Epinephrine 10250 226047752 2008-07-16T16:24:07Z Deli nk 560563 Reverted edits by [[Special:Contributions/66.236.95.66|66.236.95.66]] ([[User talk:66.236.95.66|talk]]) to last version by Evilmoo {{redirect|Adrenaline}} {{drugbox | | width = 200 | image = Adrenaline_chemical_structure.png | image2 = Epinephrine-3d-CPK.png |imagename=''(R)''-(−)-<small>L</small>-Epinephrine or ''(R)''-(−)-<small>L</small>-adrenaline |IUPAC_name = ''(R)''-4-(1-hydroxy-<br />2-(methylamino)ethyl)benzene-1,2-diol |CAS_number = 51-43-4 |ATC_prefix = A01 |ATC_suffix = AD01 |ATC_supplemental = {{ATC|B02|BC09}} {{ATC|C01|CA24}} {{ATC|R01|AA14}} {{ATC|R03|AA01}} {{ATC|S01|EA01}} |PubChem = 838 |DrugBank = APRD00450 |C = 9 | H = 13 | N = 1 | O = 3 |molecular_weight = 183.204 g/mol |bioavailability = Nil (oral) |metabolism = [[synapse|adrenergic synapse]] ([[Monoamine oxidase|MAO]] and [[Catechol-O-methyl transferase|COMT]]) |elimination_half-life = 2 minutes |excretion = Urine |pregnancy_AU = A |pregnancy_US = C |legal_AU = S4 |legal_US = Rx-only |legal_UK = POM |routes_of_administration = [[intravenous|IV]], [[intramuscular|IM]], [[endotracheal tube|endotracheal]] }} '''Epinephrine''' (also referred to as '''adrenaline'''; ''see [[#Terminology|Terminology]]'') is a [[hormone]] and [[neurotransmitter]]. It is a [[catecholamine]], a [[sympathomimetic]] monoamine derived from the [[amino acid]]s [[phenylalanine]] and [[tyrosine]]. The [[Latin]] roots ''ad-''+''renes'' and the [[Greek language|Greek]] roots ''epi-''+''nephros'' both literally mean "on/to the [[kidney]]" (referring to the [[adrenal gland]], which sits atop the kidneys and secretes epinephrine). Epinephrine is often shortened to '''epi''' or to '''EP''' in American medical [[jargon]]. ==History== In May 1886, [[William Horatio Bates|William Bates]] reported the discovery of a substance produced by the adrenal gland in the ''New York Medical Journal''. Epinephrine was isolated and identified in 1895 by [[Napoleon Cybulski]], a [[Poland|Polish]] [[physiology|physiologist]]. The discovery was repeated in 1897 by [[John Jacob Abel]].<ref>Aronson JK (2000). "[http://bmj.bmjjournals.com/cgi/content/full/320/7233/506 Where name and image meet]" - the argument for "adrenaline". ''British Medical Journal'' '''320''', 506-9.</ref> [[Jokichi Takamine]], a Japanese chemist, independently discovered the same hormone in 1900.<ref>{{cite journal |author=Yamashima T |title=Jokichi Takamine (1854-1922), the samurai chemist, and his work on adrenalin |journal=J Med Biogr |volume=11 |issue=2 |pages=95–102 |year=2003 |pmid=12717538}}</ref><ref>{{cite journal |author=Bennett M |title=One hundred years of adrenaline: the discovery of autoreceptors |journal=Clin Auton Res |volume=9 |issue=3 |pages=145–59 |year=1999 |pmid=10454061 |doi=10.1007/BF02281628}}</ref> In 1901 he isolated and purified the hormone adrenaline from cow glands. It was first artificially synthesized in 1904 by [[Friedrich Stolz]]. ==Triggers== [[Image:Adrenalin Ampulle.jpg|thumb|Epinephrine [[ampule]], 1 mg (Suprarenin<sup>®</sup>)]] Epinephrine is a "[[Fight-or-flight response|fight or flight]]" hormone, and plays a central role in the short-term [[Stress (medicine)|stress]] reaction. It is released from the adrenal glands when danger threatens or in an emergency. Such triggers may be threatening, exciting, or environmental [[stressor]] conditions such as high [[noise health effects|noise]] levels, or [[over-illumination|bright light]] (''see [[Fight-or-flight response]]''). An example of noise-induced trigger of epinephrine release is [[tinnitus]].