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EpinephrineAdrenaline


Author:Elabscience
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Epinephrine(also known as adrenaline, adrenalin, or4,5-β-trihydroxy-N-methylphenethylamine) is a hormone and aneurotransmitter.The investigation of the pharmacology of epinephrine made a major contributionto the understanding of the autonomic system and the function of thesympathetic system. Epinephrine remains a useful medicine for several emergencyindications. This is despite its non-specific action on adrenoceptors and thesubsequent development of multiple selective medicines that target subtypes ofthe adrenoceptor. The word adrenaline is used in common parlance to denoteincreased activation of the sympathetic system associated with the energy andexcitement of the flight, fight and fright response, even though this isphysiologically inaccurate.  Theinfluence of adrenaline is mainly limited to a metabolic effect andbronchodilator effect on organs devoid of direct sympathetic innervation.

In chemicalterms, epinephrine is one of a group of monoamines called the catecholamines.It is produced in some neurons of the central nervous system, and in thechromaffin cells of the adrenal medulla from the amino acids phenylalanine andtyrosine.

Physiology

The adrenalmedulla is a minor contributor to total circulating catecholamines, though itcontributes over 90% of circulating epinephrine. Little epinephrine is found inother tissues, mostly in scattered chromaffin cells. Following adrenalectomy,epinephrine disappears below the detection limit in the blood stream.

The adrenalscontribute about 7% of circulating norepinephrine, most of which is a spillover from neurotransmission with little activity as a hormone.  Pharmacological doses of epinephrinestimulate α1, α2, β1, β2, and β3 adrenoceptors of the sympathetic nervoussystem. Sympathetic nerve receptors are classified as adrenergic, based ontheir responsiveness to adrenaline.

The term“adrenergic” is often misinterpreted in that the main sympatheticneurotransmitter is norepinephrine (noradrenaline), rather than epinephrine, asdiscovered by Ulf von Euler in 1946.

Epinephrine doeshave a β2 adrenoceptor mediated effect on metabolism and the airway, therebeing no direct neural connection from the sympathetic ganglia to the airway.

The concept ofthe adrenal medulla and the sympathetic nervous system being involved in theflight, fight and fright response was originally proposed by Cannon. But theadrenal medulla, in contrast to the adrenal cortex, is not required forsurvival. In adrenalectomized patients haemodynamic and metabolic responses tostimuli such as hypoglycaemia and exercise remain normal.

Epinephrine isimportant as a central neurotransmitter. In the periphery circulatingepinephrine can stimulate the facilitatory noradrenaline pre-synaptic βreceptor, though the significance of this is not clear. Beta blockade in manand adrenalectomy in animals show that endogenous epinephrine has significantmetabolic effects.

Epinephrine and exercise

The mainphysiological stimulus to epinephrine secretion is exercise. This was firstdemonstrated using the dennervated pupil of a cat as an assay, later confirmedusing a biological assay on urine samples.Biochemical methods for measuringcatecholamines in plasma were published from 1950 onwards. Although muchvaluable work has been published using fluorimetric assays to measure totalcatecholamine concentrations, the method is too non-specific and insensitive toaccurately determine the very small quantities of epinephrine in plasma. Thedevelopment of extraction methods and enzyme-isotope derivate radio-enzymaticassays (REA) transformed the analysis down to a sensitivity of 1 pg forepinephrine. Early REA plasma assays indicated that epinephrine and totalcatecholamines rise late in exercise, mostly when anaerobic metabolismcommences

During exercisethe epinephrine blood concentration rises partially from increased secretionfrom the adrenal medulla and partly from decreased metabolism because ofreduced hepatic blood flow Infusion of epinephrine to reproduce exercisecirculating concentrations of epinephrine in subjects at rest has littlehaemodynamic effect, other than a small β2 mediated fall in diastolic bloodpressure. Infusion of epinephrine well within the physiological rangesuppresses human airway hyper-reactivity sufficiently to antagonist theconstrictor effects of inhaled histamine.

