{
  "id": "epinephrine",
  "title": "Epinephrine",
  "lang": "en",
  "source_lang": "en",
  "summary": "Epinephrine (adrenaline) is a catecholamine hormone and neurotransmitter that drives the body's fight-or-flight response and is a core emergency drug.",
  "category": "health",
  "subcategory": "anatomy-physiology",
  "type": "concept",
  "aliases": [
    "adrenaline",
    "adrenalin"
  ],
  "generated_at": "2026-10-08",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/epinephrine/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/epinephrine/",
      "json": "https://aiwiki.page/zh/epinephrine.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "Epinephrine, also known as adrenaline, is a catecholamine that acts both as a hormone released into the blood and as a neurotransmitter in the brain. Its best-known role is coordinating the \"fight-or-flight\" response: it raises heart rate and blood pressure, opens the airways, and mobilizes stored glucose and fat so that the body can respond quickly to stress or danger. Because of these effects, it is one of the most important drugs in emergency medicine, used first-line for anaphylaxis and as part of cardiac arrest protocols.\n\nThe article first explains the molecule itself: its structure, its relation to norepinephrine and dopamine, and the stereochemistry that makes one enantiomer biologically active. It then traces how the compound was discovered and how its receptors were classified, and describes how the adrenal medulla synthesizes and breaks it down. The core of the entry covers how epinephrine binds adrenergic receptors and signals through second messengers, and what these signals do in the heart, lungs, blood vessels, liver, muscle, and eyes.\n\nThe later sections turn to applied topics: its clinical uses and the routes by which it is given, its adverse effects and drug interactions, and the methods used to measure it in blood and urine, including its role in diagnosing tumors that release catecholamines. The entry closes with its regulation in sport and its illicit use."
    },
    {
      "heading": "Definition, name and chemical structure",
      "text": "Epinephrine is a catecholamine, a class of molecules built from a catechol ring (a benzene ring carrying hydroxyl groups at positions 3 and 4) attached to an ethylamine side chain. In epinephrine, the nitrogen at the end of the side chain carries a methyl group, so the amine is secondary rather than primary. The carbon adjacent to the aromatic ring (the beta carbon) bears a hydroxyl group. The molecular formula is C9H13NO3, and the systematic IUPAC name is 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol. The same molecule works as a hormone when the adrenal medulla releases it into the bloodstream, and as a neurotransmitter in a small number of central neurons.\n\nThe two common names have separate origins. \"Epinephrine\" comes from the Greek epi (\"upon\") and nephros (\"kidney\"). \"Adrenaline\" comes from the Latin ad (\"near\") and renes (\"kidneys\"). Both refer to the adrenal glands, which sit on top of the kidneys. Epinephrine is the International Nonproprietary Name (INN) and is the preferred term in the United States and most international usage. Adrenaline is the British Approved Name and remains common in the United Kingdom and some other countries. The word \"adrenalin\" was originally a commercial trade name, and the two terms entered use around 1900 through different researchers.\n\nEpinephrine has one stereocentre, the beta carbon, so it exists as two enantiomers that are mirror images of each other. The naturally occurring and pharmacologically active form is the (R)-enantiomer, also called levorotatory or (−)-epinephrine. The (S)-enantiomer binds adrenergic receptors far less effectively. This difference arises because adrenergic receptors are chiral protein ligands-binding sites. Binding is thought to involve three contact points: a protonated amine that interacts with a conserved aspartate residue, catechol hydroxyls that hydrogen-bond with serine residues, and the beta-hydroxyl group, which must sit in a specific spatial orientation. The mirror-image molecule can make only some of these contacts, so it fits poorly. Racemic epinephrine, a 1:1 mixture of both forms, is used in some inhaled preparations, and its effect is attributed mainly to the (R)-form.\n\nEpinephrine sits in a series with two closely related compounds. Dopamine has the catechol ring and an unsubstituted ethylamine side chain, but no beta-hydroxyl group. Adding that hydroxyl group produces norepinephrine (noradrenaline), which has a primary amine. Methylating the nitrogen of norepinephrine then gives epinephrine. The three share the catechol ring, which makes them susceptible to the same oxidative and enzymatic breakdown pathways. The N-methyl group is the main structural feature that distinguishes epinephrine from norepinephrine, and it contributes to epinephrine's relatively greater activity at beta-adrenergic receptors."
