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«Norepinephrine 1 Norepinephrine Norepinephrine[1] Identifiers [2] [3] CAS number (l) 51-41-2 (l),  138-65-8 (dl) [4] ChemSpider 388394 Properties ...»

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Norepinephrine 1




[2] [3]

CAS number (l) 51-41-2 (l),  138-65-8 (dl)


ChemSpider 388394


Molecular formula C8H11NO3

Molar mass −1

169.18 g mol Melting point L: 216.5–218 °C (decomp.) D/L: 191 °C (decomp.) Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox references Norepinephrine (INN) (abbreviated norepi or NE) or noradrenaline (BAN) (abbreviated NA or NAd) is a catecholamine with multiple roles including as a hormone and a neurotransmitter.[5] As a stress hormone, norepinephrine affects parts of the brain where attention and responding actions are controlled.

Along with epinephrine, norepinephrine also underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing blood flow to skeletal muscle. Norepinephrine can also suppress neuroinflammation when released diffusely in the brain from the locus ceruleus.[6] When norepinephrine acts as a drug it increases blood pressure by increasing vascular tone through α-adrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia.

Norepinephrine is synthesized from dopamine by dopamine β-hydroxylase.[7] It is released from the adrenal medulla into the blood as a hormone, and is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons. The actions of norepinephrine are carried out via the binding to adrenergic receptors.

Norepinephrine 2 Etymology The term "norepinephrine" is derived from the chemical prefix nor-, which indicates that norepinephrine is the next lower homolog of epinephrine. The two structures differ only in that epinephrine has a methyl group attached to its nitrogen, while the methyl group is replaced by a hydrogen atom in norepinephrine.

Chemistry Norepinephrine is a catecholamine and a phenethylamine. The natural stereoisomer is L-(−)-(R)-norepinephrine. The prefix nor-, is derived from the German abbreviation for "N ohne Radikal" (N, the symbol for nitrogen, without radical),[8] referring to the absence of the methyl functional group at the nitrogen atom.

Origins Norepinephrine is released when a host of physiological changes are activated by a stressful event.

In the brain, this is caused in part by activation of an area of the brain stem called the locus ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Noradrenergic neurons project bilaterally (send signals to both sides of the brain) from the locus ceruleus along distinct pathways to many locations, including the cerebral cortex, limbic system, and the spinal cord, forming a neurotransmitter system.

Norepinephrine is also released from postganglionic neurons of the sympathetic nervous system, to transmit the fight-or-flight response in each tissue respectively. The adrenal medulla can also be counted to such postganglionic nerve cells, although they release norepinephrine into the blood.

–  –  –

Mechanism Norepinephrine is synthesized from tyrosine as a precursor, and packed into synaptic vesicles. It performs its action by being released into the synaptic cleft, where it acts on adrenergic receptors, followed by the signal termination, either by degradation of norepinephrine, or by uptake by surrounding cells.

Biosynthesis Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla and postganglionic neurons of

the sympathetic nervous system from the amino acid tyrosine:

• The first reaction is the hydroxylation into dihydroxyphenylalanine (L-DOPA) (DOPA = 3,4-DiHydroxy-L-Phenylalanine), catalyzed by tyrosine hydroxylase. This is the rate-limiting step.

• This is followed by decarboxylation into the neurotransmitter dopamine, catalyzed by pyridoxal phosphate & DOPA decarboxylase.

• Last is the final β-oxidation into norepinephrine by dopamine beta hydroxylase, requiring ascorbate as a cofactor (electron donor).

Tyrosine Levodopa Dopamine Norepinephrine Vesicular transport Between the decarboxylation and the final β-oxidation, norepinephrine is transported into synaptic vesicles. This is accomplished by vesicular monoamine transporter (VMAT) in the lipid bilayer. This transporter has equal affinity for norepinephrine, epinephrine and isoprenaline.[9] Release To perform its functions, norepinephrine needs to be released from synaptic vesicles. Many substances modulate this release, some inhibiting it and some stimulating it.

For instance, there are inhibitory α2 adrenergic receptors presynaptically, that gives negative feedback on release by homotropic modulation.

Receptor binding Norepinephrine performs its actions on the target cell by binding to and activating adrenergic receptors. The target cell expression of different types of receptors determines the ultimate cellular effect, and thus norepinephrine has different actions on different cell types.

Termination Signal termination is a result of reuptake and degradation.

–  –  –

Noradrenergic agents By indication Norepinephrine may be used for the indications attention-deficit/hyperactivity disorder, depression and hypotension.

Norepinephrine, as with other catecholamines, itself cannot cross the blood-brain barrier, so drugs such as amphetamines are necessary to increase brain levels.