{{unclear}} The fight-or-flight response caused by tinnitus is a contributor to physical stress seen in tinnitus patients,<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=tinnitus%20fight%20flight Personality of the tinnitus patient.] House PR. 1: Ciba Found Symp. 1981;85:193-203</ref> exacerbating the case.{{unclear}} ==Actions in the body== When secreted into the bloodstream, it rapidly prepares the body for action in emergency situations. The hormone boosts the supply of [[oxygen]] and [[glucose]] to the [[brain]] and [[muscle]]s, while suppressing other non-emergency bodily processes ([[digestion]] in particular). It increases [[heart rate]] and [[stroke volume]], dilates the [[pupil]]s, and constricts [[arterioles]] in the skin and [[gastrointestinal tract]] while dilating arterioles in [[skeletal muscles]]. It elevates the [[blood sugar]] level by increasing [[catabolism]] of [[glycogen]] to glucose in the liver, and at the same time begins the breakdown of [[lipid]]s in [[adipocyte|fat cells]]. Like some other stress hormones, epinephrine has a suppressive effect on the [[immune system]].<ref name="omd">[http://cancerweb.ncl.ac.uk/cgi-bin/omd?epinephrine Epinephrine] - Online Medical Dictionary</ref> Although epinephrine does not have any psychoactive effects, stress or arousal also releases [[norepinephrine]] in the brain. Norepinephrine has similar actions in the body, but is also psychoactive. The type of action in various [[cell types]] depends on their expression of adrenergic receptors. ===Adrenergic receptors=== [[Image:G protein signal transduction (epinephrin pathway).png|thumb|400px|β-adrenergic receptors]] :''Further reading: [[adrenergic receptor]]'' Epinephrine's actions are mediated through adrenergic receptors: * It binds to ''α<sub>1</sub> receptors'' of [[liver]] cells, which activate [[inositol-phospholipid signaling pathway]], signaling the phosphorylation of glycogen synthase and phosphorylase kinase (inactivating and activating them, respectively), leading to the latter activating another enzyme - glycogen phosphorylase - which catalises breakdown of glycogen (glycogenolysis) so as to release glucose to the bloodstream. Simultaneously protein phosphatase-1 (PP1) is inactivated, as in the active state PP1 would reverse all the previous phosphorylations. * Epinephrine also activates ''β-adrenergic receptors'' of the liver and muscle cells, thereby activating the [[adenylate cyclase]] signaling pathway, which will in turn increase [[glycogenolysis]]. β<sub>2</sub> receptors are found primarily in [[skeletal muscle]] blood vessels where they trigger [[vasodilation]]. However, α-adrenergic receptors are found in most [[smooth muscle]]s and [[Intestine|splanchnic]] vessels, and epinephrine triggers [[vasoconstriction]] in those vessels. ===Therapeutic use=== Epinephrine is used as a [[medication|drug]] to treat [[cardiac arrest]] and other [[cardiac dysrhythmia]]s resulting in diminished or absent [[cardiac output]]; its action is to increase peripheral resistance via [[alpha adrenergic receptor|α<sub>1</sub>-adrenoceptor]] [[vasoconstriction]], so that blood is shunted to the body's core, and the [[beta adrenergic receptor|β<sub>1</sub>-adrenoceptor]] response which is increased cardiac rate and output (the speed and pronouncement of heart beats). This beneficial action comes with a significant negative consequence&mdash;increased cardiac irritability&mdash;which may lead to additional complications immediately following an otherwise successful resuscitation. Alternatives to this treatment include [[vasopressin]], a powerful [[antidiuretic]] which also increases peripheral vascular resistance leading to blood shunting via vasoconstriction, but without the attendant increase in myocardial irritability.