Cardiovascular DrugsAnticoagulantsNorepinephrine

Norepinephrine

Generic Name

Norepinephrine

Brand Names

Levophed

Pronunciation

nor-ep-i-NEF-rin

Pharmacologic Class

Alpha/Beta Agonist (Sympathomimetic / Vasopressor)

ISMP High-Alert

Yes

DEA Schedule

None

Pregnancy & Lactation

  • Pregnancy Category C: May severely decrease uterine blood flow causing fetal hypoxia. Use only if maternal benefit (life-saving shock reversal) outweighs fetal risk.
  • Lactation: Unknown if excreted in breast milk; caution advised (though oral bioavailability is poor, making systemic absorption by the infant unlikely).

Black Box Warning

Extravasation Risk (Severe Necrosis)

  • Extravasation causes profound localized vasoconstriction, leading to severe tissue ischemia and necrosis.
  • Antidote: Infiltrate the ischemic area with Phentolamine (an alpha-adrenergic antagonist) as soon as possible.

Mechanism of Action

  • Directly stimulates Alpha-1 adrenergic receptors, causing profound peripheral vasoconstriction and increased Systemic Vascular Resistance (SVR).
  • Directly stimulates Beta-1 adrenergic receptors (to a lesser extent), producing a mild positive inotropic and chronotropic effect to increase Cardiac Output (CO).

Receptor Binding

  • Alpha-1: ++++ (Profound Vasoconstriction)
  • Beta-1: ++ (Mild Inotropy/Chronotropy)
  • Beta-2: + (Minimal Vasodilation)
  • Dopaminergic: 0 (None)

Cellular Transport

  • Endogenous catecholamine; actively transported into nerve terminals by the Norepinephrine Transporter (NET) for reuptake.

Barrier Penetration

Blood-Brain Barrier (BBB)Blood-Brain Barrier (BBB): Poor (Does not readily cross)
Bone / Synovial FluidBone / Synovial Fluid: N/A
Placental TransferPlacental Transfer: Crosses placenta; restricts uterine blood flow.

Pharmacokinetics

Absorption & BioavailabilityAbsorption: IV administration only (100% bioavailable). Destroyed in GI tract.
Hepatic Metabolism / CYP450 Profile<p>Metabolism / CYP450: Rapidly metabolized in liver and tissues by <strong>COMT</strong> and <strong>MAO</strong>. (Not CYP450 dependent).</p>
Active & Toxic MetabolitesActive & Toxic Metabolites: Normetanephrine and VMA (inactive).
Excretion Pathway & Half-LifeExcretion Pathway & Half-Life: Urine (as metabolites). Half-life: <strong>1 to 2.5 minutes</strong>.

Indications & Dosing

Indication NameApproval StatusAdult DosingPediatric/Neonatal Dosing
Septic Shock / Distributive Shockfda<ul> <li><strong>Initial:</strong> <strong>8 to 12 mcg/min</strong> IV continuous infusion.</li> <li><strong>Titration:</strong> Titrate by 1 to 2 mcg/min every 3-5 minutes to maintain MAP ≥ 65 mmHg.</li> <li><strong>Maximum:</strong> <strong>30 to 100 mcg/min</strong> (Max doses vary by institution; consider adding Vasopressin if > 15 mcg/min is required).</li> </ul> <ul> <li><strong>Initial:</strong> <strong>0.05 to 0.1 mcg/kg/min</strong> IV continuous infusion.</li> <li><strong>Titration:</strong> Titrate to effect; maximum dose typically <strong>2 mcg/kg/min</strong>.</li> </ul>

Organ Impairment Dosing

Renal Adjustments (CrCl)<ul> <li> <p data-path-to-node="28,0,1,0,0"><i data-path-to-node="28,0,1,0,0" data-index-in-node="0">Renal Adjustments:</i> No adjustment required.</p> </li> <li> <p data-path-to-node="28,0,1,1,0"><i data-path-to-node="28,0,1,1,0" data-index-in-node="0">Hepatic Adjustments:</i> No adjustment required.</p> </li> <li> <p data-path-to-node="28,0,1,2,0"><i data-path-to-node="28,0,1,2,0" data-index-in-node="0">Dialysis, CRRT:</i> Not dialyzed. No adjustment required.</p> </li> </ul>

Special Populations

Geriatric (Beers Criteria)<p><i data-path-to-node="28,1,1,0,0" data-index-in-node="0">Geriatric (Beers):</i> Use caution; increased risk of ischemia in patients with severe peripheral vascular disease.</p>

Preparation & Stability

  • Diluent: Must be diluted in D5W or D5W/NS. (Dextrose protects against oxidation/loss of potency). Administration in plain NS alone is NOT recommended.
  • Standard Concentration: 4 mg/250 mL (16 mcg/mL) or 8 mg/250 mL (32 mcg/mL).
  • Storage: Protect from light. Do not use if solution is brown or contains precipitate.