    },
    {
      "heading": "Discovery and history of research",
      "text": "Adrenal extracts and blood pressure\n\nThe earliest clear evidence for the hormone came in 1894. George Oliver and Edward Schäfer of the University of London reported an adrenal gland extract that strongly affected blood vessels, the heart and skeletal muscle. When the extract was given to animals, they recorded faster heart rates and higher blood pressure. Because the active principle was present in a complex mixture, several investigators then tried to isolate it in pure form, and the effort involved considerable priority disputes.\n\nIsolation, naming and the first synthesis\n\nIn 1897, John Jacob Abel, working with Albert Crawford at Johns Hopkins, obtained a crystalline product from sheep adrenal glands that appeared to be the blood pressure-raising substance, and he named it \"epinephrin.\" Later work showed that Abel and Crawford had actually isolated a benzoyl derivative rather than the pure hormone. Some accounts date the name \"epinephrine\" to 1899 rather than 1897, so the sources differ on this detail.\n\nThe pure compound was obtained by Jokichi Takamine, a chemist trained in Japan and Scotland. He visited Abel's laboratory at Johns Hopkins in 1900, and he filed five patents on November 5, 1900, before publishing any scientific papers. Parke-Davis marketed the extract under the trade name \"Adrenalin.\" Because the isolate was patented before publication, it was a landmark in the commercialization of hormones as well as in their chemistry.\n\nA chemical synthesis followed. Friedrich Stolz and Henry Drysdale Dakin developed a synthesis in 1904 that went through a ketone form of the molecule. Another account places the final conversion step in 1906, so the dating of the first synthesis should be treated with caution. Early synthetic material was racemic, and the separation of the biologically active enantiomer is described in the stereochemistry section.\n\nCannon and the \"fight-or-flight\" concept\n\nWalter Bradford Cannon, a Harvard physiologist, studied how emotional states change the body. He first described the response in 1914 and referred to it as \"the necessities of fighting or flight\" in 1915. In his 1915 monograph, he coined the term \"fight or flight\" to describe an animal's response to threats. He argued that psychological emergencies, such as antagonistic encounters between members of the same species, could evoke adrenaline release into the bloodstream, not only physical injuries such as blood loss.\n\nCannon's methods included denervating the heart and comparing animals with intact and removed adrenal glands. If heart rate rose after a stressor in an animal whose cardiac nerves had been removed, the increase had to be caused by a hormone. His model treated the sympathetic nervous system and the adrenal medulla as a single functional unit. He did not recognize that postganglionic sympathetic nerves use norepinephrine as their chemical transmitter.\n\nReceptor classification\n\nCannon's model explained the effects of the hormone but not its mechanism at the cell surface. In 1948, Raymond Ahlquist proposed that two kinds of adrenergic receptors existed, which he named alpha and beta. His paper showed that one sympathetic mediator could produce both excitatory and inhibitory responses, and that receptors could be distinguished by the rank order of potency of agonists. Ahlquist's scheme was initially dismissed and took some time to be accepted. Its value became clear in drug development: his work contributed to the discovery of tolazoline and, in 1958, dichloroisoprenaline, the first beta-blocker.\n\nSubsequent pharmacology refined the scheme. Beta receptors were later divided into beta-1 receptors, which occur chiefly in the heart, and beta-2 receptors, found elsewhere. Alpha receptors were later split into alpha-1 and alpha-2 subtypes, and a beta-3 subtype was defined later still.\n\nMolecular cloning and the GPCR family\n\nLater work moved from pharmacology to molecular biology. Adrenoceptors are a group of nine seven-transmembrane receptors comprising three main types, each with three subtypes. The classification now rests on both pharmacological evidence and the molecular cloning of the nine adrenergic receptors. Cloning established that these receptors belong to the G protein-coupled receptor superfamily, which links extracellular signals to intracellular G proteins. The cloning of the beta-2 adrenergic receptor in the mid-1980s and subsequent structural studies by Robert Lefkowitz and Brian Kobilka, who shared the 2012 Nobel Prize in Chemistry for this work, transformed the understanding of how epinephrine activates its targets."
    },
    {
      "heading": "Biosynthesis, storage and degradation",
      "text": "Biosynthesis\n\nEpinephrine is made from the amino acids phenylalanine and tyrosine, through the same intermediates that give rise to dopamine and norepinephrine. Tyrosine is hydroxylated to DOPA, DOPA is decarboxylated to dopamine, dopamine is converted to norepinephrine, and only then is norepinephrine methylated to epinephrine. Each step is catalysed by a specific enzyme. Cells that release epinephrine need a fourth enzyme for the last step: a cell that uses epinephrine as its transmitter contains four enzymes (TH, AADC, DBH, and PNMT), whereas norepinephrine neurons contain only three enzymes (lacking PNMT) and dopamine cells only two.\n\nThe final step is catalysed by phenylethanolamine N-methyltransferase (PNMT), which is the enzyme that catalyzes the S-adenosyl-L-methionine-dependent methylation of (-)norepinephrine to (-)epinephrine in the adrenal medulla. Within mammals, the enzyme is localized almost exclusively in the adrenal gland with trace amounts also present in the heart and brain. The pathway itself was postulated by Blaschko in 1939. Because PNMT is the limiting factor for the final conversion, its regulation matters. Elevated PNMT expression is one of the ways that the stress response positively feeds back on itself. Glucocorticoids cause the induction of the enzyme noradrenaline N-methyltransferase, and so are particularly important for the synthesis of epinephrine.\n\nStorage and co-release\n\nAdrenal chromaffin cells hold the hormone in dense-core vesicles. The large dense core vesicles (LDCVs), or chromaffin granules, store catecholamines, chromogranin and ATP. Catecholamines are packed in these granules together with ATP, Ca2+, and protein. The granules are structurally distinct by type: norepinephrine-containing granules appear highly electron dense, whereas epinephrine granules are less dense with finely granular matrices.\n\nRelease occurs by exocytosis, and the granule contents leave together. The granins are a structurally and functionally related family of proteins including Chromogranin A (CGA), Chromogranin B (CGB) and Secretogranins (SG) II-VII which are stored in secretory (chromaffin) granules and are released together with the catecholamines. Chromogranin A was named after this co-release pattern, having been identified on splanchnic nerve stimulation. ATP is released alongside as well, although some sources describe the co-released proteins and nucleotides as having little direct hormonal activity. Exocytosis of the granular content releases epinephrine (E), NE, DA, dopamine β-hydroxylase, ATP, peptides, and chromaffin-specific proteins that are biologically inert. Circulating epinephrine is overwhelmingly adrenal in origin: nearly all of the epinephrine in the circulation derives from the adrenal medulla, whereas most of the norepinephrine derives from sympathetic nerve terminals in the peripheral tissues and the brain.