Epinephrine

From Wikipedia, the free encyclopedia

"Adrenaline" and "Adrenalin" redirect here. For other uses, see Adrenaline
(disambiguation).
(R)-(–)-L-Epinephrine or (R)-(–)-L-adrenaline

Systematic (IUPAC) name

(R)-4-(1-hydroxy-
2-(methylamino)ethyl)benzene-1,2-diol
Identifiers
CAS number 51-43-4
ATC code A01AD01 B02BC09 C01CA24
R01AA14 R03AA01 S01EA01
PubChem CID 5816
IUPHAR 509
ligand
DrugBank DB00668
ChemSpider 5611
UNII YKH834O4BH
KEGG D00095
ChEMBL CHEMBL679
Chemical data
Formula C9H13NO3
Mol. mass 183.204 g/mol
SMILES eMolecules & PubChem
InChI
[show]
Pharmacokinetic data
Bioavailabilit Nil (oral)
y
Metabolism adrenergic synapse (MAO and
COMT)
Half-life 2 minutes
Excretion Urine
Therapeutic considerations
Pregnancy A(AU) C(US)
cat.
Legal status Prescription Only (S4) (AU) POM
(UK) ℞-only (US)
Routes IV, IM, endotracheal, IC
(what is this?) (verify)
Epinephrine (also known as adrenaline) is a hormone and a
neurotransmitter.[1] It increases heart rate, constricts blood vessels, dilates
air passages and participates in the fight-or-flight response of the
sympathetic nervous system.[2] Chemically, epinephrine is a
catecholamine, a monoamine produced only by the adrenal glands from
the amino acids phenylalanine and tyrosine.
The term adrenaline is derived from the Latin roots ad- and renes and
literally means "on the kidney", in reference to the adrenal gland's
anatomic location on the kidney. The Greek roots epi and nephros have
similar meanings, and give rise to "epinephrine". The term epinephrine is
often shortened to epi in medical jargon.[3]
Adrenal extracts containing adrenaline were first obtained by Polish
physiologist Napoleon Cybulski in 1895. These extracts, which he called
nadnerczyna, contained epinephrine and other catecholamines.[4]
Japanese chemist Jokichi Takamine and his assistant Keizo Uenaka
independently discovered adrenaline in 1900.[5][6] In 1901, Takamine
successfully isolated and purified the hormone from the adrenal glands of
sheep and oxen.[7] Adrenaline was first synthesized in the laboratory by
Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.[6]

Contents [hide]
• 1 Medical uses
 ◦ 1.1 Cardiac arrest
◦ 1.2 Shock and
anaphylaxis
◦ 1.3 Use in local
anesthetics
▪ 1.3.1
Autoinjectors
◦ 1.4 Croup
◦ 1.5 Side effects and
drug interactions
◦ 1.6 Measurement in
biological fluids
◦ 1.7 Use in full contact
sports
• 2 Mechanism of
action
• 3 Biosynthesis and
regulation
◦ 3.1 Regulation
• 4 Chemical synthesis
• 5 Adrenaline junkie
• 6 Terminology
• 7 Notes
• 8 References
• 9 External links
[edit]
Medical uses

Epinephrine ampule, 1 mg (Suprarenin)

