Adrenergic Receptor

Compared to untreated control eyes, the iris and palatial body blood flow of one eye of twelve monkeys was reduced by five percent and nine percent, respectively, after a 25 microliter volume of 1% L-adrenergic borate solution was applied to the left side of one of the eyes. Twenty percent[1]. Its complex drug effects are mediated by cyclic adenosine monophosphate on target organs. Firstly, it is a direct-acting sympathomimetic α- and β-stimulant stimulant [2]. Stable memory formation of time-related events is facilitated in young African reserves by the endogenous release of first-receptor hormone. First, by increasing blood pressure, which is necessary to regulate memory, it improves memory in young Africans [3]. Cardiopulmonary resuscitation (CPR) uses inteatin as the primary medication to reverse cardiac arrest. Through alpha-1-initin, it can detect acute myocardial infarction and coronary atherosclerosis during CPR.[4]

25 μL volume of 1% L-adrenergic borate solution administered to the left side of one eye of 12 monkeys reduced iris and palatial body blood flow by 59% and 59%, respectively, compared with untreated control eyes. 20%[1]. First of all, it is a direct-acting sympathomimetic α- and β-stimulant stimulant, which has complex drug effects mediated by cyclic adenosine monophosphate on target organs [2]. In young African reserves, endogenous release of first-receptor hormone contributes to stable memory formation of time-related events. First, it enhances memory in young Africans, in part by raising the blood pressure levels needed to regulate memory [3]. Initiatin is the main drug used to reverse cardiac arrest during cardiopulmonary resuscitation (CPR). Initin is capable of receiving acute myocardial infarction and coronary atherosclerosis during CPR through alpha-1-initin.[4]

Rats: Rats are immediately put back into the holding cage after receiving a subcutaneous injection of either saline (0.9%), glucose (250 mg/kg), or epinephrine (0.1 mg/kg) for the immunohistochemistry experiments[3].

Absorption, Distribution and Excretion
Following I.V. (intravenous) injection, epinephrine disappears rapidly from the blood stream. Subcutaneously or I.M. (intramuscular) administered epinephrine has a rapid onset and short duration of action. Subcutaneous (SC) administration during asthmatic attacks may produce bronchodilation within 5 to 10 minutes, and maximal effects may occur within 20 minutes. The drug becomes fixed in the tissues rapidly,.
The majority of the dose of epinephrine is seen excreted in the urine,. About 40% of a parenteral dose of epinephrine is excreted in urine as metanephrine, 40% as VMA, 7% as 3-methoxy-4-hydroxyphenoglycol, 2% as 3,4-dihydroxymandelic acid, and the rest as acetylated derivatives. These metabolites are excreted mainly as the sulfate conjugates and, to a lesser extent, the glucuronide conjugates. Only small amounts of the drug are excreted completely unchanged.
Intravenous injection produces an immediate and intensified response. Following intravenous injection, epinephrine disappears rapidly from the blood stream.
Following topical application of radiolabeled epinephrine to the eye in rabbits, highest concentrations of the drug in tissues and fluids other than the eye occurred in the pituitary gland, with lower concentrations in the intestine, fat, adrenal gland, kidney, heart, lung, spleen, ovary, pancreas, liver, uterus, muscle, brain, and serum. In humans, systemically absorbed epinephrine crosses the placenta but not the blood-brain barrier. Systemically absorbed epinephrine distributes into milk.
Epinephrine is not effective after oral admin because it is rapidly conjugated and oxidized in GI mucosa and liver. Absorption from sc tissues occurs slowly because of local vasoconstriction ... Absorption is more rapid after im than after sc injection ... Epinephrine is rapidly inactivated in the body.
In a prospective, randomized, five-way crossover study in rabbits, ... plasma epinephrine concentrations /were measured/ before, and at intervals up to 180 min after epinephrine administration by intramuscular or subcutaneous injection, or by inhalation, with intravenous epinephrine and intramuscular saline as the positive and negative controls, respectively. Maximum plasma epinephrine concentrations were higher, and occurred more rapidly, after intramuscular injection than after subcutaneous injection or inhalation, and were 7719+/-3943 (S.E.M.) pg/mL at 32.5+/-6.6 min, 2692+/-863 pg/mL at 111.7+/-30.8 min and 1196+/-369 pg/mL at 45. 8+/-19.2 min, respectively. Intravenous injection of epinephrine resulted in a plasma concentration of 3544+/-422 pg/mL at 5 min, and an elimination half-life (t(1/2)) of 11.0+/-2.5 min. In the saline control study, the endogenous epinephrine concentration peaked at 518+/-142 pg/mL. CONCLUSION: In this model, absorption of epinephrine was significantly faster after intramuscular injection than after subcutaneous injection or inhalation. The extent of absorption was satisfactory after both intramuscular and subcutaneous injections. Neither the rate nor the extent of absorption was satisfactory after administration by inhalation.
3 groups of 5 greyhounds received 1.5 ug/kg epinephrine 1:200,000 in either lidocaine 0.5%, bupivacaine 0.5% or 0.9% saline. Dogs were anesthetized and 40% of the allocated epinephrine solution was infiltrated beneath the perianal skin and each of the 4 quadrants of the rectal mucosa was injected with the remainder of the solution. Plasma epinephrine, lidocaine, bupivacaine, lactate, glucose and potassium concn were measured at 1, 2, 5, 10 and 30 min following infiltration. Peak plasma epinephrine concn were recorded 2 min following rectal mucosal infiltration in all 3 groups. Plasma epinephrine concn were significantly higher (p < 0.01) in the lidocaine group at 1 and 2 min following infiltration. Both plasma bupivacaine and lidocaine peaked 10 min after infiltration and thereafter tended to decr towards baseline concn. Plasma bupivacaine concn were significantly higher (p < 0.01) than plasma lidocaine concn throughout the study period. There were no significant differences in metabolic or biochemical indices within or between the 3 groups. However, both plasma glucose and lactate concn were elevated and peaked 10 min after infiltration, while plasma potassium concn remained unchanged throughout the study period. Heart rate in the bupivacaine group was significantly reduced at 30 min following infiltration (p < 0.05). There were no significant differences observed in the mean arterial and pulse pressures among the 3 groups.
Epinephrine is well absorbed after subcutaneous or IM injection; absorption can be hastened by massaging the injection site. Both rapid and prolonged absorption occur after subcutaneous injection of the longer-acting aqueous suspension (no longer commercially available in the US). Epinephrine also is absorbed following endotracheal administration, although serum concentrations achieved may be only 10% of those with an equivalent IV dose.. After oral inhalation of epinephrine in the usual dosage, absorption is slight and the effects of the drug are restricted mainly to the respiratory tract. Absorption increases somewhat when larger doses are inhaled, and systemic effects may occur.

