Discover

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| Chemical name
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| Other names
| Noradrenaline
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| Chemical formula
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| Molecular mass
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| CAS number
| D: [149-95-1]
L: [51-41-2]
D/L: [138-65-8]

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| L: °C (''decomp.'')
D/L: °C (''decomp.'')
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'Norepinephrine' (INN)(abbr. norepi or NE) or 'noradrenaline' (BAN) is a catecholamine and a phenethylamine with chemical formula C₈H₁₁NO₃. The natural stereoisomer is L-(−)-(''R'')-norepinephrine. The prefix ''nor-'', short for "normal," might also now be a mnemonic device for the German abbreviation "N (symbol for nitrogen) ohne Radikalen," meaning "Nitrogen without remainder," referring to the absence of a methyl group at the N-atom present in epinephrine/adrenaline. It is released from the medulla of the adrenal glands as a hormone into the blood, but it is also a neurotransmitter in the central nervous system and sympathetic nervous system where it is released from noradrenergic neurons during synaptic transmission. As a stress hormone, it affects parts of the human brain where attention and responding actions are controlled. Along with epinephrine, norepinephrine underlies the fight-or-flight response, directly increasing heart rate, triggering the release of glucose from energy stores, and increasing skeletal muscle readiness.
However, when norepinephrine acts as a drug, it will increase systolic and diastolic pressure, causing compensatory vagal reflex, which overcomes its direct cardioaccelerator action. Therefore, it will cause reflex bradycardia in patient.
Norepinephrine is released when a host of physiological changes are activated by a stressful event. 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. Neurons that are activated by norepinephrine 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. The 'locus ceruleus' (or "LC") is located within the dorsal wall of the rostral 'pons' in the lateral floor of the fourth ventricle (see picture).
At synapses, norepinephrine acts on both alpha and beta adrenoreceptors.

Contents

Natural Production

Clinical uses

Attention-deficit/hyperactivity disorder

Depression

Vasoconstriction

Biosynthesis

Metabolites

References

External links

Natural Production

Norepinephrine is naturally released both in the central nervous system where it helps control alertness and arousal, and from peripheral sympathetic nerves where it exerts diverse effects on its target organs.

Clinical uses

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 ADD/ADHD, psychostimulant medications such as Ritalin/Concerta (methylphenidate), Dexedrine (dextroamphetamine), and Adderall (a mixture of dextroamphetamine and racemic amphetamine salts) are prescribed to help increase levels of norepinephrine and dopamine. Strattera (atomoxetine) is a selective norepinephrine reuptake inhibitor, and is a unique ADD/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 ADD/ADHD. Consulting with a physician 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 'ADD/ADHD'.)

Depression

Differences in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors (SNRIs) 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 showing that the norepinephrine transporter also transports some dopamine as well, implying that SNRIs may also increase dopamine transmission. 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).
Tricyclic antidepressants (TCAs) increase norepinephrine activity as well. Most of them also increase serotonin activity, but tend to have side effects due to the nonspecific activation of histamine and acetylcholine receptors. Side effects include tiredness, increased hunger, dry mouth, and blurred vision. For this reason, they have largely been replaced by newer selective reuptake drugs such as Prozac.

Vasoconstriction

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 alpha-1 and alpha-2 adrenergic receptors to cause vasoconstriction. Its effect ''in vitro'' is often limited to the increasing of blood pressure through agonistic activity on alpha-1 and alpha-2 receptors and causing a resultant increase in peripheral vascular resistance. In high dose 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.

Biosynthesis

Norepinephrine is synthesized by a series of enzymatic steps in the adrenal medulla from the amino acid tyrosine:

★ The first reaction is the oxidation 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).

Metabolites

In mammals, norepinephrine is rapidly degraded to various metabolites. The principal metabolites are:

★ Normetanephrine (via the enzyme catechol-O-methyl transferase, COMT)

★ 3,4-Dihydroxymandelic acid (via monoamine oxidase, MAO)

★ 3-Methoxy-4-hydroxymandelic acid (via MAO)

★ 3-Methoxy-4-hydroxyphenylglycol (via MAO)

★ Epinephrine (via PNMT^[2])

References

Brunton, Lazo, Parker: Goodmn &Gilman's The Pharmacological Basis of Therapeutics. McGraw Hill, 11th edition. p248~249
1. ''Merck Index'', 11th Edition, '6612'.
2. "Endokrynologia Kliniczna" ISBN 83-200-0815-8, page 502

External links

★ Mental Health: A report of surgeon general. Etiology of Anxiety Disorders

★ http://www.med.upenn.edu/astonjoneslab/epapers/A-JNeuropsycho5thGen.pdf

★ http://www.biopsychiatry.com/nordop.htm