What are the pharmacokinetics, pharmacodynamics, dosing, administration route, contraindications, and monitoring considerations for noradrenaline (norepinephrine) in adult patients?

Noradrenaline (Norepinephrine) Pharmacokinetics and Pharmacodynamics

Pharmacokinetics

Norepinephrine exhibits rapid onset and short duration of action, with plasma concentrations rising proportionally to infusion rates and hemodynamic effects occurring within minutes of administration. 1

Plasma Concentration-Response Relationship

• At therapeutic infusion rates of 0.01 to 0.2 mcg/kg/min, plasma norepinephrine concentrations increase from baseline values of approximately 199 pg/mL to 7475 pg/mL during maximal infusion 1
• Hemodynamic and metabolic effects occur at similar plasma concentrations throughout the dosing range, demonstrating no selective tissue targeting 1
• The time to achieve target mean arterial pressure depends significantly on the infusion system used: double syringe pump systems with very low dead-space volume sets achieve MAP >65 mmHg in approximately 14 minutes, compared to 34 minutes with direct single-pump infusion 2

Metabolism and Elimination

• Norepinephrine is rapidly metabolized by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO), resulting in a very short half-life requiring continuous infusion for sustained effect 3
• The drug does not accumulate with prolonged infusion, allowing for rapid titration and predictable offset when discontinued 3

Pharmacodynamics

Receptor Activity and Hemodynamic Effects

Norepinephrine acts primarily as a potent α1-adrenergic agonist with moderate β1-adrenergic activity, producing marked vasoconstriction and increased systemic vascular resistance while maintaining or modestly increasing cardiac output. 3

• α1-adrenergic stimulation causes profound peripheral, renal, and splanchnic vasoconstriction, increasing systemic vascular resistance and mean arterial pressure 3
• β1-adrenergic effects provide positive inotropic support, though this is less pronounced than with epinephrine 3
• The increase in systemic vascular resistance and MAP typically ranges from baseline to 65-100 mmHg at standard therapeutic doses 3

Chronotropic Response: A Critical Nuance

Norepinephrine does NOT typically increase heart rate despite β1-receptor stimulation, and may actually cause bradycardia—this is a protective physiological response, not a complication. 3

• The direct β1-adrenergic stimulation of the sinus node is offset by baroreceptor-mediated vagal reflex triggered by rising arterial pressure 3
• At standard therapeutic ranges (0.2-1.0 mcg/kg/min), norepinephrine produces either no change or modest decrease in heart rate because vagal reflex predominates 3
• Critical pitfall to avoid: Never escalate norepinephrine doses attempting to increase heart rate—the vagal reflex will continue to dominate, risking excessive vasoconstriction and end-organ hypoperfusion 3
• If chronotropic support is needed, add dobutamine (2-20 mcg/kg/min) rather than increasing norepinephrine 3

Organ-Specific Effects

• Cardiac: Increases myocardial oxygen consumption; may increase afterload and potentially reduce cardiac output in patients with heart failure 3
• Renal: Despite causing renal vasoconstriction in normal physiology, norepinephrine may paradoxically improve renal blood flow and urine output in septic shock by restoring adequate perfusion pressure 3
• Splanchnic: Reduces mesenteric blood flow, though clinical significance in septic shock is mitigated by improved perfusion pressure 3

Metabolic Effects

• Increases plasma glucose concentrations from baseline ~92 mg/dL to ~132 mg/dL at high infusion rates (0.2 mcg/kg/min) 1
• Elevates nonesterified fatty acids from ~11 mg/dL to ~34 mg/dL 1
• Notably, insulin levels remain at baseline despite hyperglycemia, reflecting stress-induced insulin resistance 1

Dosing and Administration

Standard Adult Dosing

Initiate norepinephrine at 0.1-0.5 mcg/kg/min (approximately 7-35 mcg/min in a 70 kg adult) via continuous IV infusion, titrating to achieve MAP ≥65 mmHg. 3, 4