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Metabolism / Metabolites
Epinephrine is rapidly inactivated mainly by enzymic transformation to metanephrine or normetanephrine, either of which is then conjugated and excreted in the urine in the form of both sulfates and glucuronides. Either sequence results in the formation of 3-methoxy-4- hydroxy-mandelic acid(vanillylmandelic acid, VMA) which is shown to be detectable in the urine. Epinephrine is rapidly inactivated in the body mostly by the enzymes COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase). The liver is abundant in the above enzymes, and is a primary, although not essential, tissue in the degradation process.
The pharmacologic actions of epinephrine are terminated mainly by uptake and metabolism in sympathetic nerve endings. Circulating drug is metabolized in the liver and other tissues by a combination of reactions involving the enzymes catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO). The major metabolites are metanephrine and 3-methoxy-4-hydroxymandelic acid (vanillylmandelic acid, VMA) both of which are inactive. About 40% of a parenteral dose of epinephrine is excreted in urine as metanephrine, 40% as VMA, 7% as 3-methoxy-4-hydroxyphenoglycol, 2% as 3,4-dihydroxymandelic acid, and the remainder as acetylated derivatives. These metabolites are excreted mostly as the sulfate conjugates and, to a lesser extent, the glucuronide conjugates. Only small amounts of the drug are excreted unchanged.
Circulating epinephrine is metabolized in the liver and is taken up into adrenergic neurons and metabolized by MAO and catechol-O-methyltransferase to metadrenaline, sulfate conjugates, and hydroxy derivatives of mandelic acid.
Epinephrine has known human metabolites that include Epinephrine sulfate.

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Biological Half-Life
The plasma half-life is approximately 2-3 minutes. However, when administered by subcutaneous or intramuscular injection, local vasoconstriction may delay absorption so that epinephrine's effects may last longer than the half-life suggests.
Elimination half life is 1 minute.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of epinephrine during breastfeeding. Because of its poor oral bioavailability and short half-life, any epinephrine in milk is unlikely to affect the infant. High intravenous doses of epinephrine might reduce milk production or milk letdown. Low-dose intramuscular (such as Epi-Pen), epidural, topical, inhaled or ophthalmic epinephrine are unlikely to interfere with breastfeeding. To substantially diminish the effect of the drug after using eye drops, place pressure over the tear duct by the corner of the eye for 1 minute or more, then remove the excess solution with an absorbent tissue. Epinephrine is the first line-medication of choice for treatment of anaphylaxis; it should be used in the same manner in breastfeeding and non-breastfeeding patients.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information in nursing mothers was not found as of the revision date. Intravenous epinephrine infusion in nonnursing subjects and in women with hyperprolactinemia decreases serum prolactin concentrations. Animal data indicate that intraarterial epinephrine can decrease serum oxytocin and inhibit milk ejection. However, low-dose infusion of epinephrine as part of epidural analgesia does not impair breastfeeding in nursing mothers. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
An Egyptian study compared lidocaine 2% (n = 75) to lidocaine 2% plus epinephrine 1:200,000 (n = 70) as a wound infiltration following cesarean section. Patients who received epinephrine in combination with lidocaine began breastfeeding at 89 minutes following surgery compared to 132 minutes for those receiving lidocaine alone. The difference was statistically significant.

