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Adrenaline

"Adrenaline" and "Adrenalin" redirect here. For other uses, see Adrenaline (disambiguation).

Epinephrine (also known as adrenaline, adrenalin, or 4,5-β-trihydroxy-N-methylphenethylamine) is a hormone and a neurotransmitter.[1] Epinephrine has many functions in the body, regulating heart rate, blood vessel and air passage diameters, and metabolic shifts; epinephrine release is a crucial component of the fight-or-flight response of the sympathetic nervous system.[2] In chemical terms, epinephrine 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]

Medical uses


Adrenaline is used to treat a number of conditions including: cardiac arrest, anaphylaxis, and superficial bleeding.[4] It has been used historically for bronchospasm and hypoglycemia, but newer treatments for these, such as salbutamol, a synthetic epinephrine derivative, and dextrose, respectively, are currently preferred. Currently the maximum recommended daily dosage for patients in a dental setting requiring local anesthesia with a peripheral vasoconstrictor is 10mg/lb of total body weight [4]

Cardiac arrest

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. However, a study of outcomes of CPR suggests that epinephrine may actually lower survival and neurological recovery.[5]

Anaphylaxis

Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating anaphylaxis. Allergy[6] patients undergoing immunotherapy may receive an adrenaline rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen.

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 SC or IM injection is 0.3 - 0.5 mg 1:1,000.

Asthma

Adrenaline is also used as a bronchodilator for asthma if specific β2 agonists are unavailable or ineffective.[7]

When given by the subcutaneous or intramuscular routes for asthma, an appropriate dose is 300-500 mcg.[8][9]

Croup

Racemic epinephrine has historically been used for the treatment of croup.[10][11] Racemic adrenaline is a 1:1 mixture of the dextrorotatory (d) and levorotatory (l) isomers of adrenaline.[12] The l- form is the active component.[12] 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.[11]

In local anesthetics

Adrenaline is added to injectable forms of a number of local anesthetics, such as bupivacaine and lidocaine, as a vasoconstrictor to slow the absorption and, therefore, prolong the action of the anesthetic agent. Due to epinephrine's vasoconstricting abilities, the use of epinephrine in localized anesthetics also helps to diminish the total blood loss the patient sustains during minor surgical procedures. Some of the adverse effects of local anesthetic use, such as apprehension, tachycardia, and tremor, may be caused by adrenaline. Epinephrine/adrenalin is frequently combined with dental and spinal anesthetics and can cause panic attacks in susceptible patients at a time when they may be unable to move or speak due to twilight drugs.[13]

Autoinjectors

Adrenaline is available in an autoinjector delivery system. Auvi-Qs, Jexts, EpiPens, Emerade, Anapens, and Twinjects all use adrenaline as their active ingredient. Twinject, which is now discontinued, contained 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 effects

Adverse reactions to adrenaline include palpitations, tachycardia, arrhythmia, anxiety, panic attack, headache, tremor, hypertension, and acute pulmonary edema.[14]

Use is contraindicated in people on nonselective β-blockers, because severe hypertension and even cerebral hemorrhage may result.[15] 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.[16] Even so, administering high-dose adrenaline has not been definitively proven to improve survival or neurologic outcomes in adult victims of cardiac arrest.[17]

Terminology

Epinephrine is the hormone's United States Adopted Name and International Nonproprietary Name, though the more generic name adrenaline is frequently used. The term Epinephrine was coined by the pharmacologist John Abel, who used the name to describe the extracts he prepared from the adrenal glands as early as 1897.[18] In 1901, Jokichi Takamine patented a purified adrenal extract, and called it "adrenalin", which was trademarked by Parke, Davis & Co in the U.S.[18] In the belief that Abel's extract was the same as Takamine's, a belief since disputed, epinephrine became the generic name in the U.S.[18] 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.[19]

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.

Mechanism of action

Physiologic responses to epinephrine by organ
Organ Effects
Heart Increases heart rate
Lungs Increases respiratory rate
Systemic Vasoconstriction or vasodilation
Liver Stimulates glycogenolysis
Systemic Triggers lipolysis
Systemic Muscle contraction

File:Fish Melanophores Responding to Adrenaline.webm As a hormone and neurotransmitter, epinephrine acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of adrenergic receptors. For example, high levels of epinephrine causes smooth muscle relaxation in the airways but causes contraction of the smooth muscle that lines most arterioles.

Epinephrine acts by binding to a variety of adrenergic receptors. Epinephrine is a nonselective agonist of all adrenergic receptors, including the major subtypes α1, α2, β1, β2, and β3.[15] 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.[20] 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.[20]

Measurement in biological fluids

Adrenaline may be quantified 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.[21][22]

Biosynthesis and regulation

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. The final step is methylation of the primary 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.