Epinephrine is available in a variety of preparations for the management of
several medical conditions. Aqueous preparations of adrenaline are
obtained by the use of hydrochloric acid or tartaric acid, since it undergoes
oxidation in the absence of acid medium.[citation needed] The borate salt is
used in ophthalmology.[citation needed]
[edit]
Cardiac arrest
Adrenaline is used as a drug to treat cardiac arrest and other cardiac
dysrhythmias resulting in diminished or absent cardiac output. Its actions
are to increase peripheral resistance via α1receptor-dependent
vasoconstriction and to increase cardiac output via its binding to
β1receptors. The usual ACLS concentration for injection is epinephrine
1:10,000.
[edit]
Shock and anaphylaxis
Due to its vasoconstrictive effects, adrenaline is the drug of choice for
treating anaphylaxis. It is also useful in treating sepsis. Allergy[8] patients
undergoing immunotherapy may receive an adrenaline rinse before the
allergen extract is administered, thus reducing the immune response to the
administered allergen. It is also used as a bronchodilator for asthma if
specific β2agonists are unavailable or ineffective.[9]
Because of various expression of α1or β2receptors, depending on the
patient, administration of adrenaline may raise or lower blood pressure,
depending whether or not the net increase or decrease in peripheral
resistance can balance the positive inotropic and chronotropic effects of
adrenaline on the heart, effects which respectively increase the contractility
and rate of the heart.[citation needed]
The usual concentration for SQ or IM injection is 1:1,000.
[edit]
Use in local anesthetics
Epinephrine is added to injectable forms of a number of local anesthetics,
such as bupivacaine and lidocaine, as a vasoconstrictor to retard the
absorption and therefore prolong the action of the anesthetic agent. Some
of the adverse effects of local anesthetic use, such as apprehension,
tachycardia and tremor, may be caused by epinephrine.[10]
[edit]
Autoinjectors
Epinephrine is available in an autoinjector delivery system. EpiPens,
Anapens and Twinjects all use epinephrine as their active ingredient.
Twinjects contain a second dose of epinephrine in a separate syringe and
needle delivery system contained within the body of the autoinjector.
Though both EpiPen and Twinject are trademark names, common usage
of the terms are drifting toward the generic context of any epinephrine
autoinjector.[citation needed]
[edit]
Croup
Racemic epinephrine has historically been used for the treatment of croup.
[11][12] Racemic epinephrine is a 1:1 mixture of the dextrorotatory (D) and
levorotatory (L) isomers of epinephrine.[13] The L form is the active
component.[13] Racemic epinephrine works by stimulation of the α-
adrenergic receptors in the airway with resultant mucosal vasoconstriction
and decreased subglottic edema and by stimulation of the β-adrenergic
receptors with resultant relaxation of the bronchial smooth muscle.[12]
[edit]
Side effects and drug interactions
Adverse reactions to epinephrine include palpitations, tachycardia,
arrhythmia, anxiety, headache, tremor, hypertension, and acute pulmonary
edema.[14]
Use is contraindicated for patients on nonselective β-blockers because
severe hypertension and even cerebral hemorrhage may result.[15]
Although commonly believed that administration of epinephrine may cause
heart failure by constricting coronary arteries, this is not the case. Coronary
arteries only have β2receptors, which cause vasodilation in the presence of
epinephrine.[16] Even so, administering high-dose epinephrine has not
been definitively proven to improve survival or neurologic outcomes in
adult victims of cardiac arrest.[17]
[edit]
Measurement in biological fluids
Epinephrine may be quantitated in blood, plasma or serum as a diagnostic
aid, to monitor therapeutic administration or to identify the causative agent
in a potential poisoning victim. Endogenous plasma epinephrine
concentrations in resting adults are normally less than 10 ng/L, but may
increase by 10-fold during exercise and by 50-fold or more during times of
stress. Pheochromocytoma patients often have plasma epinephrine levels
of 1000-10,000 ng/L. Parenteral administration of epinephrine to acute-
care cardiac patients can produce plasma concentrations of 10,000 to
100,000 ng/L.[18][19]
[edit]
Use in full contact sports
In contact sports such as boxing, adrenaline chloride, usually a 1:1000
epinephrine solution, is used to stanch bleeding during matches.[20]
[edit]
Mechanism of action
See also: Adrenergic receptor
As a hormone, epinephrine acts on nearly all body tissues. Its actions vary
by tissue type and tissue expression of adrenergic receptors. For example,
epinephrine causes smooth muscle relaxation in the airways, but causes
contraction of the smooth muscle that lines most arterioles.
Epinephrine acts by binding to a variety of adrenergic receptors.
Adrenaline is a nonselective agonist of all adrenergic receptors, including
α1, α2, β1, β2, and β3 receptors.[15] Epinephrine's binding to these receptors
triggers a number of metabolic changes. Binding to α-adrenergic receptors
inhibits insulin secretion by the pancreas, stimulates glycogenolysis in the
liver and muscle, and stimulates glycolysis in muscle.[21] β-Adrenergic
receptor binding triggers glucagon secretion in the pancreas, increased
adrenocorticotropic hormone (ACTH) secretion by the pituitary gland, and
increased lipolysis by adipose tissue. Together, these effects lead to
increased blood glucose and fatty acids, providing substrates for energy
production within cells throughout the body.[21]
In addition to these metabolic changes, epinephrine also leads to broad
alterations throughout all organ systems.
Physiologic responses to epinephrine by organ
Organ Effects
Heart Increases heart rate
Lungs Increases respiratory rate
Nearly all Vasoconstriction or
tissues vasodilation
Liver Stimulates glycogenolysis
N/A, systemic Triggers lipolysis
N/A, systemic Muscle contraction
[edit]
Biosynthesis and regulation
Adrenaline is synthesized in the medulla of the adrenal gland in an
enzymatic pathway that converts the amino acid tyrosine into a series of
intermediates and ultimately adrenaline. Tyrosine is first oxidized to L-
DOPA, which is subsequently decarboxylated to give dopamine. Oxidation
gives norepinephrine, which is methylated to give epinephrine.
Adrenaline is synthesized via methylation of the primary distal amine of
noradrenaline by phenylethanolamine N-methyltransferase (PNMT) in the
cytosol of adrenergic neurons and cells of the adrenal medulla (so-called
chromaffin cells). PNMT is only found in the cytosol of cells of adrenal
medullary cells. PNMT uses S-adenosylmethionine (SAMe) as a cofactor
to donate the methyl group to noradrenaline, creating adrenaline.[citation
needed]

