Norepinephrine (Norepinephrine)

Mechanism

Mechanism of Action

Potent direct agonist of α₁ and α₂ adrenergic receptors that also exerts a moderate agonizing effect on cardiac β₁ receptors, with minimal or no activity on β₂ receptors. α₁ activation stimulates phospholipase C, increasing diacylglycerol and inositol triphosphate (IP₃), which induces the release of calcium from the sarcoplasmic reticulum of vascular smooth muscle, causing a drastic increase in systemic vascular resistance (SVR). This directly increases systolic and diastolic blood pressures. The transient β₁ stimulus in the sinus node is usually counteracted by a reflex bradycardia mediated by the baroreceptor in response to the sudden increase in blood pressure.

Pharmacokinetics

Key Pharmacokinetics

• Routes: Mandatory continuous intravenous infusion through a central venous line to reduce the risk of peripheral local tissue necrosis.
• Distribution: Limited; It does not cross the blood-brain barrier significantly due to its polar structure.
• Metabolism: Mainly by oxidative deamination and tissue o-methylation by MAO and COMT at the liver and tissue level.
• Half-life: Approximately 1 to 2 minutes.
• Excretion: Renal, mostly as rapidly excreted inactive metabolites.

Indicators and dose

Approved and Off-label Indications

Approved: Distributive vasodilator shock (septic, neurogenic, refractory anaphylactic) as a first-line vasopressor to restore organic tissue perfusion pressure.

Off-label: Refractory hypotension post-cardiopulmonary bypass.

Dosage and Adjustments

Continuous Infusion: Usual dosage range between 0.05 to 1.0 µ g/kg/min, adjusting the infusion rate dynamically to maintain an objective mean arterial pressure (MAP) of 65 mmHg.

Renal/hepatic adjustment: Quantitative dosimetric adjustment guidelines have not been described, but continuous invasive clinical and hemodynamic monitoring is required.

Security

Contraindications

Absolute: Uncorrected hypovolemia prior to the start of the infusion (except as a temporary emergency measure to maintain coronary and cerebral perfusion).

Relative: Mesenteric or peripheral vascular thrombosis (risk of exacerbation of focal tissue ischemia).

Adverse Effects (ADR)

Common: Tension headache, anxiety, mild tremor, secondary compensatory reflex bradycardia.

Serious: Extremity ischemia ("blue fingers" or distal necrosis), renal ischemia due to intense splanchnic vasoconstriction, mesenteric ischemia with necrosis of the intestinal mucosa, ventricular arrhythmias, excessive increase in myocardial oxygen consumption that can induce acute myocardial infarction in patients with preexisting obstructive coronary artery disease.

Interactions

MAOIs and serotonin and norepinephrine reuptake inhibitors (SNRIs): Coadministration contraindicated or under extreme monitoring due to the risk of inducing hyperpyretic hypertensive crises.

Inhaled anesthetics: Noticeable increase in myocardial susceptibility to arrhythmias.

Pregnancy and Breastfeeding

FDA Classification: Category C. It can drastically reduce uteroplacental blood flow and induce fetal bradycardia and premature uterine contractions. Its use is not recommended except in refractory maternal life-threatening scenarios.