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norepinephrine; noradrenaline (Levophed)

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: 1) septic shock 2) 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: 1) onset of action 1-2 minutes 2) duration of action: 1-2 minutes 3) metabolized by: a) adrenergic nerve uptake b) catechol-O-methyl transferase (COMT) c) monoamine oxidase (MAO) 4) 1/2life is 2.5 minutes Adverse effects: 1) most common (1-10%) - dizziness, headache, trembling, insomnia, thyroid gland enlargement 2) uncommon (<1%) - hypertension, gangrene of extremities, cardiac arrhythmias, palpitations, tachycardia, bradycardia (treat with atropine) 3) other [3] a) lactic acidosis b) extravasation: - treated with 5-10 mg of phentolamine in 10-15 mL of NS - infiltrate involved area Drug interactions: 1) beta-blockers antagonize the effects of norepinephrine 2) general anesthetics in combination increase cardiac irritability 3) MAO inhibitors potentiate the direct pressor response Mechanism of action: 1) directly stimulates a) alpha-1 adrenergic receptors b) alpha-2 adrenergic receptors c) beta-1 adrenergic receptors 2) affinity for alpha-adrenergic receptors > beta-1 adrenergic receptors [5] 3) no direct action on beta-2 adrenergic receptors 4) positive inotropic effects 5) increases systolic & diastolic blood pressure 6) increases myocardial oxygen consumption 7) positive chronotrope overcome by vagal activity with resultant bradycardia 8) increases in coronary blood flow 8) decreases renal, skin, cerebral & muscle blood flow 10) increases glycogenolysis & inhibits insulin release, resulting in hyperglycemia 11) increases lipolysis Notes: - patients with septic shock more likely to die during a norepinephrine shortage [6]

Interactions

molecular events drug adverse effects (more general classes)

Related

adrenergic receptor Na+ dependent noradrenaline transporter; norepinephrine transporter; NET; solute carrier family 6 member 2 (SLC6A2, NAT1, NET1, SLC6A5) norepinephrine in plasma norepinephrine metabolism

General

alpha adrenergic receptor agonist antiasthmatic agent beta-1 adrenergic receptor agonist catecholamine vasoconstrictor agent or vasopressor

Properties

SIZE: MW = 169 G/MOL AGONIST-FOR: alpha adrenergic receptor beta adrenergic receptor MISC-INFO: elimination route PLASMA pregnancy-category ? safety in lactation ?

Database Correlations

PUBCHEM correlations

References

  1. The Pharmacological Basis of Therapeutics, 9th ed. Gilman et al, eds. Permagon Press/McGraw Hill, 1996
  2. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  3. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  4. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 221
  5. Medical Knowledge Self Assessment Program (MKSAP) 16, 17. American College of Physicians, Philadelphia 2012, 2015
  6. 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. PMID: 28322415 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 PMID: 28322412 http://jamanetwork.com/journals/jama/article-abstract/2612910