Noradrenaline

Noradrenaline (Norepinephrine)

Uses

Noradrenaline is a potent vasopressor used primarily in critical care settings to manage:

1. Acute Hypotension: Profound hypotension due to acute volume loss or vasodilation.
2. Septic Shock: First-line vasopressor to maintain mean arterial pressure (MAP) ≥65 mmHg.
3. Cardiogenic Shock: Supports blood pressure in cases with low systemic vascular resistance.

Dosage and Administration

Continuous Intravenous Infusion

• Adults:

  • Initial: 0.01–0.5 µg/kg/min IV infusion.
  • Maximum: Up to 3 µg/kg/min (higher doses may be required in refractory shock).
  • Titrate to maintain desired MAP.

• Pediatrics:

  • Initial: 0.05–2 µg/kg/min IV infusion.

Presentation

• Injectable Solution:
  • 2 mg/mL (ampoules/vials).
  • Dilution: Typically mixed in 5% dextrose or normal saline (e.g., 4 mg in 250 mL solution).

Pharmacokinetics

1. Absorption:

   • Ineffective orally; requires IV administration due to rapid metabolism.

2. Distribution:

   • Volume of distribution (Vd): ~8 L.
   • Rapidly distributes into tissues.

3. Metabolism:

   • Primarily metabolized in the liver and kidneys by catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO).

4. Excretion:

   • Metabolites (normetanephrine and vanillylmandelic acid) excreted via urine.
   • ~80–90% excreted within 24 hours.

5. Plasma Half-Life:

   • ~2–3 minutes, necessitating continuous IV infusion.

Pharmacodynamics

Noradrenaline acts by stimulating adrenergic receptors:

1. Alpha-1 Adrenergic Receptors:

   • Primary Action: Vasoconstriction, increasing systemic vascular resistance and blood pressure.

2. Beta-1 Adrenergic Receptors:

   • Secondary Action: Increases heart rate and myocardial contractility, modestly enhancing cardiac output.

3. Beta-2 Adrenergic Receptors:

   • Minimal effect due to low affinity, with negligible bronchodilation or vasodilation.

4. Baroreceptor Reflex:

   • Elevated blood pressure from alpha-1 activation may trigger reflex bradycardia, countering beta-1 effects.

Dose Adjustments

Renal Impairment

• No specific dose adjustments required, as noradrenaline metabolism is hepatic.
• Monitor urine output to ensure renal perfusion.

Hepatic Impairment

• Dose adjustments are typically unnecessary; however, careful monitoring is advised due to altered metabolism.

Pregnancy

• Category C (FDA):
  • Animal studies indicate potential risks (e.g., reduced uterine blood flow), but data in humans are limited.
  • Use only if potential benefits justify risks to the fetus (e.g., life-threatening hypotension in pregnancy-related sepsis).

Pediatrics and Elderly

• Titrate cautiously to minimize risks of excessive vasoconstriction and ischemia, especially in the elderly.

Drug Interactions

1. Monoamine Oxidase Inhibitors (MAOIs):

   • Potentiates noradrenaline’s effects, increasing the risk of severe hypertension.

2. Tricyclic Antidepressants (TCAs):

   • Enhances noradrenaline’s vasopressor activity, leading to exaggerated responses.

3. Beta-Blockers:

   • May unmask alpha-1 effects, causing unopposed vasoconstriction and severe hypertension.

4. General Anesthetics:

   • Halogenated anesthetics (e.g., halothane) may sensitize the myocardium to catecholamines, increasing the risk of arrhythmias.

5. Linezolid:

   • Acts as a weak MAOI, potentially enhancing noradrenaline’s pressor effects.

6. Digoxin:

   • Increases the risk of arrhythmias when used concomitantly.

Onset, Duration, and Monitoring

• Onset of Action: Within 1–2 minutes after IV administration.
• Duration of Action: Short, dissipating 1–2 minutes after stopping infusion.

Monitoring Parameters

1. Blood Pressure: Maintain MAP ≥65 mmHg (septic shock) or individualized targets.
2. Heart Rate: Monitor for arrhythmias and reflex bradycardia.
3. Urine Output: Ensure adequate renal perfusion.
4. Lactate Levels: Monitor for metabolic improvement in septic shock.
5. Peripheral Perfusion: Prevent ischemic complications from excessive vasoconstriction.

Precautions and Special Considerations

1. Central Line Administration:

   • Administer via central venous catheter to minimize extravasation risk.

2. Extravasation:

   • Treat with phentolamine (alpha-adrenergic blocker) or saline infiltration to prevent tissue necrosis.

3. Volume Resuscitation:

   • Ensure adequate intravascular volume before starting noradrenaline.

4. Coronary Artery Disease:

   • Use cautiously as increased afterload may exacerbate myocardial ischemia.

5. Prolonged Infusion:

   • Continuous infusion without monitoring may lead to reduced organ perfusion, particularly in the extremities and gastrointestinal tract.

Side Effects

Common:

• Tachycardia, hypertension, and peripheral vasoconstriction.

Severe:

• Tissue necrosis (extravasation).
• Arrhythmias (especially with concomitant beta-1 stimulation).
• Ischemic complications (renal, mesenteric, or peripheral ischemia).

Recent Guidelines and Updates

1. Surviving Sepsis Campaign (2023):

   • Noradrenaline remains the first-line vasopressor for septic shock.
   • Adjuncts like vasopressin or epinephrine may be added if the target MAP is not achieved.

2. Cardiogenic Shock Guidelines (2022):

   • Focuses on balancing vasopressors and inotropes to optimize systemic perfusion without increasing myocardial oxygen demand.

3. FDA Safety Update (2021):

   • Reinforces central line administration to reduce the risk of extravasation and tissue injury.

References

1. Surviving Sepsis Campaign Guidelines (2023).
2. Goodman & Gilman’s: The Pharmacological Basis of Therapeutics (13th Edition).
3. Stoelting RK, Hillier SC: “Pharmacology and Physiology in Anesthetic Practice” (6th Edition).
4. FDA Safety Communication: Vasopressors and Extravasation Risk (2021).
5. Cardiogenic Shock Management Guidelines, American Heart Association (2022).