Epinephrine
From DrugPedia: A Wikipedia for Drug discovery
Epinephrine Pubchem(5816)
The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics.
Epinephrine (also referred to as adrenaline; see Terminology) is a hormone and neurotransmitter. It is a catecholamine, a sympathomimetic monoamine derived from the amino acids phenylalanine and tyrosine. The Latin roots ad-+renes and the Greek roots epi-+nephros both literally mean "on/to the kidney" (referring to the adrenal gland, which sits atop the kidneys and secretes epinephrine). Epinephrine is often shortened to E or to EPI in Medical jargon. Epinephrine increases the response of the sympathetic division of the Autonomic Nervous System.
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[edit] History
Epinephrine was isolated and identified in 1895 by Napoleon Cybulski, a Polish physiologist. In May 1896, William Bates reported the discovery of a substance produced by the adrenal gland in the New York Medical Journal.<ref name="bates-eye">Template:Cite web</ref> The discovery was repeated in 1897 by John Jacob Abel.<ref>Aronson JK (2000). "Where name and image meet" - the argument for "adrenaline". British Medical Journal 320, 506-9.</ref>
Jokichi Takamine, a Japanese chemist, independently discovered the same hormone in 1900.<ref>Yamashima T (2003). "Jokichi Takamine (1854–1922), the samurai chemist, and his work on adrenalin". J Med Biogr 11 (2): 95–102. PMID 12717538.</ref><ref>Bennett M (1999). "One hundred years of adrenaline: the discovery of autoreceptors". Clin Auton Res 9 (3): 145–59. doi:. PMID 10454061.</ref> In 1901 he isolated and purified the hormone epinephrine from cow glands.
Epinephrine was first artificially synthesized in 1904 by Friedrich Stolz.
[edit] Triggers
Epinephrine is a "fight or flight" hormone, and plays a central role in the short-term stress reaction. It is released from the adrenal glands when danger threatens or in an emergency, hence an Adrenaline rush. Such triggers may be threatening, exciting, or environmental stressor conditions such as high noise levels, or bright light and high ambient temperature (see Fight-or-flight response).
[edit] Actions in the body
When in the bloodstream, it rapidly prepares the body for action in emergency situations. The hormone boosts the supply of oxygen and glucose to the brain and muscles, while suppressing other non-emergency bodily processes (digestion in particular).
It increases heart rate and stroke volume, dilates the pupils, and constricts arterioles in the skin and gastrointestinal tract while dilating arterioles in skeletal muscles. It elevates the blood sugar level by increasing catabolism of glycogen to glucose in the liver, and at the same time begins the breakdown of lipids in fat cells. Like some other stress hormones, epinephrine has a suppressive effect on the immune system.<ref name="omd">Epinephrine - Online Medical Dictionary</ref>
Although epinephrine does not have any psychoactive effects, stress or arousal also releases norepinephrine in the brain. Norepinephrine has similar actions in the body, but is also psychoactive.
The type of action in various cell types depends on their expression of adrenergic receptors.
[edit] Mechanism of action
- Further reading: adrenergic receptor
Epinephrine's actions are mediated through adrenergic receptors. Epinephrine is a non-selective agonist of all adrenergic receptors. It activates α1, α2, β1, and β2 receptors to different extents.<ref name=pharmnemonics>Template:Cite book</ref> Specific functions include:
- It binds to α1 receptors of liver cells, which activate inositol-phospholipid signaling pathway, signaling the phosphorylation of glycogen synthase and phosphorylase kinase (inactivating and activating them, respectively), leading to the latter activating another enzyme—glycogen phosphorylase—which catalises breakdown of glycogen (glycogenolysis) so as to release glucose to the bloodstream. Simultaneously protein phosphatase-1 (PP1) is inactivated, as in the active state PP1 would reverse all the previous phosphorylations.
- Epinephrine also activates β-adrenergic receptors of the liver and muscle cells, thereby activating the adenylate cyclase signaling pathway, which will in turn increase glycogenolysis.
β2 receptors are found primarily in skeletal muscle blood vessels where they trigger vasodilation. However, α-adrenergic receptors are found in most smooth muscles and splanchnic vessels, and epinephrine triggers vasoconstriction in those vessels.
[edit] Therapeutic use
Epinephrine is used as a drug to treat cardiac arrest and other cardiac dysrhythmias resulting in diminished or absent cardiac output; its action is to increase peripheral resistance via α1-adrenoceptor vasoconstriction, so that blood is shunted to the body's core, and the β1-adrenoceptor response which is increased cardiac rate and output (the speed and pronouncement of heart beats). This beneficial action comes with a significant negative consequence—increased cardiac irritability—which may lead to additional complications immediately following an otherwise successful resuscitation. Alternatives to this treatment include vasopressin, a powerful antidiuretic which also increases peripheral vascular resistance leading to blood shunting via vasoconstriction, but without the attendant increase in myocardial irritability.<ref name="omd" />
Due to its suppressive effect on the immune system, epinephrine is the drug of choice for treating anaphylaxis. It is also useful in treating sepsis. Allergy patients undergoing immunotherapy may receive an epinephrine rinse before the allergen extract is administered, thus reducing the immune response to the administered allergen. It is also used as a bronchodilator for asthma if specific beta2-adrenergic receptor agonists are unavailable or ineffective.
