beta-1 antagonist

MECHANISM: β1 receptors are Gs-coupled, so they increase adenylyl cyclase, cAMP, and PKA activity. In the heart, PKA phosphorylates L-type Ca2+ channels, which raises intracellular Ca2+. The result is positive chronotropy, inotropy, and dromotropy. In juxtaglomerular cells, β1 stimulation increases renin release. β1-blockers antagonize these effects, so they reduce HR (SA node, phase 4 slope), contractility, AV nodal conduction (prolonged PR interval), myocardial O2 demand, and renin/angiotensin II/aldosterone.

DRUGS (selective β1: A–M mnemonic "A through M = β1"): Acebutolol (partial agonist/ISA), Atenolol, Betaxolol, Bisoprolol, Esmolol (ultra-short acting, IV), Metoprolol, Nebivolol (also stimulates NO release, causing vasodilation). Nonselective agents (N–Z: propranolol, nadolol, timolol, pindolol) block β1 and β2. Carvedilol and labetalol block β plus α1. Selectivity is dose-dependent and is lost at high doses.

INDICATIONS: - Hypertension - Chronic stable angina (reduced O2 demand and longer diastolic filling) - Post-MI (decreases mortality and remodeling) - HFrEF (only metoprolol succinate, bisoprolol, and carvedilol reduce mortality; start low and avoid in acute decompensation) - Supraventricular tachyarrhythmias (class II antiarrhythmics: slow AV node, rate control in AFib/flutter, SVT) - Perioperative cardiac risk reduction in selected patients - Esmolol: acute aortic dissection (with the goal of reducing dP/dt, then add a vasodilator), thyroid storm, and intraoperative tachycardia - Propranolol (nonselective): migraine prophylaxis, essential tremor, performance anxiety, and thyrotoxicosis symptoms

ADVERSE EFFECTS: - Bradycardia, AV block, and hypotension - Acute exacerbation of decompensated HF - Fatigue, exercise intolerance, and depression/sleep disturbance (more with lipophilic agents) - Erectile dysfunction - Masking of hypoglycemia symptoms (tachycardia, tremor) in diabetics, though sweating is preserved - Bronchospasm (less with β1-selective agents, but still use caution in asthma/COPD) - Mild adverse lipid effects (↑ TG, ↓ HDL with older agents) - Abrupt withdrawal causes rebound tachycardia, hypertension, and angina (upregulated receptors), so taper gradually

CONTRAINDICATIONS/CAUTIONS: - Severe bradycardia, 2nd/3rd-degree AV block, and sick sinus syndrome - Decompensated HF or cardiogenic shock - Severe reactive airway disease (nonselective agents especially) - Cocaine-associated chest pain and pheochromocytoma (unopposed α stimulation → hypertensive crisis; give α-blocker first) - Prinzmetal (vasospastic) angina (unopposed α, nonselective agents) - Concurrent non-dihydropyridine CCBs (verapamil/diltiazem) → additive AV block/bradycardia

OVERDOSE: Bradycardia, hypotension, hypoglycemia, and bronchospasm. Treat with atropine, then IV glucagon (raises cAMP via a non-β-receptor pathway), plus calcium, high-dose insulin/glucose, and pacing or pressors as needed.

HIGH-YIELD PEARLS: - Intrinsic sympathomimetic activity (ISA): acebutolol and pindolol cause less resting bradycardia and are preferred in patients prone to bradycardia. - β-blockers lower the heart rate and thereby lengthen diastole, which improves coronary perfusion. - They do NOT improve survival in uncomplicated hypertension as first-line therapy in many guidelines. - In HFrEF they reverse maladaptive neurohormonal activation. - Do not give a β-blocker alone in cocaine toxicity or in hyperthyroid crisis without considering the underlying cause.