• Alternative dosing scheme: Start at 0.5 mg/h (approximately 8 mcg/min), increase by 0.5 mg/h every 4 hours as needed, maximum 3 mg/h 4
• Typical therapeutic range: 0.1-2 mcg/kg/min for septic shock 3
• European guidelines suggest 0.2-1.0 mcg/kg/min for acute heart failure 3

Preparation and Concentration

• Standard concentration: Add 4 mg norepinephrine to 250 mL D5W to yield 16 mcg/mL 4
• Alternative concentration: Add 1 mg to 100 mL saline for 10 mcg/mL solution 4
• Never mix with sodium bicarbonate or alkaline solutions—norepinephrine is inactivated in alkaline pH 4

Pediatric Dosing

• Start at 0.1 mcg/kg/min, titrate to clinical effect 4
• Typical range: 0.1-1.0 mcg/kg/min; maximum doses up to 5 mcg/kg/min may be necessary in exceptional circumstances 4
• "Rule of 6" for simplified preparation: 0.6 × body weight (kg) = mg of norepinephrine diluted to 100 mL saline; then 1 mL/h delivers 0.1 mcg/kg/min 4

Route of Administration

Central vs. Peripheral Access

Central venous access is strongly preferred to minimize extravasation risk, but peripheral administration is safe and effective when proper protocols are followed. 3, 5

• The American Heart Association recommends central venous line whenever possible to prevent tissue necrosis 3
• Recent high-quality evidence: A 2024 prospective observational study of 635 patients demonstrated that peripheral norepinephrine administration avoided 1 CVC day per patient, with 51.6% never requiring CVC insertion 5
• Extravasation occurred in 75.8 events per 1,000 days of peripheral infusion, but most caused no or minimal tissue injury—no patient required surgical intervention 5
• If central access is unavailable or delayed, peripheral IV or intraosseous administration can be used temporarily with strict monitoring 3, 4

Intraosseous Administration

• All IV medications including norepinephrine can be administered via IO route with comparable onset and drug levels to IV 4
• Follow each dose with saline flush to promote central circulation entry 4
• May require manual pressure or infusion pump for adequate flow 4
• Transition to central access as soon as practical 4

Target Blood Pressure and Titration

MAP Goals

Target MAP of 65 mmHg for most patients with septic shock, representing the minimum threshold for adequate organ perfusion. 3, 4

• Patients with chronic hypertension may require higher MAP targets 4
• Younger normotensive patients may tolerate lower pressures 4
• Titrate based on both MAP and tissue perfusion markers: lactate clearance, urine output >50 mL/h, mental status, capillary refill 4

Monitoring Requirements

• Monitor blood pressure and heart rate every 5-15 minutes during initial titration 4
• Place arterial catheter as soon as practical in all patients requiring vasopressors 3
• Continuous hemodynamic monitoring is essential 3
• Assess peripheral perfusion regularly: skin temperature, capillary refill 3

Escalation Strategy for Refractory Hypotension

When norepinephrine reaches 0.25 mcg/kg/min and hypotension persists, add vasopressin 0.03-0.04 units/min as second-line therapy rather than continuing to escalate norepinephrine alone. 4

• Alternative: Add epinephrine 0.1-0.5 mcg/kg/min if vasopressin unavailable 4
• For persistent hypoperfusion despite adequate vasopressors with evidence of myocardial dysfunction, add dobutamine up to 20 mcg/kg/min 4
• Consider hydrocortisone 50 mg IV every 6 hours for refractory shock requiring high-dose vasopressors 4
• Critical warning: Higher doses >10 mcg/min are associated with increased mortality and should be avoided if possible 3

Critical Pre-Administration Requirements

Address hypovolemia FIRST with minimum 30 mL/kg crystalloid bolus before or concurrent with norepinephrine initiation—vasoconstriction in hypovolemic patients causes severe organ hypoperfusion despite "normal" blood pressure. 4

• Balanced crystalloids (lactated Ringer's, Plasma-Lyte) are preferred over normal saline 4
• In severe hypotension (systolic <70 mmHg), start norepinephrine as emergency measure while fluid resuscitation continues 4
• Never delay norepinephrine waiting for complete volume repletion in life-threatening hypotension 4