IV Administration Rules

Central Line Required?✔
IV Push Rate / Bolus LimitsDo not administer as an undiluted IV push.
Y-Site Incompatibilities<ul> <li><strong>Incompatible with:</strong> Sodium Bicarbonate, Propofol, Pantoprazole, Insulin regular.</li> <li><strong>Alkaline solutions:</strong> Rapidly degrades norepinephrine.</li> </ul>

Adverse Effects

SystemSide EffectFrequency
CardiovascularSevere Hypertension, Tachycardia, Arrhythmias Common (>10%)
DermatologicPeripheral digital ischemia / GangreneOccasional (1-10%)
NeurologicAnxiety, Severe HeadacheOccasional (1-10%)

Contraindications

  • Absolute: Hypovolemic shock (must adequately fluid-resuscitate first).
  • Absolute: Mesenteric or peripheral vascular thrombosis (unless life-saving).
  • Relative: Profound hypoxia or hypercapnia (increases risk of fatal arrhythmias).

Drug Interactions

  • MAO Inhibitors & TCAs: Severe, prolonged hypertension (decreased NE metabolism).
  • Alpha/Beta Blockers: Antagonize the vasopressor effects.
  • Inhalational Anesthetics: Increased risk of ventricular arrhythmias.

Toxicology / Overdose

  • Presentation: Severe hypertension, photophobia, retrosternal pain, intense sweating, cerebral hemorrhage, and reflex bradycardia.
  • Management: Discontinue infusion immediately (short half-life resolves symptoms rapidly).
  • Antidote for HTN Crisis: Phentolamine (IV alpha-blocker).

Dialyzable?

Highly Dialyzable

Monitoring Parameters

  • Continuous: Invasive arterial blood pressure monitoring (A-line), ECG, Heart Rate.
  • Routine: Peripheral perfusion (capillary refill, digit color), Lactate clearance, Urine output (target > 0.5 mL/kg/hr).

Mnemonics

  • “Levophed leaves ’em dead”: Historical nursing adage referring to the profound peripheral vasoconstriction and digital necrosis seen in high doses or prolonged use.

Buzzwords

Alpha-1 Agonist, Extravasation, Phentolamine, SVR increase.

Board Focus

  • Receptor Profile: Boards love to test that NE works primarily on Alpha-1 > Beta-1, with almost zero Beta-2 activity (unlike Epinephrine).
  • Baroreceptor Reflex: NE increases MAP, which can trigger the vagus nerve, causing a reflex bradycardia (masking the direct Beta-1 chronotropic effect).
  • Antidote: Always choose Phentolamine for IV line extravasation causing blanching/necrosis.

Trivia

Discovered in 1946 by Ulf von Euler, who won the Nobel Prize in Medicine in 1970 for mapping sympathetic neurotransmitters.

Relative Cost

$ (Low Cost)

Availability

Hospital Only

Patient Education

(Not applicable for outpatient use. ICU communication for families):

“This medication is a powerful blood pressure supporter used in the ICU. It squeezes the blood vessels to ensure blood reaches vital organs like the brain and heart during severe infections or shock.”

Specialty Template

T1: Critical Care & Resuscitation

Titration Tables

Phase Action
Initiation Start at 2 to 5 mcg/min
Titration Increase by 1 to 2 mcg/min every 3-5 minutes
Target MAP ≥ 65 mmHg
Weaning Decrease by 1 mcg/min every 10-30 mins when hemodynamically stable

Extravasation Protocols

  • 1. Stop Infusion: Immediately stop the pump.
  • 2. Do NOT remove IV: Aspirate any residual drug from the catheter, then remove it.
  • 3. Antidote: Administer Phentolamine 5 to 10 mg diluted in 10 mL of Normal Saline.
  • 4. Technique: Inject subcutaneously in multiple small injections (using a fine hypodermic needle) concentrically around the blanched/ischemic area.
  • 5. Adjunct: Apply warm compresses (causes vasodilation) and elevate the limb.

Personal Clinical Notes