A link betweenwhat we now know as the sympathetic system and the lung was shown in 1887 whenGrossman showed that stimulation of cardiac accelerator nerves reversedmuscarine induced airway constriction. In elegant experiments in the dog, wherethe sympathetic chain was cut at the level of the diaphragm, Jackson showedthat there was no direct sympathetic innervation to the lung, but thatbronchoconstriction was reversed by release of epinephrine from the adrenalmedulla. An increased incidence of asthma has not been reported foradrenalectomized patients; those with a predisposition to asthma will have someprotection from airway hyper-reactivity from their corticosteroid replacementtherapy. Exercise induces progressive airway dilation in normal subjects thatcorrelates with work load and is not prevented by beta blockade. The progressivedilation of the airway with increasing exercise is mediated by a progressivereduction in resting vagal tone. Beta blockade with propranolol causes arebound in airway resistance after exercise in normal subjects over the sametime course as the bronchoconstriction seen with exercise induced asthma. Thereduction in airway resistance during exercise reduces the work of breathing.

Pathology

Increasedepinephrine secretion is observed in phaeochromocytoma, hypoglycaemia,myocardial infarction and to a lesser degree in benign essential familialtremor. A general increase in sympathetic neural activity is usuallyaccompanied by increased adrenaline secretion, but there is selectivity duringhypoxia and hypoglycaemia, when the ratio of adrenaline to noradrenaline isconsiderably increased. Therefore, there must be some autonomy of the adrenalmedulla from the rest of the sympathetic system.

ForPheochromocytoma see:  

Myocardialinfarction is associated with high levels of circulating epinephrine and noepinephrine,particularly in cardiogenic shock.

Benign familiartremor (BFT) is responsive to peripheral β-adrenergic blockers and beta 2stimulation is known to cause tremor. Patients with BFT were found to haveincreased plasma epinephrine, but not norepinephrine.

Low, or absent,concentrations of epinephrine can be seen in autonomic neuropathy or followingadrenalectomy. Failure of the adrenal cortex, as with Addisons disease, cansuppress epinephrine secretion as the activity of the synthesing enzyme,phenylethanolamine-N-methyltransferase, depends on the high concentration ofcortisol that drains from the cortex to the medulla.

Pharmacology

Medical Uses

Adrenaline isused to treat a number of conditions including: cardiac arrest, anaphylaxis,and superficial bleeding. It has been used historically for bronchospasm andhypoglycemia, but newer treatments for these that are selective for beta2adrenoceptors, such as salbutamol, a synthetic epinephrine derivative, anddextrose, respectively, are currently preferred. Currently the maximumrecommended daily dosage for patients in a dental setting requiring localanesthesia with a peripheral vasoconstrictor is 10 mg/lb of total bodyweight  

Cardiac arrest

Adrenaline isused as a drug to treat cardiac arrest and other cardiac dysrhythmias resultingin diminished or absent cardiac output. Its actions are to increase peripheralresistance via α1receptor-dependentvasoconstriction and to increase cardiacoutput via its binding to β1receptors. The goal of reducing peripheralcirculation is to increase coronary and cerebral perfusion pressures andtherefore increase oxygen exchange at the cellular level. While epinephrinedoes increase aortic, cerebral, and carotid circulation pressure, it lowerscarotid blood flow andend-tidal CO2 or ETCO2 levels. It appears thatepinephrine may be improving macrocirculation at the expense of the capillarybeds where actual perfusion is taking place. ETCO2 levels have become themarker that predicts the effectiveness of CPR and return of spontaneouscirculation. The ability of epinephrine to increase macrocirculatory pressuresdoes not necessarily increase blood flow through end organs. ETCO2 levels mightmore accurately reflect tissue perfusion instead of perfusion pressure markers.

Epinephrine hasnot demonstrated its ability to improve tissue perfusion or positively impactlong term survival, and could be reducing the survival rates of patients incardiac arrest.

Anaphylaxis

Epinephrine/adrenalineis the drug of choice for treating anaphylaxis. Allergy patientsundergoingimmunotherapy may receive an adrenaline rinse before the allergenextract is administered, thus reducing the immune response to the administeredallergen.

Differentstrengths, doses and routes of administration of epinephrine are used forseveral medical emergencies. The commonly used Epipen Auto-Injector delivers0.3 mg epinephrine injection (0.3 mL, 1:1000) is indicated in the emergencytreatment of allergic reactions (Type I) including anaphylaxis to stings,contrast agents, medicines or patients with a history of anaphylactic reactionsto known triggers. A single dose is recommended for patients who weigh 30 kg ormore, repeated if necessary. A lower strength product is available forpaediatric use This dose causes vasoconstriction at the site of subcutaneousinjection, delaying absorption. The pharmacokinetic profile produces plasmaconcentrations in the region of 2 nmol/l, a concentration that be also be achievedwith the repeated use of an epinephrine inhaler. This concentration is similarto that achieved during intense exercise and is too low to have significantbeta 1 adrenoceptor, or alpha vasoconstrictor activity, but has marked beta 2adrenceptor activity causing a fall in plasma potassium, an elevation in plasmaglucose and enhanced finger tremor with additional bronchodilation andbronchoprotection.