\n\nDegradation\n\nMost circulating epinephrine is cleared in the liver and kidney. The enzymes largely responsible for this degradation are catecholamine O-methyl transferase (COMT) and a combination of mono amine oxidase (MAO) and aldehyde oxidase (AO). COMT (catechol-O-methyltransferase) methylates the catechol ring to form metanephrine, whereas MAO (monoamine oxidase) oxidatively deaminates the side chain. MAO catalyzes the oxidative deamination of dopamine into 3,4 dihydroxyphenylacetic acid (DOPAC), and norepinephrine and epinephrine into 3,4 dihydroxyphenylglycol (DHPG). The two pathways can act in sequence: the metabolites catalyzed by MAO can be metabolized further by COMT, and those metabolites catalyzed by COMT can be metabolized further by MAO. The end products include vanillylmandelic acid and homovanillic acid-type compounds, and the metanephrines are biologically inactive markers of extraneuronal and intra-adrenal metabolism of catecholamines and they can be measured in the free and conjugated forms in both plasma and urine. A portion of the hormone may also be taken up and metabolized outside neurons, and the adrenal medulla itself contributes much of the circulating metanephrine. Over 90% of metanephrine and about 23% of normetanephrine in circulation are formed within the adrenal medulla from CA leaking from granules into the cytosol.\n\nHalf-life and duration of action\n\nEpinephrine is cleared from plasma very quickly. Reported values vary by source: one review gives their half-lives are about 1–3 min and their metabolic clearances are from 2 to 6 L min−1, another puts the half-life (t1/2) of epinephrine at approximately 2 minutes. A pharmacokinetic overview reports that in healthy male volunteers the plasma clearance of epinephrine is 35 to 89 mL/kg/min. The rapid clearance means that the hormone's effects are short-lived. The drug reference entry for the compound describes its onset as Rapid and its duration of action as Few minutes. Thus, the body relies on continuous secretion and rapid enzymatic removal to keep circulating levels responsive to changing demand."
    },
    {
      "heading": "Adrenergic receptors and signal transduction",
      "text": "Receptor families and G protein coupling\n\nEpinephrine acts through adrenergic receptors, which belong to the G protein-coupled receptor superfamily. They are divided into α and β classes, and each class has subtypes that couple to different G proteins. α1 receptors couple to Gq, which typically produces calcium signals. α2 receptors couple to Gi, which usually inhibits adenylyl cyclase, opens GIRK potassium channels, or suppresses certain calcium channels. β1, β2 and β3 receptors couple mainly to Gs, which stimulates adenylyl cyclase.\n\nCoupling is not always fixed. β2 receptors can also engage Gi, and in some cells this dual coupling produces two separate signaling branches. Phosphorylation by protein kinase A can shift a β2 receptor from Gs toward Gi, which means that the signal a cell receives depends on its own kinase activity as well as on the ligand. β1 receptors were long regarded as coupling only to Gs, but later work has reported Gi coupling for them as well, so the classical scheme is a useful simplification rather than a complete account.\n\nSecond-messenger pathways\n\nWhen a Gs-coupled receptor is activated, the Gαs subunit stimulates adenylyl cyclase, which converts ATP into cyclic AMP. Cyclic AMP binds the regulatory subunits of protein kinase A (PKA), releasing its catalytic subunits to phosphorylate targets. In cardiac muscle, this pathway raises heart rate and contractility, partly through phosphorylation of L-type calcium channels at the plasma membrane. Because cAMP signals are confined to nearby effectors, the cell can respond selectively to a given stimulus.\n\nThe Gi branch works differently. In heart cells, β2 receptor signaling through Gi is associated with a pro-survival pathway that runs through the Gβγ subunits, phosphoinositide 3-kinase and Akt, and it can oppose apoptosis triggered by Gs-driven stress.\n\nGq-coupled α1 receptors activate phospholipase C, which cleaves phosphatidylinositol bisphosphate into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. IP3 binds receptors on the endoplasmic reticulum and releases stored calcium into the cytoplasm, while diacylglycerol activates protein kinase C. The resulting rise in intracellular calcium drives smooth muscle contraction in vessels and other tissues. Gβγ subunits released from Gi and Gs proteins can also act directly on ion channels, for example by opening GIRK channels and inhibiting some voltage-gated calcium channels.\n\nDesensitization, internalization and downregulation\n\nSustained exposure to epinephrine reduces the response of β2 receptors. Agonist-occupied receptors are phosphorylated by G protein-coupled receptor kinases (GRKs), and this phosphorylation recruits β-arrestin proteins. β-arrestin binding sterically hinders further G protein coupling, which is the basis of homologous desensitization. PKA-mediated phosphorylation contributes as well, and it can uncouple receptors for other agonists, which is called heterologous desensitization. For β2 receptors, β-arrestin binding is required for desensitization and for internalization through clathrin-coated pits. Notably, β-arrestin tends to dissociate from β2 receptors before internalization, unlike some other receptor classes that carry it into endosomes.\n\nOnce internalized, receptors can be dephosphorylated and returned to the membrane in a resensitized state, or they can be sorted to lysosomes and degraded. Loss of receptors through degradation lowers the total number available on the cell surface, which is downregulation. Changes in GRK activity are inversely reflected in receptor sensitivity, and models of heart failure with elevated GRK activity show reduced responsiveness to β-agonists.\n\nAffinity differences and concentration dependence\n\nEpinephrine binds β1 and β2 receptors with similar affinity, whereas norepinephrine is about tenfold more selective for β1. α receptors bind norepinephrine more strongly than epinephrine, and the affinities of the two hormones are reversed at β receptors. Some pharmacology sources report that epinephrine has a higher affinity for β2 than for α1 receptors, so the exact ranking depends on the study and the tissue examined.\n\nBecause receptors with higher affinity become occupied first as concentration rises, the dominant response shifts with dose. In clinical infusion pharmacology, β effects predominate at low doses (roughly 0.01–0.04 µg/kg per minute), whereas α1-mediated vasoconstriction becomes prominent at higher doses (roughly 0.05–0.2 µg/kg per minute). Affinity alone does not explain the whole pattern. Receptor density, the efficacy of activation in each tissue, and the amount of receptor reserve also matter. Structural studies suggest that hydrogen bonds between epinephrine's β-carbon hydroxyl and N-methyl groups and conserved asparagine residues in the receptor help determine binding at both α and β subtypes."