The biosynthesis of adrenaline involves a series of enzymatic reactions.

For noradrenaline to be acted upon by PNMT in the cytosol, it must first be
shipped out of granules of the chromaffin cells. This may occur via the
catecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for
transporting newly synthesized adrenaline from the cytosol back into
chromaffin granules in preparation for release.[citation needed]
In liver cells, adrenaline binds to the β-adrenergic receptor which changes
conformation and helps Gs, a G protein, exchange GDP to GTP. This
trimeric G protein dissociates to Gs alpha and Gs beta/gamma subunits.
Gs alpha binds to adenyl cyclase, thus converting ATP into cyclic AMP.
Cyclic AMP binds to the regulatory subunit of protein kinase A: Protein
kinase A phosphorylates phosphorylase kinase. Meanwhile, Gs
beta/gamma binds to the calcium channel and allows calcium ions to enter
the cytoplasm. Calcium ions bind to calmodulin proteins, a protein present
in all eukaryotic cells, which then binds to phosphorylase kinase and
finishes its activation. Phosphorylase kinase phosphorylates glycogen
phosphorylase which then phosphorylates glycogen and converts it to
glucose-6-phosphate.[citation needed]
[edit]
Regulation
The major physiologic triggers of adrenaline release center upon stresses,
such as physical threat, excitement, noise, bright lights, and high ambient
temperature. All of these stimuli are processed in the central nervous
system.[22]
Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system
stimulate the synthesis of adrenaline precursors by enhancing the activity
of tyrosine hydroxylase and dopamine-β-hydroxylase, two key enzymes
involved in catecholamine synthesis.[citation needed] ACTH also stimulates
the adrenal cortex to release cortisol, which increases the expression of
PNMT in chromaffin cells, enhancing adrenaline synthesis. This is most
often done in response to stress.[citation needed] The sympathetic nervous
system, acting via splanchnic nerves to the adrenal medulla, stimulates the
release of adrenaline. Acetylcholine released by preganglionic sympathetic
fibers of these nerves acts on nicotinic acetylcholine receptors, causing cell
depolarization and an influx of calcium through voltage-gated calcium
channels. Calcium triggers the exocytosis of chromaffin granules and thus
the release of adrenaline (and noradrenaline) into the bloodstream.[citation
needed]

Adrenaline (as with noradrenaline) does exert negative feedback to down-

regulate its own synthesis at the presynaptic alpha-2 adrenergic receptor.
[
citation needed] Abnormally elevated levels of adrenaline can occur in a
variety of conditions, such as surreptitious epinephrine administration,
pheochromocytoma, and other tumors of the sympathetic ganglia.
Its action is terminated with reuptake into nerve terminal endings, some
minute dilution, and metabolism by monoamine oxidase and catechol-o-
methyl transferase.
[edit]
Chemical synthesis
Epinephrine may be synthesized by the reaction of catechol with
chloroacetyl chloride, followed by the reaction with methylamine to give the
ketone, which is reduced to the desired hydroxy compound. The racemic
mixture may be separated using tartaric acid.

