nonselective beta blocker

**Mechanism:** Competitive antagonism at β1 (Gs-coupled → ↓cAMP → ↓PKA → ↓Ca2+ influx) and β2 receptors. β1 blockade in heart: ↓HR (negative chronotropy), ↓contractility (negative inotropy), ↓AV node conduction (prolongs PR), ↓myocardial O2 demand. β1 in kidney (JG cells): ↓renin release → ↓angiotensin II/aldosterone. β2 blockade: bronchoconstriction, ↓glycogenolysis/gluconeogenesis, ↓aqueous humor production (timolol, ciliary body), unopposed α-mediated vasoconstriction, ↓tremor.

**Nonselective agents (mnemonic: "Non-selective = A to M" is for selective; nonselective = N to Z):** - Propranolol, nadolol, timolol, pindolol (partial agonist/ISA), penbutolol, carteolol, sotalol (class III antiarrhythmic also). - Carvedilol and labetalol: nonselective β + α1 blockade (vasodilation; labetalol is used in hypertensive emergency, pregnancy/preeclampsia, and pheochromocytoma or cocaine toxicity cautiously with other considerations). - Selective β1 blockers (A-M: atenolol, metoprolol, esmolol, bisoprolol, acebutolol, betaxolol, nebivolol [also NO-mediated vasodilation]) are preferred in patients with lung disease.

**Clinical uses:** - HTN, angina, post-MI (↓mortality), chronic HFrEF (carvedilol, metoprolol succinate, bisoprolol – not propranolol) - SVT/rate control in AF; thyroid storm (propranolol also blocks peripheral T4→T3 conversion) - Portal hypertension/variceal bleeding prophylaxis (propranolol, nadolol, carvedilol): β1 ↓CO and β2 blockade → unopposed α1 splanchnic vasoconstriction → ↓portal inflow - Essential tremor, performance anxiety, migraine prophylaxis - Glaucoma (timolol topical) - Infantile hemangioma (propranolol) - Pheochromocytoma only AFTER α blockade

**Adverse effects:** Bronchospasm (contraindicated in asthma/COPD), bradycardia, AV block, acute decompensated HF if started during decompensation, fatigue, depression, sexual dysfunction, sleep disturbances/vivid dreams (lipophilic agents like propranolol cross BBB), cold extremities/Raynaud exacerbation, ↑LDL/TG and ↓HDL (less with vasodilating agents), masking of hypoglycemia symptoms (tachycardia, tremor) in diabetics (sweating preserved), and delayed recovery from hypoglycemia (↓glycogenolysis). Abrupt withdrawal → rebound tachycardia/HTN/angina (receptor upregulation).

**Contraindications/cautions:** Asthma/COPD, severe bradycardia, 2nd/3rd-degree AV block, decompensated HF, cocaine-induced chest pain (unopposed α; use benzodiazepines, and labetalol/carvedilol are sometimes considered), unopposed α-stimulation in pheochromocytoma, vasospastic (Prinzmetal) angina, and acute cocaine/amphetamine intoxication.

**Overdose:** Bradycardia, hypotension, hypoglycemia, seizures. Treat with atropine, then **glucagon** (↑cAMP independent of β receptor), IV fluids, high-dose insulin euglycemia therapy, calcium, pacing as needed.

**Pearls:** Pindolol and acebutolol have intrinsic sympathomimetic activity (partial agonists), so cause less bradycardia and are useful in patients with resting bradycardia. Sotalol can cause QT prolongation/torsades. Nadolol is renally cleared, whereas propranolol undergoes extensive hepatic first-pass metabolism. Beta blockers that reduce mortality in HFrEF: carvedilol, metoprolol succinate, bisoprolol.