Contraindications and Precautions

Relative Contraindications

• Hypovolemia: Relatively contraindicated until volume status corrected 3
• Ischemic heart disease: Use cautiously as norepinephrine increases myocardial oxygen requirements 3
• Cardiogenic shock: Use only transiently due to risk of increasing afterload and further decreasing end-organ blood flow 3

Drug Interactions

• Concurrent use with phosphodiesterase inhibitors may cause severe hypotension 3
• Has additive effects when combined with other vasopressors 3
• Often combined with dobutamine to improve hemodynamics in cardiogenic shock 3

Adverse Effects and Complications

Common Adverse Effects

• Increased myocardial oxygen consumption 3
• Arrhythmias at higher doses 3
• Excessive vasoconstriction leading to end-organ hypoperfusion 3
• Transient increase in serum lactate (not clinically relevant) 4

Extravasation Management

If extravasation occurs, infiltrate 5-10 mg phentolamine diluted in 10-15 mL saline into the site immediately to prevent tissue necrosis. 3, 4

• Pediatric dose: 0.1-0.2 mg/kg up to 10 mg 4
• Do NOT remove the IV catheter before administering phentolamine—the catheter serves as landmark for precise infiltration 4
• Stop infusion immediately but leave line in place 4
• Observe patient for at least 24 hours after treatment 4

Weaning Protocol

• Decrease dose by 25% of current dose every 30 minutes as tolerated 3
• Monitor for recurrent hypotension during weaning 3
• Ensure adequate volume status before weaning 3

Special Clinical Scenarios

Septic Shock

Norepinephrine is the mandatory first-choice vasopressor for septic shock over dopamine, epinephrine, or phenylephrine (strong recommendation, moderate quality evidence). 3, 4

• Dopamine associated with higher mortality and more arrhythmias—use only in highly selected patients with absolute bradycardia and low arrhythmia risk 3
• Never use low-dose dopamine for "renal protection"—it provides no benefit 4
• Phenylephrine NOT recommended as first-line—may raise blood pressure while worsening tissue perfusion 4

Post-Cardiac Arrest Shock

• Norepinephrine is strongly preferred over epinephrine for post-resuscitation shock: A 2022 multicenter study of 766 patients demonstrated that epinephrine was associated with significantly higher all-cause mortality (OR 2.6,95% CI 1.4-4.7) and cardiovascular mortality (OR 5.5,95% CI 3.0-10.3) compared to norepinephrine 6

Hepatorenal Syndrome

• Start at 0.5 mg/h, increase every 4 hours by 0.5 mg/h to maximum 3 mg/h 4
• Goal: increase MAP by ≥10 mmHg and/or urine output >50 mL/h for at least 4 hours 4
• Similar efficacy to terlipressin in improving renal function 4

Anaphylaxis

• Use only in cases not responding to epinephrine injections and volume resuscitation 4
• Infusion rate: 0.05-0.1 mcg/kg/min for persistent hypotension after 10 minutes despite epinephrine boluses 4
• Alternative 1:100,000 solution (1 mg in 100 mL saline) at 30-100 mL/h (5-15 mcg/min) 4

Pregnancy

• Start at 0.02 mcg/kg/min with target MAP 65 mmHg 4
• Consider more restrictive initial fluid boluses (1-2 L) due to lower colloid oncotic pressure and higher pulmonary edema risk 4
• Add vasopressin 0.04 units/min for refractory shock with fetal monitoring when appropriate 4

Comparative Potency

Norepinephrine is approximately 13 times more potent than phenylephrine for equivalent blood pressure control when administered as continuous infusion. 7

• This potency ratio (12.6,95% CI 9.92-15.9) was demonstrated in a 2024 randomized controlled trial using up-down sequential allocation 7
• Recommended variable-rate prophylactic infusion: 1.9-3.8 mcg/min for cesarean delivery under spinal anesthesia 7