Formula for the synthesis of adrenaline

For isolation from the adrenal glands tissue of livestock:
▪ J. Takamine, J. Soc. Chem. Ind., 20, 746 (1901).
▪ J. B. Aldrich, Am. J. Physiol., 5, 457 (1901).
Synthetic production:
▪ A. F. Stolz, Chem. Ber., 37, 4149 (1904).
▪ K. R. Payne, Ind. Chem. Chem. Manuf., 37, 523 (1961).
▪ H. Loewe, Arzneimittel-Forsch., 4, 583 (1954).
▪ Farbwerke Meister Lucins & Bruning in Hochst a.M., DE 152814
(1903).
▪ Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 157300
(1903).
▪ Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 222451
(1908).
▪ Tullar, B. F. (1948). "The resolution of dl-arterenol". Journal of the
American Chemical Society 70 (6): 2067. doi:10.1021/ja01186a024.
PMID 18863798. edit
▪ D. Flacher, Z. Physiol. Chem., 58, 189 (1908).
[edit]
Adrenaline junkie
Adrenaline junkie is a term used to describe somebody who appears to be
addicted to epinephrine (endogenous) and such a person is sometimes
described as getting a "high" from life. The term adrenaline junkie was
popularly used in the 1991 movie Point Break to describe individuals who
enjoyed dangerous activities (such as extreme sports, e.g. BASE jumping)
for the adrenaline "rush". Adrenaline junkies appear to favour stressful
activities for the release of epinephrine as a stress response. Doing this
may result in physical harm because of the potential danger. Whether or
not the positive response is caused specifically by epinephrine is difficult to
determine, as endorphins are also released during the fight-or-flight
response to such activities.[23][24]
[edit]
Terminology
This chemical is widely referred to as "adrenaline" outside of the United
States; however, its United States Adopted Name and International
Nonproprietary Name is "epinephrine". Epinephrine was chosen because
adrenaline bore too much similarity to the Parke, Davis & Co trademark
Adrenalin (without the "e"), which was registered in the United States. The
British Approved Name and European Pharmacopoeia term for this
chemical is adrenaline, and is indeed now one of the few differences
between the INN and BAN systems of names.[25]
Amongst American health professionals and scientists, the term
epinephrine is used over adrenaline. However, it should be noted that
pharmaceuticals that mimic the effects of epinephrine are often called
adrenergics, and receptors for epinephrine are called adrenergic receptors
or adrenoceptors.
[edit]
Notes
1. ^ Berecek KH, Brody MJ (1982). "Evidence for a neurotransmitter role for
epinephrine derived from the adrenal medulla". Am J Physiol 242 (4):
H593–601. PMID 6278965. edit
2. ^ Cannon, W. B. (1929). American Journal of Physiology 89: 84–107.[Full
citation needed]
3. ^ Gail Askew and Marilyn Smith-Stoner. (2001). The Pharmacy Assistant
(Clinical Allied Heathcare Series). Clifton Park, NY: Thomson Delmar
Learning. pp. 4–6. ISBN 0-89262-438-8.
4. ^ "Polish Thread in the History of Circulatory Physiology". Retrieved 2011-
04-24.
5. ^ Yamashima T (2003). "Jokichi Takamine (1854–1922), the samurai
chemist, and his work on adrenalin". J Med Biogr 11 (2): 95–102.
PMID 12717538.
6. ^ a b Bennett M (1999). "One hundred years of adrenaline: the discovery
of autoreceptors". Clin Auton Res 9 (3): 145–59.
doi:10.1007/BF02281628. PMID 10454061.
7. ^ Takamine J (1901). The isolation of the active principle of the suprarenal
gland. Great Britain: Cambridge University Press. pp. xxix-xxx.
8. ^ Sicherer, Scott H. M.D., Understanding and Managing Your Child's Food
Allergy. Baltimore: The Johns Hopkins University Press, 2006.
9. ^ "Asthma Causes, Types, Symptoms, Treatment, Medication, Facts and
the Link to Allergies by MedicineNet.com".
