Mechanism of Action of Beta Blockers
Beta blockers work by competitively blocking catecholamines (epinephrine and norepinephrine) from binding to beta-adrenergic receptors on cell membranes, thereby preventing the sympathetic nervous system from stimulating the heart and blood vessels. 1
Primary Receptor Blockade Effects
Beta-1 Adrenergic Receptor Blockade (Cardiac Effects):
- Beta-1 receptors are located primarily in the myocardium 1
- Blocking these receptors reduces myocardial contractility (negative inotropic effect) 1, 2
- Decreases sinus node rate, slowing heart rate (negative chronotropic effect) 1, 2
- Reduces AV node conduction velocity 1
- Lowers systolic blood pressure 1
- All these effects collectively reduce myocardial oxygen demand (MVO2) 1
Beta-2 Adrenergic Receptor Blockade (Peripheral Effects):
- Beta-2 receptors are located primarily in vascular and bronchial smooth muscle 1
- Blocking these receptors produces vasoconstriction and bronchoconstriction 1
- This explains why non-selective beta blockers can worsen asthma and peripheral vascular disease 1
Cardiovascular Benefits Through Sympathetic Antagonism
In Heart Failure:
- Chronic sympathetic activation in heart failure leads to sustained norepinephrine release, which raises cardiac output and heart rate, increasing myocardial oxygen demand, ischemia, and oxidative stress 1
- Peripheral vasoconstriction from sympathetic activation increases both preload and afterload, causing additional stress on the failing ventricle 1
- Norepinephrine promotes cardiac fibrosis and necrosis, contributing to cardiac remodeling and a dilated, less contractile cardiac chamber 1
- Norepinephrine down-regulates β1-adrenergic receptors and uncouples β2-adrenergic receptors, leaving the myocyte less responsive to adrenergic stimuli 1
- Long-term beta blocker administration reverses these deleterious changes, increasing ejection fraction and cardiac index while decreasing left ventricular end diastolic pressure 1
- Beta blockers reverse LV remodeling, decrease myocardial mass and LV volume, leading to improved hemodynamics 1
In Angina and Ischemic Heart Disease:
- Slowing heart rate increases the duration of diastole and diastolic pressure-time, which are determinants of forward coronary flow and collateral flow 1
- Beta blockers reduce oxygen requirements by blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure 2, 3
- This makes the heart more efficient at any given level of effort, delaying onset of anginal pain and increasing work capacity 3
Antihypertensive Mechanisms
The exact mechanism of blood pressure reduction is not fully elucidated, but involves multiple pathways 2, 3:
- Competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output 2, 3
- A central effect leading to reduced sympathetic outflow to the periphery 2, 3
- Suppression of renin activity 2, 3
Antiarrhythmic Effects
- Beta blockers regulate heart rate and decrease cardiac arrhythmias 1
- They exert antiarrhythmic effects through concentrations associated with beta-adrenergic blockade 3
- At higher doses, some beta blockers (like propranolol) also exert a quinidine-like or anesthetic-like membrane action affecting the cardiac action potential, though the significance of this for arrhythmia treatment is uncertain 3
Important Pharmacologic Distinctions
Receptor Selectivity:
- Beta-1 selective agents (metoprolol, atenolol, bisoprolol) preferentially block cardiac beta-1 receptors at lower doses but lose selectivity at higher concentrations 1, 2
- Non-selective agents (propranolol, nadolol) block both beta-1 and beta-2 receptors equally 1, 3
- Third-generation agents (carvedilol, labetalol) also block alpha-1 receptors, providing additional vasodilation 1
Critical Clinical Caveat: