Inderal - Drug Monograph

Introduction

Inderal (propranolol hydrochloride) is a non-selective beta-adrenergic receptor blocking agent that has been widely used in clinical practice since the 1960s. As a first-generation beta-blocker, it remains a cornerstone therapy for various cardiovascular, neurological, and endocrine conditions. This comprehensive monograph provides evidence-based information for healthcare professionals regarding its pharmacology, clinical applications, and safety profile.

Mechanism of Action

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

• Negative chronotropic effect (decreased heart rate)
• Negative inotropic effect (decreased myocardial contractility)
• Reduced conduction velocity through the AV node
• Decreased renin secretion from renal juxtaglomerular cells
• Inhibition of peripheral vasodilation mediated by beta-2 receptors
• Central nervous system effects including reduced sympathetic outflow

The drug's mechanism in migraine prophylaxis involves inhibition of cerebral arterial vasodilation and modulation of serotonergic pathways. For essential tremor, it acts primarily through peripheral beta-2 receptor blockade in skeletal muscle.

Indications

• Hypertension (monotherapy or combination therapy)
• Angina pectoris due to coronary atherosclerosis
• Cardiac arrhythmias (supraventricular tachycardia, ventricular tachycardia, digitalis-induced arrhythmias)
• Hypertrophic subaortic stenosis
• Pheochromocytoma (preoperatively and in conjunction with alpha-blockade)
• Migraine prophylaxis
• Essential tremor

• Performance anxiety and situational anxiety
• Portal hypertension in cirrhosis
• Thyroid storm adjunctive therapy
• Post-myocardial infarction prophylaxis
• Akathisia induced by antipsychotic medications

Dosage and Administration

• Initial: 40 mg twice daily
• Maintenance: 120-240 mg daily in divided doses (maximum: 640 mg/day)

• Initial: 80-320 mg daily in divided doses (2-4 times daily)

• 10-30 mg 3-4 times daily before meals and at bedtime

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

• Initial: 40 mg twice daily
• Maintenance: 120-320 mg daily in divided doses

• Hepatic impairment: Reduce dose by 50-75%
• Renal impairment: No significant adjustment needed
• Geriatric patients: Initiate with lower doses
• Pediatric patients: 2-4 mg/kg/day in divided doses (not FDA-approved for hypertension under age 18)

• Should be taken with food to enhance bioavailability
• Immediate-release formulation should be administered in divided doses
• Extended-release formulation (Inderal LA) allows once-daily dosing
• Abrupt discontinuation should be avoided (taper over 1-2 weeks)

Pharmacokinetics

• Rapid and nearly complete gastrointestinal absorption
• Extensive first-pass metabolism (bioavailability: ~25%)
• Peak plasma concentration: 1-4 hours (immediate-release)
• Food increases bioavailability by 50-100%

• Volume of distribution: 3-6 L/kg
• Protein binding: 90-96%
• Crosses blood-brain barrier and placenta
• Appears in breast milk (milk:plasma ratio ~0.5)

• Extensive hepatic metabolism via CYP2D6, CYP1A2, and CYP2C19
• Four major active metabolites: 4-hydroxypropranolol, naphthoxylactic acid, and others
• Exhibits genetic polymorphism in CYP2D6 poor metabolizers

• Half-life: 3-6 hours (immediate-release), 8-11 hours (extended-release)
• Primarily renal excretion of metabolites (<1% unchanged drug)
• Hemodialysis does not significantly remove propranolol

Contraindications

• Cardiogenic shock
• Sinus bradycardia and heart block greater than first degree
• Bronchial asthma and severe COPD
• Decompensated heart failure (unless secondary to tachyarrhythmia)
• Hypersensitivity to propranolol or related compounds
• Pheochromocytoma (without concomitant alpha-blockade)
• Severe peripheral arterial disease
• Metabolic acidosis

Warnings and Precautions

• May precipitate heart failure in susceptible patients
• Can mask signs of hypoglycemia in diabetics
• Abrupt withdrawal may cause exacerbation of angina, MI, or ventricular arrhythmias
• May reduce effectiveness of glucagon in treating hypoglycemia