Because of various expression of α1 or β2-receptors, depending on the patient, administration of epinephrine may raise or lower blood pressure, depending whether or not the net increase or decrease in peripheral resistance can balance the positive inotropic and chronotropic effects of epinephrine on the heart, effects which respectively increase the contractility and rate of the heart.
Epinephrine can also be found in some brands of nasal spray. Its use in this form is to open air passages, however short-term this use may be.
KEGG Pathway(C00788,D00095)
- Tyrosine metabolism
- Neuroactive ligand-receptor interaction
Target
- alpha1a-adrenergic receptor agonist
- alpha1b-adrenergic receptor agonist
- alpha1d-adrenergic receptor agonist
- alpha2a-adrenergic receptor agonist
- alpha2b-adrenergic receptor agonist
- alpha2c-adrenergic receptor agonist
- beta1-adrenergic receptor agonist
- beta2-adrenergic receptor agonist
- beta3-adrenergic receptor agonist
Activity Adrenergic [vasoconstrictor]
| Physical Property | Value | Units | Temp (deg C) | Source |
|---|---|---|---|---|
| Melting Point | 211.5 | deg C | EXP | |
| pKa Dissociation Constant | 8.59 | (none) | 25 | EXP |
| log P (octanol-water) | (-1.37E+00) | (none) | EXP | |
| Water Solubility | 180 | mg/L | 20 | EXP |
| Vapor Pressure | 7.37E-07 | mm Hg | 25 | EST |
| Henry's Law Constant | 7.06E-19 | atm-m3/mole | 25 | EST |
| Atmospheric OH Rate Constant | 1.38E-10 | cm3/molecule-sec | 25 | EST |
| Organism | Test Type | Route | Reported Dose (Normalized Dose) | Effect | Source |
|---|---|---|---|---|---|
| cat | LDLo | intravenous | 500ug/kg (0.5mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| cat | LDLo | subcutaneous | 20mg/kg (20mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| dog | LD50 | intravenous | 100ug/kg (0.1mg/kg) | Drugs in Japan Vol. 6, Pg. 120, 1982. | |
| dog | LD50 | subcutaneous | 5mg/kg (5mg/kg) | Drugs in Japan Vol. 6, Pg. 120, 1982. | |
| dog | LDLo | parenteral | 5ug/kg (0.005mg/kg) | CARDIAC: ARRHYTHMIAS (INCLUDING CHANGES IN CONDUCTION) | Pharmacology: International Journal of Experimental and Clinical Pharmacology. Vol. 1, Pg. 189, 1968. |
| guinea pig | LDLo | intravenous | 100ug/kg (0.1mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| guinea pig | LDLo | subcutaneous | 800ug/kg (0.8mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| infant | TDLo | multiple routes | 625ug/kg/I (0.625mg/kg) | CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP
LUNGS, THORAX, OR RESPIRATION: CYANOSIS KIDNEY, URETER, AND BLADDER | "CHANGES IN TUBULES (INCLUDING ACUTE RENAL FAILURE, ACUTE TUBULAR NECROSIS)" Southern Medical Journal. Vol. 78, Pg. 874, 1985. |
| man | LDLo | subcutaneous | 7ug/kg (0.007mg/kg) | BRAIN AND COVERINGS: OTHER DEGENERATIVE CHANGES
CARDIAC: OTHER CHANGES | Annals of Emergency Medicine. Vol. 28, Pg. 725, 1996. |
| man | TDLo | intramuscular | 2ug/kg (0.002mg/kg) | VASCULAR: REGIONAL OR GENERAL ARTERIOLAR CONSTRICTION | American Journal of Emergency Medicine. Vol. 8, Pg. 46, 1990. |
| man | TDLo | intravenous | 16ug/kg (0.016mg/kg) | BEHAVIORAL: "HALLUCINATIONS, DISTORTED PERCEPTIONS"
CARDIAC: CHANGE IN RATE VASCULAR: BP LOWERING NOT CHARACTERIZED IN AUTONOMIC SECTION | American Journal of Emergency Medicine. Vol. 5, Pg. 64, 1987. |
| man | TDLo | intravenous | 285ug/kg (0.285mg/kg) | CARDIAC: EKG CHANGES NOT DIAGNOSTIC OF ABOVE | American Journal of Emergency Medicine. Vol. 7, Pg. 485, 1989. |
