Epinephrine is a
hormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
and a
neurotransmitterNeurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
. It increases heart rate, constricts blood vessels, dilates air passages and participates in the
fight-or-flight responseThe fight-or-flight response was first described by Walter Bradford Cannon....
of the
sympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
. In chemical terms, adrenaline is one of a group of monoamines called the
catecholamineCatecholamines are molecules that have a catechol nucleus consisting of benzene with two hydroxyl side groups and a side-chain amine. They include dopamine, as well as the "fight-or-flight" hormones adrenaline and noradrenaline released by the adrenal medulla of the adrenal glands in response to...
s. It is produced in some
neuronA neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s of the central nervous system, and in the chromaffin cells of the
adrenal medullaThe adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...
from the
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s
phenylalaninePhenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
and
tyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
.
Extracts of the
adrenal glandIn mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
were first obtained by Polish physiologist
Napoleon CybulskiNapoleon Cybulski was a Polish physiologist and one of pioneers of endocrinology and electroencephalography. The discoverer of adrenaline, he was the first to isolate and identify the substance in 1895.-References:...
in 1895. These extracts, which he called
nadnerczyna, contained adrenaline and other catecholamines. Japanese chemist
Jokichi Takaminewas a Japanese chemist.-Early life and education:Takamine was born in Takaoka, Toyama Prefecture, in November 1854. His father was a doctor; his mother a member of a family of sake brewers. He spent his childhood in Kanazawa, capital of present-day Ishikawa Prefecture in central Honshū, and was...
and his assistant Keizo Uenaka independently discovered adrenaline in 1900. In 1901, Takamine successfully isolated and purified the hormone from the adrenal glands of sheep and oxen. Adrenaline was first synthesized in the laboratory by
Friedrich StolzFriedrich Stolz was a German chemist and, in 1904, the first person to artificially synthesize epinephrine .-References:...
and
Henry Drysdale DakinHenry Drysdale Dakin FRS was an English chemist.He was born in London as the youngest of 8 children to a family of steel merchants from Leeds. As a school boy he did water analysis with the Leeds City Analyst. He studied chemistry at the University of Leeds with Julius B...
, independently, in 1904.
Medical uses
Adrenaline is used to treat a number of conditions including:
cardiac arrestCardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
,
anaphylaxisAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
, and superficial bleeding. It has been used historically for
bronchospasmBronchospasm or a bronchial spasm is a sudden constriction of the muscles in the walls of the bronchioles. It is caused by the release of substances from mast cells or basophils under the influence of anaphylatoxins...
and
hypoglycemiaHypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
, but better treatments for these, such as
salbutamolSalbutamol or albuterol is a short-acting β2-adrenergic receptor agonist used for the relief of bronchospasm in conditions such as asthma and chronic obstructive pulmonary disease. It is marketed as Ventolin among other brand names....
and dextrose, respectively, are now preferred.
Cardiac arrest
Adrenaline is used as a
drugA pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
to treat
cardiac arrestCardiac arrest, is the cessation of normal circulation of the blood due to failure of the heart to contract effectively...
and other
cardiac dysrhythmiaCardiac dysrhythmia is any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.Some arrhythmias are life-threatening medical emergencies that can result in cardiac...
s resulting in diminished or absent
cardiac outputCardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
. Its actions are to increase peripheral resistance via
α1receptorThe alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
-dependent
vasoconstrictionVasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
and to increase
cardiac outputCardiac output is the volume of blood being pumped by the heart, in particular by a left or right ventricle in the time interval of one minute. CO may be measured in many ways, for example dm3/min...
via its binding to β
1 receptors.
Anaphylaxis
Due to its vasoconstrictive effects, adrenaline is the drug of choice for treating
anaphylaxisAnaphylaxis is defined as "a serious allergic reaction that is rapid in onset and may cause death". It typically results in a number of symptoms including throat swelling, an itchy rash, and low blood pressure...
. Allergy patients undergoing
immunotherapyImmunotherapy is a medical term defined as the "treatment of disease by inducing, enhancing, or suppressing an immune response". Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies. While immunotherapies that reduce or suppress are...
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
bronchodilatorA bronchodilator is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lungs. Bronchodilators may be endogenous , or they may be medications administered for the treatment of breathing difficulties...
for
asthmaAsthma is the common chronic inflammatory disease of the airways characterized by variable and recurring symptoms, reversible airflow obstruction, and bronchospasm. Symptoms include wheezing, coughing, chest tightness, and shortness of breath...
if specific β
2 agonists are unavailable or ineffective.
