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(R)-(–)-L-Epinephrine or (R)-(–)-L-adrenalineEpinephrine

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	838
DrugBank	APRD00450
ChemSpider	5611
Chemical data
Formula	C9H13NO3
Mol. mass	183.204 g/mol
Pharmacokinetic data
Bioavailability	Nil (oral)
Metabolism	adrenergic synapse (MAO and COMT)
Half life	2 minutes
Excretion	Urine
Therapeutic considerations
Pregnancy cat.	A(AU) C(US)
Legal status	Prescription Only (S4)(AU) POM(UK) ℞-only(US)
Routes	IV, IM, endotracheal, IC
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Adrenaline (also referred to as Epinephrine; see Terminology) is a hormone and neurotransmitter.^[1] When produced in the body it increases heart rate, contracts blood vessels and dilates air passages and participates in the "fight or flight" response of the sympathetic nervous system.^[2] It is a catecholamine, a sympathomimetic monoamine produced 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 gland's anatomic location. 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]

Japanese chemist Jokichi Takamine and his assistant Keizo Uenaka independently discovered Adrenaline in 1900.^[4][5] In 1901 Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen.^[6] Adrenaline was first synthesized by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.^[5]

[edit] Triggers

Adrenaline is a powerful action, "fight or flight", hormone and also plays a central role in the short-term stress reaction. It is released from the adrenal glands when danger threatens or in an emergency, hence an Adrenaline rush. Such triggers may be threatening, exciting, or environmental stressor conditions such as high noise levels, or bright light and high ambient temperature (see Fight-or-flight response).^{[citation needed]}

[edit] Actions in the body

When in 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 muscles, while suppressing other non-emergency bodily processes (digestion in particular).^{[citation needed]}

It increases heart rate and stroke volume, dilates the pupils, 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 lipids in fat cells. Like some other stress hormones, Adrenaline has a suppressive effect on the immune system.^[7]

Although Adrenaline does not have any psychoactive effects, stress or arousal also releases noradrenaline in the brain. Noradrenaline has similar actions in the body, but is also psychoactive.^{[citation needed]}

The type of action in various cell types depends on their expression of adrenergic receptors.^{[citation needed]}

[edit] Mechanism of action

β-adrenergic receptors

Further reading: adrenergic receptor

Adrenaline's actions are mediated through adrenergic receptors. Adrenaline is a non-selective agonist of all adrenergic receptors. It activates α₁, α₂, β₁, and β₂ receptors to different extents.^[8] Specific functions include:

• It binds to α₁ 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 catalyzes 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.

• Adrenaline also activates β-adrenergic receptors of the liver and muscle cells, thereby activating the adenylate cyclase signaling pathway, which will in turn increase glycogenolysis.

β₂ receptors are found primarily in skeletal muscle blood vessels where they trigger vasodilation. However, α-adrenergic receptors are found in most smooth muscles and splanchnic vessels, and adrenaline triggers vasoconstriction in those vessels.^{[citation needed]}

Adrenaline is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output; its action is to increase peripheral resistance via α₁-adrenoceptor vasoconstriction, so that blood is shunted to the body's core, and the β₁-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—increased cardiac irritability—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.^[7]

Due to its vasocontriction effects, adrenaline is the drug of choice for treating anaphylaxis. It is also useful in treating sepsis. Allergy 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 beta₂-adrenergic receptor agonists are unavailable or ineffective.^{[citation needed]}

Because of various expression of α₁ or β₂-receptors, 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]}

Adrenaline can also be found in some brands of nasal spray. Its use in this form is to open air passages, however short-term this use may be.^{[citation needed]}

Adrenaline is synthesized from noradrenaline in a synthetic pathway shared by all catecholamines.

Adrenaline is synthesized from noradrenaline in a synthetic pathway shared by all catecholamines, including L-dopa, dopamine, and adrenaline.^{[citation needed]}

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]}

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]}

[edit] Regulation

Adrenaline synthesis is solely under the control of the Central Nervous System (CNS). Several levels of regulation dominate adrenaline synthesis.^{[citation needed]}

Adrenocorticotropic hormone (ACTH) and the sympathetic nervous system stimulate the synthesis of adrenaline precursors by enhancing the activity of enzymes involved in catecholamine synthesis. The specific enzymes are tyrosine hydroxylase in the synthesis of dopa and enzyme dopamine-β-hydroxylase in the synthesis of noradrenaline.^{[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]}

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 adrenaline.^{[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 Phosphorylase which then phosphorylates glycogen and converts it to glucose-6-phosphate.^{[citation needed]}

[edit] Terminology

This chemical is widely referred to as adrenaline outside of the United States; however, the United States Approved Name and International Nonproprietary Name for this chemical 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.^[9]

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] Therapeutic use

Epinephrine ampule, 1 mg (Suprarenin)

[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. The larger Twinject dose (0.3mg) contains a third dose as well.

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] 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.^{[citation needed]}

Borate salt is used in ophthalmology.^{[citation needed]}

[edit] Side effects and drug interactions

Adverse reactions to epinephrine include palpitations, tachycardia, arrhythmia, anxiety, headache, tremor, hypertension, and acute pulmonary edema.^[10]

Use is contraindicated for patients on non-selective β-blockers because severe hypertension and even cerebral hemorrhage may result.^[8] Although, use of Epinephrine during life threatening Anaphylaxis has no absolute contraindications.

[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) for the adrenaline "rush". Adrenaline junkies appear to favour stressful activities for the release of epinephrine as a stress response. 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.^[11][12]

[edit] See also

Wikimedia Commons has media related to: Epinephrine (category)

• Anaphylaxis
• Adrenochrome
• Catechol-O-methyl transferase
• Adrenergic receptor

[edit] References

[edit] Notes

[edit] General 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.