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Norepinephrine

PubChem CID
439260
Structure
Norepinephrine_small.png
Norepinephrine_3D_Structure.png
Molecular Formula
Synonyms
  • norepinephrine
  • noradrenaline
  • L-Noradrenaline
  • 51-41-2
  • Levarterenol
Molecular Weight
169.18 g/mol
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Dates
  • Create:
    2004-09-16
  • Modify:
    2025-01-18
Description
(R)-noradrenaline is the R-enantiomer of noradrenaline. It has a role as a vasoconstrictor agent, an alpha-adrenergic agonist, a sympathomimetic agent, a mouse metabolite and a neurotransmitter. It is a conjugate base of a (R)-noradrenaline(1+). It is an enantiomer of a (S)-noradrenaline.
Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic.
Norepinephrine is a Catecholamine.
See also: Droxidopa (is active moiety of); Norepinephrine Bitartrate (active moiety of); Norepinephrine hydrochloride (is active moiety of) ... View More ...

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Norepinephrine.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol
Computed by Lexichem TK 2.7.0 (PubChem release 2024.11.20)

2.1.2 InChI

InChI=1S/C8H11NO3/c9-4-8(12)5-1-2-6(10)7(11)3-5/h1-3,8,10-12H,4,9H2/t8-/m0/s1
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.3 InChIKey

SFLSHLFXELFNJZ-QMMMGPOBSA-N
Computed by InChI 1.07.0 (PubChem release 2024.11.20)

2.1.4 SMILES

C1=CC(=C(C=C1[C@H](CN)O)O)O
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C8H11NO3
Computed by PubChem 2.2 (PubChem release 2024.11.20)

2.3 Other Identifiers

2.3.1 CAS

51-41-2

2.3.3 Deprecated CAS

4899-05-2, 66197-73-7
4899-05-2

2.3.4 European Community (EC) Number

2.3.5 UNII

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DrugBank ID

2.3.9 DSSTox Substance ID

2.3.10 HMDB ID

2.3.11 KEGG ID

2.3.12 Metabolomics Workbench ID

2.3.13 NCI Thesaurus Code

2.3.14 Nikkaji Number

2.3.15 NSC Number

2.3.16 PharmGKB ID

2.3.17 Pharos Ligand ID

2.3.18 RXCUI

2.3.19 Wikidata

2.3.20 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Arterenol
  • Levarterenol
  • Levonor
  • Levonorepinephrine
  • Levophed
  • Levophed Bitartrate
  • Noradrénaline tartrate renaudin
  • Noradrenaline
  • Noradrenaline Bitartrate
  • Norepinephrin d-Tartrate (1:1)
  • Norepinephrine
  • Norepinephrine Bitartrate
  • Norepinephrine d-Tartrate (1:1)
  • Norepinephrine Hydrochloride
  • Norepinephrine Hydrochloride, (+)-Isomer
  • Norepinephrine Hydrochloride, (+,-)-Isomer
  • Norepinephrine l-Tartrate (1:1)
  • Norepinephrine l-Tartrate (1:1), (+,-)-Isomer
  • Norepinephrine l-Tartrate (1:1), Monohydrate
  • Norepinephrine l-Tartrate (1:1), Monohydrate, (+)-Isomer
  • Norepinephrine l-Tartrate (1:2)
  • Norepinephrine l-Tartrate, (+)-Isomer
  • Norepinephrine, (+)-Isomer
  • Norepinephrine, (+,-)-Isomer

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
169.18 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
XLogP3
Property Value
-1.2
Reference
Computed by XLogP3 3.0 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Donor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Rotatable Bond Count
Property Value
2
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Exact Mass
Property Value
169.07389321 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Monoisotopic Mass
Property Value
169.07389321 Da
Reference
Computed by PubChem 2.2 (PubChem release 2024.11.20)
Property Name
Topological Polar Surface Area
Property Value
86.7 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Heavy Atom Count
Property Value
12
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
142
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2024.11.20)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
1
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Colorless microcrystals
Pugsley TA; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Epinephrine and Norepinephrine. Online Posting Date: December 4, 2000.

3.2.3 Melting Point

217 dec °C
PhysProp
217 °C (decomposes)
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-400
145.2 - 146.4 °C

3.2.4 Solubility

Slightly soluble in water, ethanol, diethyl ether; very soluble in alkali, dilute hydrochloric acid
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 3-400
849 mg/mL

3.2.5 LogP

-1.24
HANSCH,C ET AL. (1995)
log Kow = -1.24
Hansch, C., Leo, A., D. Hoekman. Exploring QSAR - Hydrophobic, Electronic, and Steric Constants. Washington, DC: American Chemical Society., 1995., p. 46
-1.24
HANSCH,C ET AL. (1995)

3.2.6 Optical Rotation

Specific optical rotation: -37.3 deg at 25 °C/D (c = 5 in water with 1 equiv hydrochloric acid)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1157

3.2.7 Decomposition

When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746

3.2.8 Dissociation Constants

pKa
8.58
PERRIN,DD (1965)
pKa = 8.58 (conjugate acid)
Perrin DD; Dissociation constants of organic bases in aqueous solution. IUPAC Chem Data Ser, Buttersworth, London (1965)
pKa1 = 8.64; pKa2 = 9.70
Lide, D.R. CRC Handbook of Chemistry and Physics 88TH Edition 2007-2008. CRC Press, Taylor & Francis, Boca Raton, FL 2007, p. 8-48

3.2.9 Collision Cross Section

128.52 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

131.04 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

Ross et al. JASMS 2022; 33; 1061-1072. DOI:10.1021/jasms.2c00111
132.6 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

137.3 Ų [M+H-H2O]+ [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

136.8 Ų [M+H-H2O]+ [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

131.99 Ų [M-H]- [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

137.2 Ų [M-H2O+H]+ [CCS Type: DT; Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]

134.2 Ų [M-H]- [CCS Type: DT; Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]

137.1 Ų [M+H-H2O]+

134.4 Ų [M-H]-

S50 | CCSCOMPEND | The Unified Collision Cross Section (CCS) Compendium | DOI:10.5281/zenodo.2658162

3.3 Chemical Classes

3.3.1 Drugs

Pharmaceuticals -> Sympathomimetics
S57 | GREEKPHARMA | Suspect Pharmaceuticals from the National Organization of Medicine, Greece | DOI:10.5281/zenodo.3248883
Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Adrenergic Agonists; Adrenergic Alpha-Agonists; Catecholamines; Sympathomimetics; Vasoconstrictor Agents
Human drug -> Prescription

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 1H NMR Spectra

1 of 2
Spectra ID
Instrument Type
Varian
Frequency
500 MHz
Solvent
Water
pH
8.00
Shifts [ppm]:Intensity
6.95:100.00, 3.24:38.16, 6.84:30.80, 3.19:35.00, 3.23:35.99, 6.93:92.57, 3.26:14.01, 6.95:90.26, 3.21:36.76, 3.25:15.51, 6.84:35.78, 3.18:14.19, 6.86:45.73, 3.17:14.54, 6.86:52.77, 6.94:79.38
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2 of 2
Copyright
Database Compilation Copyright © 2021-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.1.2 13C NMR Spectra

