Norepinephrine is a potent **α₁ agonist** and moderate **β₁ agonist**, producing **powerful vasoconstriction** and modest inotropy.
It is the **first-line vasopressor** in septic, cardiogenic, and post-cardiac bypass vasodilatory shock.
Dose **0.02–0.3 mcg/kg/min**, titrated to MAP 65–75 mmHg; always via central line; treat extravasation with **phentolamine.
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# 1) Receptor-level action → clinical effects
**Primary receptor activity:**
* **α₁ agonist (dominant):** intense arterial & venous vasoconstriction → ↑ SVR, ↑ MAP.
* **β₁ agonist (moderate):** ↑ contractility and heart rate *slightly* but offset by baroreflex-mediated bradycardia.
* **β₂ agonist (minimal):** clinically negligible.
**Net effects:**
* ↑ MAP primarily via **↑ SVR**.
* Slight ↑ myocardial contractility & CO in moderate doses (depends on preload).
* Reflex **bradycardia** common due to baroreceptor activation.
* Improves coronary and cerebral perfusion pressure.
**Clinical summary of effects:**
* **Vascular:** potent vasoconstrictor, preserves perfusion pressure.
* **Cardiac:** improves inotropy modestly; no direct chronotropy in intact baroreflex.
* **Renal/splanchnic:** vasoconstriction; at adequate MAP, **net renal perfusion improved** by higher pressure.
* **Metabolic:** can cause mild hyperglycaemia, hyperlactataemia (β-effect on metabolism).
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# 2) Vial strength, preparation & basic pharmacokinetics (+ disadvantages)
**Formulation:**
* Standard ampoule: **4 mg/4 mL (1 mg/mL)**.
* Common ICU dilution: **4 mg in 50 mL** → **80 mcg/mL** (1 mL/h = 1.33 mcg/min).
* Alternative: **8 mg/50 mL** (160 mcg/mL) for central use.
**Pharmacokinetics:**
* **Onset:** <1 min.
* **Duration:** 1–2 min (terminated rapidly by reuptake/metabolism).
* **Metabolism:** MAO & COMT → inactive metabolites.
* **Half-life:** ~2.5 min.
* **Elimination:** renal excretion of metabolites.
**Disadvantages:**
* **Requires continuous infusion**, short half-life.
* **Peripheral extravasation → severe tissue necrosis.**
* Excessive vasoconstriction → impaired peripheral, mesenteric, or renal flow if MAP overshoot.
* **Arrhythmia risk** lower than dopamine, but possible with high doses.
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# 3) Practical dosing
## A. Anaesthesia / Post–cardiac bypass
**Indications:** hypotension due to vasodilation, vasoplegia, or low SVR after CPB, sepsis, or anaesthetic-induced vasodilation.
* **Starting dose:** **0.02–0.05 mcg/kg/min**.
* **Titrate up:** by 0.01–0.02 mcg/kg/min increments.
* **Typical range:** **0.02–0.3 mcg/kg/min** (occasionally higher in refractory vasoplegia).
* **Usual ICU practice:** aim for **MAP 65–75 mmHg** (individualised).
**Preparation examples (for 70 kg):**
* 70 × 0.1 mcg/kg/min = 7 mcg/min.
Using 80 mcg/mL solution → rate = **5.25 mL/h.**
**Peripheral use (if emergency):**
* Use **max 15–20 min** only through **large antecubital vein**; monitor closely; change to central line ASAP.
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# 4) Special populations — dosing cautions
### Pregnancy
* Used for **maternal hypotension** during spinal/epidural anaesthesia; maintains **better fetal acid–base status** than phenylephrine (lower reflex bradycardia).
* Crosses placenta minimally; **safe in obstetric anaesthesia** when titrated carefully.
### Lactation
* Short t½ and poor oral absorption → minimal transfer risk.
### Hepatic impairment
* Metabolised widely (not dependent on hepatic clearance). No dose adjustment required; **titrate to effect**.
### Renal impairment
* Metabolite excretion renal but inactive; **safe**.
* Improves renal perfusion indirectly via better MAP.
### Obesity
* Dose by **ideal body weight** to avoid excessive pressor effect.
### Paediatrics
* **Starting:** 0.05 mcg/kg/min; titrate to 1–2 mcg/kg/min if required (specialist monitoring).
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# 5) Drug interactions (clinically key)
* **MAOIs:** marked pressor response → start at **1/10th** normal dose or avoid.
* **TCAs / SNRIs:** exaggerated BP response.
* **Halogenated volatiles (esp. halothane):** myocardial sensitisation → **ventricular arrhythmia risk.**
* **β-blockers:** may cause unopposed α-stimulation → **severe hypertension/bradycardia**.
* **Ergot alkaloids, oxytocin:** additive vasoconstriction.
* **Phosphodiesterase inhibitors (milrinone):** synergistic—useful combination for inodilator + vasopressor balance.
* **General anaesthetics / propofol:** counteract vasodilation; titrate slowly.
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# 6) Significant complications & management
| Complication | Mechanism / Features | Management |
| ----------------------------------------- | ------------------------------------------ | ---------------------------------------------------------------------------------------------------------------------------------------------- |
| **Peripheral extravasation necrosis** | α₁ vasoconstriction → ischaemia | Stop infusion, leave cannula, **phentolamine 5–10 mg in 10–15 mL saline** infiltrated around site; warm compress; surgical review if necrosis. |
| **Digital/mesenteric ischaemia** | Excess vasoconstriction | Lower dose, reassess MAP goal, switch/add inodilator. |
| **Arrhythmia (AF/VT)** | β₁ effect, usually in high dose or hypoxia | Correct electrolytes, reduce dose; antiarrhythmics as indicated. |
| **Reflex bradycardia** | Baroreceptor response | Often mild; if MAP adequate, observe. Severe → **atropine/glycopyrrolate** if symptomatic. |
| **Metabolic acidosis / hyperlactataemia** | From high β-stimulation (non-hypoxic) | Usually benign; evaluate perfusion if severe. |
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