The allergicreaction dose of epinephrine (0.3 mg 1/1,000 SC) suppresses the experimentallyinduced wheal of the wheal and flare response to intradermally injectedantigen. This suppression of the wheal is mediated by beta 2 adrenoceptors. Themechanism of the suppression of the edema is to reduce the vascular leak offluid through the inter-endothelial junction of post capillary venules via betareceptor stimulation on the endothelial surface. Repeated doses, or higherdoses, may cause additional microvascular constriction via alpha receptorstimulation, which also suppresses inflammatory edema.

When givenintravenously (iv), or intra-muscularly (im), the potency of epinephrine isgreatly enhanced. For this reason for refactory anaphylactic shock or cardiacarrest a dilute epinephrine preparation is used of 1/10,000, the iv or im routebeing used for faster onset of action. The adult dose for refractoryanaphylactic shock is usually 0.1 mg (1:10,000)IVover5min and for cardiacarrest1 mg(1:10,000)as an IV push. Whengiven IV a major mechanism is via alpha adrenoceptor mediated vasoconstriction,increasing central blood pressure, making more selective alpha adrenoceptor agonists an alternative treatment Intramuscular injection can becomplicated in that the depth of subcutaneous fat varies and may result insubcutaneous injection, or may be injected intravenously in error, or the wrongstrength used. Intramuscular injection does give a faster and higherpharmacokinetic profile when compared to SC injection  

Because ofvarious expressions of α1 or β2 receptors, depending on the patient,administration of adrenaline may raise or lower blood pressure, depending onwhether or not the net increase or decrease in peripheral resistance canbalance the positive inotropic and chronotropic effects of adrenaline on theheart, effects that increase the contractility and rate, respectively, of theheart.

The usualconcentration for SC or IM injection is 0.3 - 0.5 ml of 1:1,000. It isavailable in the trade asepipen

Asthma

Adrenaline isalso used as a bronchodilator for asthma if specific β2 agonists are unavailableor ineffective.

When given bythe subcutaneous or intramuscular routes for asthma, an appropriate dose is300-500 mcg.

Croup

Racemicepinephrine has historically been used for the treatment of croup. Racemicadrenaline is a 1:1 mixture of the dextrorotatory (d) and levorotatory (l)isomers of adrenaline. The l- form is the active component. Racemic adrenalineworks by stimulation of the α-adrenergic receptors in the airway, withresultant mucosal vasoconstriction and decreased subglottic edema, and bystimulation of the β-adrenergic receptors, with resultant relaxation of thebronchial smooth muscle.

In local anesthetics

Adrenaline isadded to injectable forms of a number of local anesthetics, such as bupivacaineand lidocaine, as a vasoconstrictor to slow the absorption and, therefore,prolong the action of the anesthetic agent. Due to epinephrine'svasoconstricting abilities, the use of epinephrine in localized anestheticsalso helps to diminish the total blood loss the patient sustains during minorsurgical procedures. Some of the adverse effects of local anesthetic use, suchas apprehension, tachycardia, and tremor, may be caused by adrenaline.Epinephrine/adrenalin is frequently combined with dental and spinal anestheticsand can cause panic attacks in susceptible patients at a time when they may beunable to move or speak due to twilight drugs.

Autoinjectors

Main article:Epinephrine autoinjector

Adrenaline isavailable in an autoinjector delivery system. Auvi-Qs, Jexts, EpiPens, Emerade,Anapens, andTwinjects all use adrenaline as their active ingredient. Twinject,which is now discontinued, contained a second dose of adrenaline in a separatesyringe and needle delivery system contained within the body of theautoinjector. Though both EpiPen and Twinject are trademark names, common usageof the terms is drifting toward the generic context of any adrenalineautoinjector.

Adverse effects

Adversereactions to adrenaline include palpitations, tachycardia, arrhythmia, anxiety,panic attack, headache,tremor, hypertension, and acute pulmonary edema.

Use iscontraindicated in people on nonselective β-blockers, because severehypertension and even cerebral hemorrhage may result. Although commonlybelieved that administration of adrenaline may cause heart failure byconstricting coronary arteries, this is not the case. Coronary arteries haveonly β2 receptors, which cause vasodilation in the presence of adrenaline. Evenso, administering high-dose adrenaline has not been definitively proven toimprove survival or neurologic outcomes in adult victims of cardiac arrest.

