Propranolol

Mechanism

Mechanism of Action

Pure and non-selective competitive antagonist of β₁ and β₂ adrenergic receptors, without significant intrinsic sympathomimetic activity (ISA). It exhibits notable membrane stabilizing activity (blocking of voltage-gated sodium channels) at high serum concentrations. By blocking cardiac β₁ receptors, it decreases adenylate cyclase activity and cAMP levels, markedly reducing heart rate, myocardial contractility, atrioventricular conduction velocity, and tissue oxygen consumption. Blockade of peripheral β₂ receptors increases airway resistance in predisposed patients and inhibits adrenaline-mediated vasodilation.

Pharmacokinetics

Key Pharmacokinetics

• Routes: Oral (tablets, extended-release capsules, oral solution), intravenous (restricted to arrhythmogenic emergencies).
• Absorption and bioavailability: Complete oral absorption (>90%), but undergoes intense hepatic first-pass metabolism, which reduces its actual bioavailability to approximately 25%.
• Lipophilia: Very high; It crosses the blood-brain barrier extremely easily, which explains both its neurological efficacy and its profile of central adverse effects.
• Metabolism: Hepatic oxidative almost exclusively mediated by the CYP2D6 and CYP1A2 isoenzymes. Its main metabolite, 4-hydroxypropranolol, retains transient pharmacological activity.
• Half-life: 3-6 hours for standard shapes.
• Excretion: Renal, with less than 1% of the active ingredient eliminated unchanged in urine.

Indicators and dose

Approved and Off-label Indications

Approved: Essential arterial hypertension; chronic stable angina pectoris; secondary prophylaxis after acute myocardial infarction; control of atrial and supraventricular tachyarrhythmias; essential tremor; pheochromocytoma (only associated with an alpha-blocker); migraine prophylaxis; treatment of infantile hemangioma in the proliferative phase.

Off-label: Performance anxiety (stage fright); unbalanced thyroid storm (also inhibits the peripheral conversion of thyroxine T₄ to triiodothyronine T₃ by deiodination); esophageal varices to prevent recurrent bleeding (reduces portal pressure through splanchnic vasoconstriction).

Dosage and Adjustments

Hypertension (Oral): 40 to 80 mg twice a day orally, usually dosing between 120 to 240 mg/day according to the clinical response obtained.

Esophageal Varixes (Prophylaxis): Start with 20-40 mg twice a day, adjusting individually until the resting heart rate is reduced by 25% or up to a limit of 55 bpm.

Renal adjustment: It does not require a systematic initial reduction regimen, but monitoring of clearance is recommended.

Hepatic adjustment: Dominant hepatic-dependent metabolism. It is advisable to start with minimum effective doses and make progressive and spaced increases.

Security

Contraindications

Absolute: Active bronchial asthma or history of severe bronchospasm, severe COPD, severe sinus bradycardia (< 50 bpm), second or third degree atrioventricular block without pacemaker, cardiogenic shock, acute decompensated heart failure.

Relative: Diabetes mellitus (masks adrenergic warning symptoms of hypoglycemia such as tachycardia and tremors), advanced Raynaud's phenomenon or severe peripheral arterial disease.

Adverse Effects (ADR)

Common: Generalized fatigue, sinus bradycardia, coldness and peripheral hypoperfusion of extremities, sleep disorders (vivid nightmares and insomnia due to its high penetration into the CNS), erectile dysfunction.

Serious: Severe acute bronchospasm, complete heart block, recent-onset major depression, acute decompensated heart failure, masking and prolongation of episodes of severe insulin-dependent hypoglycemia.

Interactions

Non-dihydropyridine calcium antagonists (verapamil, diltiazem): Severe cardiodepressant synergistic effect; risk of extreme bradycardia, asystole and complete atrioventricular block.

CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine): Marked increase in plasma levels of propranolol and increased risk of systemic toxicity.

NSAIDs (eg, indomethacin, ibuprofen): Reduction of the antihypertensive effect by inhibition of the synthesis of vasodilatory prostaglandins.

Pregnancy and Breastfeeding

FDA Classification: Category C. Crosses the placenta and can induce fetal bradycardia, intrauterine growth retardation (IUGR) and risk of hypoglycemia or respiratory depression in the immediate neonatal period. It is secreted in breast milk in small quantities; Close pediatric monitoring is required.