<ref name="omd" /> Because of its suppressive effect on the immune system, epinephrine is used to treat [[anaphylaxis]] and [[sepsis]]. Allergy patients undergoing [[immunotherapy]] may receive an epinephrine 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 [[beta2-adrenergic receptor agonist|beta<sub>2</sub>-adrenergic receptor agonist]]s are unavailable or ineffective. Adverse reactions to epinephrine include [[palpitation]]s, [[tachycardia]], anxiety, headache, tremor, [[hypertension]], and acute [[pulmonary edema]].<ref> [http://stress.about.com/od/stressmanagementglossary/g/Epinephrine.htm About.com] - "The Definition of Epinephrine"</ref> Because of various expression of α1 or β2-receptors, depending on the patient, administration of epinephrine 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 epinephrine on the heart, effects which respectively increase the [[contractility]] and [[heart rate|rate]] of the heart. ==Biosynthesis== [[Image:Catecholamines biosynthesis.svg|thumb|400px|Epinephrine is synthesized from norepinephrine in a synthetic pathway shared by all catecholamines.]] Epinephrine is synthesized from [[norepinephrine]] in a synthetic pathway shared by all catecholamines, including [[L-dopa]], [[dopamine]], norepinephrine, and epinephrine. Epinephrine is synthesized via methylation of the primary distal amine of [[norepinephrine]] by [[phenylethanolamine N-methyltransferase]] (PNMT) in the [[cytosol]] of [[adrenergic neuron]]s and cells of the [[adrenal medulla]] (so-called [[chromaffin cell]]s). PNMT is only found in the cytosol of cells of adrenal medullary cells. PNMT uses [[S-Adenosylmethionine|''S''-adenosylmethionine]] (SAMe) as a cofactor to donate the [[methyl]] group to norepinephrine, creating epinephrine. For norepinephrine to be acted upon by PNMT in the cytosol, it must first be shipped out of [[chromaffin granule|granules]] of the chromaffin cells. This may occur via the catecholamine-H<sup>+</sup> exchanger [[VMAT1]]. VMAT1 is also responsible for transporting newly synthesized epinephrine from the cytosol back into chromaffin granules in preparation for release. ==Regulation== Epinephrine synthesis is solely under the control of the [[central nervous system]] (CNS). Several levels of regulation dominate epinephrine synthesis. [[Adrenocorticotropic hormone]] (ACTH) and the [[sympathetic nervous system]] stimulate the synthesis of epinephrine precursors by enhancing the activity of enzymes involved in catecholamine synthesis. The specific enzymes are [[tyrosine hydroxylase]] in the synthesis of [[Levodopa|dopa]] and enzyme [[dopamine-β-hydroxylase]] in the synthesis of [[norepinephrine]]. ACTH also stimulates the [[adrenal cortex]] to release [[cortisol]], which increases the expression of PNMT in chromaffin cells, enhancing epinephrine synthesis. This is most often done in response to stress. The sympathetic nervous system, acting via [[splanchnic nerve]]s to the adrenal medulla, stimulates the release of epinephrine. [[Acetylcholine]] released by preganglionic sympathetic fibers of these nerves acts on [[nicotinic acetylcholine receptor]]s, causing cell depolarization and an influx of [[calcium]] through [[voltage-gated calcium channel]]s. Calcium triggers the exocytosis of chromaffin granules and thus the release of epinephrine (and norepinephrine) into the bloodstream. Epinephrine (as with norepinephrine) does exert [[negative feedback]] to [[down-regulate]] its own synthesis at the presynaptic alpha-2 adrenergic receptor. A [[pheochromocytoma]] is a tumor of the adrenal gland (or, rarely, the ganglia of the [[sympathetic