What is the mechanism of action of propranolol (beta-blocker)?

Mechanism of Action of Propranolol

Propranolol is a nonselective beta-adrenergic receptor-blocking agent that competitively blocks both beta-1 and beta-2 adrenergic receptors, inhibiting the effects of catecholamines at these receptor sites. 1

Primary Mechanisms of Action

• Propranolol competes with beta-adrenergic receptor-stimulating agents (like epinephrine and norepinephrine) for available receptor sites, blocking their effects on target tissues 1, 2
• It antagonizes both beta-1 receptors (primarily located in the myocardium) and beta-2 receptors (located in vascular and bronchial smooth muscle) 1
• At higher doses, propranolol also exerts a quinidine-like or anesthetic-like membrane action that affects cardiac action potential, though the clinical significance of this effect is uncertain 1

Cardiovascular Effects

• Cardiac effects (beta-1 blockade):

  • Decreases heart rate (negative chronotropic effect) 3
  • Reduces myocardial contractility (negative inotropic effect) 3
  • Slows AV node conduction velocity 1
  • Blunts heart rate response to exertion and other stimuli 1

• Vascular effects:

  • Initially may increase total peripheral resistance, but with chronic use, resistance typically readjusts to or below pretreatment levels 1
  • Causes vasoconstriction through beta-2 receptor blockade 2

Antihypertensive Mechanism

The precise mechanism of propranolol's antihypertensive effect involves multiple pathways:

• Decreased cardiac output through beta-1 blockade 1
• Inhibition of renin release by the kidneys 1, 4
• Diminution of tonic sympathetic nerve outflow from vasomotor centers in the brain 1, 4
• Possible dampening of sensory input to the central nervous system from a heart with blunted capacity to respond to exercise and stress 4

Anti-Anginal Mechanism

• Reduces myocardial oxygen demand by blocking catecholamine-induced increases in heart rate, blood pressure, and myocardial contractility 1
• Increases exercise capacity and delays onset of pain in angina patients 1

Stereoselectivity

• Propranolol is administered as a racemic mixture of (R)- and (S)-enantiomers 5
• Only the (S)-enantiomer exerts significant beta-blocking activity at therapeutic doses 5
• The (R)-enantiomer has other non-beta blocking actions, such as inhibiting the conversion of thyroxine to triiodothyronine 5
• Both enantiomers exhibit class 1 antiarrhythmic activity and can decrease intraocular pressure 5

Other Proposed Mechanisms (Specific to Infantile Hemangiomas)

While not directly related to its primary cardiovascular effects, propranolol has been found effective in treating infantile hemangiomas through mechanisms hypothesized to include:

• Vasoconstriction 3
• Inhibition of angiogenesis (via suppression of VEGF-A and downregulation of matrix metalloproteinases and interleukin 6) 3
• Induction of apoptosis (though evidence is equivocal) 3
• Inhibition of nitric oxide production 3
• Regulation of the renin-angiotensin system 3

Clinical Implications

• The nonselective nature of propranolol means it blocks both beta-1 and beta-2 receptors, which explains its contraindication in patients with asthma or reactive airway disease 3, 2
• In heart failure, propranolol's beneficial effects in inhibiting the adverse effects of sympathetic nervous system activation outweigh its negative inotropic effects 3
• The multiple mechanisms of action explain propranolol's utility across various conditions including hypertension, angina, arrhythmias, and non-cardiovascular conditions like migraine and essential tremor 6