1 of 5
View All
Spectra ID
Instrument Type
Bruker
Frequency
125 MHz
Solvent
Water
pH
7.00
Shifts [ppm]:Intensity
134.92:6.71, 119.10:18.83, 147.12:9.70, 72.10:17.12, 0.00:1.79, 48.15:18.83, 121.20:19.00, 116.64:18.33
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2 of 5
View All
Spectra ID
Frequency
400 MHz
Solvent
H2O
Shifts [ppm]
48.15, 116.64, 119.10, 72.10, 121.20, 134.92, 147.12
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4.2 2D NMR Spectra

4.2.1 1H-13C NMR Spectra

2D NMR Spectra Type
1H-13C HSQC
Spectra ID
Instrument Type
Bruker
Frequency
600 MHz
Solvent
Water
pH
7.00
Shifts [ppm] (F2:F1):Intensity
6.86:121.24:0.37, 3.21:48.18:0.16, 6.94:119.19:0.35, 3.26:48.25:0.26, 6.95:116.70:1.00
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4.3 Mass Spectrometry

4.3.1 GC-MS

1 of 8
View All
Spectra ID
Instrument Type
EI-B
Ionization Mode
positive
Top 5 Peaks

139.0 99.99

93.0 39.70

30.0 34.60

140.0 27.90

169.0 12.40

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Notes
instrument=HITACHI M-80
2 of 8
View All
Spectra ID
Instrument Type
GC-MS
Top 5 Peaks

174.0 1

175.0 0.21

86.0 0.17

176.0 0.10

355.0 0.08

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4.3.2 MS-MS

1 of 6
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

77.03818 100

118.92095 51.50

58.99424 44.70

56.96442 42.80

104.04917 40.70

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2 of 6
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

107.0478 100

79.05408 71.21

46.06441 32.92

55.93148 25.76

134.0599 24.59

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4.3.3 LC-MS

1 of 3
View All
MoNA ID
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
170
Instrument
API 3000
Instrument Type
QqQ
Ionization
ESI
Ionization Mode
positive
Collision Energy
10->40V
Top 5 Peaks

170 100

107 100

106 100

152 100

135 100

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2 of 3
View All
MS Category
Experimental
MS Type
LC-MS
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
170.0811692
Instrument
Thermo Q Exactive HF
Instrument Type
LC-ESI-QFT
Ionization Mode
positive
Collision Energy
HCD (NCE 20-30-40%)
Top 5 Peaks

152.07063 100

135.04404 55.80

107.04917 31

141.00046 12.60

77.0386 11

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4.3.4 Other MS

1 of 4
View All
Other MS
MASS: 6578 (NIST/EPA/MSDC Mass Spectral Database 1990 version)
2 of 4
View All
MS Category
Experimental
MS Type
Other
MS Level
MS2
Precursor Type
[M+H]+
Precursor m/z
170.08081767339584
Ionization Mode
positive
Retention Time
0.29
Top 5 Peaks

77.03854947668131 100

107.05084673306807 95.50

79.05430383062158 54.74

106.06436786601436 27.25

51.024757740505876 19.35

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4.4 UV Spectra

UV: 280 H2O pH 7 (HBCP)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V1: 894

4.5 Other Spectra

Unstable in light and air, especially at neutral and alkaline pH. Oxidation to noradrenochrome occurs in the presence of oxygen and such divalent metal ions as copper, manganese, and nickel.
Pugsley TA; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Epinephrine and Norepinephrine. Online Posting Date: December 4, 2000.
Crystals; decomposes at 191 °C; sparingly soluble in water; very slightly soluble in alcohol, ether; readily soluble in dilute acids, caustic. /dl-form/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1157

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Mainly used to treat patients in vasodilatory shock states such as septic shock and neurogenic shock and has shown a survival benefit over dopamine. Also used as a vasopressor medication for patients with critical hypotension.

7.2 Drug Classes

Breast Feeding; Lactation; Milk, Human; Adrenergic Agonists; Adrenergic Alpha-Agonists; Catecholamines; Sympathomimetics; Vasoconstrictor Agents

7.3 FDA National Drug Code Directory

7.4 Drug Labels

Homeopathic product and label

7.5 Clinical Trials

7.5.1 ClinicalTrials.gov

7.5.2 EU Clinical Trials Register

7.5.3 NIPH Clinical Trials Search of Japan

7.6 Therapeutic Uses

Norepinephrine is used to produce vasoconstriction and cardiac stimulation as an adjunct to correct hemodynamic imbalances in the treatment of shock that persists after adequate fluid volume replacement. /Included in US product label/
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1397
Epinephrine is the drug of choice in the emergency treatment of severe acute anaphylactic reactions, including anaphylactic shock. Once adequate ventilation is assured, maintenance of blood pressure in patients with anaphylactic shock may be achieved with other pressor agents, such as norepinephrine. /Included in US product label/
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1397
In hypotension associated with myocardial infarction, cautious administration of norepinephrine may be of value and some clinicians consider it to be the pressor drug of choice. However, this type of shock generally has a poor prognosis even when pressor agents are used, and norepinephrine-induced increases in myocardial oxygen demand and the work of the heart may outweigh the beneficial effects of the drug. In addition, cardiac arrhythmias due to the drug are more likely to occur in patients with myocardial infarction. If severe congestive heart failure is also present, dopamine may be preferable because it increases renal blood flow as well as stroke volume. If peripheral vascular resistance is elevated, isoproterenol may be used in conjunction with norepinephrine, but dosage of both drugs must be carefully adjusted according to the specific hemodynamic imbalances present. /Included in US product label/
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1397
Norepinephrine may be used to treat hypotension occurring during spinal anesthesia, but other vasopressors having a longer duration of action and which can be administered IM such as metaraminol, methoxamine, or phenylephrine are more commonly used. Norepinephrine may be used to treat hypotension occurring during general anesthesia; however, the possibility of cardiac arrhythmias should be considered. /Included in US product label/
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1398
For more Therapeutic Uses (Complete) data for Norepinephrine (7 total), please visit the HSDB record page.

7.7 Drug Warnings

Norepinephrine can cause severe peripheral and visceral vasoconstriction, reduced blood flow to vital organs, decreased renal perfusion and therefore decreased urine output, tissue hypoxia, and metabolic acidosis. These effects are most likely to occur in hypovolemic patients. In addition, prolonged use of norepinephrine may cause plasma volume depletion which may result in perpetuation of the shock state or recurrence of hypotension when the drug is discontinued.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1398
Prolonged administration of norepinephrine has caused edema, hemorrhage, focal myocarditis, subpericardial hemorrhage, necrosis of the intestine, or hepatic and renal necrosis. These effects have generally occurred in patients with severe shock and it is not clear if the drug or the shock state itself was the cause.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1399
Norepinephrine can cause tissue necrosis and sloughing at the site of injection as a result of local vasoconstriction. Impairment of circulation and sloughing of tissue may also occur without obvious extravasation. Gangrene of the extremities has been reported rarely and has occurred in a lower extremity when norepinephrine was injected into an ankle vein.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1398
Norepinephrine increases myocardial oxygen consumption and the work of the heart. Cardiac output may be decreased following prolonged use of the drug or administration of large doses because venous return to the heart may be diminished because of increased peripheral vascular resistance. Decreased cardiac output may be especially harmful to elderly patients or those with initially poor cerebral or coronary circulation. Norepinephrine may cause palpitation and bradycardia as well as potentially fatal cardiac arrhythmias, including ventricular tachycardia, bigeminal rhythm, nodal rhythm, atrioventricular dissociation, and fibrillation. Bradycardia may be treated by administration of atropine. Arrhythmias are especially likely to occur in patients with acute myocardial infarction, hypoxia, or hypercapnia, or those receiving other drugs which may increase cardiac irritability such as cyclopropane or halogenated hydrocarbon general anesthetics.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1398
For more Drug Warnings (Complete) data for Norepinephrine (19 total), please visit the HSDB record page.

