Beta blockers
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Beta Blockers - Complete Overview
Mechanism of Action
Beta blockers competitively antagonize catecholamines (epinephrine, norepinephrine) at beta-adrenergic receptors. By blocking beta-1 receptors in the heart they reduce:
- Heart rate (negative chronotropy)
- Myocardial contractility (negative inotropy)
- AV conduction velocity (negative dromotropy)
The decrease in heart rate prolongs diastole, increasing coronary blood flow to the left ventricle, enhancing collateral perfusion to ischemic myocardium, and improving oxygen delivery to the coronary microcirculation - net effect is reduced myocardial O2 demand and increased supply. Beta blockers also inhibit platelet aggregation, relevant during acute ischemia.
- Barash's Clinical Anesthesia, 9e, p. 977
Classification (Generations)
| Generation | Drugs | Key Feature |
|---|---|---|
| 1st gen (non-selective) | Propranolol, Nadolol, Timolol, Sotalol, Pindolol | Block both β1 and β2 |
| 2nd gen (cardioselective β1) | Metoprolol, Atenolol, Bisoprolol, Esmolol, Betaxolol, Acebutolol | Preferential β1 blockade (selectivity is relative - lost at high doses) |
| 3rd gen (mixed α+β blockade) | Carvedilol, Labetalol, Nebivolol | Additional vasodilatory properties |
Intrinsic Sympathomimetic Activity (ISA): Some agents (pindolol, acebutolol) partially stimulate beta receptors while blocking them. These cause less resting bradycardia and are less likely to cause cold extremities.
Lipid solubility: Lipophilic drugs (propranolol) cross the BBB and enter the CNS; hydrophilic drugs (atenolol) have less CNS penetration and longer half-lives (renally cleared).
- Barash's Clinical Anesthesia, 9e, p. 977
- Katzung's Basic and Clinical Pharmacology, 16e
Clinical Indications
| Condition | Notes |
|---|---|
| Hypertension | First-line; especially with comorbid angina, post-MI, or HF |
| Angina pectoris | Reduce O2 demand; decrease frequency of attacks |
| Heart failure (HFrEF) | Bisoprolol, carvedilol, and metoprolol succinate are the 3 proven agents. Must initiate low and titrate slowly |
| Post-MI | Proven mortality reduction; reduce infarct size and prevent reinfarction |
| Arrhythmias | Rate control in AF/flutter; SVT; antiarrhythmic via negative chronotropy |
| Hypertrophic cardiomyopathy | Reduce LVOT obstruction |
| Acute aortic dissection | Reduce dP/dt |
| Thyrotoxicosis | Control tachycardia and sympathetic symptoms |
| Pheochromocytoma | Only after alpha blockade is established first |
| Migraine prophylaxis | Propranolol, timolol |
| Glaucoma | Topical timolol, betaxolol, levobunolol (reduce aqueous humor production) |
| Essential tremor | Propranolol |
| Anxiety / performance anxiety | Propranolol (blocks peripheral sympathetic effects) |
- Barash's Clinical Anesthesia, 9e, p. 977-978
Heart Failure - Special Considerations
In HFrEF (EF < 40%), the effects of beta-blocker therapy are biphasic:
- Short term: Transient deterioration in cardiac function (withdrawal of adrenergic drive - negative inotropy). May worsen fluid retention within 3-5 days.
- Long term: Reverse LV remodeling, improved LVEF, reduced symptoms, reduced hospitalizations, prolonged survival.
The 3 mortality-proven agents in HF:
- Carvedilol (blocks α1, β1, β2)
- Bisoprolol (selective β1)
- Metoprolol succinate SR (selective β1)
Titrate slowly (no sooner than 2-week intervals). Optimize diuretic therapy before initiation.
- Braunwald's Heart Disease, p. 154
Contraindications
- Absolute: Severe bradycardia, high-degree AV block (without pacemaker), cardiogenic shock, decompensated HF
- Relative: Asthma / reactive airway disease (β2 blockade causes bronchoconstriction - use cardioselective agents with caution if needed), significant peripheral artery disease, Raynaud's phenomenon, cocaine toxicity (use may cause unopposed alpha vasoconstriction)
- Pheochromocytoma: Never give beta blockers before alpha blockade - risk of hypertensive crisis from unopposed α-receptor stimulation
Adverse Effects
| Effect | Mechanism |
|---|---|
| Bradycardia, heart block | β1 blockade |
| Hypotension | ↓ CO, vasodilation (3rd gen) |
| Bronchoconstriction | β2 blockade |
| Cold extremities, Raynaud's | Peripheral β2 blockade (↓ vasodilation) |
| Fatigue, exercise intolerance | ↓ CO response to exertion |
| Hyperglycemia / hypoglycemia masking | Inhibit glycogenolysis (β2); mask tachycardia of hypoglycemia |
| CNS effects | Fatigue, depression, nightmares (lipophilic agents) |
| Sexual dysfunction |
Abrupt withdrawal can precipitate rebound hypertension, angina, or MI due to beta-receptor upregulation. Taper gradually.
Key Individual Drugs
| Drug | Selectivity | Special Features |
|---|---|---|
| Propranolol | Non-selective | Prototype; lipophilic; CNS effects; most toxic in overdose |
| Metoprolol | β1-selective | Available tartrate (IR) and succinate (SR); widely used in HF and MI |
| Atenolol | β1-selective | Hydrophilic; once daily; renally cleared |
| Bisoprolol | β1-selective | High β1 selectivity; HF mortality benefit |
| Carvedilol | Non-selective + α1 | Vasodilatory; antioxidant properties; HF use |
| Labetalol | Non-selective + α1 | IV use in hypertensive emergency, aortic dissection, eclampsia |
| Esmolol | β1-selective | Ultra-short acting (t½ ~9 min); IV only; intraoperative rate control |
| Nebivolol | β1-selective + NO release | Vasodilation via nitric oxide; well tolerated |
| Sotalol | Non-selective | Also class III antiarrhythmic (K+ channel block); QT prolongation risk |
| Pindolol | Non-selective + ISA | Less bradycardia at rest |
| Timolol | Non-selective | Ophthalmic (glaucoma); oral for post-MI |
Overdose / Toxicity
The most dangerous in overdose is propranolol - toxic at 2-3x therapeutic dose due to:
- Sodium channel blockade (like TCAs) - wide QRS, seizures
- Lipophilicity - CNS penetration
Manifestations: Bradycardia, hypotension, cardiac conduction block. Agents with ISA (pindolol) can paradoxically cause tachycardia/hypertension in overdose.
Treatment:
-
Standard β-agonists and atropine are often ineffective
-
Glucagon (5-10 mg IV) is the key antidote - raises intracellular cAMP independent of β-receptors
-
High-dose insulin, calcium, lipid emulsion therapy for refractory cases
-
Katzung's Basic and Clinical Pharmacology, 16e, p. 1624
Summary Mnemonics
ABCDE of beta-blocker indications: Angina, Blood pressure, Congestive HF, Dysrhythmia, post-MI (Emergency/prevention)
Cardioselective beta-1 blockers (A-M rule): Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol, Nebivolol
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