Information about Epinephrine

Epinephrine (INN) (IPA: [ˌɛpɪˈnɛfrən]) or adrenaline (European Pharmacopoeia and BAN) (IPA: [əˈdrɛnələn]), sometimes spelled "epinephrin" or "adrenalin" respectively, is a hormone when carried in the blood and a neurotransmitter when it is released across a neuronal synapse. It is a catecholamine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine. The Latin roots ad-+renes and the 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 sometimes shortened to epi or to EP in medical jargon.

History

In May 1886, 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 Polish physiologist. The discovery was repeated in 1897 by John Jacob Abel.^[1]

Jokichi Takamine, a Japanese chemist, independently discovered the same hormone in 1900.^[2][3]

It was first artificially synthesized in 1904 by Friedrich Stolz.

Actions in the body

Epinephrine is a "fight or flight" hormone which is released from the adrenal glands when danger threatens or in an emergency. 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 muscles, while suppressing other non-emergency bodily processes (digestion in particular).

Epinephrine plays a central role in the short-term stress reaction—the physiological response to threatening, exciting, or environmental stressor conditions such as high noise levels or bright light (see Fight-or-flight response). It is secreted by the adrenal medulla. When released into the bloodstream, epinephrine binds to multiple receptors and has numerous effects throughout the body. It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gut while dilating arterioles in leg muscles. It elevates the blood sugar level by increasing catalysis 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, epinephrine has a suppressive effect on the immune system.^[4]

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.

Epinephrine 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.<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 agonists are unavailable or ineffective. Adverse reactions to epinephrine include palpitations, tachycardia, anxiety, headache, tremor, hypertension, and acute pulmonary edema.^[5]

Biosynthesis

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 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 norepinephrine, creating epinephrine.

For norepinephrine 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 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 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.

The sympathetic nervous system, acting via splanchnic nerves to the adrenal medulla, stimulates the release of epinephrine. 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 epinephrine (and norepinephrine) into the bloodstream.

Unlike many other hormones, epinephrine (as with other catecholamines) does not exert any negative feedback to down-regulate its own synthesis.

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. Ga 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.

Pharmacology

Epinephrine's actions are mediated through adrenergic receptors:

• It binds to α₁ receptors of liver cells, which activate inositol-phospholipid signaling pathway, signaling the phosphorylation of insulin, leading to reduced ability of insulin to bind to its receptors.
• 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.

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 epinephrine triggers vasoconstriction in those vessels.

Thus, 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 rate of the heart.

Terminology

Although widely referred to as adrenaline outside of the US, and the lay public worldwide, the USAN and INN for this chemical is epinephrine because adrenaline bore too much similarity to the Parke, Davis & Co trademark adrenalin (without the "e") which was registered in the US. The BAN and 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 US 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.

Isomers

Natural epinephrine is the (R)-(−)-L-epinephrine stereoisomer.

Autoinjectors

Epinephrine is now also used in EpiPens and Twinjects. EpiPens are long narrow auto-injectors that administer epinephrine, Twinjects are similar but contain two doses of epinephrine.

Though both EpiPen and Twinject are trademark names, common usage of the terms are drifting toward the generic context of any epinephrine autoinjector.

See also

• EpiPen
• Twinject
• Anaphylaxis
• Adrenaline junkie
• Adrenochrome
• Catechol-O-methyl transferase

References

Notes

General references

• Walter F. Boron, Emile L. Boulpaep (2005). Medical Physiology: A Cellular And Molecular Approach. Philadelphia, PA: Elsevier/Saunders. ISBN 1-4160-2328-3. 