    },
    {
      "heading": "Physiological effects in the body",
      "text": "Epinephrine acts on several adrenergic receptor subtypes, each with its own distribution in tissues and its own intracellular signal, so its net effect depends on which receptors are occupied and how much hormone is present. Its effects also vary with dose. Low circulating levels favour β-receptor responses, while higher levels bring α₁-mediated constriction to the fore.\n\nCardiovascular effects\n\nStimulation of β₁ receptors in the heart increases heart rate (chronotropy) and the force of ventricular contraction (inotropy). Because both rate and stroke volume rise, cardiac output increases. The cost is a higher myocardial oxygen demand, which matters in patients with coronary disease. Excessive stimulation can cause sinus tachycardia and atrial or ventricular arrhythmias, and it can also produce marked metabolic disturbances such as hypokalemia and lactic acidosis.\n\nVascular effects and blood pressure\n\nThe vascular response depends on the receptor type in each bed. α₁ receptors on arterioles in the skin and splanchnic (gut) circulation cause vasoconstriction, which reduces blood flow to those organs. β₂ receptors on arterioles supplying skeletal muscle cause vasodilation, which increases muscle perfusion. At low infusion rates, β₂-mediated dilation in muscle beds can offset vasoconstriction elsewhere, so diastolic pressure often changes little. As concentrations rise, α₁ vasoconstriction spreads to most vascular beds, raising total peripheral resistance and systemic blood pressure. This dose-dependent shift is the reason epinephrine can be used to raise pressure in shock.\n\nRespiratory effects\n\nβ₂ receptors on bronchial smooth muscle relax it, widening the airways and lowering airway resistance. This bronchodilation is the physiological basis for its use in acute bronchospasm, including the bronchospasm of anaphylaxis and severe asthma. α₁-mediated constriction of blood vessels in the upper airway mucosa also reduces swelling, which is one reason it relieves laryngeal and nasal obstruction.\n\nMetabolic effects\n\nIn the liver, adrenergic stimulation activates the enzymes that break down glycogen, releasing free glucose into the blood; glycogen in skeletal muscle is broken down as well, but muscle lacks the enzyme needed to export glucose, so its products are used locally or released as lactate. Increased cyclic AMP also promotes gluconeogenesis, the synthesis of glucose from non-carbohydrate precursors. In adipose tissue, β-receptor signalling activates lipolysis, releasing glycerol and free fatty acids into the circulation. At the same time, α₂ receptors on pancreatic β cells suppress insulin secretion, while β₂ stimulation promotes glucagon release. The combined result is raised blood glucose and fatty acid availability, a shift that supplies fuel for the muscles and brain.\n\nOther effects\n\nContraction of the radial muscle of the iris, driven by α₁ receptors, dilates the pupil (mydriasis). Contraction of the arrector pili muscles, also α₁-mediated, produces piloerection. During acute stress, sympathetic and hormonal signals together redistribute blood flow away from the skin, gut and kidneys and toward the heart, brain and skeletal muscle, so that tissues most needed for rapid action receive the greatest share of cardiac output."
    },
    {
      "heading": "Regulation of secretion",
      "text": "Neural control through the splanchnic nerves\n\nSecretion from the adrenal medulla depends mainly on nerve signals rather than on circulating hormone levels. The secretion of hormones from the adrenal medulla is controlled by descending nerve fibers which pass into the gland, referred to as splanchnic nerves. These fibers end on chromaffin cells, which keep their hormones in dense-core granules. Transmission at this synapse is driven largely by acetylcholine. Its binding triggers calcium-dependent exocytosis, which releases the granule contents into the circulation. The main regulator of catecholamine release from the adrenal medulla is cholinergic stimulation, which causes calcium-dependent exocytosis of the contents of the secretory granules.\n\nOutput depends strongly on how fast the nerves fire. At rest, the splanchnic discharge is low. In humans, splanchnic discharge rates have been estimated to dwell at ∼1 Hz at rest and between 10 and 20 Hz when the sympathetic nervous system is fully activated. Under resting sympathetic tone, release stays modest, but activation of the sympathoadrenal stress reflex raises catecholamine output sharply. Under sympathetic tone, catecholamine release is modest. However, upon activation of the sympathoadrenal stress reflex, and increased splanchnic firing, adrenal catecholamine output increases dramatically.\n\nFrequency dependence and stimulus specificity\n\nThe gland does not release epinephrine and norepinephrine in fixed proportions. In an older study of cat adrenal glands, stimulation between 1 and 10 pulses per second produced an effluent of about 65% epinephrine, while 20 pulses per second shifted it to about 84%. Stimulation in the frequency range of 1 to 10 pulses per second discharged an effluent containing 65 ± 2% epinephrine. A shift favoring the release of epinephrine was noted at a frequency of 20 pulses per second. The values obtained were 84 ± 2% epinephrine.\n\nParticular stressors also favour one hormone over the other. Specific stressors can preferentially increase release of either epinephrine (i.e., hypoglycemia) or norepinephrine (i.e., cold stress). A 2020-era ex vivo rat study with intact splanchnic innervation found that epinephrine comes mainly from the outer part of the medulla and needs a higher stimulus threshold than norepinephrine. Epinephrine is secreted preferentially from the periphery of the medulla and exhibits a higher threshold and steeper stimulus‐secretion function than norepinephrine. The same study indicated that elevated epinephrine release depends on stimulating both divisions of the nerve together. This recruitment of Epinephrine release is only supported by stimulation of the whole nerve and is lost by specific stimulation of one or the other divisions alone.