Terminology

Epinephrine isthe hormone's United States Adopted Name and International Nonproprietary Name,though the more generic name adrenaline is frequently used. The termEpinephrine was coined by the pharmacologist John Abel, who used the name todescribe the extracts he prepared from the adrenal glands as early as 1897. In1901,Jokichi Takamine patented a purified adrenal extract, and called it"adrenalin", which was trademarked byParke, Davis & Co in theU.S. In the belief that Abel's extract was the same as Takamine's, a beliefsince disputed, epinephrine became the generic name in the U.S. The BritishApproved Name and European Pharmacopoeia term for this chemical is adrenalineand is indeed now one of the few differences between the INN and BAN systems ofnames.

Among Americanhealth professionals and scientists, the term epinephrine is used overadrenaline. However, pharmaceuticals that mimic the effects of epinephrine areoften called adrenergics, and receptors for epinephrine are called adrenergicreceptors or adrenoceptors.

Mechanismof action

As a hormone andneurotransmitter, epinephrine acts on nearly all body tissues. Its actions varyby tissue type and tissue expression ofadrenergic receptors. For example, highlevels of epinephrine causes smooth musclerelaxation in the airways but causescontraction of the smooth muscle that lines mostarterioles.

Physiologicresponses to epinephrine by organ

Organ Effects

Heart Increasesheart rate

Lungs Increasesrespiratory rate

SystemicVasoconstriction and vasodilation

Liver Stimulatesglycogenolysis

SystemicTriggers lipolysis

Systemic Musclecontraction

Epinephrine actsby binding to a variety of adrenergic receptors. Epinephrine is a nonselectiveagonist of all adrenergic receptors, including the major subtypes α1, α2,β1,β2, and β3. Epinephrine's binding to these receptors triggers a number ofmetabolic changes. Binding to α-adrenergic receptors inhibits insulin secretionby the pancreas, stimulates glycogenolysis in the liver andmuscle, andstimulates glycolysis in muscle. β-Adrenergic receptor binding triggersglucagon secretion in the pancreas, increased adrenocorticotropic hormone(ACTH) secretion by the pituitary gland, and increasedlipolysis by adiposetissue. Together, these effects lead to increased blood glucose and fattyacids, providing substrates for energy production within cells throughout thebody.

Measurementin biological fluids

Adrenaline maybe quantified in blood, plasma, or serum as a diagnostic aid, to monitortherapeutic administration, or to identify the causative agent in a potentialpoisoning victim. Endogenous plasma adrenaline concentrations in resting adultsare normally less than 10 ng/L, but may increase by 10-fold during exercise andby 50-fold or more during times of stress. Pheochromocytoma patients often haveplasma adrenaline levels of 1000-10,000 ng/L. Parenteral administration ofadrenaline to acute-care cardiac patients can produce plasma concentrations of10,000 to 100,000 ng/L.

Biosynthesisand regulation

Adrenaline issynthesized in the medulla of the adrenal gland in an enzymatic pathway thatconverts the amino acid tyrosine into a series of intermediates and,ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA, which issubsequently decarboxylated to give dopamine. Oxidation gives norepinephrine.The final step in adrenaline biosynthesis is the methylation of the primaryamine of noradrenaline. This reaction is catalyzed by the enzymephenylethanolamine N-methyltransferase (PNMT) which utilizesS-adenosylmethionine (SAMe) as themethyl donor. While PNMT is found primarilyin the cytosol of the endocrine cells of the adrenal medulla(also known as chromaffincells), it has been detected at low levels in both the heart and brain.

Epinephrineand Psychology

Epinephrine and Emotional Response

Every emotionalresponse has a behavioral component, an autonomic component, and a hormonalcomponent. The hormonal component includes the release of epinephrine, anadrenomedullary response that occurs in response to stress and that iscontrolled by the sympathetic nervous system. The major emotion studied inrelation to epinephrine is fear. In an experiment, subjects who were injectedwith epinephrine expressed more negative and fewer positive facial expressionsto fear films compared to a control group. These subjects also reported a moreintense fear from the films and greater mean intensity of negative memoriesthan control subjects. The findings from this study demonstrate that there arelearned associations between negative feelings and levels of epinephrine.Overall, the greater amount of epinephrine is positively correlated with anarousal state of negative feelings. These findings can be an effect in partthat epinephrine elicits physiological sympathetic responses including anincreased heart rate and knee shaking, which can be attributed to the feelingof fear regardless of the actual level of fear elicited from the video.Although studies have found a definite relation between epinephrine and fear,other emotions have not had such results. In the same study, subjects did notexpress a greater amusement to an amusement film nor greater anger to an anger film.Similar findings were also supported in a study that involved rodent subjectsthat either were able or unable to produce epinephrine. Findings support theidea that epinephrine does have a role in facilitating the encoding ofemotionally arousing events, contributing to higher levels of arousal due tofear.

