cardioselective beta blocker

**Receptor physiology** - β1 (Gs-coupled → ↑cAMP → ↑PKA): heart (SA node, AV node, myocardium → ↑HR, ↑conduction velocity, ↑contractility) and juxtaglomerular cells (↑renin release). - β2 (Gs): bronchial smooth muscle (bronchodilation), vascular smooth muscle (vasodilation), uterus (relaxation), liver/skeletal muscle (glycogenolysis), pancreas (insulin release), and lipolysis; also mediates K+ uptake into cells. - Cardioselective agents block β1 at usual therapeutic doses; selectivity is lost at high doses.

**Key agents ("A BEAM" mnemonic)** - Acebutolol (also has partial agonist activity/ISA), Betaxolol, Bisoprolol, Esmolol, Atenolol, Metoprolol. (Add nebivolol: β1-selective plus NO-mediated vasodilation.) - Esmolol: ultra-short half-life (~10 min) IV, used for perioperative/acute rate control, aortic dissection, and SVT. - Metoprolol, bisoprolol (and carvedilol, nonselective with α1 block) have mortality benefit in HFrEF; metoprolol succinate is the formulation used in HF. - Atenolol: renally cleared (adjust dose in CKD). - Betaxolol: also used topically for glaucoma (reduces aqueous humor production).

**Mechanism and effects** - ↓HR (negative chronotropy), ↓contractility (negative inotropy), ↓AV conduction (prolonged PR interval), ↓renin → ↓angiotensin II/aldosterone → ↓BP. - ↓Myocardial O2 demand → anti-anginal; ↓ventricular remodeling and sudden death post-MI and in HFrEF. - Class II antiarrhythmics: slow phase 4 depolarization in SA node and slow AV nodal conduction (used for rate control in AF/flutter, AVNRT).

**Clinical uses** - Hypertension (no longer first-line in uncomplicated HTN, but used with compelling indications), chronic stable angina, post-MI secondary prevention, HFrEF (evidence-based agents only: metoprolol succinate, bisoprolol, carvedilol), supraventricular tachyarrhythmias/rate control, perioperative cardiac risk reduction, aortic dissection (with esmolol), and hyperthyroidism symptom control (propranolol often preferred, as it also blocks T4→T3 conversion).

**Why use cardioselective over nonselective agents** - Asthma/COPD: nonselective blockers (propranolol, nadolol, timolol) can cause bronchospasm by blocking β2. Cardioselective agents are safer (use cautiously; still relatively contraindicated in severe/active asthma). - Diabetes (insulin-treated): nonselective β blockade masks adrenergic hypoglycemia symptoms (tachycardia, tremor; sweating is cholinergic and preserved) and impairs glycogenolysis/gluconeogenesis recovery. β1-selective agents are less problematic. - Peripheral artery disease/Raynaud: nonselective blockade leaves α-mediated vasoconstriction unopposed; cardioselective agents are better tolerated.

**Adverse effects and contraindications (class effects)** - Bradycardia, AV block (contraindicated in 2nd/3rd-degree AV block, sick sinus syndrome without pacemaker), hypotension, fatigue, exercise intolerance, sexual dysfunction, depression/sleep disturbances/vivid dreams (more with lipophilic agents like metoprolol and propranolol that cross the BBB). - Acute decompensated HF or cardiogenic shock: avoid initiating. - Abrupt withdrawal → rebound tachycardia, hypertension, angina, MI (due to receptor upregulation); taper gradually. - Cocaine/stimulant-associated chest pain: traditionally avoid β blockers (concern for unopposed α stimulation), though evidence is debated. In pheochromocytoma, start α blocker first (phenoxybenzamine) before β blocker to avoid unopposed α-mediated hypertensive crisis. - Overdose: bradycardia, hypotension, hypoglycemia → treat with IV fluids, atropine, glucagon (bypasses the β receptor via direct adenylyl cyclase activation), high-dose insulin/glucose, and pacing as needed. - Do not combine with non-dihydropyridine CCBs (verapamil, diltiazem) due to risk of severe bradycardia/AV block/HF.

**Exam pearls** - Selectivity is dose-dependent. At high doses, β2 blockade occurs. - Partial agonists (acebutolol, pindolol) have intrinsic sympathomimetic activity (ISA), causing less bradycardia; they are less ideal post-MI. - Nonselective blockers: propranolol, nadolol, timolol, pindolol, (labetalol and carvedilol also block α1). Mnemonic: agents A–M are β1-selective; N–Z are nonselective (exceptions: nebivolol, which is selective, and carvedilol/labetalol, which are mixed). - β blockers in glaucoma (timolol, betaxolol) ↓aqueous humor secretion by the ciliary epithelium. - Esmolol is rapidly metabolized by RBC esterases. - Metoprolol is CYP2D6 metabolized (interacts with CYP2D6 inhibitors such as fluoxetine, paroxetine, and quinidine).