\n\nCentral control by the hypothalamus and the stress axis\n\nStress signals reach the sympathetic output neurons from the brain. Information regarding stressors may reach the IML directly from descending neuronal pathways in the hypothalamus and forebrain or via the RVLM. Here IML refers to the intermediolateral cell column of the spinal cord and RVLM to the rostral ventrolateral medulla. In parallel, stress stimulates the sympathetic branch of the autonomic nervous system followed by activation of the HPA axis. Glucocorticoids from the cortex reach the medulla at high concentrations through venous drainage, and they promote the enzyme that converts norepinephrine into epinephrine, so they support epinephrine production as well as the hormonal response.\n\nThe emotional content of a stressor matters. Response to emotional stress such as written or oral examinations involves an increase only in epinephrine, whereas the adrenal response to anticipation involves primarily norepinephrine. Physical exertion shows a similar pattern of dose dependence. Epinephrine secretion is not influenced by moderate exercise, but it is markedly increased during long-distance running. The stimuli listed in the outline, including hypoglycaemia, low blood pressure, fear and cold exposure, all act through this same neural pathway, although the hypotension and cold-related inputs are less thoroughly characterised in the sources reviewed here.\n\nLimits on the response\n\nThe body restrains adrenal secretion through several mechanisms. The most direct is a short feedback loop within the gland itself. In mice, two alpha2-adrenoceptor subtypes regulate catecholamine release, with alpha2A acting on sympathetic nerve endings and alpha2C acting on the adrenal medulla. In isolated mouse chromaffin cells, alpha2-receptor activation inhibited the electrically stimulated increase in cell capacitance (a correlate of exocytosis), voltage-activated Ca2+ current, as well as secretion of epinephrine and norepinephrine. Removing alpha2C raised circulating epinephrine in vivo, and the loss of this brake was partly offset by higher tyrosine hydroxylase activity. In vivo, deletion of sympathetic or adrenal feedback control led to increased plasma and urine norepinephrine (alpha 2A-knockout) and epinephrine levels (alpha 2C-knockout), respectively. Loss of feedback inhibition was compensated by increased tyrosine hydroxylase activity, as detected by elevated tissue dihydroxyphenylalanine levels.\n\nCentrally, glucocorticoids dampen the stress response. Glucocorticoids inhibit the HPA axis activity by a negative-feedback mechanism. Clearance of the hormone also shapes the response. Epinephrine released from the gland is not recycled by neuronal reuptake, so its removal depends on circulating enzymes. Two enzymes contribute to catecholamine catabolism: monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT). The details of these degradation pathways are covered in a separate section."
    },
    {
      "heading": "Clinical applications",
      "text": "Epinephrine is used in medicine for several emergencies and some specialised purposes. Its main emergency role is the treatment of anaphylaxis, but it is also used in cardiac arrest, in shock, to prolong the effect of some local anesthetics, and in some respiratory and eye conditions.\n\nAnaphylaxis\n\nEpinephrine is the first-line drug for anaphylaxis, a severe systemic allergic reaction. Guidelines place intramuscular injection into the anterolateral thigh (the vastus lateralis) at the head of treatment. The usual adult dose is 0.01 mg/kg of a 1:1000 (1 mg/mL) solution, up to a maximum initial dose of 0.5 mg, and it may be repeated every 5 to 15 minutes if symptoms persist. Onset is usually three to five minutes. Antihistamines and corticosteroids are regarded as adjuncts that do not replace epinephrine, and intravenous use is generally reserved for refractory cases because of the risk of serious cardiac events. Repeated injections into the same site should be avoided, since the resulting vasoconstriction can cause tissue necrosis.\n\nBecause the drug must be given quickly and often outside hospital, epinephrine autoinjectors are the standard self-treatment for people at risk. Commercial autoinjectors come in fixed doses, such as 0.3 mg for adults and 0.15 mg for smaller patients. Their needles are not always long enough for every adult. A study of adults with food allergy found that, in some patients with greater skin-to-muscle distance, the needle of a common device could fail to reach muscle, which has prompted attention to injection technique and device design in patients with higher body mass index.\n\nCardiac arrest\n\nIn advanced cardiac life support, epinephrine is given intravenously during cardiopulmonary resuscitation, typically as a 1 mg bolus repeated every three to five minutes. Its rationale is to raise coronary and cerebral perfusion pressure through α1-mediated vasoconstriction and thereby increase the chance of return of spontaneous circulation (ROSC).\n\nIts effect on long-term outcome is contested. The PARAMEDIC2 trial, a randomised, double-blind study of 8014 adults with out-of-hospital cardiac arrest in the United Kingdom, found a higher 30-day survival rate with epinephrine than with placebo. However, there was no significant difference in survival with a favourable neurological outcome at discharge, because more survivors in the epinephrine group had severe neurological impairment (31.0% versus 17.8%). Observational studies have reported similar associations between higher cumulative doses and poorer neurological recovery, though these studies are vulnerable to confounding. Trials comparing lower doses with the standard 1 mg dose are ongoing, and the question remains unresolved in clinical guidance.\n\nShock and local anesthesia\n\nIn septic shock, vasopressors including epinephrine can be used to restore perfusion pressure when fluid resuscitation is insufficient. Its use is accompanied by concern about arrhythmias and ischaemia in the heart, gut, brain and extremities, and in current practice norepinephrine is generally preferred as the first-line vasopressor. Epinephrine is given intravenously as a continuous infusion, with the rate titrated to a blood pressure target. Similar vasopressor use appears in other forms of shock, including cardiogenic shock, where it may also act as an inotrope.