Mechanism of nonepinephrine and indications side effects normal' dose how to give how much to dilute

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Norepinephrine (Noradrenaline) - Complete Clinical Reference

1. Mechanism of Action

Norepinephrine is an endogenous catecholamine and the primary neurotransmitter of postganglionic sympathetic fibers. It acts on adrenergic receptors with the following receptor profile:

Receptor	Effect	Clinical Result
α1 (dominant at therapeutic doses)	Smooth muscle contraction	Intense vasoconstriction of arteries AND veins
β1	Increases heart rate & contractility	Positive inotropy; tachycardia (often masked)
β2 (very weak)	Minimal vasodilation in skeletal muscle	Negligible - this is why it causes MORE vasoconstriction than epinephrine

Molecular pathway: α1 receptors couple to Gq → PLC → IP3/DAG → Ca²⁺ → PKC, causing vascular smooth muscle contraction. β1 receptors couple to Gs → adenylyl cyclase → cAMP → PKA, increasing myocardial contractility.

Net cardiovascular effect:

Systolic BP ↑ (vasoconstriction + inotropy)
Diastolic BP ↑ (vasoconstriction)
Pulse pressure narrows
Reflex bradycardia - the rise in BP stimulates baroreceptors → increased vagal tone → HR falls (this masks the β1 tachycardia). If you pre-treat with atropine, tachycardia becomes evident.

Cardiovascular effects of norepinephrine infusion showing reflex bradycardia, increased BP, and elevated peripheral resistance

Fig: During NE infusion - peripheral resistance rises, both systolic and diastolic BP rise, and reflex bradycardia occurs. - Lippincott Illustrated Reviews: Pharmacology

2. Indications

Septic shock - first-line vasopressor of choice (Surviving Sepsis guidelines) when refractory to adequate fluid resuscitation
Vasodilatory / vasoplegic shock (e.g., post-cardiac surgery vasoplegia, distributive shock)
Cardiogenic shock - associated with improved outcomes vs. dopamine, especially in cardiogenic shock
Acute hypotension refractory to fluid resuscitation
Intraoperative hypotension - has largely replaced phenylephrine as primary intraoperative vasoconstrictor in many centers

It does NOT have a role in bronchospasm or anaphylaxis because of its weak β2 activity. Epinephrine is used for those. - Lippincott Illustrated Reviews: Pharmacology

3. Dosing

Source	Dose Range
Morgan & Mikhail's Clinical Anesthesiology	2 to 20 mcg/min (= 30-300 ng/kg/min)
Current Surgical Therapy	0.01 to 0.4 mcg/kg/min
Tintinalli's Emergency Medicine	Titrated to MAP target

Practical dosing:

Starting dose: 0.01-0.1 mcg/kg/min (or 2-4 mcg/min in adults)
Usual maintenance: 0.1-0.5 mcg/kg/min
High-dose / refractory shock: up to 1-3 mcg/kg/min (though at these levels, consider adding vasopressin)
Always titrate to effect - target MAP ≥ 65 mmHg

It must be given as a continuous IV infusion because the half-life is very short (~1-2 minutes); the drug is rapidly metabolized by MAO (monoamine oxidase) and COMT (catechol-O-methyltransferase), with inactive metabolites excreted in urine.

4. How to Give (Administration)

Route

Central venous access is strongly preferred - extravasation from a peripheral line can cause severe tissue necrosis and gangrene (due to intense local vasoconstriction)
Peripheral line is a temporizing measure only; switch to CVC as soon as possible

Preparation / Dilution

Standard preparation (most common in ICU/OR):

Method	How to prepare	Concentration
Standard concentration	Add 4 mg (1 ampoule of 4 mg/4 mL) to 250 mL NS or D5W	16 mcg/mL
Double concentration	Add 8 mg to 250 mL NS or D5W	32 mcg/mL
High concentration (fluid-restricted patients)	Add 4 mg to 100 mL NS or D5W	40 mcg/mL

Ampoules typically contain 4 mg norepinephrine in 4 mL of solution. - Morgan & Mikhail's Clinical Anesthesiology

Dilution example (standard 16 mcg/mL):

Patient weight 70 kg, starting dose 0.1 mcg/kg/min = 7 mcg/min
Rate = 7 mcg/min ÷ 16 mcg/mL = ~26 mL/hr

Compatible diluents: Normal saline (NS), Dextrose 5% in water (D5W) Do NOT mix with alkaline solutions (bicarbonate) - causes degradation

5. Side Effects / Adverse Effects

Cardiovascular

Reflex bradycardia (most common, from baroreceptor reflex)
Hypertension (if overdosed)
Decreased cardiac output - vasoconstriction increases afterload; if LV function is compromised, CO may fall
Arrhythmias
Increased myocardial oxygen demand
Cardiac arrest (with severe overdose)

Tissue Ischemia (serious)

Peripheral ischemia - fingers, toes (intense vasoconstriction)
Renal ischemia - reduces renal and splanchnic blood flow (major concern in prolonged use)
Mesenteric ischemia - gut hypoperfusion
Tissue necrosis at injection site if extravasation occurs

Treatment of extravasation:

Phentolamine (α-blocker) - inject intradermally into affected area
Alternatives: intradermal terbutaline or topical nitroglycerin

Other

Nausea, vomiting
Headache
Anxiety / tremors

6. Key Pharmacokinetic Points

Property	Value
Onset	Almost immediate (IV)
Duration of action	1-2 minutes after infusion stopped
Metabolism	MAO + COMT (liver, sympathetic nerve endings)
Excretion	Urine (as inactive metabolites)
Route	IV infusion ONLY (not IM/SC - causes local necrosis)

7. Quick Clinical Memory Aid

NE = α1 >>> β1 >> β2 (negligible)

Effect:  ↑BP (systolic + diastolic)
         ↑SVR (vasoconstriction ALL beds)
         ↓HR (reflex bradycardia)
         ↑Inotropy (β1)

1st line: Septic shock
Dose: 0.01-0.5 mcg/kg/min IV infusion
Dilute: 4 mg in 250 mL NS = 16 mcg/mL
Danger: Extravasation → necrosis → use CVC
Antidote for extravasation: Phentolamine

Sources: Lippincott Illustrated Reviews: Pharmacology | Morgan & Mikhail's Clinical Anesthesiology 7e | Tintinalli's Emergency Medicine | Current Surgical Therapy 14e | Goodman & Gilman's Pharmacological Basis of Therapeutics

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