7.8 Biomarker Information

8 Food Additives and Ingredients

8.1 Associated Foods

9 Pharmacology and Biochemistry

9.1 Pharmacodynamics

Noradrenaline acts on both alpha-1 and alpha-2 adrenergic receptors to cause vasoconstriction. Its effect in-vitro is often limited to the increasing of blood pressure through antagonising alpha-1 and alpha-2 receptors and causing a resultant increase in systemic vascular resistance.

9.2 MeSH Pharmacological Classification

Sympathomimetics
Drugs that mimic the effects of stimulating postganglionic adrenergic sympathetic nerves. Included here are drugs that directly stimulate adrenergic receptors and drugs that act indirectly by provoking the release of adrenergic transmitters. (See all compounds classified as Sympathomimetics.)
Adrenergic alpha-Agonists
Drugs that selectively bind to and activate alpha adrenergic receptors. (See all compounds classified as Adrenergic alpha-Agonists.)
Vasoconstrictor Agents
Drugs used to cause constriction of the blood vessels. (See all compounds classified as Vasoconstrictor Agents.)

9.3 FDA Pharmacological Classification

1 of 2
FDA UNII
X4W3ENH1CV
Active Moiety
NOREPINEPHRINE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Catecholamine
Pharmacological Classes
Chemical Structure [CS] - Catecholamines
FDA Pharmacology Summary
Norepinephrine is a Catecholamine.
2 of 2
Non-Proprietary Name
NOREPINEPHRINE
Pharmacological Classes
Catecholamines [CS]; Catecholamine [EPC]

9.4 ATC Code

S76 | LUXPHARMA | Pharmaceuticals Marketed in Luxembourg | Pharmaceuticals marketed in Luxembourg, as published by d'Gesondheetskeess (CNS, la caisse nationale de sante, www.cns.lu), mapped by name to structures using CompTox by R. Singh et al. (in prep.). List downloaded from https://cns.public.lu/en/legislations/textes-coordonnes/liste-med-comm.html. Dataset DOI:10.5281/zenodo.4587355

C - Cardiovascular system

C01 - Cardiac therapy

C01C - Cardiac stimulants excl. cardiac glycosides

C01CA - Adrenergic and dopaminergic agents

C01CA03 - Norepinephrine

9.5 Absorption, Distribution and Excretion

Norepinephrine localizes mainly in sympathetic nervous tissue. The drug crosses the placenta but not the blood-brain barrier.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1400
Orally ingested norepinephrine is destroyed in the GI tract, and the drug is poorly absorbed after subcutaneous injection. After IV administration, a pressor response occurs rapidly. The drug has a short duration of action, and the pressor action stops within 1-2 minutes after the infusion is discontinued.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1400
Norepinephrine, like epinephrine, is ineffective when given orally and is absorbed poorly from sites of subcutaneous injection. It is rapidly inactivated in the body by the same enzymes that methylate and oxidatively deaminate epinephrine. Small amounts normally are found in the urine. The excretion rate may be greatly increased in patients with pheochromocytoma.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2006., p. 248

9.6 Metabolism / Metabolites

The pharmacologic actions of norepinephrine are terminated primarily by uptake and metabolism in sympathetic nerve endings. The drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are normetanephrine and 3-methoxy-4-hydroxy mandelic acid (vanillylmandelic acid, VMA), both of which are inactive. Other inactive metabolites include 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglycol. Norepinephrine metabolites are excreted in urine primarily as the sulfate conjugates and, to a lesser extent, as the glucuronide conjugates. Only small quantities of norepinephrine are excreted unchanged.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1400
Uremic toxins tend to accumulate in the blood either through dietary excess or through poor filtration by the kidneys. Most uremic toxins are metabolic waste products and are normally excreted in the urine or feces.

9.7 Mechanism of Action

Norepinephrine functions as a peripheral vasoconstrictor by acting on alpha-adrenergic receptors. It is also an inotropic stimulator of the heart and dilator of coronary arteries as a result of it's activity at the beta-adrenergic receptors.
The pharmacological actions of norepinephrine and epinephrine have been extensively compared in vivo and in vitro. Both drugs are direct agonists on effector cells, and their actions differ mainly in the ratio of their effectiveness in stimulating alpha and beta2-receptors. They are approximately equipotent in stimulating beta1-receptors. Norepinephrine is a potent alpha agonist and has relatively little action on beta-2 receptors; however, it is somewhat less potent than epinephrine on the alpha receptors of most organs.
Hardman, J.G., L.E. Limbird, P.B., A.G. Gilman. Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill, 2006., p. 248
During cold exposures there is an immediate release of catecholamines (e.g., norepinephrine, dopamine), which activate the sympathetic nervous system to reduce heat loss via peripheral vasoconstriction and shift substrate utilization toward fatty acid metabolism for heat production.
Mahar H; Patty's Toxicology CD-ROM (2005). NY, NY: John Wiley & Sons; Cold Stress and Strain. Online Posting Date: April 16, 2001.

9.8 Human Metabolite Information

9.8.1 Tissue Locations

  • Adipose Tissue
  • Adrenal Cortex
  • Adrenal Gland
  • Adrenal Medulla
  • Bladder
  • Brain
  • Epidermis
  • Fibroblasts
  • Heart
  • Intestine
  • Kidney
  • Leukocyte
  • Neuron
  • Ovary
  • Pancreas
  • Placenta
  • Platelet
  • Prostate
  • Skeletal Muscle
  • Testis

9.8.2 Cellular Locations

Extracellular

9.8.3 Metabolite Pathways

9.9 Biochemical Reactions

10 Use and Manufacturing

10.1 Uses

Therapeutic Category: Adrenergic (vasopressor); antihypotensive
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1157
Therapeutic Category (VET): Sympathomimetic; vasopressor in shock
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 1157

Use (kg; approx.) in Germany (2009): >25

Consumption (g per capita; approx.) in Germany (2009): 0.000305

Calculated removal (%): 92.1

Mainly used to treat patients in vasodilatory shock states such as septic shock and neurogenic shock and has shown a survival benefit over dopamine. Also used as a vasopressor medication for patients with critical hypotension.

10.2 Methods of Manufacturing

... Obtained from 4-chloroacetylcatechol which is prepared from catechol by reaction with chloroacetic acid and POCl3.
Sandow J et al; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (2008). NY, NY: John Wiley & Sons; Hormones. Online Posting Date: June 15, 2000

10.3 Impurities

Adrenaline
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5071 (2006)
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5071 (2006)
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5071 (2006)
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th ed., Supplement 5.7; Strasbourg, France, p. 5071 (2006)
For more Impurities (Complete) data for Norepinephrine (7 total), please visit the HSDB record page.