10. ^ R. Rahn and B. Ball. Local Anesthesia in Dentistry, 3M ESPE AG, ESPE
Platz, Seefeld, Germany, 2001, 44 pp.
11. ^ Bjornson CL, Johnson DW (2008). "Croup". The Lancet 371 (9609):
329–339. doi:10.1016/S0140-6736(08)60170-1. PMID 18295000.
12. ^ a b Thomas LP, Friedland LR (1998). "The cost-effective use of
nebulized racemic epinephrine in the treatment of croup". American
 Journal of Emergency Medicine 16 (1): 87–89. doi:10.1016/S0735-
6757(98)90073-0. PMID 9451322.
13. ^ a b Malhotra A, Krilov LR (2001). "Viral Croup". Pediatrics in Review 22
(1): 5–12. doi:10.1542/pir.22-1-5. PMID 11139641.
14. ^ About.com - "The Definition of Epinephrine"
15. ^ a b Shen, Howard (2008). Illustrated Pharmacology Memory Cards:
PharMnemonics. Minireview. pp. 4. ISBN 1-59541-101-1.
16. ^ Sun, D; Huang, A; Mital, S; Kichuk, MR; Marboe, CC; Addonizio, LJ;
Michler, RE; Koller, A et al. (2002). "Norepinephrine elicits beta2-receptor-
mediated dilation of isolated human coronary arterioles". Circulation 106
(5): 550–5. doi:10.1161/01.CIR.0000023896.70583.9F.
PMID 12147535. edit
17. ^ Stiell, I. G.; Hebert, P. C.; Weitzman, B. N.; Wells, G. A.; Raman, S.;
Stark, R. M.; Higginson, L. A. J.; Ahuja, J. et al. (1992). "High-Dose
Epinephrine in Adult Cardiac Arrest". New England Journal of Medicine
327 (15): 1045. doi:10.1056/NEJM199210083271502. PMID 1522840. edit
18. ^ Raymondos K, Panning B, Leuwer M, Brechelt G, Korte T, Niehaus M,
Tebbenjohanns J, Piepenbrock S. Absorption and hemodynamic effects of
airway administration of adrenaline in patients with severe cardiac
disease. Ann. Intern. Med. 132: 800-803, 2000.
19. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition,
Biomedical Publications, Foster City, CA, 2008, pp. 545-547.
20. ^ "Cut man". BoxRec Boxing Encyclopaedia. Retrieved 2010-07-10.
21. ^ a b Sabyasachi Sircar (2007). Medical Physiology. Thieme Publishing
Group. pp. 536. ISBN 3-13-144061-9.
22. ^ L. Nelson, M. Cox, (2004) “Principles of Biochemstry 4th Ed Lehninger”
Freeman pp. 908
23. ^ What Is An Adrenaline Junkie? What Can You Do If You Are One? by
Elizabeth Scott, M.S. (updated: November 1, 2007) About.com Health's
Disease and Condition content is reviewed by the Medical Review Board
24. ^ Fight-or-flight reaction - Explanations - Brain - ChangingMinds.org
25. ^
http://www.mhra.gov.uk/Howweregulate/Medicines/Namingofmedicines/C
hangestomedicinesnamesBANstorINNs/index.htm
[edit]
References
▪ Boron WF, Boulpaep EL (2005). Medical Physiology: A Cellular And
Molecular Approach. Philadelphia, PA: Elsevier/Saunders. ISBN 1-4160-
2328-3. OCLC 56191776.
▪ Voet D, Voet J (2004). Biochemistry (3rd ed.). USA: Wiley. ISBN 0-471-
19350-x. OCLC 154657578.
[edit]
External links
▪ U.S. National Library of Medicine: Drug Information Portal -
Epinephrine

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Phenethylamines

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Endocrine system: hormones
(Peptide hormones · Steroid
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Cardiac stimulants excluding
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Drugs for obstructive airway
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v·d·e
Health science > Medicine >
Emergency medicine

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Adrenergics

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Neurotransmitters

Categories: Hormones of the suprarenal medulla | Hormones of the

hypothalamus-pituitary-adrenal axis | Catecholamines | Cardiac stimulants
| Neurotransmitters | Bronchodilators | Stress | Anxiety | World Health
Organization essential medicines

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