Epinephrine and Memory

It has beenfound that adrenergic hormones, such as epinephrine, can produce retrogradeenhancement of long-term memory in humans. The release of epinephrine due toemotionally stressful events, which is endogenous epinephrine, can modulatememory consolidation of the events, insuring memory strength that isproportional to memory importance. Post-learning epinephrine activity alsointeracts with the degree of arousal associated with the initial coding. Thereis evidence that suggests epinephrine does have a role in long-term stressadaptation and emotional memory encoding specifically. Epinephrine may alsoplay a role in elevating arousal and fear memory under particular pathologicalconditions including post-traumatic stress disorder. Overall, the generalfindings through most studies supports that “endogenous epinephrine releasedduring learning modulate the formation of long-lasting memories for arousingevents”. Studies have also found that recognition memory involving epinephrinedepends on a mechanism that depends on B-adrenoceptors. Epinephrine does notreadily cross the blood-brain barrier, so its effects on memory consolidationare at least partly initiated by B-adrenoceptors in the periphery. Studies havefound that sotalol, a B-adrenoceptor antagonist that also does not readilyenter the brain, blocks the enhancing effects of peripherally administeredepinephrine on memory. These findings suggest that B-adrenoceptors arenecessary for epinephrine to have an effect on memory consolidation.

Fornoradrenaline to be acted upon by PNMT in the cytosol, it must first be shippedout of granules of the chromaffin cells. This may occur via thecatecholamine-H+ exchanger VMAT1. VMAT1 is also responsible for transportingnewly synthesized adrenaline from the cytosol back into chromaffin granules inpreparation for release.

In liver cells,adrenaline binds to the β-adrenergic receptor, which changes conformation andhelps Gs, a G protein, exchange GDP to GTP. This trimeric G protein dissociatesto Gs alpha and Gs beta/gamma subunits. Gs alpha binds to adenyl cyclase, thusconverting ATP into cyclic AMP. Cyclic AMP binds to the regulatory subunit ofprotein kinase A: Protein kinase A phosphorylates phosphorylase kinase.Meanwhile, Gs beta/gamma binds to the calcium channel and allows calcium ionsto enter the cytoplasm. Calcium ions bind to calmodulin proteins, a proteinpresent in all eukaryotic cells, which then binds to phosphorylase kinase andfinishes its activation. Phosphorylase kinase phosphorylatesglycogenphosphorylase, which then phosphorylates glycogen and converts it toglucose-6-phosphate.

Regulation

The majorphysiologic triggers of adrenaline release center uponstresses, such asphysical threat, excitement, noise, bright lights, and high ambienttemperature. All of these stimuli are processed in thecentral nervous system.

Adrenocorticotropichormone (ACTH) and the sympathetic nervous systemstimulate the synthesis of adrenalineprecursors by enhancing the activity of tyrosine hydroxylase anddopamine-β-hydroxylase, two key enzymes involved in catecholamine synthesis.ACTH also stimulates the adrenal cortex to release cortisol, which increasesthe expression of PNMT in chromaffin cells, enhancing adrenaline synthesis.This is most often done in response to stress. The sympathetic nervous system,acting via splanchnic nerves to the adrenal medulla, stimulates the release ofadrenaline. Acetylcholine released by preganglionic sympathetic fibers of thesenerves acts on nicotinic acetylcholine receptors, causing cell depolarizationand an influx of calcium through voltage-gated calcium channels. Calciumtriggers the exocytosis of chromaffin granules and, thus, the release of adrenaline(and noradrenaline) into the bloodstream.

Unlike manyother hormones adrenaline (as with other catecholamines) does not exertnegative feedback to down-regulate its own synthesis. Abnormally elevatedlevels of adrenaline can occur in a variety of conditions, such assurreptitious epinephrine administration, pheochromocytoma, and other tumors ofthe sympathetic ganglia.

Its action isterminated with reuptake into nerve terminal endings, some minute dilution, andmetabolism bymonoamine oxidase and catechol-O-methyl transferase.


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