nervous system]]), which results in the uncontrolled secretion of catecholamines, usually epinephrine. In liver cells, epinephrine 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 Phosphorylase which then phosphorylates glycogen and converts it to glucose-6-phosphate. ==Terminology== Although widely referred to as ''adrenaline'' outside of the US, and the [[laity|lay public]] worldwide, the [[United States Approved Name|USAN]] and [[International Nonproprietary Name|INN]] for this chemical is ''epinephrine'' because ''adrenaline'' bore too much similarity to the [[Parke-Davis|Parke, Davis & Co]] trademark ''Adrenalin'' (without the "e") which was registered in the U.S. The [[British Approved Name|BAN]] and [[European Pharmacopoeia|EP]] term for this chemical is ''adrenaline'', and is indeed now one of the few differences between the INN and BAN systems of names. Amongst U.S. health professionals, the term ''epinephrine'' is used over ''adrenaline''. However, it should be noted that universally, pharmaceuticals that mimic the effects of epinephrine are called ''adrenergics'', and receptors for epinephrine are called ''adrenoceptors''. It can also be spelled ''epinephrin'' (without the "e"). == Isomers == Natural epinephrine is the ''(R)''-(−)-<small>L</small>-epinephrine [[stereoisomer]]. ==Autoinjectors== Epinephrine is now also used in [[EpiPen]]s and [[Twinject]]s. EpiPens are long narrow [[autoinjector]]s that administer epinephrine, [[Twinject]]s are similar but contain two doses of epinephrine. It is also used in medicines and usually the Epinephrine is extracted from adrenal glands of hogs, cattle, and sheep. Though both ''EpiPen'' and ''Twinject'' are trademark names, common usage of the terms are drifting toward the [[Genericized trademark|generic context]] of any epinephrine autoinjector. ==Pharmaceutical Preparations== Aqueous preparations of adrenaline are obtained by use of [[hydrochloric acid]] or [[tartaric acid]], because in the absence of acid medium, it undergoes oxidation. Borate salt is used in ophthalmology. ==See also== *[[Anaphylaxis]] *[[Adrenaline junkie]] *[[Adrenochrome]] *[[Catechol-O-methyl transferase]] *[[Adrenergic receptor]] ==References== ===Notes=== {{reflist}} ===General references=== *{{cite book | author = [[Walter F. Boron]], [[Emile L. Boulpaep]] | title = Medical Physiology: A Cellular And Molecular Approach | publisher = Elsevier/Saunders | location = Philadelphia, PA| year = 2005 | id = ISBN 1-4160-2328-3}} *{{cite book | author = Voet D. and J.| title = Biochemistry, 3rd ed | publisher = Wiley| location = USA| year = 2004 | id = ISBN 0-471-19350-x}} {{Phenethylamines}} {{Hormones}} {{Adrenergic and dopaminergic agents}} {{Drugs for obstructive airway diseases}} {{Antihemorrhagics}} {{Emergency medicine}} [[Category:Aromatic compounds]] [[Category:Hormones]] [[Category:Catecholamines]] [[Category:Neurotransmitters]] [[Category:Bronchodilators]] [[ar:أدرينالين]] [[az:Adrenalin]] [[bs:Adrenalin]] [[bg:Адреналин]] [[ca:Adrenalina]] [[cs:Adrenalin]] [[da:Adrenalin]] [[de:Adrenalin]] [[dv:އެޑްރެނަލިން]] [[et:Adrenaliin]] [[el:Επινεφρίνη]] [[es:Adrenalina]] [[eo:Adrenalino]] [[fr:Adrénaline]] [[gl:Adrenalina]] [[ko:아드레날린]] [[hr:Adrenalin]] [[io:Adrenalino]] [[it:Adrenalina]] [[he:אדרנלין]] [[la:Adrenalinum]] [[lt:Adrenalinas]] [[hu:Adrenalin]] [[mk:Адреналин]] [[nl:Adrenaline]] [[ja:アドレナリン]] [[no:Adrenalin]] [[pl:Adrenalina]] [[pt:Adrenalina]] [[ro:Adrenalină]] [[ru:Адреналин]] [[sq:Adrenalina]] [[simple:Epinephrine]] [[sk:Epinefrín]] [[sl:Adrenalin]] [[sr:Адреналин]] [[fi:Adrenaliini]] [[sv:Adrenalin]] [[vi:Adrenaline]] [[tr:Adrenalin]] [[uk:Адреналін]] [[zh:肾上腺素]]