10.4 Formulations / Preparations

Adrenor
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
Aktamin
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
Arterenol
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
1-Arterenol
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
For more Formulations/Preparations (Complete) data for Norepinephrine (10 total), please visit the HSDB record page.

11 Identification

11.1 Analytic Laboratory Methods

Analyte: norepinephrine bitartrate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
Analyte: norepinephrine bitartrate; matrix: chemical identification; procedure: dissolution in water; addition of ferric chloride; development of intense green color /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
Analyte: norepinephrine bitartrate; matrix: chemical identification; procedure: addition of iodine; addition of sodium thiosulfate; development of colorless or slightly pink or slightly violet color /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
Analyte: norepinephrine bitartrate; matrix: chemical purity; procedure: dissolution in acetic acid; addition of crystal violet indicator; titration with perchloric acid /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
For more Analytic Laboratory Methods (Complete) data for Norepinephrine (7 total), please visit the HSDB record page.

11.2 Clinical Laboratory Methods

Analyte: norepinephrine bitartrate; matrix: pharmaceutical preparation (injection solution); procedure: dissolution in water; addition of ferric chloride; development of intense green color (chemical identification) /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
Analyte: norepinephrine bitartrate; matrix: pharmaceutical preparation (injection solution); procedure: addition of iodine; addition of sodium thiosulfate; development of colorless or slightly pink or slightly violet color (chemical identification) /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
Analyte: norepinephrine bitartrate; matrix: pharmaceutical preparation (injection solution); procedure: liquid chromatography with ultraviolet detection at 280 nm and comparison to standards (chemical purity) /Norepinephrine bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 31/The National Formulary, NF 26; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p. 2824 (2008)
Analyte: norepinephrine; matrix: blood (whole), urine; procedure: high-performance liquid chromatography with ultraviolent detection at 220 nm
Gaillard Y, Pepin G; J Chromatogr A 763: 149-63 (1997). As cited in Lunn G; HPLC and CE methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
For more Clinical Laboratory Methods (Complete) data for Norepinephrine (8 total), please visit the HSDB record page.

12 Safety and Hazards

12.1 Hazards Identification

12.1.1 GHS Classification

Pictogram(s)
Acute Toxic
Signal
Danger
GHS Hazard Statements

H300 (97.8%): Fatal if swallowed [Danger Acute toxicity, oral]

H310 (87%): Fatal in contact with skin [Danger Acute toxicity, dermal]

H330 (89.1%): Fatal if inhaled [Danger Acute toxicity, inhalation]

Precautionary Statement Codes

P260, P262, P264, P270, P271, P280, P284, P301+P316, P302+P352, P304+P340, P316, P320, P321, P330, P361+P364, P403+P233, P405, and P501

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 46 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

12.1.2 Hazard Classes and Categories

Acute Tox. 1 (97.8%)

Acute Tox. 2 (87%)

Acute Tox. 1 (89.1%)

12.1.3 Fire Potential

This material is assumed to be combustible. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)

12.1.4 Skin, Eye, and Respiratory Irritations

Eye, skin, ... and/or respiratory tract irritation. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)

12.2 Fire Fighting

12.2.1 Fire Fighting Procedures

Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials. This material is assumed to be combustible. As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity. As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)

12.3 Accidental Release Measures

12.3.1 Cleanup Methods

Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately-labelled container for disposal. Wash spill site. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)

12.3.2 Disposal Methods

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.
SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

12.3.3 Preventive Measures

SRP: The scientific literature for the use of contact lenses by industrial workers is inconsistent. The benefits or detrimental effects of wearing contact lenses depend not only upon the substance, but also on factors including the form of the substance, characteristics and duration of the exposure, the uses of other eye protection equipment, and the hygiene of the lenses. However, there may be individual substances whose irritating or corrosive properties are such that the wearing of contact lenses would be harmful to the eye. In those specific cases, contact lenses should not be worn. In any event, the usual eye protection equipment should be worn even when contact lenses are in place.

12.4 Handling and Storage

12.4.1 Storage Conditions

Store at 20 deg to 25 °C (68 deg to 77 °F). ... Protect from light.
US Natl Inst Health; DailyMed. Current Medication Information for Norepinephrine (norephinephrine bitartrate) injection (April 2004). Available from, as of October 19, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6610

12.5 Exposure Control and Personal Protection

12.5.1 Personal Protective Equipment (PPE)

Wear approved respiratory protection, chemically compatible gloves and protective clothing. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)

12.6 Regulatory Information

12.6.1 FDA Requirements

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl norepinephrine bitartrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Norepinephrine bitartrate/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations.

12.7 Other Safety Information

Chemical Assessment

IMAP assessments - 1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-: Human health tier I assessment

IMAP assessments - 1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-: Environment tier I assessment

12.7.1 Toxic Combustion Products

Emits toxic fumes under fire conditions. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)

13 Toxicity

13.1 Toxicological Information

13.1.1 Toxicity Summary

Uremic toxins such as noradrenalin are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (A7868). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (A7869). Norepinephrine functions as a peripheral vasoconstrictor by acting on alpha-adrenergic receptors. It is also an inotropic stimulator of the heart and dilator of coronary arteries as a result of it's activity at the beta-adrenergic receptors.
A7868: Schulz AM, Terne C, Jankowski V, Cohen G, Schaefer M, Boehringer F, Tepel M, Kunkel D, Zidek W, Jankowski J: Modulation of NADPH oxidase activity by known uraemic retention solutes. Eur J Clin Invest. 2014 Aug;44(8):802-11. doi: 10.1111/eci.12297. PMID:25041433
A7869: Young GH, Wu VC: KLOTHO methylation is linked to uremic toxins and chronic kidney disease. Kidney Int. 2012 Apr;81(7):611-2. doi: 10.1038/ki.2011.461. PMID:22419041

13.1.2 Drug Induced Liver Injury

Compound
norepinephrine
DILI Annotation
No-DILI-Concern
Label Section
No match
References

M Chen, V Vijay, Q Shi, Z Liu, H Fang, W Tong. FDA-Approved Drug Labeling for the Study of Drug-Induced Liver Injury, Drug Discovery Today, 16(15-16):697-703, 2011. PMID:21624500 DOI:10.1016/j.drudis.2011.05.007

M Chen, A Suzuki, S Thakkar, K Yu, C Hu, W Tong. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today 2016, 21(4): 648-653. PMID:26948801 DOI:10.1016/j.drudis.2016.02.015

13.1.3 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

13.1.4 Health Effects

Chronic exposure to uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.

13.1.5 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

No information is available on the use of norepinephrine during breastfeeding. Because of its poor oral bioavailability and short half-life, any norepinephrine in milk is unlikely to affect the infant. High intravenous doses of norepinephrine might reduce milk production or milk letdown as well as decrease the concentration of beta-casein in milk.

◉ Effects in Breastfed Infants

Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk

Norepinephrine inhibits the synthesis of beta-casein via stimulation of adrenergic beta-2 receptors. Animal data indicate that norepinephrine can decrease serum prolactin and reduce milk production, as well as inhibit the release of oxytocin, which inhibits milk ejection.