| man | TDLo | intravenous | 3mg/kg (3mg/kg) | VASCULAR: CONTRACTION (ISOLATED TISSUES) | American Journal of Emergency Medicine. Vol. 8, Pg. 46, 1990. |
| man | TDLo | oral | 77mg/kg (77mg/kg) | BEHAVIORAL: "HALLUCINATIONS, DISTORTED PERCEPTIONS"
BEHAVIORAL: EXCITEMENT GASTROINTESTINAL: NAUSEA OR VOMITING | Annals of Emergency Medicine. Vol. 19, Pg. 671, 1990. |
| man | TDLo | subcutaneous | 8571ng/kg/80M (0.008571mg/kg) | CARDIAC: CARDIOMYOPATHY INCLUDING INFARCTION | American Heart Journal. Vol. 111, Pg. 1193, 1986. |
| man | TDLo | subcutaneous | 43ug/kg (0.043mg/kg) | CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP
GASTROINTESTINAL: NAUSEA OR VOMITING SKIN AND APPENDAGES (SKIN): SWEATING: OTHER | Annals of Emergency Medicine. Vol. 19, Pg. 680, 1990. |
| mouse | LD50 | intraperitoneal | 4mg/kg (4mg/kg) | Journal of Pharmacology and Experimental Therapeutics. Vol. 90, Pg. 110, 1947. | |
| mouse | LD50 | intravenous | 217ug/kg (0.217mg/kg) | BEHAVIORAL: CHANGES IN MOTOR ACTIVITY (SPECIFIC ASSAY)
CARDIAC: PULSE RATE INCREASE WITHOUT FALL IN BP SKIN AND APPENDAGES (SKIN): HAIR: OTHER | Acta Pharmacologica et Toxicologica. Vol. 38, Pg. 474, 1976. |
| mouse | LD50 | subcutaneous | 1470ug/kg (1.47mg/kg) | Naunyn-Schmiedeberg's Archiv fuer Experimentelle Pathologie und Pharmakologie. Vol. 202, Pg. 658, 1943. | |
| mouse | LDLo | oral | 50mg/kg (50mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| mouse | LDLo | unreported | 10mg/kg (10mg/kg) | BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
LUNGS, THORAX, OR RESPIRATION: DYSPNEA BEHAVIORAL: EXCITEMENT | Naunyn-Schmiedeberg's Archiv fuer Experimentelle Pathologie und Pharmakologie. Vol. 162, Pg. 46, 1931. |
| rabbit | LD50 | intravenous | 50ug/kg (0.05mg/kg) | LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION | Schweizerische Medizinische Wochenschrift. Vol. 71, Pg. 554, 1941. |
| rabbit | LD50 | subcutaneous | 4mg/kg (4mg/kg) | LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION | Schweizerische Medizinische Wochenschrift. Vol. 71, Pg. 554, 1941. |
| rabbit | LDLo | oral | 30mg/kg (30mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| rat | LD50 | intramuscular | 3500mg/kg (3500mg/kg) | "Drug Dosages in Laboratory Animals - A Handbook," Rev. ed., Barnes, C.D., and L.G. Eltherington, Berkeley, Univ. of California Press, 1973Vol. -, Pg. 105, 1973. | |
| rat | LD50 | intravenous | 150ug/kg (0.15mg/kg) | Archives Internationales de Pharmacodynamie et de Therapie. Vol. 41, Pg. 365, 1931. | |
| rat | LD50 | skin | 62mg/kg (62mg/kg) | BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY)
BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD BEHAVIORAL: EXCITEMENT | Gigiena Truda i Professional'nye Zabolevaniya. Labor Hygiene and Occupational Diseases. Vol. 8(4), Pg. 30, 1964. |
| rat | LD50 | subcutaneous | 5mg/kg (5mg/kg) | LUNGS, THORAX, OR RESPIRATION: RESPIRATORY STIMULATION | Schweizerische Medizinische Wochenschrift. Vol. 71, Pg. 554, 1941. |
| rat | LDLo | intraperitoneal | 10mg/kg (10mg/kg) | BEHAVIORAL: CONVULSIONS OR EFFECT ON SEIZURE THRESHOLD
BEHAVIORAL: MUSCLE WEAKNESS LUNGS, THORAX, OR RESPIRATION: DYSPNEA | Journal of Pharmacology and Experimental Therapeutics. Vol. 88, Pg. 268, 1946. |
| rat | LDLo | oral | 30mg/kg (30mg/kg) | "Structure et Activite Pharmacodyanmique des Medicaments du Systeme Nerveux Vegetatif," Bovet, D., and F. Bovet-Nitti, New York, S. Karger, 1948Vol. -, Pg. 22, 1948. | |
| women | TDLo | intravenous | 6ug/kg (0.006mg/kg) | CARDIAC: ARRHYTHMIAS (INCLUDING CHANGES IN CONDUCTION) | British Medical Journal. Vol. 286, Pg. 519, 1983. |
