beta-2 antagonist

**Receptor physiology (β2, Gs-coupled → ↑cAMP → PKA):** - Bronchial smooth muscle: relaxation (bronchodilation) - Vascular smooth muscle (skeletal muscle arterioles): vasodilation - Uterus: relaxation (tocolysis) - Liver/skeletal muscle: ↑glycogenolysis, ↑gluconeogenesis - Pancreatic β cells: ↑insulin release - Adipose: ↑lipolysis - Kidney (JG cells): β1 mainly → ↑renin (β1, not β2) - Ciliary body: ↑aqueous humor production (β blockers, esp. timolol, reduce it) - Mast cells: ↓mediator release - Potassium: ↑cellular K+ uptake via Na+/K+-ATPase

**Effects of blocking β2:** - Bronchoconstriction → can precipitate severe asthma/COPD exacerbation (the main board point). - Unopposed α1-mediated vasoconstriction → cold extremities, worsening of Raynaud phenomenon and peripheral artery disease/claudication. - Masked/prolonged hypoglycemia: blocked glycogenolysis/gluconeogenesis and blunted adrenergic warning symptoms (tremor, palpitations; sweating is cholinergic and preserved) in insulin-treated diabetics. - Mild hyperkalemia (impaired cellular K+ uptake). - Unfavorable lipid effects (↑TG, ↓HDL) with nonselective agents. - Uterine tone changes (minor). - Unopposed α stimulation in pheochromocytoma or cocaine toxicity → hypertensive crisis (beta blocker given before alpha blockade). Cocaine: avoid pure β-blockers in acute intoxication; labetalol/carvedilol or benzodiazepines/phentolamine are alternatives.

**Drugs:** - Nonselective β1/β2 blockers: propranolol, nadolol, timolol, pindolol (partial agonist/ISA), sotalol (also class III antiarrhythmic), labetalol and carvedilol (also α1 blockade → vasodilation, so less peripheral vasoconstriction). - Selective β1 blockers (cardioselective): acebutolol (ISA), betaxolol, bisoprolol, esmolol, atenolol, nebivolol (also ↑NO), metoprolol. Selectivity is dose-dependent and lost at high doses. - Highly selective β2 antagonist: ICI-118,551 (research tool only; no clinical use).

**Contrast with β2 agonists:** albuterol, terbutaline, levalbuterol (SABAs), salmeterol, formoterol (LABAs) cause bronchodilation, tocolysis, and shift K+ into cells (treat hyperkalemia); side effects: tremor, tachycardia, hypokalemia.

**Clinical pearls:** - Asthma/COPD: avoid nonselective β blockers; if a β blocker is required (e.g., post-MI in COPD), use a cardioselective agent. - Overdose: bradycardia, hypotension, hypoglycemia, bronchospasm. Treat with atropine, IV glucagon (↑cAMP bypassing β receptor via Gs-coupled glucagon receptor), high-dose insulin/euglycemic therapy, calcium, and pressors. - Timolol eye drops can cause systemic β2 effects (bronchospasm) via nasolacrimal absorption. - Other contraindications to β blockers generally: acute decompensated HF, severe bradycardia, high-grade AV block, vasospastic (Prinzmetal) angina (nonselective). - Do not abruptly withdraw β blockers: rebound tachycardia, hypertension, angina (receptor upregulation). - Indications overall: HTN, angina, post-MI, HFrEF (metoprolol succinate, carvedilol, bisoprolol), arrhythmias (SVT, AF rate control), essential tremor and performance anxiety (propranolol), migraine prophylaxis, thyrotoxicosis (propranolol also inhibits peripheral T4→T3 conversion), esophageal varices prophylaxis (nadolol, propranolol), glaucoma (timolol, betaxolol).