Epinephrine By: Dr. Vahid Nikoui Email: firstname.lastname@example.org
•It is a catecholamine, a sympathomimetic monoamine derived from theamino acids phenylalanine and tyrosine.•The Latin roots ad-+renes and the Greek roots epi-+nephros both literallymean "on/to the kidney" (referring to the adrenal gland, which secretesepinephrine). Epinephrine is sometimes shortened to epi in medicaljargon.•Epinephrine is now also used in EpiPen and Twinject. EpiPen is longnarrow auto-injectors that administer epinephrine, Twinject is similar butcontain two doses of epinephrine.
Adrenal Anatomy• small, triangular glands loosely attachedto the kidneys• divided into two morphologically anddistinct regions - adrenal cortex (outer) - adrenal medulla (inner)
Anatomy and Origin• embryologically derived frompheochromoblasts• differentiate into modified neuronal cells • more gland than nerve • chromaffin cells• acts like sympathetic ganglion
Function of the Adrenal Medulla• an extension of the sympathetic nervoussystem• acts as a peripheral amplifier• activated by same stimuli as thesympathetic nervous system (examples – exercise, cold, stress, hemorrhage, etc.)
Biosynthesis of norepinephrine and epinephrine HO NH2 HO NH2 NH2 Tyrosine DopaHO CO2H hydroxylase HO CO2H Decarboxylase HO L-Tyrosine Levodopa Dopamine OH OH HO NHMe Dopamine HO NH2 N-methyl transferase -hydroxylase HO (in Adrenal medulla) HO Epinephrine Norepinephrine (Adrenaline) (Noradrenaline)
Metabolism involves two key enzymes: MAO and COMT
Differences between Epinephrine and Norepinephrine Epinephrine >> norepinephrine – in terms of cardiac stimulation leading to greater cardiac output ( stimulation). Epinephrine < norepinephrine – in terms of constriction of blood vessels – leading to increased peripheral resistance – increased arterial pressure. Epinephrine >> norepinephrine – in terms of increasing metabolism
Effects of Epinephrine• metabolism - glycogenolysis in liver and skeletal muscle • can lead to hyperglycemia - mobilization of free fatty acids - increased metabolic rate • O2 consumption increases
Fight or Flight Response These catecholamine hormones facilitate immediate physical reactions associated with a preparation for violent muscular action. These include the following: Acceleration of heart and lung action and Inhibition of stomach and intestinal action Constriction of blood vessels in many parts of the body Liberation of nutrients for muscular action Dilation of blood vessels for muscles Inhibition of tear glands and salivation Dilation of pupil Relaxation of bladder Inhibition of erection(Gleitman, et al, 2004)
Pheochromocytoma• a catecholamine-secreting tumour ofchromaffin cells of the adrenal medulla adrenal pheochromocytoma (90%)• paraganglioma – a catecholaminesecreting tumour of the sympatheticparaganglia extra-adrenal pheochromocytoma
Classes of G proteinGs→ s→ AC → cAMP↑Gi→ i→ AC → cAMP↓G q→ q→ PLC → IP3+ DAG
Types of -adrenergic receptor -adrenergic receptors are adrenergic receptors that respond to norepinephrine and to such blocking agents as phenoxybenzamine. They are subdivided into two types: 1, found in smooth muscle, heart, and liver, with effects including vasoconstriction, intestinal relaxation, uterine contraction and pupillary dilation, 2, found in platelets, vascular smooth muscle, nerve termini, and pancreatic islets, with effects including platelet aggregation, vasoconstriction, and inhibition of norepinephrine release and of insulin secretion.
Types of β-adrenergic receptor -adrenergic receptors respond particularly to epinephrine and to such blocking agents as propranolol. There are three known types of beta receptor, designated β1, β2 and β3. β1-Adrenergic receptors are located mainly in the heart. β2-Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β3-receptors are located in fat cells.
Receptors and signal transduction in the ANS Adrenergic Receptors 1 21A 1B 1D 2A 2B 2C 1 2 3
Direct acting adrenergic receptor agonists: 1 receptors NH 3 Phospho - lipase C Phenylephrine (Neosynephrine) Methoxamine (Vasoxyl) Oxymetazoline (Visine) (+) Gq PIP 2HO COOH IP 3 Diacylglycerol CH C H 2 NH C H3 2+ Increase Ca Activate Protein Kinase C OH P henylephrine Response
Direct acting adrenergic receptor agonists: 2 receptors NH 3 Clonidine (Catapres) Methyldopa (Aldomet) Guanabenz (Wytensin) Guanfacine (Tenex) Tizanidine (Zanaflex) (-) Adenylate Cyclase GI Cl N K+ (+) X H N ATP cAMP COOH N H Reduce cAMP -Dependent Cl Protein Kinase Activity C lonidine Response
Direct acting adrenergic receptor agonists: receptors NH 3 (+) Adenylate Cyclase GS ATP cAMP COOH Increase cAMP -Dependent Protein Kinase Activity Response
β3 adrenergic agonistAmibegron (SR-58,611A)It is the first orally active β3 agonistdeveloped that is capable of enteringthe Central Nervous System, and hasantidepressant and anxiolytic effects.Solabegron (GW-427,353)It is being developed for thetreatment of overactive bladder andirritable bowel syndrome. It has beenshown to produce visceral analgesiaby releasing somatostatin fromadipocytes.
Classification of Adrenergic Hormone Receptors Second Receptor Agonists G protein Messengeralpha1 ( 1) NE > E IP3/Ca2+; DAG Gqalpha2 ( 2) E > NE cyclic AMP Gi beta1 ( 1) E = NE cyclic AMP Gs beta2 ( 2) E >> NE cyclic AMP Gs E = epinephrine; NE = norepinephrine
Cardiovascular effects of adrenergic agonists in man (injected iv) A ( + ) NA ( >> ) Iso ( )
DosageIn cardiac arrest1 mg (10 mL 1:10,000 solution)If this fails, higher doses of epinephrine (up to 0.2 mg/kg) are acceptable but not recommended (there is growing evidence that it may be harmful).PrecautionsCan precipitate myocardial ischemiaAvoid mixing with alkaline solutionsCan induce myocardial ectopy
EpiPenEpiPen is a registered trademark for the most commonly used autoinjector ofepinephrine (aka adrenaline), used in medicine to treat anaphylactic shock. http://www.epipen.com/howtouse_high.aspx
AnaphylaxisAnaphylaxis is a severe and rapid multi-system allergicreaction. The term comes from the Greek words ana(against) and phyllus (protection). Anaphylaxis occurs whena person is exposed to a trigger substance, called anallergen, to which they have already become sensitized.Minute amounts of allergens may cause a life-threateninganaphylactic reaction. Anaphylaxis may occur after ingestion,inhalation, skin contact or injection of an allergen. The mostsevere type of anaphylaxis—anaphylactic shock—willusually lead to death in minutes if left untreated.Most common presentation is sudden cardiovascularcollapse.
Ephinephrine can be injected directly into the heart to stimulate itafter it as stopped beating due to drowning, suffocation, shock,electrocution, and anesthesia.The epinephrine dramatically restores the heart beat.In cases of shock, norepinephrine has been used to restore andmaintain sufficient blood pressure and ensure adequate blood flowto vital organs.When local anesthetics are used to reduce or eliminate pain in aspecific area, epinephrine is frequently used in conjunction withthese agents to constrict the blood vessels at the area and preventdrug diffusion from that area.