norepinephrine; noradrenaline (Levophed)
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Function
- inhibitory neurotransmitter of the central nervous system & the sympathetic nervous system
- the most prominent nucleus in the CNS containing noradrenergic neurons is the locus ceruleus
- most of the remaining noradrenergic neurons are clustered in the lateral tegmental area
- also released by chromaffin cells of the adrenal medulla in response to stress.
- effects are mediated via adrenergic receptors
Pharmacology
Tradenames: Levarterenol, Levophed. Norepinephrine bitartrate.
Indications
- septic shock
- hypotension persistent after adequate fluid volume replacement
Contraindications
- Caution: in patients with hyperthyroidism
* progressive mobility program in ICU patients on low-dose vasodilators safe[5]
Dosage
4 mg in 500 mL D5W (8 ug/mL):
initiate at 2-4 ug/min (adults), 0.05-0.1 ug/kg/min (children)*
20 mL/hr = 3 ug/min
titrate to desired response
adults: 2-20 ug/min
dose ug/kg/min x weight kg x 60 min/hr
* Rate mL/hr = --------------------------------------
concentration ug/mL
Pharmacokinetics
- onset of action 1-2 minutes
- duration of action: 1-2 minutes
- metabolized by:
- adrenergic nerve uptake
- catechol-O-methyl transferase (COMT)
- monoamine oxidase (MAO)
- 1/2life is 2.5 minutes
elimination via plasma
Adverse effects
- most common (1-10%)
- dizziness, headache, trembling, insomnia, thyroid gland enlargement
- uncommon (<1%)
- hypertension, gangrene of extremities, cardiac arrhythmias, palpitations, tachycardia, bradycardia (treat with atropine)
- other[3]
- lactic acidosis
- extravasation:
- treated with 5-10 mg of phentolamine in 10-15 mL of NS
- infiltrate involved area
- drug adverse effects of adrenergic receptor agonists
- drug adverse effects of beta-adrenergic receptor agonists
- drug adverse effects of alpha-adrenergic receptor agonists
- drug adverse effects of sympathomimetic(s)
Drug interactions
- beta-blockers antagonize the effects of norepinephrine
- general anesthetics in combination increase cardiac irritability
- MAO inhibitors potentiate the direct pressor response
Mechanism of action
- directly stimulates
- affinity for alpha-adrenergic receptors > beta-1 adrenergic receptors[5]
- no direct action on beta-2 adrenergic receptors
- positive inotropic effects
- increases systolic & diastolic blood pressure
- increases myocardial oxygen consumption
- positive chronotrope overcome by vagal activity with resultant bradycardia
- increases in coronary blood flow
- decreases renal, skin, cerebral & muscle blood flow
- increases glycogenolysis & inhibits insulin release, resulting in hyperglycemia
- increases lipolysis
Notes
- patients with septic shock more likely to die during a norepinephrine shortage[6]
More general terms
- catecholamine
- alpha adrenergic receptor agonist
- beta-1 adrenergic receptor agonist
- vasoconstrictor agent or vasopressor
- antiasthmatic agent
Additional terms
- adrenergic receptor
- Na+ dependent noradrenaline transporter; norepinephrine transporter; NET; solute carrier family 6 member 2 (SLC6A2, NAT1, NET1, SLC6A5)
- norepinephrine in plasma
- norepinephrine metabolism
References
- ↑ The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 3.0 3.1 Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 221
- ↑ 5.0 5.1 5.2 Medical Knowledge Self Assessment Program (MKSAP) 16, 17. American College of Physicians, Philadelphia 2012, 2015
- ↑ 6.0 6.1 Vail E, Gershengorn HB, Hua M, Walkey AJ, Rubenfeld G, Wunsch H. Association between US norepinephrine shortage and mortality among patients with septic shock. JAMA 2017 Apr 11; 317:1433. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28322415 <Internet> http://jamanetwork.com/journals/jama/article-abstract/2612912
Donohue JM, Angus DC. National shortages of generic sterile injectable drugs: Norepinephrine as a case study of potential harm. JAMA 2017 Apr 11; 317:1415 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/28322412 <Internet> http://jamanetwork.com/journals/jama/article-abstract/2612910
Database
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=951
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5814
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=439260
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=297812
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5813
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=168929
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9488
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3047796