What are the predominant receptors activated by norepinephrine (Levophed) and how do they change with increasing infusion doses?

Norepinephrine (Levophed) Receptor Activity and Dose-Dependent Effects

Norepinephrine predominantly stimulates alpha-1 adrenergic receptors at all therapeutic doses, with consistent beta-1 activity that remains relatively stable across the dosing range, unlike epinephrine which shows clear dose-dependent receptor shifts. 1

Primary Receptor Profile

Norepinephrine acts primarily as an alpha-1 agonist with significant beta-1 activity but minimal beta-2 effects at any dose. 2, 3

• Alpha-1 receptors: Norepinephrine potently stimulates alpha-1 adrenergic receptors throughout its entire dosing range, producing peripheral vasoconstriction and increased systemic vascular resistance 1, 2

• Beta-1 receptors: Norepinephrine provides consistent beta-1 receptor stimulation that helps preserve or increase cardiac output while producing vasoconstriction 1, 2

• Beta-2 receptors: Unlike epinephrine, norepinephrine has minimal beta-2 activity and does not produce the vasodilation seen with low-dose epinephrine 1

Dose-Dependent Receptor Changes

The critical distinction is that norepinephrine does NOT exhibit the dramatic dose-dependent receptor shift seen with epinephrine—its alpha-1 predominance remains constant across therapeutic doses. 1

Standard Dosing Range (0.05-3.0 mcg/kg/min)

• Norepinephrine maintains its alpha-1 predominant profile throughout the typical infusion range of 2-20 mcg/kg/min used in shock states 1

• The balance between alpha-1 vasoconstriction and beta-1 cardiac stimulation remains relatively stable, though higher doses intensify both effects proportionally 1

• At all therapeutic doses, alpha-1 effects dominate the hemodynamic response, producing consistent increases in systemic vascular resistance and blood pressure 1, 2

Contrast with Epinephrine's Dose-Dependent Profile

This is fundamentally different from epinephrine, which shows clear dose-dependent receptor transitions:

• Low-dose epinephrine (<0.3 mcg/kg/min): Predominantly beta-2 effects with vasodilation and decreased systemic vascular resistance 4

• High-dose epinephrine (>0.3 mcg/kg/min): Alpha-1 effects become dominant, causing vasoconstriction 4

• Norepinephrine lacks this beta-2 mediated vasodilation at any dose, maintaining alpha-1 predominance throughout 1

Cardiovascular Effects Across Doses

Cardiac Effects (Beta-1 Mediated)

• Norepinephrine increases stroke volume and coronary blood flow through beta-1 and coronary vessel beta-2 receptor stimulation 1

• The positive chronotropic effects are often counterbalanced by vagal reflex activity from increased blood pressure, preventing excessive tachycardia 1

• These cardiac effects remain relatively consistent across the dosing range, though they may be transient and time-dependent 1

Vascular Effects (Alpha-1 Mediated)

• Peripheral vasoconstriction and increased systemic vascular resistance occur at all doses 1

• Norepinephrine increases pulmonary artery pressure and pulmonary vascular resistance similarly to epinephrine 1

• The drug increases venous return by shifting unstressed to stressed volume, which can transiently increase cardiac output 1

Clinical Implications by Dose

Low to Moderate Doses (0.05-0.3 mcg/kg/min)

• Provide alpha-1 mediated vasoconstriction with preserved cardiac output through beta-1 activity 1, 2

• First-line choice for vasodilatory (septic) shock where both pressure support and cardiac output maintenance are needed 2

Higher Doses (>0.3 mcg/kg/min)

• Intensify both alpha-1 vasoconstriction and beta-1 cardiac stimulation proportionally 1

• At very high doses, excessive vasoconstriction may impair splanchnic and renal perfusion 1

• Unlike high-dose dopamine (10-20 mcg/kg/min), which increases MAP primarily through cardiac output, norepinephrine maintains its vasoconstrictive mechanism 1

Important Clinical Caveats

The key pitfall is assuming norepinephrine behaves like epinephrine with dose-dependent receptor shifts—it does not. 1

• Norepinephrine's alpha-1 predominance is consistent across all therapeutic doses, making it predictably vasoconstrictive 1, 2

• Extravasation causes severe tissue necrosis at any dose; phentolamine (0.1-0.2 mg/kg up to 10 mg diluted in 10 mL saline) should be infiltrated locally if extravasation occurs 1

• The effects on cardiac output are inconsistent and time-dependent, potentially related to baseline cardiovascular state and ventriculo-arterial coupling 1

• At high doses, regional perfusion (splanchnic, renal) may be compromised despite adequate blood pressure 1