13.1.6 Exposure Routes

Endogenous, Ingestion, Dermal (contact)

13.1.7 Symptoms

As a uremic toxin, this compound can cause uremic syndrome. Uremic syndrome may affect any part of the body and can cause nausea, vomiting, loss of appetite, and weight loss. It can also cause changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma. Abnormal bleeding, such as bleeding spontaneously or profusely from a very minor injury can also occur. Heart problems, such as an irregular heartbeat, inflammation in the sac that surrounds the heart (pericarditis), and increased pressure on the heart can be seen in patients with uremic syndrome. Shortness of breath from fluid buildup in the space between the lungs and the chest wall (pleural effusion) can also be present.

13.1.8 Acute Effects

13.1.9 Treatment

Kidney dialysis is usually needed to relieve the symptoms of uremic syndrome until normal kidney function can be restored.

13.1.10 Interactions

Cyclopropane and halothane anesthetics increase cardiac autonomic irritability and therefore seem to sensitize the myocardium to the action of intravenously administered epinephrine or norepinephrine bitartrate injection. Hence, the use of norepinephrine bitartrate injection during cyclopropane and halothane anesthesia is generally considered contraindicated because of the risk of producing ventricular tachycardia or fibrillation.
US Natl Inst Health; DailyMed. Current Medication Information for Norepinephrine (norephinephrine bitartrate) injection (April 2004). Available from, as of October 19, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6610
Enhanced pressor response may occur in patients taking monoamine oxidase (MAO) inhibitors owing to inhibition of neuronal metabolic degradation.
Olson, K.R. (Ed.); Poisoning & Drug Overdose. 5th ed. Lange Medical Books/McGraw-Hill. New York, N.Y. 2007., p. 487
Administration of furosemide or other diuretics may decrease arterial responsiveness to pressor drugs such as norepinephrine.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1399
Tricyclic antidepressants (e.g., imipramine), some antihistamines (especially diphenhydramine, tripelennamine, and dexchlorpheniramine), parenteral ergot alkaloids, guanethidine, or methyldopa may potentiate the pressor effects of norepinephrine, resulting in severe, prolonged hypertension. Norepinephrine should be given cautiously and in small doses to patients receiving these drugs. Potentiation may result from inhibition of tissue uptake of norepinephrine or by increased adrenoreceptor sensitivity to the drug. Monoamine oxidase (MAO) is one of the enzymes responsible for norepinephrine metabolism. Although some clinicians have reported that MAO inhibitors do not appear to potentiate the effects of norepinephrine to a clinically important extent, the manufacturer states that norepinephrine should be administered with extreme caution to patients receiving an MAO inhibitor because severe, prolonged hypertension may result.
American Society of Health System Pharmacists; AHFS Drug Information 2009. Bethesda, MD. (2009), p. 1399
For more Interactions (Complete) data for Norepinephrine (8 total), please visit the HSDB record page.

13.1.11 Antidote and Emergency Treatment

Remove from exposure. Remove contaminated clothing. Persons developing serious hypersensitivity (anaphylactic) reactions must receive immediate medical attention. If person is not breathing give artificial respiration. If breathing is difficult give oxygen. Obtain medical attention. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)
In the event of on overdose, supportive and symptomatic measures should be used. If blood pressure fails to lower, a short-acting alpha adrenergic blocking agent may be administered. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)
/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160
/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1

13.1.12 Human Toxicity Excerpts

/SIGNS AND SYMPTOMS/ Overdosage with norepinephrine may result in headache, severe hypertension, reflex bradycardia, marked increase in peripheral resistance, and decreased cardiac output. In case of accidental overdosage, as evidenced by excessive blood pressure elevation, discontinue norepinephrine until the condition of the patient stabilizes.
US Natl Inst Health; DailyMed. Current Medication Information for Norepinephrine (norephinephrine bitartrate) injection (April 2004). Available from, as of October 19, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6610
/SIGNS AND SYMPTOMS/ Overdoses or conventional doses in hypersensitive persons (e.g., hyperthyroid patients) cause severe hypertension with violent headache, photophobia, stabbing retrosternal pain, pallor, intense sweating, and vomiting.
US Natl Inst Health; DailyMed. Current Medication Information for Norepinephrine (norephinephrine bitartrate) injection (April 2004). Available from, as of October 19, 2009: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=6610
/SIGNS AND SYMPTOMS/ Possible allergic reaction to material if inhaled, ingested or in contact with skin. /Norepinephrine bitartrate/
United States Pharmacopeial Convention, Inc (USP); MSDS Database Online; Material Safety Data Sheet: Norepinephrine Bitartrate; Catalog Number: 1468501; (Revision Date: September 22, 2005)
/CASE REPORTS/ The syndrome of symmetrical peripheral gangrene is characterised by distal ischaemic damage in two or more extremities, without large vessel obstruction. Four patients with bilateral pedal ischaemia are described and their haemodynamic profiles presented. In all four cases the syndrome developed in association with noradrenaline administration, sepsis and DIC, despite a high cardiac output and a low calculated systemic vascular resistance index. Early treatment with epoprostenol was instituted in the final case and was successful.
Hayes MA et al; Intensive Care Med 18 (7): 433-6 (1992).
/OTHER TOXICITY INFORMATION/ A rare case of cardiac failure due to hypertensive crisis in pheochromocytoma in a 25-year-old young man is presented. In the Emergency Department the patient complained of persisting headache and vomiting; he was distressed but fully alert, his heart rate was 110 b/min and blood pressure 180/80 mmHg. Few hours after admission, the clinical course suddenly got worse with signs and symptoms of fatal cardiac shock (dyspnea, cyanosis, pulmonary edema, hypocontractility of left ventricle). Autopsy revealed a large tumor of the left adrenal gland. Histological examination confirmed macroscopic suspicion of pheochromocytoma. Catecholamine serum levels were analysed by high pressure liquid chromatography (HPLC) with electrochemical detection. The urine contained 35 ug/24 hr norepinephrine and 184 ug/24 hr epinephrine (normal range < or = 64 and < or = 36 ug/24 hr respectively). These laboratory findings impressively demonstrate that the tumor was active, secreting high levels of epinephrine. Cardiac failure due to an acute catecholamine-related hypertensive crisis was established as the cause of death.
D'Errico S et al; Forensic Sci Int 187 (1-3): e13-7 (2009).