Epinephrine and Psychology

Epinephrine and Emotional Response

Every emotional response has a behavioral component, an autonomic component, and a hormonal component. The hormonal component includes the release of epinephrine, an adrenomedullary response that occurs in response to stress and that is controlled by the sympathetic nervous system. The major emotion studied in relation to epinephrine is fear. In an experiment, subjects who were injected with epinephrine expressed more negative and fewer positive facial expressions to fear films compared to a control group. These subjects also reported a more intense fear from the films and greater mean intensity of negative memories than control subjects.[23] The findings from this study demonstrate that there are learned associations between negative feelings and levels of epinephrine. Overall, the greater amount of epinephrine is positively correlated with an arousal state of negative feelings. These findings can be an effect in part that epinephrine elicits physiological sympathetic responses including an increased heart rate and knee shaking, which can be attributed to the feeling of 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 not express a greater amusement to an amusement film nor greater anger to an anger film.[23] Similar findings were also supported in a study that involved rodent subjects that either were able or unable to produce epinephrine. Findings support the idea that epinephrine does have a role in facilitating the encoding of emotionally arousing events, contributing to higher levels of arousal due to fear.[24]

Epinephrine and Memory

It has been found that adrenergic hormones, such as epinephrine, can produce retrograde enhancement of long-term memory in humans. The release of epinephrine due to emotionally stressful events, which is endogenous epinephrine, can modulate memory consolidation of the events, insuring memory strength that is proportional to memory importance. Post-learning epinephrine activity also interacts with the degree of arousal associated with the initial coding.[25] There is evidence that suggests epinephrine does have a role in long-term stress adaptation and emotional memory encoding specifically. Epinephrine may also play a role in elevating arousal and fear memory under particular pathological conditions including post-traumatic stress disorder.[24] Overall, the general findings through most studies supports that “endogenous epinephrine released during learning modulate the formation of long-lasting memories for arousing events”.[26] Studies have also found that recognition memory involving epinephrine depends on a mechanism that depends on B-adrenoceptors.[26] Epinephrine does not readily cross the blood-brain barrier, so its effects on memory consolidation are at least partly initiated by B-adrenoceptors in the periphery. Studies have found that sotalol, a B-adrenoceptor antagonist that also does not readily enter the brain, blocks the enhancing effects of peripherally administered epinephrine on memory.[27] These findings suggest that B-adrenoceptors are necessary for epinephrine to have an effect on memory consolidation.


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.

Regulation

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.[28]

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.

Unlike many other hormones adrenaline (as with other catecholamines) does not exert negative feedback to down-regulate its own synthesis.[29] 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.

Chemical synthesis

Epinephrine may be synthesized by the reaction of catechol (1) with chloroacetyl chloride (2), followed by reaction with methylamine to give the ketone (4), which is reduced to the desired hydroxy compound (5). The racemic mixture may be separated using tartaric acid.

For isolation from the adrenal glands tissue of livestock:

  • J. Takamine, J. Soc. Chem. Ind., 20, 746 (1901).
  • J. B. Aldrich, Am. J. Physiol., 5, 457 (1901).

Synthetic production:

  • A. F. Stolz, Chem. Ber., 37, 4149 (1904).
  • K. R. Payne, Ind. Chem. Chem. Manuf., 37, 523 (1961).
  • H. Loewe, Arzneimittel-Forsch., 4, 583 (1954).
  • Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 152814  (1903).
  • Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 157300  (1903).
  • Farbenwerke Meister Lucins & Bruning in Hochst a.M., DE 222451  (1908).
  • expand by hand
  • D. Flacher, Z. Physiol. Chem., 58, 189 (1908).

History

Main article: History of catecholamine research

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.[30] Japanese chemist Jokichi Takamine and his assistant Keizo Uenaka independently discovered adrenaline in 1900.[31][32] In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen.[33] Adrenaline was first synthesized in the laboratory by Friedrich Stolz and Henry Drysdale Dakin, independently, in 1904.[32]

Adrenaline junkie

"Adrenaline junkie" redirects here. For the British reality TV series, see Jack Osbourne: Adrenaline Junkie.

An adrenaline junkie is somebody who appears to be addicted to endogenous epinephrine. The "high" is caused by self-inducing a fight-or-flight response by intentionally engaging in stressful or risky behavior, which causes a release of epinephrine by the adrenal gland. 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.[34][35]

References

General references

External links

  • U.S. National Library of Medicine: Drug Information Portal - Epinephrine

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