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Interactions
Use in patients taking propranolol and other nonselective beta blockers may produce severe hypertension owing to blockade of beta-2-mediated vasodilation, resulting in unopposed alpha-vasoconstriction.
Epinephrine should not be administered concomitantly with other sympathomimetic agents because of the possibility of additive effects and increased toxicity.
Administration of epinephrine in patients receiving cyclopropane or halogenated hydrocarbon general anesthetics that increase cardiac irritability and seem to sensitize the myocardium to epinephrine may result in arrhythmias including PVCs, tachycardia, or fibrillation. Epinephrine is contraindicated for use with chloroform, trichloroethylene, or cyclopropane and should be used cautiously, if at all, with other halogenated hydrocarbon anesthetics such as halothane. Epinephrine may not be absorbed rapidly enough to cause serious adverse effects when applied topically as a hemostatic in patients undergoing short surgical procedures such as tonsillectomy and adenoidectomy using halothane anesthesia. Prophylactic administration of lidocaine or prophylactic IV administration of propranolol 0.05 mg/kg may protect against ventricular irritability if epinephrine is used during anesthesia with a halogenated hydrocarbon anesthetic. In one study, arrhythmias occurring after parenteral use of epinephrine during general anesthesia responded promptly to IV propranolol 0.05 mg/kg.
The effects of epinephrine 1/200,000 added to mg of epidural morphine were investigated in 3 healthy male volunteers, during 26 hr observation sessions. Cutaneous hypalgesia was intense, faster in onset, and longer in duration after epinephrine-morphine than after plain morphine. Apparently, epinephrine 1/200,000 reduces manifestations of cord and brainstem uptake. The need for the reduction of the customary dose of epidural morphine, while epinephrine is used as an adjuvant, is discussed.
For more Interactions (Complete) data for EPINEPHRINE (20 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat dermal 62 mg/kg
LD50 Rat sc 62 mg/kg
LD50 Rat iv 0.15 mg /kg
LD50 Rat im 3500 mg/kg
For more Non-Human Toxicity Values (Complete) data for EPINEPHRINE (9 total), please visit the HSDB record page.

[1]. The effect of topical l-epinephrine on regional ocular blood flow in monkeys. Invest Ophthalmol Vis Sci. 1980 May;19(5):487-91.

[2]. First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol. 2004 May;113(5):837-44.

[3]. Epinephrine and glucose modulate training-related CREB phosphorylation in old rats: relationships to age-related memory impairments. Exp Gerontol. 2013 Feb;48(2):115-27.

[4]. Epinephrine for cardiac arrest. Curr Opin Cardiol. 2013 Jan;28(1):36-42.

Therapeutic Uses
Adrenergic alpha-Agonists; Adrenergic beta-Agonists; Adrenergic Agonists; Bronchodilator Agents; Mydriatics; Sympathomimetics; Vasoconstrictor Agents
Epinephrine is the drug of choice in the emergency treatment of severe acute anaphylactic reactions including anaphylactic shock. Symptoms such as urticaria, pruritus, angioedema, and swelling of the lips, eyelids, and tongue which may result from reactions to drugs, sera, insect stings, food, or other allergens may be relieved by epinephrine. Epinephrine should be given to all patients with signs of systemic reactions, particularly hypotension, airway swelling, or definite breathing difficulty. Circulatory support during anaphylactic shock requires rapid volume resuscitation and vasopressor therapy to support blood pressure; epinephrine is the drug of choice for the treatment of both vasodilation/hypotension and cardiac arrest associated with anaphylaxis. /Included in US product label/
Epinephrine may be added to solutions of some local anesthetics to decrease the rate of vascular absorption of the anesthetic, thereby localizing anesthesia and prolonging the duration of anesthesia; the risk of systemic toxicity from the local anesthetic is also decreased. Epinephrine may be applied topically to control superficial bleeding from arterioles or capillaries in the skin, mucous membranes, or other tissues. Bleeding from larger vessels is not controllable by topical application of epinephrine. /Included in US product label/
Epinephrine is used for its a-adrenergic stimulatory effects to increase blood flow in advanced cardiovascular life support (ACLS) during cardiopulmonary resuscitation (CPR). The principal beneficial effects of the drug in patients with cardiac arrest result from increases in aortic diastolic blood pressure and in myocardial and cerebral blood flow during resuscitation. The value and safety of the beta-adrenergic effects of epinephrine are controversial because they may increase myocardial work and reduce subendocardial perfusion. Epinephrine remains a drug of choice and a high priority for ACLS in cardiac arrest to facilitate return of spontaneous circulation. /Included in US product label/
For more Therapeutic Uses (Complete) data for EPINEPHRINE (15 total), please visit the HSDB record page.