\n\nIn regional anaesthesia, a small amount of epinephrine is added to local anesthetic solutions. Its vasoconstrictive effect reduces local blood flow, which slows the absorption of the anesthetic into the circulation. This prolongs the duration of nerve block, reduces peak blood levels and lowers the risk of systemic toxicity. Dental cartridges, for example, commonly contain epinephrine at a maximum concentration of 1:100,000. The benefit has limits, however: the effect on local anesthesia is typically around an hour in well-perfused tissue, and excessive vasoconstriction can cause tissue ischaemia.\n\nAsthma and glaucoma\n\nIn acute severe asthma, inhaled β2-selective agonists are the usual first treatment, and epinephrine is reserved for cases that do not respond, or for emergency situations where other options are unavailable. Its bronchodilating effect is mediated by β2 receptors, though its use is limited by cardiac side effects. In ophthalmology, topical epinephrine has historically been used to lower intraocular pressure in open-angle glaucoma, mainly by increasing aqueous outflow. It is now used less often than prostaglandin analogues and beta-blockers, which have largely replaced it."
    },
    {
      "heading": "Routes of administration and pharmacokinetics",
      "text": "Epinephrine is used mainly by injection, by inhalation, or topically, because the oral route is largely ineffective. The route chosen determines how quickly the drug reaches the circulation and how long its effect lasts.\n\nInjection routes\n\nIntravenous dosing gives the fastest response. After a bolus, plasma concentration falls quickly, and the effective half-life is under five minutes (Following intravenous injection, epinephrine is rapidly cleared from the plasma with an effective half-life of < 5 min.). A continuous infusion takes about 10 to 15 minutes to reach a steady concentration (pharmacokinetic steady state following continuous intravenous infusion is achieved within 10-15 min.). Intramuscular injection is slower, with an onset of about five to ten minutes (intramuscular administration has an onset of five to ten minutes).\n\nComparative trials show that the time to peak plasma level varies by device. In an integrated analysis of four phase 1 trials, the median time to peak was 45 minutes for manual 0.3 mg intramuscular injection, but 20 minutes for the EpiPen autoinjector and 30 minutes for Symjepi (The longest median time to maximum concentration occurred after Epinephrine 0.3 mg IM (45 minutes), followed by Symjepi (30 minutes), neffy (30 minutes), and EpiPen (20 minutes)). Peak concentrations were also higher with the autoinjectors, at 503 pg/mL for EpiPen and 438 pg/mL for Symjepi, compared with 254 pg/mL for manual intramuscular injection (The highest mean C_max values were observed after EpiPen (503 pg/mL) and Symjepi (438 pg/mL). The mean C_max of neffy (258 pg/mL) was comparable with Epinephrine 0.3 mg IM (254 pg/mL)).\n\nSubcutaneous injection generally absorbs somewhat more slowly. In one crossover comparison, the mean peak in the first 15 minutes was 137 pg/mL after intramuscular dosing and 107 pg/mL after subcutaneous dosing, a difference that was not statistically significant (The mean C_max for the first 15 minutes was 137 pg/mL after IM injection and 107 pg/mL after SC injection (P = .70).).\n\nInhaled, endotracheal and topical routes\n\nInhalation acts quickly on the airways. Bronchodilation occurs within 1 minute after administration of orally inhaled epinephrine. Endotracheal administration is possible, but absorption is variable and less dependable (absorption is variable and less reliable). Ophthalmic preparations are applied topically to the eye, which is the basis for the glaucoma use described elsewhere in this article (Epinephrine is administered by intravenous, intramuscular, and subcutaneous injection, by inhalation, or topically to the eye.).\n\nIntranasal formulations\n\nIn the nose, the drug is absorbed through the capillaries of the nasal mucosa and enters the systemic circulation (following neffy, epinephrine is absorbed through the capillaries in the nasal mucosa and enters systemic circulation.). The approved 1 mg nasal spray (neffy) gave a mean peak of 258 pg/mL, close to that of manual intramuscular injection, with a median time to peak of 30 minutes (neffy 1.0 mg 135 258 (69.8) 23,700 (59.1) 30 (2-150)). Concentrations from 30 to 360 minutes after dosing were greater with neffy than with EpiPen or manual injection (From 30 to 360 minutes after dosing, greater mean epinephrine concentrations were observed with neffy compared with EpiPen and Epinephrine IM.). Despite the lower peak, the increase in systolic blood pressure was comparable or modestly larger (Intranasal delivery of epinephrine using neffy increases systolic blood pressure more efficiently than do manual intramuscular injection and epinephrine autoinjectors, despite lower maximum plasma concentrations.). An investigational 13.2 mg spray produced a higher and earlier peak than the 0.3 mg autoinjector, with a peak at about 20 minutes (Pharmacokinetic parameters for opposite-nostril and same-nostril dosing were higher than both intramuscular doses, except time to reach maximum observed concentration, which was bracketed between the 2 intramuscular doses). Pharmacodynamic responses also level off: regardless of route of administration, the maximum PD effects are subject to a ceiling effect.\n\nOral inactivity\n\nBy mouth, epinephrine has little effect because the drug is destroyed before it reaches the systemic circulation. The pharmacokinetics of epinephrine reveal a rapid onset with low oral bioavailability due to first-pass metabolism. The liver inactivates the drug quickly (The pharmacologic activity of epinephrine is rapidly inactivated in the liver.), and the catecholamine-degrading enzymes catechol-O-methyltransferase and monoamine oxidase act in the liver, kidney and other tissues (Circulating drug is metabolized by the enzymes catechol-O-methyltransferase and monoamine oxidase in the liver, kidney, and in other extraneuronal tissues.). Routes that drain outside the portal circulation avoid this barrier; sublingual absorption is one example, since the mucosa there reaches the systemic circulation directly (buccally- or sublingually-delivered drugs can gain direct access to the systemic circulation and are not subject to first-pass hepatic metabolism.).