Because of various expressions of α
1 or β
2 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
chronotropicChronotropic effects are those that change the heart rate.Chronotropic drugs may change the heart rate by affecting the nerves controlling the heart, or by changing the rhythm produced by the sinoatrial node...
effects of adrenaline on the heart, effects that increase the
contractilityMyocardial contractility is the intrinsic ability of the heart to contract independent of preload and afterload. Changes in the ability to produce force during contraction result from different degrees of binding between myosin and actin filaments...
and
rateHeart rate is the number of heartbeats per unit of time, typically expressed as beats per minute . Heart rate can vary as the body's need to absorb oxygen and excrete carbon dioxide changes, such as during exercise or sleep....
, respectively, of the heart.
The usual concentration for SQ or IM injection is 0.3 - 0.5 mg 1:1,000.
Croup
Racemic epinephrineRacemic epinephrine is a racemic mixture of epinephrine and is a sympathomimetic bronchodilator which is delivered by aerosol. Commonly used in croup and when stridor is present after removal of an endotracheal tube ....
has historically been used for the treatment of croup. Racemic adrenaline is a 1:1 mixture of the dextrorotatory (d) and levorotatory (l)
isomerIn chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
s of adrenaline. The l- form is the active component. 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.
In local anesthetics
Adrenaline is added to injectable forms of a number of local anesthetics, such as
bupivacaineBupivacaine is a local anaesthetic drug belonging to the amino amide group. AstraZeneca commonly markets it under various trade names, including Marcain, Marcaine, Sensorcaine and Vivacaine.-Indications:...
and
lidocaineLidocaine , Xylocaine, or lignocaine is a common local anesthetic and antiarrhythmic drug. Lidocaine is used topically to relieve itching, burning and pain from skin inflammations, injected as a dental anesthetic or as a local anesthetic for minor surgery.- History :Lidocaine, the first amino...
, 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.
Autoinjectors
Adrenaline is available in an
autoinjectorAn autoinjector is a medical device designed to deliver a single dose of a particular drug....
delivery system.
EpiPenAn epinephrine autoinjector is a medical device used to deliver a measured dose of epinephrine using autoinjector technology, most frequently for the treatment of acute allergic reactions to avoid or treat the onset of anaphylactic shock.Trade names for this device include EpiPen, Twinject,...
s, 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 contextA genericized trademark is a trademark or brand name that has become the colloquial or generic description for, or synonymous with, a general class of product or service, rather than as an indicator of source or affiliation as intended by the trademark's holder...
of any adrenaline autoinjector.
Adverse effects
Adverse reactions to adrenaline include
palpitationA palpitation is an abnormality of heartbeat that causes a conscious awareness of its beating, whether it is too slow, too fast, irregular, or at its normal frequency. The word may also refer to this sensation itself...
s,
tachycardiaTachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
, arrhythmia,
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
,
headacheA headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
,
tremorA tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
,
hypertensionHypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, and acute
pulmonary edemaPulmonary edema , or oedema , is fluid accumulation in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and may cause respiratory failure...
.
Use is contraindicated in people on nonselective
β-blockersBeta blockers or beta-adrenergic blocking agents, beta-adrenergic antagonists, beta-adrenoreceptor antagonists or beta antagonists, are a class of drugs used for various indications. They are particularly for the management of cardiac arrhythmias, cardioprotection after myocardial infarction ,...
, because severe hypertension and even cerebral hemorrhage may result. Although commonly believed that administration of adrenaline may cause heart failure by constricting coronary arteries, this is not the case. Coronary arteries have only β
2 receptors, which cause vasodilation in the presence of adrenaline. Even so, administering high-dose adrenaline has not been definitively proven to improve survival or neurologic outcomes in adult victims of cardiac arrest.
Measurement in biological fluids
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.
PheochromocytomaA pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
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.
Mechanism of action
As a hormone, adrenaline acts on nearly all body tissues. Its actions vary by tissue type and tissue expression of
adrenergic receptorThe adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s. For example, adrenaline causes
smooth muscleSmooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
relaxation in the airways but causes contraction of the smooth muscle that lines most
arterioleAn arteriole is a small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries.Arterioles have muscular walls and are the primary site of vascular resistance...
s.