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Drug Warnings
Epinephrine should not be used in cardiogenic shock because it increases myocardial oxygen demand, nor should it be used in hemorrhagic or traumatic shock.
Vet: epinephrine injection (1:1000): do not use in acute hypotension produced by phenothiazine derived tranquilizers, since further depression of blood pressure can occur. Do not use when cyclopropane or halogenated anesthetics are used because of possible cardiac collapse. Do not use in treatment of vascular shock. Do not use in patients known to be sensitive to epinephrine ... Use with caution in hyperthyroid animals; animals being treated with thyroid, digitalis, or mercurial diuretics. Do not use injection if it is brown or contains a precipitate.
A prospective study where topical epinephrine was used on burn and non-burn patients and five patients served as controls without epinephrine usage. Catecholamine concentrations were measured and to estimate the systemic effects of epinephrine, serum lactate and pyruvate concentrations were analyzed and perioperative haemodynamic changes recorded. Compared to the baseline values, there was a significant increase in the heart rate, serum epinephrine and lactate concentrations and LP-ratios in the burn patients and an increase in the epinephrine concentrations in the non-burn patients at 1 and 2 h. Epinephrine and lactate concentrations and LP-ratios were also higher in the burn patients compared to the other groups. Altogether, there were no changes in the control group. This study showed that the use of topical epinephrine has systemic effects on hemodynamics and serum epinephrine concentrations. Increased epinephrine concentrations in burn patients suggest increased absorption properties in these patients. The increased lactate concentrations and LP-ratios suggest tissue ischaemia, likely in skin.
Some manufacturers state that epinephrine is contraindicated for parenteral use during the second stage of labor; parenteral administration of the drug to maintain blood pressure during spinal anesthesia for delivery can cause acceleration of fetal heart rate and should not be used in obstetric patients when maternal systolic/diastolic blood pressure exceeds 130/80 mm Hg. Epinephrine should be administered cautiously by oral inhalation to pregnant patients. Epinephrine should be used during pregnancy only if the potential benefits justify the possible risks to the fetus. There is some evidence that epidural administration of lidocaine with epinephrine during labor is safe.
For more Drug Warnings (Complete) data for EPINEPHRINE (21 total), please visit the HSDB record page.

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Pharmacodynamics
Epinephrine is a sympathomimetic drug. It causes an adrenergic receptive mechanism on effector cells and mimics all actions of the sympathetic nervous system except those on the facial arteries and sweat glands. Important effects of epinephrine include increased heart rate, myocardial contractility, and renin release via beta-1 receptors. Beta-2 effects produce bronchodilation which may be useful as an adjunct treatment of asthma exacerbations as well as vasodilation, tocolysis, and increased aqueous humor production. In croup, nebulized epinephrine is associated with both clinically and statistically significant transient reduction of croup symptoms 30 minutes post-treatment. Epinephrine also alleviates pruritus, urticaria, and angioedema and may be helpful in relieving gastrointestinal and genitourinary symptoms associated with anaphylaxis because of its relaxing effects on the smooth muscle of the stomach, intestine, uterus, and urinary bladder.

C9H13NO3

183.2

183.089

C, 59.00; H, 7.15; N, 7.65; O, 26.20

51-43-4

L-Epinephrine sulfate; 52455-32-0

5816

White to off-white solid powder

1.3±0.1 g/cm3

413.1±40.0 °C at 760 mmHg

208-211ºC

207.9±17.9 °C

0.0±1.0 mmHg at 25°C

1.608

-0.63

4

4

3

13

154

1

O[C@H](C1=CC(O)=C(O)C=C1)CNC

UCTWMZQNUQWSLP-VIFPVBQESA-N

InChI=1S/C9H13NO3/c1-10-5-9(13)6-2-3-7(11)8(12)4-6/h2-4,9-13H,5H2,1H3/t9-/m0/s1

4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.  (3). This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)