13.1.13 Non-Human Toxicity Values

LD50 Rat iv 100 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
LD50 Mouse oral 20 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
LD50 Mouse ip 6 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
LD50 Mouse sc 5 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2746
LD50 Mouse iv 550 ug/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 3746

13.2 Ecological Information

13.2.1 Environmental Fate / Exposure Summary

Norepinephrine's production and use as adrenergic and antihypotensive medicines may result in its release to the environment through various waste streams. Norepinephrine is a naturally occurring neurotransmitter in the periphery and in adrenergic neurons in the central nervous system, which is released from sympathetic nerve terminals. If released to air, an estimated vapor pressure of 7.5X10-8 mm Hg at 25 °C indicates norepinephrine will exist solely in the particulate phase in the atmosphere. Particulate-phase norepinephrine will be removed from the atmosphere by wet or dry deposition. Norepinephrine is unstable in light and air, especially at neutral and alkaline pH; oxidation to noradrenochrome occurs. If released to soil, norepinephrine is expected to have very high mobility based upon an estimated Koc of 5.0. Values for pKa1 and pKa2 of 8.64 and 9.70, respectively, indicate that norepinephrine will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 3.2X10-19 atm-cu m/mole. Norepinephrine is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Biodegradation data for norepinephrine were not available. If released into water, norepinephrine is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. Values for pKa1 and pKa2 of 8.64 and 9.70, respectively, indicate that norepinephrine will exist partially in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 3.2 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to norepinephrine may occur through inhalation of dust and dermal contact with this compound at workplaces where norepinephrine is produced or used. Exposure to norepinephrine among the general population may be limited to those administered drugs containing norepinephrine, a catecholamine. (SRC)

13.2.2 Natural Pollution Sources

Norepinephrine is a naturally occurring neurotransmitter in the periphery and in adrenergic neurons in the central nervous system, which is released from sympathetic nerve terminals(1).
(1) Pugsley TA; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Epinephrine and Norepinephrine. Online Posting Date: December 4, 2000.

13.2.3 Artificial Pollution Sources

Norepinephrine's production and use as adrenergic and antihypotensive medicines(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 14th ed., Whitehouse Station, NJ: Merck and Co., Inc., p. 1157 (2006)

13.2.4 Environmental Fate

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 5.0(SRC), determined from a log Kow of -1.24(2) and a regression-derived equation(3), indicates that norepinephrine is expected to have very high mobility in soil(SRC). Values for pKa1 and pKa2 of 8.64 and 9.70, respectively(4), indicate that norepinephrine will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization of norepinephrine from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.2X10-19 atm-cu m/mole(SRC), using a fragment constant estimation method(6). Norepinephrine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.5X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(7). Biodegradation data for norepinephrine were not available(SRC,2009).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc (1995)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of October 19, 2009.
(4) Lide DR, ed; CRC Handbook of Chemistry and Physics 88th ed., 2007-2008. Boca Raton, FL: CRC Press, Taylor & Francis, p. 8-48 (2007)
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(6) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(7) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 5.0(SRC), determined from a log Kow of -1.24(2) and a regression-derived equation(3), indicates that norepinephrineis not expected to adsorb to suspended solids and sediment(SRC). Values for pKa1 and pKa2 of 8.64 and 9.70, respectively(4), indicate that norepinephrine will exist partially in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(5). According to a classification scheme(6), an estimated BCF of 3.2(SRC), from its log Kow(2) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data for norepinephrine were not available(SRC,2009).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 46 (1995)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of October 19, 2009.
(4) Lide DR, ed; CRC Handbook of Chemistry and Physics 88th ed., 2007-2008. Boca Raton, FL: CRC Press, Taylor & Francis, p. 8-48 (2007)
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds, Boca Raton, FL: Lewis Publ (2000)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
(7) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), norepinephrine, which has an estimated vapor pressure of 7.5X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase norepinephrine may be removed from the air by wet or dry deposition(SRC). Norepinephrine is unstable in light and air, especially at neutral and alkaline pH; oxidation to noradrenochrome occurs(3).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)
(3) Pugsley TA; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Epinephrine and Norepinephrine. Online Posting Date: December 4, 2000.

13.2.5 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of norepinephrine with photochemically-produced hydroxyl radicals has been estimated as 9.5X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 4.1 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Norepinephrine is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Norepinephrine is unstable in light and air, especially at neutral and alkaline pH; oxidation to noradrenochrome occurs(3).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)
(3) Pugsley TA; Kirk-Othmer Encyclopedia of Chemical Technology. (2005). NY, NY: John Wiley & Sons; Epinephrine and Norepinephrine. Online Posting Date: December 4, 2000.

13.2.6 Environmental Bioconcentration

An estimated BCF of 3.2 was calculated for norepinephrine(SRC), using a log Kow of -1.24(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 46 (1995)
(2) Meylan WM et al; Environ Toxicol Chem 18: 664-72 (1999)
(3) Franke C et al; Chemosphere 29: 1501-14 (1994)

13.2.7 Soil Adsorption / Mobility

The Koc of norepinephrine is estimated as 5.0(SRC), using a log Kow of -1.24(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that norepinephrine is expected to have very high mobility in soil. Values for pKa1 and pKa2 of 8.64 and 9.70, respectively(4), indicate that norepinephrine will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).
(1) Hansch C et al; Exploring QSAR. Hydrophobic, Electronic, and Steric Constants. ACS Prof Ref Book. Heller SR, consult. ed., Washington, DC: Amer Chem Soc p. 46 (1995)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.0. Jan, 2009. Available from https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm as of October 19, 2009.
(3) Swann RL et al; Res Rev 85: 17-28 (1983)
(4) Lide DR, ed; CRC Handbook of Chemistry and Physics 88th ed., 2007-2008. Boca Raton, FL: CRC Press, Taylor & Francis, p. 8-48 (2007)
(5) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)

13.2.8 Volatilization from Water / Soil

The Henry's Law constant for norepinephrine is estimated as 3.2X10-19 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that neutral norepinephrine is expected to be essentially nonvolatile from water surfaces(2). Norepinephrine's Henry's Law constant indicates that volatilization from moist soil surfaces is not expected to occur(SRC). Furthermore, values for pKa1 and pKa2 of 8.64 and 9.70, respectively(3), indicate that norepinephrine will exist partially in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(4). Norepinephrine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 7.5X10-8 mm Hg(SRC), determined from a fragment constant method(5).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) Lide DR, ed; CRC Handbook of Chemistry and Physics 88th ed., 2007-2008. Boca Raton, FL: CRC Press, Taylor & Francis, p. 8-48 (2007)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Lyman WJ; p. 31 in Environmental Exposure From Chemicals Vol I, Neely WB, Blau GE, eds, Boca Raton, FL: CRC Press (1985)

13.2.9 Environmental Water Concentrations

While data specific to norepinephrine were not located(SRC, 2009), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).
(1) Heberer T; Tox Lett 131: 5-17 (2002)
(2) Koplin DW et al; Environ Sci Toxicol 36: 1202-211 (2002)

13.2.10 Probable Routes of Human Exposure

NIOSH (NOES Survey 1981-1983) has statistically estimated that 613 workers (175 of these were female) were potentially exposed to norepinephrine in the US(1). Occupational exposure to norepinephrine may occur through inhalation of dust and dermal contact with this compound at workplaces where norepinephrine is produced or used. Exposure to norepinephrine among the general population may be limited to those administered drug containing norepinephrine, a catecholamine(SRC).
(1) NIOSH; NOES. National Occupational Exposure Survey conducted from 1981-1983. Estimated numbers of employees potentially exposed to specific agents by 2-digit standard industrial classification (SIC). Available from, as of October 19, 2009: https://www.cdc.gov/noes/

