| Systematic (IUPAC) name | |
|---|---|
| (R)-4-(1-hydroxy- 2-(methylamino)ethyl)benzene-1,2-diol |
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| Clinical data | |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a603002 |
| Pregnancy cat. | A(AU) C(US) |
| Legal status | Prescription Only (S4) (AU) POM (UK) ℞-only (US) |
| Routes | IV, IM, endotracheal, IC |
| Pharmacokinetic data | |
| Bioavailability | Nil (oral) |
| Metabolism | adrenergic synapse (MAO and COMT) |
| Half-life | 2 minutes |
| Excretion | Urine |
| Identifiers | |
| CAS number | 51-43-4 |
| ATC code | A01AD01 B02BC09 C01CA24 R01AA14 R03AA01 S01EA01 |
| PubChem | CID 5816 |
| IUPHAR ligand | 509 |
| DrugBank | DB00668 |
| ChemSpider | 5611 |
| UNII | YKH834O4BH |
| KEGG | D00095 |
| ChEBI | CHEBI:28918 |
| ChEMBL | CHEMBL679 |
| Chemical data | |
| Formula | C9H13NO3 |
| Mol. mass | 183.204 g/mol |
| SMILES | eMolecules & PubChem |
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| (what is this?) (verify) |
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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] In chemical terms, adrenaline is one of a group of monoamines called the catecholamines. It is produced in some neurons of the central nervous system, and in the chromaffin cells of the adrenal medulla from the amino acids phenylalanine and tyrosine.[3]
Extracts of the adrenal gland were first obtained by Polish physiologist Napoleon Cybulski in 1895. These extracts, which he called nadnerczyna, contained adrenaline 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]
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Adrenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and superficial bleeding.[8] It has been used historically for bronchospasm and hypoglycemia, but newer treatments for these, such as salbutamol, a synthetic epinephrine derivitive, and dextrose, respectively, are currently preferred.[8]
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 β1 receptors.
Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating anaphylaxis. Allergy[9] 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 β2 agonists are unavailable or ineffective.[10]
Because of various expressions of α1 or β2 receptors, depending on the patient, administration of adrenaline may raise or lower blood pressure, depending on 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 that increase the contractility and rate, respectively, of the heart.
The usual concentration for SQ or IM injection is 0.3 - 0.5 mg 1:1,000.
Racemic epinephrine has historically been used for the treatment of croup.[11][12] Racemic adrenaline is a 1:1 mixture of the dextrorotatory (d) and levorotatory (l) isomers of adrenaline.[13] The l- form is the active component.[13] Racemic adrenaline 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]
Adrenaline 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 adrenaline.[14]
Adrenaline is available in an autoinjector delivery system. EpiPens, Anapens, and Twinjects all use adrenaline as their active ingredient. Twinjects contain a second dose of adrenaline 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 is drifting toward the generic context of any adrenaline autoinjector.
Adverse reactions to adrenaline include palpitations, tachycardia, arrhythmia, anxiety, headache, tremor, hypertension, and acute pulmonary edema.[15]
Use is contraindicated in people on nonselective β-blockers, because severe hypertension and even cerebral hemorrhage may result.[16] Although commonly believed that administration of adrenaline may cause heart failure by constricting coronary arteries, this is not the case. Coronary arteries have only β2 receptors, which cause vasodilation in the presence of adrenaline.[17] Even so, administering high-dose adrenaline has not been definitively proven to improve survival or neurologic outcomes in adult victims of cardiac arrest.[18]
Adrenaline 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 adrenaline 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 adrenaline levels of 1000-10,000 ng/L. Parenteral administration of adrenaline to acute-care cardiac patients can produce plasma concentrations of 10,000 to 100,000 ng/L.[19][20]
As a hormone, adrenaline acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, adrenaline causes smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles.
Adrenaline 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.[16] 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.
| Organ | Effects |
|---|---|
| Heart | Increases heart rate |
| Lungs | Increases respiratory rate |
| Nearly all tissues | Vasoconstriction or vasodilation |
| Liver | Stimulates glycogenolysis |
| N/A, systemic | Triggers lipolysis |
| N/A, systemic | Muscle contraction |
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 found in the cytosol of only cells of adrenal medullary cells. PNMT uses S-adenosylmethionine (SAMe) as a cofactor to donate the methyl group to noradrenaline, creating adrenaline.
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.
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.
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. 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. 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.
Adrenaline (as with noradrenaline) does exert negative feedback to down-regulate its own synthesis at the presynaptic alpha-2 adrenergic receptor. 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.
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.
For isolation from the adrenal glands tissue of livestock:
Synthetic production:
Adrenaline junkie is a term used to describe somebody appearing 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 enjoying dangerous activities (such as extreme sports, e.g. BASE jumping) for the adrenaline "rush". Adrenaline junkies appear to favor 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.[23][24]
Adrenaline addiction is not officially included in the DSM; however, that does not mean it is not a topic of intense debate or will not be included in the future. Psychology Today defines it as Always overwhelmed, adrenaline junkies seem to have a constant need for urgency, even panic, to get them through the day. They cannot grasp the race driver's motto: you have to slow down to go fast. Instead, they keep their foot on the pedal at full throttle, convinced that any deceleration is lost opportunity.[25] The same source describes the reason for the addiction is that someone has experienced a traumatic event past but has become "stuck."[25] The traumatic event is over but the body keeps seeking adrenaline. Endorphins are thus highly effective painkillers-numbing physical pain and emotional pain too.[25]
Symptoms include:
These individuals have developed the belief that they will be highly successful when they are speeding along in life. However, when this becomes a pattern of behavior, it can cause health and performance issues to surface.
Unlike other addicts whose behaviors are socially frowned-upon, adrenaline addicts are often praised for their frantic activity, even promoted for it during their careers. (which helps it to be such a pervasive disorder, adrenaline addiction can be very difficult to conquer)[25]
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.[27]
Among American health professionals and scientists, the term epinephrine is used over adrenaline. However, pharmaceuticals that mimic the effects of epinephrine are often called adrenergics, and receptors for epinephrine are called adrenergic receptors or adrenoceptors.
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