\n\nFormulation and stability\n\nEpinephrine in solution is chemically unstable. The solution deteriorates rapidly on exposure to air or light, turning pink from oxidation. Oxidation lowers potency and produces coloured by-products, and this is the main reason for stabilisers. For many years, commercial products used sulfites, which react with the drug to form a sulfonic acid derivative and lose potency (The sulfite related compounds can directly react with epinephrine, resulting in a substantial loss of epinephrine potency and generating degradation products, such as epinephrine sulfonic acid (ESA)). Sulfites can also cause reactions in sensitive patients, including flushing, hives and a fall in lung function (some people have experienced severe reactions from sulfite-containing medications including intravenous drugs and inhaled medications, these reactions including flushing, hives, and a drop in lung function.). Earlier work showed that boric acid can protect the catechol group by forming a cyclic ester, which also reduces sulfite attack (boric acid buffers stabilized epinephrine to oxidation, racemization, and reaction with the antioxidant sodium bisulfite by reacting with the catechol group of epinephrine to form a cyclic ester). Sulfite-free solutions create their own problem: in a preservative-free, sulfite-free, l-epinephrine solution, racemization was a more significant problem than expected, even more so than oxidation. This is why formulators must control both oxidation and the loss of the active (R)-configuration."
    },
    {
      "heading": "Adverse effects, contraindications and interactions",
      "text": "Common reactions and their dependence on dose and route\n\nMost unwanted effects are extensions of the drug's sympathetic action. Even therapeutic doses can produce anxiety, fear, restlessness, headache, dizziness, palpitations, pallor and tremor. Prescribing information adds sweating, nausea and vomiting, cold extremities and breathing difficulty to the frequent reactions after systemic use (headache; anxiety; apprehensiveness; restlessness; tremor; weakness; dizziness; sweating; palpitations; pallor; peripheral coldness; nausea/vomiting; and/or respiratory difficulties).\n\nSeverity depends largely on how much drug reaches the bloodstream. In a canine study, endotracheal instillation produced peak blood concentrations roughly one-tenth of those after an equal intravenous dose, which is why the route of administration shapes the risk of systemic effects.\n\nSerious adverse events\n\nSerious reactions are uncommon but can be fatal. Published reports include ventricular dysrhythmias, angina, myocardial infarction, pulmonary edema, sudden sharp increases in blood pressure, and intracranial hemorrhage. Labeling notes that epinephrine may induce potentially serious cardiac arrhythmias and myocardial ischemia, particularly in patients with underlying heart disease.\n\nPulmonary edema is linked to the drug's cardiac and vascular actions: by boosting cardiac output while tightening peripheral vessels, it can push fluid into the lungs. Intracranial bleeding is the most feared complication in older patients. One case report links the intracranial hemorrhage to a single, therapeutic dose given intramuscularly, and intracerebral hemorrhage can occur after adrenaline administration via any route, including in patients undergoing therapeutic upper-gastrointestinal endoscopy and those with asthma. Because of these risks, the drug is generally used with monitoring, though intramuscular injection remains the first-line treatment for anaphylaxis.\n\nInteractions\n\nMonoamine oxidase inhibitors. Monoamine oxidase normally degrades epinephrine, and inhibition of monoamine oxidase results in increased concentrations of these amines. The clinical evidence, however, is disputed. One reference states that potentiation of the hypertensive effect has been claimed, but there is no good clinical evidence of such an interaction, while still advising care. A 2016 commentary argues that adrenaline and noradrenaline act as direct post-synaptic agonists and therefore do not cause any significant interaction with MAOIs.\n\nTricyclic antidepressants. These drugs are more consistently linked to the problem. Tricyclic antidepressants potentiate the pressor effect of direct-acting sympathomimetics (norepinephrine, epinephrine), and one commentary describes this as a pronounced interaction.\n\nNonselective beta-blockers. This is the best-documented interaction. Because beta-2 receptors mediate the vasodilation that normally offsets the vasoconstriction of alpha receptors, blockade of beta-2 adrenergic receptors in the peripheral vasculature results in unopposed alpha-adrenergic effect of epinephrine that is responsible for vasoconstriction. In one controlled study of ten healthy men given propranolol or nadolol, the results confirmed the concept of unopposed alpha-constriction for epinephrine. Clinically, severe hypertension accompanied by bradycardia has been reported in patients treated with a noncardioselective beta-blocker like propranolol or nadolol prior to receiving epinephrine, and in rare cases, cardiac arrest and stroke have occurred. Cardioselective agents are considered much less likely to cause this reaction. Beta-blockade can also blunt the drug's benefit in anaphylaxis, since all beta-blockers antagonize its cardiac effects, and noncardioselective beta-blockers, in particular, can antagonize the bronchodilating effects of epinephrine. Some clinicians argue that the theoretical hypertensive risk in anaphylaxis is outweighed by the need for vasoconstriction, and that the risk lacks case-level support.\n\nOverdose and management\n\nBecause the hormone is cleared rapidly, toxicity management is largely supportive. Overdose may cause transient bradycardia followed by tachycardia, and premature ventricular contractions may appear within one minute after injection. Excessive pressor effects may be countered with rapidly acting α-adrenergic blocking drugs such as phentolamine, while treatment of arrhythmias consists of administration of a beta-adrenergic blocking drug (such as propranolol). Pulmonary edema is managed with a rapidly acting alpha-adrenergic blocking drug (such as phentolamine mesylate) and respiratory support. Prolonged hypotension may follow, and another pressor agent such as norepinephrine may be required. Clinicians should also watch for respiratory difficulties including hyperventilation sometimes preceded by a brief period of apnea, and for blood lactic acid levels, renal insufficiency and failure, which have been reported."
