α1-adrenergic receptor; α2-adrenergic receptor; Beta-1 adrenergic receptor; Microbial Metabolite; Human Endogenous Metabolite

Norepinephrine (NE) is typically thought to be a β2-initiator receptor and an β1-subtype β1-initiator agonist. At lower concentrations, norepinephrine (NE) also exhibits direct activity on β2-initiator receptors [1]. From newborn wild-type C57BL/6J mice, the inguinal fat pad (iWA) or intershoulder fat pad (BA) were separated and cultured. cAMP production in response to co-treatment with norepinephrine (NE, 10 μM) with or without CGP (10 nM) was first measured in order to investigate the impact of activating AT2 on β-primergic signaling. NE, or norepinephrine, raises cAMP. As anticipated in iWA, CGP doesn't change this result. In addition to stimulating heat production and requiring released media for the functional activation of the UCP1 protein, norepinephrine (NE) is also known to cause fat loss.

Norepinephrine can be utilized to create animal models in animal models.

Subcutaneous preadipocytes are immortalized with TERT and HPV E6/E7 from a 38-year-old female donor who is not diabetic. To facilitate the current investigations, ring cloning is used to isolate a stable diploid clone (called clone B) with a constant capacity for differentiation. Proadipocyte PGM2 medium is used to cultivate cells. Incubation in differentiation media containing dexamethasone, IBMX, indomethacin, and extra insulin induces differentiation in cells once they are confluent. During ten days, cells differentiate. The media used for treatments is changed to serum-free media overnight after being replaced with PGM2 media for a day. NE (10 μM), CGP (10 nM), vehicle, or NE and CGP are the treatments given to adipocytes for six hours[2].

Absorption, Distribution and Excretion
Norepinephrine localizes mainly in sympathetic nervous tissue. The drug crosses the placenta but not the blood-brain barrier.
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.
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.

---

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.
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.

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.

---

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.

---

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.
Enhanced pressor response may occur in patients taking monoamine oxidase (MAO) inhibitors owing to inhibition of neuronal metabolic degradation.
Administration of furosemide or other diuretics may decrease arterial responsiveness to pressor drugs such as norepinephrine.
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.
For more Interactions (Complete) data for Norepinephrine (8 total), please visit the HSDB record page.

---

Non-Human Toxicity Values
LD50 Rat iv 100 ug/kg
LD50 Mouse oral 20 mg/kg
LD50 Mouse ip 6 mg/kg
LD50 Mouse sc 5 mg/kg
LD50 Mouse iv 550 ug/kg

[1]. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther. 2007 Mar;113(3):523-36.

[2]. Relative efficacy and potency of beta-adrenoceptor agonists for generating cAMP in human lymphocytes. Chest. 1996 Jan;109(1):194-200.

[3]. Suppression of Resting Metabolism by the Angiotensin AT2 Receptor. Cell Rep. 2016 Aug 9;16(6):1548-60.

[4]. Binding pathway determines norepinephrine selectivity for the human β 1 AR over β 2 AR. Cell Res. 2021 May;31(5):569-579.

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/
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/
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/
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/
For more Therapeutic Uses (Complete) data for Norepinephrine (7 total), please visit the HSDB record page.

---

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.
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.
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.
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.
For more Drug Warnings (Complete) data for Norepinephrine (19 total), please visit the HSDB record page.

---

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.

C8H11NO3

169.1778

169.073

C, 56.80; H, 6.55; N, 8.28; O, 28.37

51-41-2

Norepinephrine hydrochloride; 329-56-6; Norepinephrine bitartrate monohydrate; 108341-18-0; Norepinephrine tartrate; 51-40-1; (Rac)-Norepinephrine-d3 (formate)

439260

White to yellow solid powder

1.4±0.1 g/cm3

442.6±40.0 °C at 760 mmHg

220-230°C

221.5±27.3 °C

0.0±1.1 mmHg at 25°C

1.659

-0.88

4

4

2

12

142

1

OC1=CC=C([C@@H](O)CN)C=C1O

SFLSHLFXELFNJZ-QMMMGPOBSA-N

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

4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol

Norepinephrine; Noradrenaline; Noradrenalin; Levarterenol; Levophed Arterenol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~25 mg/mL (~147.8 mM) H2O: < 0.1 mg/mL

Solubility in Formulation 1: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (12.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)