharmacokinetics

• Oral bioavailability: ~25% (extensive first-pass metabolism)
• Peak plasma concentration: 1-4 hours
• Food increases bioavailability by 30-50%

• Protein binding: 90-95%
• Volume of distribution: 3-4 L/kg
• Crosses blood-brain barrier and placenta

• Extensive hepatic metabolism via CYP2D6, CYP1A2, and CYP2C19
• Active metabolite: 4-hydroxypropranolol
• Significant genetic polymorphism in metabolism

• Half-life: 3-6 hours (immediate-release)
• Excretion: Primarily renal (less than 1% unchanged)
• Dialysis: Not effectively removed

Contraindications

• Cardiogenic shock
• Sinus bradycardia and heart block greater than first degree
• Bronchial asthma and severe COPD
• Decompensated heart failure
• Hypersensitivity to propranolol or components
• Pheochromocytoma (without alpha-blockade)
• Severe peripheral arterial disease

Warnings and Precautions

• Abrupt withdrawal may exacerbate angina and cause myocardial infarction

• May precipitate heart failure in susceptible patients
• Can mask signs of hypoglycemia in diabetics
• May reduce effectiveness of epinephrine in anaphylaxis

• Can cause bronchospasm in susceptible patients
• Use with extreme caution in patients with asthma or COPD

• Depression reported in some patients
• May cause vivid dreams and sleep disturbances

• Pregnancy Category C: Use only if potential benefit justifies risk
• Lactation: Excreted in breast milk; use with caution
• Diabetes: May mask hypoglycemic symptoms

Drug Interactions

• Fluoxetine, paroxetine, quinidine: Increase propranolol levels

• Rifampin: Decrease propranolol levels

• Verapamil, diltiazem: Enhanced bradycardia and AV block
• Clonidine: Rebound hypertension with concurrent use
• Digoxin: Additive bradycardia

• Warfarin: Increased anticoagulant effect
• Insulin/oral hypoglycemics: Masked hypoglycemia
• NSAIDs: Reduced antihypertensive effect
• Epinephrine: Unopposed alpha-adrenergic effects

Adverse Effects

• Fatigue
• Bradycardia
• Dizziness
• Nausea
• Cold extremities

• Depression
• Sleep disturbances
• Bronchospasm
• Hypotension
• Impotence

• Heart failure exacerbation
• AV block
• Thrombocytopenic purpura
• Lupus-like syndrome
• Hallucinations

Monitoring Parameters

• Complete blood count
• Liver function tests
• Renal function
• Electrocardiogram
• Blood pressure and heart rate
• Pulmonary function tests (if indicated)

• Blood pressure and heart rate at each visit
• Weight monitoring in heart failure patients
• Mental status assessment
• Signs of bronchospasm
• Glucose monitoring in diabetics

• Hypertension: BP <140/90 mmHg (individualized)
• Angina: Reduced frequency of attacks
• Migraine: ≥50% reduction in frequency
• Tremor: Functional improvement

Patient Education

• Take with food to improve absorption consistency
• Do not crush or chew sustained-release formulations
• Do not stop abruptly - taper under medical supervision

• Rise slowly from sitting/lying position to prevent dizziness
• Avoid alcohol as it may enhance blood pressure effects
• Monitor for signs of hypoglycemia if diabetic

• Shortness of breath or wheezing
• Heart rate <50 bpm
• Swelling in extremities
• Depression or mood changes
• Unusual fatigue

• Inform all healthcare providers about propranolol use
• Carry medical identification indicating beta-blocker use
• Be aware that exercise tolerance may be reduced

References

1. Frishman WH. Beta-adrenergic receptor blockers. In: Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill; 2017. 2. Propranolol hydrochloride prescribing information. FDA Orange Book; 2022. 3. Cruickshank JM. Beta-blockers and heart failure. Indian Heart J. 2010;62(2):101-110. 4. Pringsheim T, Davenport WJ, Becker WJ. Propranolol for migraine prophylaxis. Cochrane Database Syst Rev. 2019;2019(9):CD011545. 5. Steenen SA, van Wijk AJ, van der Heijden GJ, et al. Propranolol for the treatment of anxiety disorders: systematic review and meta-analysis. J Psychopharmacol. 2016;30(2):128-139. 6. Zaccara G, Messori A, Cincotta M, et al. Comparison of the efficacy and tolerability of propranolol and other beta-blockers in the treatment of essential tremor: a meta-analysis. Clin Neuropharmacol. 2018;41(5):210-218. 7. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2D6 and Beta-Blocker Therapy. 2021 update.