13.2.11 Body Burden

In eight cases of injection of norepinephrine into healthy volunteers age 22 to 26 years old, blood plasma samples contained a mean norepinephrine concentration of 0.48 ng/mL (control), 0.58 ng/mL (1 mg/kg ethanol), 0.85 ng/mL (24 ng/kg/min IV for 20 min), 1.22 ng/mL (24 ng/kg/min IV for 20 min, after 1 mg/kg ethanol), 1.26 ng/mL (48 ng/kg/min IV for 20 min), 1.76 ng/mL (48 ng/kg/min IV for 20 min, after 1 mg/kg ethanol), 2.06 ng/mL (90 ng/kg/min IV for 20 min), and 2.49 ng/mL (90 ng/kg/min IV for 20 min, after 1 mg/kg ethanol)(1).
(1) Cone MV et al; National Body-Burden Database Chemicals Identified in Human Biological Media, 1984 Volume VII, Part 1,2,3. EPA-560-5-84-003. (1986)

14 Associated Disorders and Diseases

Disease
Subarachnoid hemorrhage
References
Disease
Heat stress
References
PubMed: 16309771
Disease
Pheochromocytoma
References
Disease
Uremia
References

PubMed: 11865086, 10509899, 9607216, 7482520, 6520173, 22626821, 21359215, 2026685, 9573551, 24023812, 15353324, 19309105, 8087979, 17132244, 12675874

Merck Manual of Diagnosis and Therapy.

David F. Putnam Composition and Concentrative Properties of Human Urine. NASA Contractor Report. July 1971

Geigy Scientific Tables, 8th Rev edition, pp. 130. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp. Basel, Switzerland c1981-1992.

Geigy Scientific Tables, 8th Rev edition, pp. 165-177. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp., Basel, Switzerland c1981-1992.

National Health and Nutrition Examination Survey (NHANES Survey) 2013

Geigy Scientific Tables, 8th Rev edition, pp. 80-82. Edited by C. Lentner, West Cadwell, N.J.: Medical education Div., Ciba-Geigy Corp., Basel, Switzerland c1981-1992.

Disease
Dopamine Beta-Hydroxylase Deficiency
References
GeneReviews: Dopamine Beta-Hydroxylase Deficiency: https://www.ncbi.nlm.nih.gov/books/NBK1474/
Disease
Methamphetamine (MAP) psychosis
References
PubMed: 8878306
Disease
Hypothyroidism
References
Disease
Cerebral infarction
References
Disease
Bacterial meningitis
References
Disease
Encephalitis
References
Disease
Dopamine-serotonin Vesicular Transport Defect
References
PubMed: 23363473

15 Literature

15.1 Consolidated References

15.2 NLM Curated PubMed Citations

15.3 Springer Nature References

15.4 Thieme References

15.5 Wiley References

15.6 Nature Journal References

15.7 Chemical Co-Occurrences in Literature

15.8 Chemical-Gene Co-Occurrences in Literature

15.9 Chemical-Disease Co-Occurrences in Literature

16 Patents

16.1 Depositor-Supplied Patent Identifiers

16.2 WIPO PATENTSCOPE

16.3 Chemical Co-Occurrences in Patents

16.4 Chemical-Disease Co-Occurrences in Patents

16.5 Chemical-Gene Co-Occurrences in Patents

17 Interactions and Pathways

17.1 Protein Bound 3D Structures

17.1.1 Ligands from Protein Bound 3D Structures

PDBe Ligand Code
PDBe Structure Code
PDBe Conformer

17.2 Chemical-Target Interactions

17.3 Drug-Drug Interactions

17.4 Pathways

18 Biological Test Results

18.1 BioAssay Results

19 Taxonomy

WormJam Metabolites Local CSV for MetFrag | DOI:10.5281/zenodo.3403364
WormJam: A consensus C. elegans Metabolic Reconstruction and Metabolomics Community and Workshop Series, Worm, 6:2, e1373939, DOI:10.1080/21624054.2017.1373939
Zebrafish Pathway Metabolite MetFrag Local CSV (Beta) | DOI:10.5281/zenodo.3457553
The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106
A metabolome atlas of the aging mouse brain. Nat Commun. 2021 Oct 15;12(1):6021. DOI:10.1038/s41467-021-26310-y. PMID:34654818; PMCID:PMC8519999.
The Metabolome Atlas of the Aging Mouse Brain: https://mouse.atlas.metabolomics.us