    },
    {
      "heading": "Measurement, diagnosis and regulation in sport",
      "text": "Laboratory measurement\n\nEpinephrine and its metabolites are measured in both plasma and urine. Older assays relied on high-performance liquid chromatography (HPLC) with electrochemical detection. A 2009 study found that a single tandem mass spectrometry method could measure catecholamines and metanephrines together in urine, reducing labour and consumable costs, and its results were close to the older HPLC method, with mean biases of about 1% for adrenaline and about 5% for dopamine (The assay of urinary catecholamines and metanephrines can be achieved simultaneously using one LC-MSMS method, which is rapid and reduces labour and consumable costs for routine application. The LC-MSMS assay gave similar results to HPLC with ECD, with the mean percent biases being −2.6% for noradrenalin, 1.1% for adrenalin and 4.9% for dopamine.) Specificity is a central concern, because related compounds can interfere. One validated urinary method reported that the catecholamine measurements were not affected by 35 structurally-related drugs and metabolites. Sample timing also matters: second-morning urine showed the least day-to-day variation, and epinephrine excretion showed a consistent diurnal pattern (catecholamine excretions for second morning sampling had least day-to-day within-subject variation and excellent reproducibility. consistent and significant diurnal variations for norepinephrine and epinephrine excretions were observed during the three-day period).\n\nDiagnosis of pheochromocytoma and paraganglioma\n\nEpinephrine testing is mainly used to screen for pheochromocytoma and paraganglioma. Measuring metabolites is preferred over measuring the amines themselves: plasma free metanephrines or urinary fractionated metanephrines are the biochemical tests of choice for the diagnosis of pheochromocytoma as they have greater sensitivity and specificity than catecholamines. Because the disease is rare, false positives are a major problem. At Mayo Clinic 97% of patients with plasma normetanephrine concentrations above the upper limit of the reference range do not have a pheochromocytoma.\n\nPre-analytical conditions strongly influence results. Reference intervals are best built from samples taken supine and fasting after rest, and samples collected under seated condition yield increased rates of false-positive results. Under optimised conditions the false-positive rate is about 5%, but can increase to over 25% when those conditions are not followed. Outpatient sampling is a notable source of error: in one study it resulted in 44% higher plasma concentrations and a 3.4-fold increase in false-positive results for normetanephrine. Venous collection technique also matters, and a percutaneous cannula instead of venipuncture is recommended for blood collection. Medications are a further cause: drugs that block norepinephrine reuptake, such as tricyclic antidepressants (TCAs), are in particular well established to increase rates of false-positive results for plasma and urinary normetanephrine.\n\nAnti-doping regulation\n\nEpinephrine is prohibited in sport as a stimulant. The WADA list places it among stimulants, and current WADA material lists it as a non-specified stimulant (Dimetamfetamine (dimethylamphetamine) Ephedrine*** Epinephrine**** (adrenaline) Etamivan), although an older version of the list classed it as a specified stimulant. Its status is limited in time and place. Yes, epinephrine is prohibited in-competition as a stimulant on the WADA Prohibited List. Use of epinephrine out of competition is not prohibited. Local use is also exempt: Epinephrine (adrenaline): Not prohibited in local administration, e.g. nasal, ophthalmologic, or co-administration with local anaesthetic agents.\n\nWhere systemic use is medically necessary, athletes may need a therapeutic use exemption. A TUE is a medical document that gives an athlete permission to take a medication listed on the World Anti-Doping Agency's (WADA) Prohibited List. For anaphylaxis, the WADA physician guidance names epinephrine as a prohibited substance (in-competition only) and treats it as first-line therapy. Athletes are advised to first prioritize life-saving treatment and pursue anti-doping approvals after a medical emergency subsides.\n\nMedical and non-medical use\n\nAthletes may have stimulants in their bodies for one of three main reasons: inadvertent consumption in a propriety medicine; deliberate consumption for misuse as a recreational drug and deliberate consumption to enhance performance. The WADA classification of \"specified\" substances reflects a different judgement: these are substances and methods which are more likely to have been consumed or used by a player for a purpose other than the enhancement of sport performance. I did not find reliable data on the scale of non-medical epinephrine use specifically, so the distinction between medical and illicit contexts rests mainly on the regulatory framework rather than on measured prevalence."
    }
  ],
  "links": [
    "hormone",
    "neurotransmitter",
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    "protein",
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  "license": "https://creativecommons.org/licenses/by/4.0/"
}