5.5 Adrenergic Receptor Blockers
Adrenergic antagonists block α and β receptors, reducing sympathetic tone. β-blockers are among the most prescribed drugs for hypertension, heart failure, and arrhythmias. α-blockers treat hypertension and benign prostatic hyperplasia.
α-Adrenergic Blockers
Non-Selective α-Blockers
Phenoxybenzamine
Mechanism: Irreversible, covalent α1 and α2 blockade
Use: Pheochromocytoma (preoperative preparation - prevents hypertensive crisis during tumor manipulation)
Adverse: Orthostatic hypotension, reflex tachycardia (α2 blockade → ↑ NE release)
Phentolamine
Mechanism: Reversible, competitive α1 and α2 blockade
Uses: Pheochromocytoma (diagnosis, crisis management), extravasation of α-agonists (local injection reverses vasoconstriction)
Duration: Short-acting (minutes to hours)
Selective α1-Blockers
Mechanism: Competitive α1 antagonism → vasodilation (arteries + veins) → ↓ BP. Also relaxes prostate/bladder neck smooth muscle.
Advantage over non-selective: No α2 blockade → less reflex tachycardia
Prazosin
Uses: Hypertension (3rd-line), BPH, PTSD nightmares (off-label)
Dosing: TID (short t½). "First-dose phenomenon" - severe orthostatic hypotension after initial dose (give at bedtime)
Doxazosin, Terazosin
Uses: Hypertension, BPH
Advantage: Longer t½ → once-daily dosing. Still risk first-dose hypotension.
Tamsulosin, Alfuzosin, Silodosin
Uroselective: Preferential binding to α1A subtype (prostate > vasculature)
Use: BPH primarily (less hypotension than non-selective α1 blockers)
Adverse: Retrograde ejaculation (especially silodosin), intraoperative floppy iris syndrome (cataract surgery complication)
Clinical Applications of α1-Blockers
Hypertension
Not first-line (ALLHAT trial: doxazosin inferior to thiazides). Used when other agents inadequate or BPH coexists.
BPH
↓ Urethral resistance, ↓ bladder outlet obstruction. Symptomatic improvement (urinary flow, frequency). Often combined with 5α-reductase inhibitors.
β-Adrenergic Blockers: Classification
By Receptor Selectivity
Non-Selective (β1 + β2)
Propranolol, nadolol, timolol, pindolol, carvedilol, labetalol
β1-Selective (Cardioselective)
Metoprolol, atenolol, bisoprolol, esmolol, acebutolol, betaxolol, nebivolol
Note: β1-selectivity is dose-dependent (lost at high doses). Still safer in asthma/COPD but not absolutely safe.
By Intrinsic Sympathomimetic Activity (ISA)
With ISA (Partial Agonists)
Pindolol, acebutolol, penbutolol
Partial β-agonist activity → less bradycardia, less ↓ CO. Theoretically better for athletes, peripheral vascular disease. Less effective in post-MI.
Without ISA (Pure Antagonists)
Most β-blockers. Greater ↓ HR and BP. Preferred for angina, heart failure, post-MI.
By Additional Properties
Mixed α + β Blockers
Carvedilol: β1, β2, α1 blockade. Antioxidant properties. Heart failure (COPERNICUS trial), hypertension.
Labetalol: β + α blockade (ratio 3:1). Hypertensive emergencies (IV), pregnancy hypertension (safe).
Vasodilatory β-Blockers
Nebivolol: β1-selective + ↑ NO release → vasodilation. Less effect on lipids/glucose. Hypertension, heart failure.
β-Blockers: Individual Agents
Propranolol
Properties: Non-selective, lipophilic (crosses BBB), extensive first-pass metabolism
Uses: Hypertension, angina, MI, arrhythmias, essential tremor, migraine prophylaxis, thyrotoxicosis (↓ T4→T3 conversion), portal hypertension (variceal bleeding), performance anxiety
Metoprolol
Properties: β1-selective, lipophilic, extensive hepatic metabolism
Forms: Tartrate (BID-TID, immediate-release), succinate (once daily, extended-release - preferred for HF)
Uses: Hypertension, angina, heart failure, post-MI
Atenolol
Properties: β1-selective, hydrophilic (no CNS effects), renal elimination (dose adjust in renal failure)
Uses: Hypertension, angina. Note: Less evidence for heart failure than metoprolol/carvedilol/bisoprolol.
