Mechanism of Action of Isoproterenol
Isoproterenol is a potent nonselective beta-adrenergic agonist with very low affinity for alpha-adrenergic receptors, producing both chronotropic and inotropic effects on cardiac myocytes while simultaneously causing peripheral vasodilation. 1
Primary Receptor Activity
- Isoproterenol acts as a nonselective beta agonist, stimulating both β1 and β2 adrenergic receptors throughout the body 2
- The drug has very low affinity for alpha-adrenergic receptors, distinguishing it from mixed catecholamines like epinephrine 1
- It is a relatively poor substrate for monoamine oxidase (MAO) and is not taken up by sympathetic neurons to the same extent as epinephrine and norepinephrine 1
Cardiovascular Effects
Cardiac Actions (β1-mediated)
- Enhances sinus node automaticity and facilitates sinoatrial conduction, increasing heart rate (positive chronotropy) 2
- Increases myocardial contractility (positive inotropy), enhancing cardiac output 2
- Enhances atrioventricular nodal function, improving conduction through the AV node 2
Vascular Effects (β2-mediated)
- Lowers peripheral vascular resistance, primarily in skeletal muscle but also in renal and mesenteric vascular beds 1
- Causes diastolic blood pressure to fall due to peripheral vasodilation 1
- Systolic blood pressure may remain unchanged or rise, although mean arterial pressure typically falls 1
- Produces pulmonary artery vasodilation 3
Metabolic Effects
- Stimulates the release of free fatty acids and energy production, equally effective as epinephrine in this regard 1
- Causes less hyperglycemia than epinephrine 1
Smooth Muscle Effects
- Relaxes bronchial smooth muscle, preventing or relieving bronchoconstriction through β2 receptor stimulation 1, 4
- Relaxes gastrointestinal smooth muscle when tone is high 1
- Tolerance to the bronchodilator effect develops with overuse 1
Pharmacokinetic Considerations
- Elimination half-life is extremely short at 2-5 minutes when administered intravenously, requiring continuous infusion for sustained effect 5
- Metabolized primarily in the liver and other tissues by catechol-O-methyltransferase (COMT) 1
- The duration of action may be longer than epinephrine but is still brief 1
Critical Clinical Implications
Oxygen Demand vs. Supply Mismatch
- Isoproterenol increases myocardial oxygen demand through β1 effects (increased heart rate and contractility) while simultaneously decreasing coronary perfusion through β2-mediated effects 2, 3
- This creates a dangerous mismatch and is why the drug should be avoided in settings where coronary ischemia is a concern 2
Hemodynamic Profile
- Cardiac output increases because of positive inotropic and chronotropic effects occurring in the face of diminished peripheral vascular resistance 1
- The combination of increased cardiac work and decreased afterload makes it useful for bradycardia but problematic in hypotensive states requiring peripheral vasoconstriction 3
Paradoxical Effects
- In rare cases (approximately 7% of patients), isoproterenol can paradoxically cause bradycardia, either sinus/junctional bradycardia or second-degree AV block, particularly in patients with underlying conduction abnormalities or hypervagotonia 6