Attention-deficit/hyperactivity disorder Norepinephrine, along with dopamine, has come to be recognized as playing a large role in attention and focus. For people with ADHD, psychostimulant medications such as methylphenidate (Ritalin/Concerta), dextroamphetamine (Dexedrine), and Adderall (a mixture of dextroamphetamine and racemic amphetamine salts) are prescribed to help increase levels of norepinephrine and dopamine. Atomoxetine (Strattera) is a selective norepinephrine reuptake inhibitor, and is a unique ADHD medication, as it affects only norepinephrine, rather than dopamine. As a result, Strattera has a lower abuse potential. However, it may not be as effective as the psychostimulants are with many people who have ADHD. Consulting with a physician, physician assistant or nurse practitioner is needed to find the appropriate medication and dosage. (Other SNRIs, currently approved as antidepressants, have also been used off-label for treatment of ADHD.) Depression Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors are antidepressants that treat depression by increasing the amount of serotonin and norepinephrine available to postsynaptic cells in the brain. There is some recent evidence implying that SNRIs may also increase dopamine transmission.[14] This is because SNRIs work by inhibiting reuptake, i.e. preventing the serotonin and norepinephrine transporters from taking their respective neurotransmitters back to their storage vesicles for later use.

If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex of the brain).

Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin activity, but tend to produce unwanted side effects due to the nonspecific inactivation of histamine, acetylcholine and alpha-1 adrenergic receptors. Common side effects include sedation, dry mouth, constipation, sinus tachycardia, memory impairment, orthostatic hypotension, blurred vision and weight gain.[15] For this reason, they have largely been replaced by newer selective reuptake drugs. These include the SSRIs, e.g. fluoxetine (Prozac), which however have little or no effect on norepinephrine, and the newer SNRIs described above, such as venlafaxine (Effexor) and duloxetine (Cymbalta).

Hypotension Norepinephrine is also used as a vasopressor medication (for example, brand name Levophed) for patients with critical hypotension. It is given intravenously and acts on both α1 and α2 adrenergic receptors to cause vasoconstriction. Its effects are often limited to the increasing of blood pressure through agonist activity on α1 and α2 receptors and causing a resultant increase in peripheral vascular resistance. At high doses, and especially when it is combined with other vasopressors, it can lead to limb ischemia and limb death. Norepinephrine is mainly used to treat patients in vasodilatory shock states such as septic shock and neurogenic shock and has shown a survival benefit over dopamine.

Norepinephrine 6 By site of action Different medications affecting norepinephrine function have their targets at different points in the mechanism, from synthesis to signal termination.

Synthesis modulators α-methyltyrosine is a substance that intervenes in norepinephrine synthesis by substituting tyrosine for tyrosine hydroxylase, and blocking this enzyme.

Vesicular transport modulators This transportation can be inhibited by reserpine and tetrabenazine.[9] Release modulators

–  –  –

Termination modulators Uptake modulators

Inhibitors[9] of uptake 1 include:

• cocaine

• tricyclic antidepressants

• desipramine

• phenoxybenzamine

• amphetamine

Inhibitors[9] of uptake 2 include:

• normetanephrine

• steroid hormones

• phenoxybenzamine Anti-Inflammatory agent role in Alzheimer’s Disease The norepinephrine from locus ceruleus cells in addition to its neurotransmitter role locally defuses from "varicosities". As such it provides an endogenous anti-inflammatory agent in the microenvironment around the neurons, glial cells, and blood vessels in the neocortex and hippocampus.[6] Up to 70% of norepinephrine projecting cells are lost in Alzheimer’s Disease. It has been shown that norepinephrine stimulates mouse microglia to suppress Aβ-induced production of cytokines and their phagocytosis of Aβ suggesting this loss might have a role in causing this disease.[6]

–  –  –

See also

• Norepinephrine bitartrate

• Catecholaminergic polymorphic ventricular tachycardia External links

• Mental Health: A report of surgeon general. Etiology of Anxiety Disorders [18]

• http://www.biopsychiatry.com/nordop.htm References [1] Merck Index, 11th Edition, 6612.

[2] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=51-41-2 [3] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=138-65-8 [4] http:/ / www. chemspider. com/ 388394 [5] "Norepinephrine definition" (http:/ / dictionary. reference. com/ browse/ Norepinephrine). dictionary.reference.com.. Retrieved 2008-11-24.

[6] Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP. (2010). Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine. (http:/ / www. pnas. org. libproxy. ucl. ac. uk/ content/ 107/ 13/ 6058. full. pdf) Proc Natl Acad Sci U S A. 107:6058–6063 doi:10.1073/pnas.0909586107 PMID 20231476 [7] "Introduction to Autonomic Pharmacology" (http:/ / www. fleshandbones. com/ readingroom/ pdf/ 225. pdf) (PDF). Elsevier International.

. Link redirected to commercial site!

[8] TIHKAL on "nor" (http:/ / www. drugsinfo. net/ tihkal/ tihkal01. html) [9] Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167 [10] These values are from rat heart. Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page 167 [11] Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page [12] Unless else specified in boxes, then ref is: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-06911-5.

[13] "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502 [14] http:/ / stahlonline. cambridge. org/ prescribers_drug. jsf?page=0521683505c95_p539-544. html. therapeutics& name=Venlafaxine& title=Therapeutics [15] http:/ / www. preskorn. com/ columns/ 9803. html [16] Unless else specified in table, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. Page [17] Kanazawa, Kazuki; Hiroyuki Sakakibara (2000). "High content of Dopamine, a strong antioxidant, in Cavendish banana" (http:/ / 152. 1.

118. 33/ Files/ Journal of Agricultural and Food Chemistry 2000 48 (3) 844-848. pdf) (PDF). Journal of Agriculture and Food Chemistry 48:

844–848. doi:10.1021/jf9909860.. Retrieved 8 November 2007.

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