Bisoprolol
Properties: β1-selective, long half-life (once daily)
Uses: Heart failure (CIBIS-II trial), hypertension
Esmolol
Properties: β1-selective, ultra-short acting (t½ ~9 min, RBC esterases)
Uses: Acute situations requiring rapid titration - supraventricular tachycardia, hypertensive emergencies, perioperative BP/HR control. IV only.
Timolol, Betaxolol
Use: Glaucoma (topical, ↓ aqueous humor production). Timolol non-selective, betaxolol β1-selective.
Caution: Systemic absorption can cause bradycardia, bronchospasm (especially timolol)
β-Blockers: Clinical Uses
Hypertension
Mechanism: ↓ CO (β1), ↓ renin (β1 in kidney), central effects, ↓ peripheral resistance (long-term)
First-line in young patients, CAD, post-MI, HF. Less effective in elderly, African Americans.
Heart Failure
Evidence-based agents: Metoprolol succinate, carvedilol, bisoprolol
Benefit: ↓ Mortality, ↓ hospitalizations, ↑ EF (counterintuitive - reduce maladaptive sympathetic activation)
Initiation: Start low, titrate slowly (can worsen HF acutely)
Coronary Artery Disease
Angina: ↓ Myocardial O2 demand (↓ HR, ↓ contractility, ↓ BP)
Post-MI: ↓ Reinfarction, ↓ sudden death, ↓ mortality (secondary prevention)
Arrhythmias
Supraventricular: Atrial fibrillation/flutter (rate control), PSVT, sinus tachycardia
Ventricular: Catecholamine-induced VT, long QT syndrome, post-MI arrhythmia prevention
Other Cardiovascular
Aortic dissection (↓ dP/dt), hypertrophic cardiomyopathy (↓ outflow obstruction), mitral valve prolapse
Non-Cardiovascular
Migraine prophylaxis (propranolol, timolol), essential tremor, thyrotoxicosis, glaucoma, portal hypertension, anxiety/performance anxiety
Adverse Effects and Contraindications
Cardiovascular Adverse Effects
- • Bradycardia: Sinus bradycardia, AV block (especially with verapamil/diltiazem combination)
- • Hypotension: Orthostatic hypotension (especially α + β blockers)
- • Heart failure exacerbation: Can acutely worsen HF (start low, go slow)
- • Raynaud's phenomenon: β2 blockade → unopposed α vasoconstriction in periphery
Respiratory Adverse Effects
Bronchospasm: β2 blockade → bronchoconstriction
Risk: Non-selective > β1-selective. COPD/asthma are relative contraindications (use β1-selective if necessary).
Metabolic Adverse Effects
- • Glucose: Masks hypoglycemia symptoms (tachycardia, tremor), impairs glycogenolysis (caution in diabetics on insulin)
- • Lipids: ↑ Triglycerides, ↓ HDL (less with carvedilol, nebivolol)
- • Potassium: Blunts β2-mediated K⁺ uptake → hyperkalemia risk (especially with ACE-I/ARB)
CNS and Other Effects
CNS (lipophilic agents): Fatigue, depression, vivid dreams, cognitive impairment
Sexual dysfunction: Erectile dysfunction (β blockade)
Exercise intolerance: ↓ Max HR, ↓ skeletal muscle blood flow
Absolute Contraindications
- • Severe bradycardia, high-grade AV block (without pacemaker)
- • Decompensated heart failure (acute pulmonary edema)
- • Severe asthma/active bronchospasm
- • Cocaine use (unopposed α → severe hypertension, coronary vasospasm)
Withdrawal Syndrome
Risk: Abrupt discontinuation after chronic use → rebound ↑ sympathetic activity
Manifestations: Tachycardia, hypertension, angina, MI, arrhythmias
Prevention: Taper over 1-2 weeks (especially in CAD patients)