•  • [ e] Phenethylamines

2C-B • 2C-C • 2C-D • 2C-E • 2C-I • 2C-N • 2C-T-2 • 2C-T-21 • 2C-T-4 • 2C-T-7 • 2C-T-8 • 3C-E • 4-FMP • Bupropion • Cathine • Cathinone • Clenbuterol • DESOXY • Dextroamphetamine • Methamphetamine • Diethylcathinone • Dimethylcathinone • DOC • DOB • DOI • DOM • bk-MBDB • Dopamine • Br-DFLY • Ephedrine • Epinephrine • Escaline • Fenfluramine • Levalbuterol • Levmetamfetamine • MBDB • MDA • MDMA • MDMC • MDEA • MDPV • Mescaline • Methcathinone • Methylphenidate • Norepinephrine • Phentermine • Salbutamol • Tyramine • Venlafaxine

•  • [ e] Endocrine system: hormones/endocrine glands (Peptide hormones, Steroid hormones)
Hypothalamic-pituitary	Hypothalamus: TRH, CRH , GnRH, GHRH, somatostatin, dopamine - Posterior pituitary: vasopressin, oxytocin - Anterior pituitary: α (FSH, LH, TSH), GH, prolactin, POMC (ACTH, MSH, endorphins, lipotropin)
Adrenal axis	Adrenal medulla: epinephrine, norepinephrine - Adrenal cortex: aldosterone, cortisol, DHEA
Thyroid axis	Thyroid: thyroid hormone (T3 and T4) - calcitonin - Parathyroid: PTH
Gonadal axis	Testis: testosterone, AMH, inhibin - Ovary: estradiol, progesterone, inhibin/activin, relaxin (pregnancy)
Other end. glands	Pancreas: glucagon, insulin, somatostatin - Pineal gland: melatonin
Non-end. glands	Placenta: hCG, HPL, estrogen, progesterone - Kidney: renin, EPO, calcitriol, prostaglandin - Heart atrium: ANP - Stomach: gastrin, ghrelin - Duodenum: CCK, GIP, secretin, motilin, VIP - Ileum: enteroglucagon - Adipose tissue: leptin, adiponectin, resistin - Thymus: Thymosin - Thymopoietin - Liver/other: Insulin-like growth factor (IGF-1, IGF-2)
Target-derived	NGF, BDNF, NT-3

•  • [ e] Cardiac stimulants excluding cardiac glycosides (C01C)
Adrenergic and dopaminergic agents	Dobutamine • Dopamine • Epinephrine • Fenoldopam • Isoprenaline • Metaraminol • Midodrine • Norepinephrine • Octopamine • Phenylephrine
Phosphodiesterase inhibitors (PDE3I)	Amrinone • Milrinone • Enoximone • Bucladesine
Other cardiac stimulants	Angiotensinamide • Xamoterol • Levosimendan

•  • [ e] Drugs for obstructive airway diseases: asthma/COPD (R03)
Adrenergics, inhalants	Short acting β2-agonists: Salbutamol • Fenoterol • Terbutaline Long acting β2-agonists (LABA): Bambuterol • Clenbuterol • Formoterol • Salmeterol other: Epinephrine • Isoproterenol • Orciprenaline
Glucocorticoids	Beclometasone • Budesonide • Ciclesonide • Fluticasone • Mometasone
Anticholinergics	Ipratropium • Tiotropium
Mast cell stabilizers	Cromoglicate • Nedocromil
Xanthines	Aminophylline • Theobromine • Theophylline
Leukotriene antagonists	Montelukast • Pranlukast • Zafirlukast
Combination products	Budesonide/formoterol • Fluticasone/salmeterol • Ipratropium/salbutamol

•  • [ e] Health Science > Medicine > Emergency medicine, medical emergency
Procedures	Advanced cardiac life support (ACLS) • Advanced Life Support (ALS) • Advanced Trauma Life Support (ATLS) • Basic life support (BLS) • Cardiopulmonary resuscitation (CPR) • First aid • Pediatric Advanced Life Support (PALS)
Trauma centers	Level I • Level II • Level III • Level IV
Equipment	Ambulance • Bag valve mask • Chest tube • Defibrillation (AED, ICD) • Electrocardiogram (ECG/EKG) • Intraosseous infusion (IO) • Intravenous therapy (IV) • Intubation
People	Certified first responder • Emergency medical technician (EMT) • Paramedic • Emergency physician • BASICS Doctor
Drugs	Atropine • Epinephrine • Amiodarone • Magnesium • Bicarbonate
Other	Golden hour • Emergency department • Emergency medical services • Emergency psychiatry • Triage