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.
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
Drug administration of atropine
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How to dilute atropine how to give
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Atropine - How to Dilute and How to Give
Available Formulations
| Form | Concentration |
|---|---|
| Vials (injection) | 0.4 mg/mL and 1 mg/mL |
| Prefilled syringe | 0.25 mg/5 mL, 0.5 mg/5 mL, 1 mg/10 mL |
| AtroPen autoinjector (IM) | 0.25 mg, 0.5 mg, 1 mg, 2 mg |
Routes of Administration
| Route | When Used | Notes |
|---|---|---|
| IV push (bolus) | Symptomatic bradycardia, cardiac arrest, organophosphate poisoning | Most common in emergency/ICU settings |
| IM | Pre-medication, organophosphate poisoning (AtroPen), field use | Use 1 mg/mL concentration for IM |
| Endotracheal (ET tube) | When IV/IO access not yet available in arrest | Dilute with NS before giving |
| IO (intraosseous) | Pediatric arrest when no IV access | Same dose as IV |
| Ophthalmic drops | Eye procedures, uveitis | 1% solution (adults), 0.5% solution (children) |
| Nebulized | Bronchospasm (rarely) | Use injectable solution in nebulizer |
How to Dilute
IV Push (most common use)
Atropine is typically given undiluted (ready to use) for IV bolus in emergency settings.
| Preparation | How |
|---|---|
| Standard | Draw up from 0.4 mg/mL or 1 mg/mL vial directly - no dilution needed for IV push |
| If using 1 mg/mL vial for a small dose | Draw up the required volume (e.g., 0.5 mg = 0.5 mL from 1 mg/mL vial) - give undiluted |
| Pediatric IV push | Can dilute with NS to a total of 5-10 mL so the small volume is easier to inject accurately |
IV doses < 0.5 mg and slow injection have been associated with paradoxical bradycardia - always give IV push rapidly (over ~1 minute or as a fast push in arrest). - Tintinalli's Emergency Medicine
Endotracheal (ET Tube) Route
When IV access is unavailable (usually in pediatric or field resuscitation):
- Draw up the dose
- Dilute with Normal Saline to a volume of 1-2 mL
- Instill down the ET tube
- Follow immediately with 1 mL NS flush
- Give several positive pressure breaths to distribute drug into lungs
ET dose = 0.04-0.06 mg/kg (2-3x the IV dose to compensate for less reliable absorption). - Harriet Lane Handbook
Nebulized (for bronchospasm)
- Use the injectable solution directly in the nebulizer
- Dose: 0.025-0.05 mg/kg (max 2.5 mg) in 2.5 mL NS
- Can be mixed with albuterol for simultaneous nebulization
IM (AtroPen autoinjector)
- No dilution needed - inject as-is into the outer thigh
- Can be given through clothing in emergencies (organophosphate poisoning)
How to Give - Dose Summary
Adults
| Indication | Dose | Route | Repeat |
|---|---|---|---|
| Symptomatic bradycardia | 0.5-1 mg IV fast push | IV | Every 5 min PRN; max total 3 mg |
| Pre-medication (before intubation/surgery) | 0.4-0.6 mg (0.01-0.02 mg/kg) | IV or IM | Single dose |
| Organophosphate poisoning | 2-4 mg IV | IV | Repeat every 5-10 min until secretions dry; no maximum in poisoning |
| Bradycardia in arrest | 1 mg IV push | IV | Every 3-5 min; max 3 mg |
Children (Pediatric Doses - Harriet Lane)
| Indication | Dose | Max Single Dose |
|---|---|---|
| Pre-intubation | 0.02 mg/kg IV/IM | 0.5 mg |
| Bradycardia/CPR | 0.02 mg/kg IV/IO Q5 min x 2-3 doses | 0.5 mg (child); 1 mg (adolescent) |
| ET tube route | 0.04-0.06 mg/kg diluted to 1-2 mL NS | - |
| Max total CPR dose | - | 1 mg (child); 2 mg (adolescent) |
| Neonates | 0.01-0.02 mg/kg IV | - |
Note: Atropine is no longer recommended for neonatal bradycardia or for asystole/PEA cardiac arrest. - Harriet Lane Handbook, Tintinalli's
Step-by-Step: Giving Atropine for Bradycardia (Adult)
1. Confirm symptomatic bradycardia (HR < 60 + hypotension/altered LOC/chest pain)
2. Draw up 0.5-1 mg from vial (undiluted)
3. Give IV FAST PUSH (over ~1 minute - do NOT give slowly)
→ Slow push or dose < 0.5 mg can worsen bradycardia (paradoxical effect)
4. Flush line with NS
5. Monitor HR and BP continuously
6. Repeat 0.5-1 mg every 5 min if needed
7. Maximum total dose = 3 mg (full vagal blockade)
8. If no response after 3 mg → consider transcutaneous pacing or dopamine/epinephrine
Key Points to Remember
| Point | Detail |
|---|---|
| Speed of injection | Always fast IV push - slow push causes paradoxical bradycardia |
| Minimum dose | 0.5 mg in adults to avoid paradoxical effect |
| Max adult total | 3 mg (except in organophosphate poisoning - no ceiling) |
| Compatible diluents | Normal saline (NS), D5W |
| Half-life | ~4 hours |
| Onset IV | ~1 minute |
| Duration | 30-60 minutes (cardiovascular effects) |
| Do NOT use in | Glaucoma (angle-closure), obstructive uropathy, tachycardia, thyrotoxicosis |
Dose-Effect by Amount (Adults)
Dose-dependent effects of atropine - Lippincott Illustrated Reviews: Pharmacology
Sources: Harriet Lane Handbook 23rd Ed | Morgan & Mikhail's Clinical Anesthesiology 7e | Tintinalli's Emergency Medicine | Lippincott Illustrated Reviews: Pharmacology | Barash's Clinical Anesthesia 9e
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