20 Classification

20.1 MeSH Tree

20.2 NCI Thesaurus Tree

20.3 ChEBI Ontology

20.4 KEGG: Metabolite

20.5 KEGG: Drug

20.6 KEGG: ATC

20.7 KEGG: Target-based Classification of Drugs

20.8 KEGG: JP15

20.9 KEGG: Drug Groups

20.10 WHO ATC Classification System

20.11 FDA Pharm Classes

20.12 ChemIDplus

20.13 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

20.14 ChEMBL Target Tree

20.15 UN GHS Classification

20.16 NORMAN Suspect List Exchange Classification

20.17 CCSBase Classification

20.18 EPA DSSTox Classification

20.19 LOTUS Tree

20.20 EPA Substance Registry Services Tree

20.21 MolGenie Organic Chemistry Ontology

21 Information Sources

  1. Australian Industrial Chemicals Introduction Scheme (AICIS)
    1,2-Benzenediol, 4-(2-amino-1-hydroxyethyl)-, (R)-
    https://services.industrialchemicals.gov.au/search-assessments/
  2. CAS Common Chemistry
    LICENSE
    The data from CAS Common Chemistry is provided under a CC-BY-NC 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc/4.0/
  3. ChemIDplus
    ChemIDplus Chemical Information Classification
    https://pubchem.ncbi.nlm.nih.gov/source/ChemIDplus
  4. DrugBank
    LICENSE
    Creative Common's Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/legalcode)
    https://www.drugbank.ca/legal/terms_of_use
  5. DTP/NCI
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  6. EPA DSSTox
    CompTox Chemicals Dashboard Chemical Lists
    https://comptox.epa.gov/dashboard/chemical-lists/
  7. European Chemicals Agency (ECHA)
    LICENSE
    Use of the information, documents and data from the ECHA website is subject to the terms and conditions of this Legal Notice, and subject to other binding limitations provided for under applicable law, the information, documents and data made available on the ECHA website may be reproduced, distributed and/or used, totally or in part, for non-commercial purposes provided that ECHA is acknowledged as the source: "Source: European Chemicals Agency, http://echa.europa.eu/". Such acknowledgement must be included in each copy of the material. ECHA permits and encourages organisations and individuals to create links to the ECHA website under the following cumulative conditions: Links can only be made to webpages that provide a link to the Legal Notice page.
    https://echa.europa.eu/web/guest/legal-notice
  8. FDA Global Substance Registration System (GSRS)
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  9. Hazardous Substances Data Bank (HSDB)
  10. Human Metabolome Database (HMDB)
    LICENSE
    HMDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (HMDB) and the original publication (see the HMDB citing page). We ask that users who download significant portions of the database cite the HMDB paper in any resulting publications.
    http://www.hmdb.ca/citing
  11. CCSbase
    CCSbase Classification
    https://ccsbase.net/
  12. NORMAN Suspect List Exchange
    LICENSE
    Data: CC-BY 4.0; Code (hosted by ECI, LCSB): Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    Noradrenaline
    NORMAN Suspect List Exchange Classification
    https://www.norman-network.com/nds/SLE/
  13. ChEBI
  14. FDA Pharm Classes
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  15. LOTUS - the natural products occurrence database
    LICENSE
    The code for LOTUS is released under the GNU General Public License v3.0.
    https://lotus.nprod.net/
  16. NCI Thesaurus (NCIt)
    LICENSE
    Unless otherwise indicated, all text within NCI products is free of copyright and may be reused without our permission. Credit the National Cancer Institute as the source.
    https://www.cancer.gov/policies/copyright-reuse
  17. Open Targets
    LICENSE
    Datasets generated by the Open Targets Platform are freely available for download.
    https://platform-docs.opentargets.org/licence
  18. Toxin and Toxin Target Database (T3DB)
    LICENSE
    T3DB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (T3DB) and the original publication.
    http://www.t3db.ca/downloads
  19. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
  20. ClinicalTrials.gov
    LICENSE
    The ClinicalTrials.gov data carry an international copyright outside the United States and its Territories or Possessions. Some ClinicalTrials.gov data may be subject to the copyright of third parties; you should consult these entities for any additional terms of use.
    https://clinicaltrials.gov/ct2/about-site/terms-conditions#Use
  21. Comparative Toxicogenomics Database (CTD)
    LICENSE
    It is to be used only for research and educational purposes. Any reproduction or use for commercial purpose is prohibited without the prior express written permission of NC State University.
    http://ctdbase.org/about/legal.jsp
  22. Drug Gene Interaction database (DGIdb)
    LICENSE
    The data used in DGIdb is all open access and where possible made available as raw data dumps in the downloads section.
    http://www.dgidb.org/downloads
  23. IUPHAR/BPS Guide to PHARMACOLOGY
    LICENSE
    The Guide to PHARMACOLOGY database is licensed under the Open Data Commons Open Database License (ODbL) https://opendatacommons.org/licenses/odbl/. Its contents are licensed under a Creative Commons Attribution-ShareAlike 4.0 International License (http://creativecommons.org/licenses/by-sa/4.0/)
    https://www.guidetopharmacology.org/about.jsp#license
    Guide to Pharmacology Target Classification
    https://www.guidetopharmacology.org/targets.jsp
  24. Therapeutic Target Database (TTD)
  25. DailyMed
  26. Drug Induced Liver Injury Rank (DILIrank) Dataset
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  27. IUPAC Digitized pKa Dataset
    ethanol, 2-amino-1-(3,4-dihydroxyphenyl)-
    https://github.com/IUPAC/Dissociation-Constants
  28. Drugs and Lactation Database (LactMed)
  29. Drugs@FDA
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  30. ECI Group, LCSB, University of Luxembourg
    LICENSE
    Data: CC-BY 4.0; Code: Artistic-2.0
    https://creativecommons.org/licenses/by/4.0/
    (R)-noradrenaline
  31. Natural Product Activity and Species Source (NPASS)
  32. West Coast Metabolomics Center-UC Davis
    Noradrenaline
  33. EU Clinical Trials Register
  34. National Drug Code (NDC) Directory
    LICENSE
    Unless otherwise noted, the contents of the FDA website (www.fda.gov), both text and graphics, are not copyrighted. They are in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from FDA. Credit to the U.S. Food and Drug Administration as the source is appreciated but not required.
    https://www.fda.gov/about-fda/about-website/website-policies#linking
  35. FooDB
    LICENSE
    FooDB is offered to the public as a freely available resource. Use and re-distribution of the data, in whole or in part, for commercial purposes requires explicit permission of the authors and explicit acknowledgment of the source material (FooDB) and the original publication.
    https://foodb.ca/about
  36. MassBank of North America (MoNA)
    LICENSE
    The content of the MoNA database is licensed under CC BY 4.0.
    https://mona.fiehnlab.ucdavis.edu/documentation/license
  37. NIST Mass Spectrometry Data Center
    LICENSE
    Data covered by the Standard Reference Data Act of 1968 as amended.
    https://www.nist.gov/srd/public-law
  38. SpectraBase
    L-alpha-(AMINOMETHYL)-3,4-DIHYDROXYBENZYL ALCOHOL
    https://spectrabase.com/spectrum/JEo3U8RmmW
  39. Japan Chemical Substance Dictionary (Nikkaji)
  40. KEGG
    LICENSE
    Academic users may freely use the KEGG website. Non-academic use of KEGG generally requires a commercial license
    https://www.kegg.jp/kegg/legal.html
    Therapeutic category of drugs in Japan
    http://www.genome.jp/kegg-bin/get_htext?br08301.keg
    Anatomical Therapeutic Chemical (ATC) classification
    http://www.genome.jp/kegg-bin/get_htext?br08303.keg
    Target-based classification of drugs
    http://www.genome.jp/kegg-bin/get_htext?br08310.keg
    Drugs listed in the Japanese Pharmacopoeia
    http://www.genome.jp/kegg-bin/get_htext?br08311.keg
  41. MarkerDB
    LICENSE
    This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
    https://markerdb.ca/
  42. Metabolomics Workbench
  43. Nature Chemical Biology
  44. NIPH Clinical Trials Search of Japan
  45. NLM RxNorm Terminology
    LICENSE
    The RxNorm Terminology is created by the National Library of Medicine (NLM) and is in the public domain and may be republished, reprinted and otherwise used freely by anyone without the need to obtain permission from NLM. Credit to the U.S. National Library of Medicine as the source is appreciated but not required. The full RxNorm dataset requires a free license.
    https://www.nlm.nih.gov/research/umls/rxnorm/docs/termsofservice.html
  46. WHO Anatomical Therapeutic Chemical (ATC) Classification
    LICENSE
    Use of all or parts of the material requires reference to the WHO Collaborating Centre for Drug Statistics Methodology. Copying and distribution for commercial purposes is not allowed. Changing or manipulating the material is not allowed.
    https://www.whocc.no/copyright_disclaimer/
  47. PharmGKB
    LICENSE
    PharmGKB data are subject to the Creative Commons Attribution-ShareALike 4.0 license (https://creativecommons.org/licenses/by-sa/4.0/).
    https://www.pharmgkb.org/page/policies
  48. Pharos
    LICENSE
    Data accessed from Pharos and TCRD is publicly available from the primary sources listed above. Please respect their individual licenses regarding proper use and redistribution.
    https://pharos.nih.gov/about
  49. Protein Data Bank in Europe (PDBe)
  50. RCSB Protein Data Bank (RCSB PDB)
    LICENSE
    Data files contained in the PDB archive (ftp://ftp.wwpdb.org) are free of all copyright restrictions and made fully and freely available for both non-commercial and commercial use. Users of the data should attribute the original authors of that structural data.
    https://www.rcsb.org/pages/policies
  51. Springer Nature
  52. Thieme Chemistry
    LICENSE
    The Thieme Chemistry contribution within PubChem is provided under a CC-BY-NC-ND 4.0 license, unless otherwise stated.
    https://creativecommons.org/licenses/by-nc-nd/4.0/
  53. Wikidata
  54. Wikipedia
  55. Wiley
  56. Medical Subject Headings (MeSH)
    LICENSE
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    https://www.nlm.nih.gov/copyright.html
  57. PubChem
  58. GHS Classification (UNECE)
  59. EPA Substance Registry Services
  60. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  61. PATENTSCOPE (WIPO)
  62. NCBI
CONTENTS