Adrenaline acts by binding to a variety of
adrenergic receptorThe adrenergic receptors are a class of metabotropic G protein-coupled receptors that are targets of the catecholamines, especially noradrenaline and adrenaline ....
s. Adrenaline is a nonselective agonist of all adrenergic receptors, including α
1, α
2, β
1, β
2, and β
3 receptors. Epinephrine's binding to these receptors triggers a number of metabolic changes. Binding to α-adrenergic receptors inhibits
insulinInsulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
secretion by the
pancreasThe pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, stimulates
glycogenolysisGlycogenolysis is the conversion of glycogen polymers to glucose monomers. Glycogen is catabolized by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1-phosphate...
in the
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and
muscleMuscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
, and stimulates
glycolysisGlycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
in muscle. β-Adrenergic receptor binding triggers
glucagonGlucagon, a hormone secreted by the pancreas, raises blood glucose levels. Its effect is opposite that of insulin, which lowers blood glucose levels. The pancreas releases glucagon when blood sugar levels fall too low. Glucagon causes the liver to convert stored glycogen into glucose, which is...
secretion in the pancreas, increased
adrenocorticotropic hormoneAdrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH) secretion by the
pituitary glandIn vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
, and increased
lipolysisLipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
by
adipose tissueIn histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
. Together, these effects lead to increased blood glucose and
fatty acidIn chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s, providing substrates for energy production within cells throughout the body.
In addition to these metabolic changes, epinephrine also leads to broad alterations throughout all organ systems.
Physiologic responses to epinephrine by organ
| Organ |
Effects |
HeartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
|
Increases heart rate |
| Lung The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s |
Increases respiratory rate |
| Nearly all tissues |
Vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
or vasodilationVasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
|
LiverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
|
Stimulates glycogenolysisGlycogenolysis is the conversion of glycogen polymers to glucose monomers. Glycogen is catabolized by removal of a glucose monomer through cleavage with inorganic phosphate to produce glucose-1-phosphate...
|
| N/A, systemic Systemic refers to something that is spread throughout, system-wide, affecting a group or system such as a body, economy, market or society as a whole. Systemic may also refer to:-In medicine:...
|
Triggers lipolysis Lipolysis is the breakdown of lipids and involves the hydrolysis of triglycerides into free fatty acids followed by further degradation into acetyl units by beta oxidation. The process produces Ketones, which are found in large quantities in ketosis, a metabolic state that occurs when the liver...
|
| N/A, systemic Systemic refers to something that is spread throughout, system-wide, affecting a group or system such as a body, economy, market or society as a whole. Systemic may also refer to:-In medicine:...
|
Muscle contraction |
Biosynthesis and regulation
Adrenaline is synthesized in the medulla of the adrenal gland in an enzymatic pathway that converts the
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
tyrosineTyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
into a series of intermediates and, ultimately, adrenaline. Tyrosine is first oxidized to L-DOPA, which is subsequently decarboxylated to give
dopamineDopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
. Oxidation gives
norepinephrineNorepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
, which is methylated to give epinephrine.
Adrenaline is synthesized via methylation of the primary distal amine of noradrenaline by
phenylethanolamine N-methyltransferasePhenylethanolamine N-methyltransferase is an enzyme found in the adrenal medulla that converts Norepinephrine to Epinephrine .PNMT is positively influenced by cortisol, which is produced in the adrenal cortex....
(PNMT) in the
cytosolThe cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
of adrenergic neurons and cells of the
adrenal medullaThe adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...
(so-called
chromaffin cellChromaffin cells are neuroendocrine cells found in the medulla of the adrenal gland and in other ganglia of the sympathetic nervous system. They are modified post-synaptic sympathetic neurons that receive sympathetic input...
s). 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
VMAT1VMAT1 is a protein that transports the monoamines into intracellular vesicles.In chromaffin cells, it is responsible for transporting newly synthesized epinephrine from the cytosol back into chromaffin granules in preparation for release.For norepinephrine to be acted upon by PNMT in the cytosol,...
. 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 phosphorylaseGlycogen phosphorylase is one of the phosphorylase enzymes . Glycogen phosphorylase catalyzes the rate-limiting step in the degradation of glycogen in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond...
, which then phosphorylates glycogen and converts it to glucose-6-phosphate.
Regulation
The major physiologic triggers of adrenaline release center upon
stressesStress is a term in psychology and biology, borrowed from physics and engineering and first used in the biological context in the 1930s, which has in more recent decades become commonly used in popular parlance...
, such as physical threat, excitement, noise, bright lights, and high ambient temperature. All of these stimuli are processed in the
central nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
.
Adrenocorticotropic hormoneAdrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH) and the
sympathetic nervous systemThe sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...
stimulate the synthesis of adrenaline precursors by enhancing the activity of
tyrosine hydroxylaseTyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . It does so using tetrahydrobiopterin as a coenzyme. DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine ...
and dopamine-β-hydroxylase, two key enzymes involved in catecholamine synthesis. ACTH also stimulates the
adrenal cortexSituated along the perimeter of the adrenal gland, the adrenal cortex mediates the stress response through the production of mineralocorticoids and glucocorticoids, including aldosterone and cortisol respectively. It is also a secondary site of androgen synthesis.-Layers:Notably, the reticularis in...
to release
cortisolCortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
, 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.
AcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
released by preganglionic sympathetic fibers of these nerves acts on
nicotinic acetylcholine receptorNicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...
s, causing cell depolarization and an influx of
calciumCalcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
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 feedbackNegative feedback occurs when the output of a system acts to oppose changes to the input of the system, with the result that the changes are attenuated. If the overall feedback of the system is negative, then the system will tend to be stable.- Overview :...
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,
pheochromocytomaA pheochromocytoma or phaeochromocytoma is a neuroendocrine tumor of the medulla of the adrenal glands , or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually noradrenaline , and adrenaline to a lesser extent...
, and other tumors of the
sympathetic gangliaSympathetic ganglia are the ganglia of the sympathetic nervous system. They deliver information to the body about stress and impending danger, and are responsible for the familiar fight-or-flight response. They contain approximately 20000–30000 nerve cell bodies and are located close to and...
.
Its action is terminated with reuptake into nerve terminal endings, some minute dilution, and metabolism by
monoamine oxidaseL-Monoamine oxidases are a family of enzymes that catalyze the oxidation of monoamines. They are found bound to the outer membrane of mitochondria in most cell types in the body. The enzyme was originally discovered by Mary Bernheim in the liver and was named tyramine oxidase...
and
catechol-O-methyl transferaseCatechol-O-methyltransferase is one of several enzymes that degrade catecholamines such as dopamine, epinephrine, and norepinephrine. In humans, catechol-O-methyltransferase protein is encoded by the COMT gene...
.
Chemical synthesis
Epinephrine may be synthesized by the reaction of catechol with
chloroacetyl chlorideChloroacetyl chloride is a chlorinated acyl chloride. It is a bifunctional compound, making it a useful building block chemical.-Production:Industrially, it is produced by the carbonylation of methylene chloride, oxidation of vinylidene chloride, or the addition of chlorine to ketene...
, followed by the reaction with
methylamineMethylamine is the organic compound with a formula of CH3NH2. This colourless gas is a derivative of ammonia, but with one H atom replaced by a methyl group. It is the simplest primary amine. It is sold as a solution in methanol, ethanol, THF, and water, or as the anhydrous gas in pressurized...
to give the ketone, which is reduced to the desired hydroxy compound. The racemic mixture may be
separatedChiral resolution in stereochemistry is a process for the separation of racemic compounds into their enantiomers. It is an important tool in the production of optically active drugs...
using
tartaric acidTartaric acid is a white crystalline diprotic organic acid. It occurs naturally in many plants, particularly grapes, bananas, and tamarinds; is commonly combined with baking soda to function as a leavening agent in recipes, and is one of the main acids found in wine. It is added to other foods to...
.
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., (1903).
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Adrenaline junkie
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 BreakPoint Break is a 1991 action film directed by Kathryn Bigelow and starring Patrick Swayze, Keanu Reeves, Lori Petty and Gary Busey. The title refers to the surfing term point break, where a wave breaks as it hits a point of land jutting out from the coastline.The film was a box office success upon...
to describe individuals enjoying dangerous activities (such as
extreme sportAn extreme sport is a popular term for certain activities perceived as having a high level of inherent danger...
s, e.g.
BASE jumpingBASE jumping, also sometimes written as B.A.S.E jumping, is an activity that employs an initially packed parachute to jump from fixed objects...
) 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
endorphinEndorphins are endogenous opioid peptides that function as neurotransmitters. They are produced by the pituitary gland and the hypothalamus in vertebrates during exercise, excitement, pain, consumption of spicy food, love and orgasm, and they resemble the opiates in their abilities to produce...
s are also released during the fight-or-flight response to such activities.
Terminology
This chemical is widely referred to as "adrenaline" outside of the United States; however, its
United States Adopted NameUnited States Adopted Names are unique nonproprietary names assigned to pharmaceuticals marketed in the United States. Each name is assigned by the USAN Council, which is co-sponsored by the American Medical Association , the United States Pharmacopeial Convention , and the American Pharmacists...
and
International Nonproprietary NameAn International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...
is epinephrine.
Epinephrine was chosen because
adrenaline bore too much similarity to the
Parke, Davis & CoParke-Davis is a subsidiary of the pharmaceutical company Pfizer. Although no longer an independent corporation, it was once America's oldest and largest drug maker, and played an important role in medical history.- History :...
trademark Adrenalin (without the
e), which was registered in the United States. The
British Approved NameA British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...
and
European PharmacopoeiaThe European Pharmacopoeia of the Council of Europe is a pharmacopoeia, listing a wide range of active substances and excipients used to prepare pharmaceutical products in Europe...
term for this chemical is adrenaline and is indeed now one of the few differences between the INN and BAN systems of names.
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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