• Can cause life-threatening bronchospasm in patients with reactive airway disease
• Requires caution in patients with chronic bronchitis and emphysema

• May cause depression, hallucinations, or vivid dreams
• Can exacerbate myasthenia gravis

• Continued use during major surgery is controversial due to impaired cardiac responsiveness
• Recommended to continue in most cardiac patients undergoing surgery

• Pregnancy Category C: Use only if potential benefit justifies potential risk
• Lactation: Consider alternative feeding options due to secretion in breast milk

Drug Interactions

• Verapamil, diltiazem: Additive bradycardia and AV block
• Clonidine: Exaggerated rebound hypertension upon withdrawal
• Insulin, oral hypoglycemics: Masked hypoglycemic symptoms, impaired recovery
• Theophylline: Antagonistic effects on bronchodilation

• CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): Increased propranolol levels
• CYP1A2 inducers (smoking, rifampin): Decreased propranolol levels
• Cimetidine: Increased propranolol bioavailability and half-life
• Lidocaine: Reduced clearance leading to potential toxicity

• Warfarin: Possible increased anticoagulant effect
• NSAIDs: May antagonize antihypertensive effect
• Epinephrine: Unopposed alpha-adrenergic effects causing hypertension

Adverse Effects

• Fatigue, dizziness
• Nausea, diarrhea
• Cold extremities
• Bradycardia
• Sleep disturbances

• Depression, vivid dreams
• Impotence
• Hypotension
• Bronchospasm
• Heart failure exacerbation

• Lupus-like syndrome
• Agranulocytosis
• Thrombocytopenic purpura
• Visual disturbances
• Hallucinations

Monitoring Parameters

• Complete blood count, liver function tests
• Renal function assessment
• Electrocardiogram (heart rate, PR interval)
• Blood pressure (supine and standing)
• Pulmonary function tests if history of lung disease

• Heart rate and blood pressure at each visit
• Signs of heart failure (weight gain, edema, dyspnea)
• Mental status changes, especially in elderly
• Glucose monitoring in diabetics
• Exercise tolerance in angina patients

• Not routinely required
• Consider in suspected toxicity or lack of efficacy
• Therapeutic range: 50-100 ng/mL

Patient Education

• Take with meals to improve absorption
• Do not crush or chew extended-release capsules
• Take at the same time(s) each day
• Do not stop abruptly without medical supervision

• Rise slowly from sitting/lying position to prevent dizziness
• Avoid alcohol due to additive hypotensive effects
• Monitor for signs of low blood sugar if diabetic
• Report breathing difficulties immediately

• Heart rate below 50 beats per minute
• Significant weight gain or swelling
• Shortness of breath, especially when lying down
• Depression or mood changes
• Cold hands and feet that don't improve with warming

• Inform all healthcare providers of propranolol use before procedures
• Use effective contraception while taking propranolol
• Discuss breastfeeding alternatives with healthcare provider

References

1. Frishman WH. β-Adrenergic receptor blockers. Circulation. 2003;107(18):e117-e119. 2. Cruickshank JM. The modern role of beta-blockers in cardiovascular medicine. In: Godfraind T, ed. Advances in Pharmacology. Academic Press; 2019:133-160. 3. Propranolol hydrochloride [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2021. 4. Winter WE, Hardt NS, Engler RM. Beta-blockers: a review of their pharmacological and physiological diversity. Ann Pharmacother. 2014;48(6):723-733. 5. National Institute for Health and Care Excellence. Hypertension in adults: diagnosis and management. NICE guideline [NG136]. 2019. 6. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults. Neurology. 2012;78(17):1337-1345. 7. Zesiewicz TA, Elble R, Louis ED, et al. Practice parameter: therapies for essential tremor. Neurology. 2005;64(12):2008-2020. 8. American Diabetes Association. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2021;44(Suppl 1):S111-S124.