Epinephrine

1. Epinephrine By: Dr. Vahid Nikoui Email: [email protected]

2. 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 secretes epinephrine). Epinephrine is sometimes shortened to epi in medical jargon. Epinephrine is now also used in EpiPen and Twinject. EpiPen is long narrow auto-injectors that administer epinephrine, Twinject is similar but contain two doses of epinephrine.

3. Adrenal Anatomy small, triangular glands loosely attached to the kidneys divided into two morphologically and distinct regions adrenal cortex (outer) adrenal medulla (inner)

4. Anatomy and Origin embryologically derived from pheochromoblasts differentiate into modified neuronal cells acts like sympathetic ganglion more gland than nerve chromaffin cells

5. Function of the Adrenal Medulla an extension of the sympathetic nervous system acts as a peripheral amplifier activated by same stimuli as the sympathetic nervous system (examples – exercise, cold, stress, hemorrhage, etc.)

6. Biosynthesis of norepinephrine and epinephrine

7. Metabolism involves two key enzymes: MAO and COMT

8. 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

9. Effects of Epinephrine metabolism glycogenolysis in liver and skeletal muscle mobilization of free fatty acids increased metabolic rate can lead to hyperglycemia O 2 consumption increases

10. 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)

11. Pheochromocytoma a catecholamine-secreting tumour of chromaffin cells of the adrenal medulla paraganglioma – a catecholamine secreting tumour of the sympathetic paraganglia adrenal pheochromocytoma (90%) extra-adrenal pheochromocytoma

12. Signs and Symptoms of Pheochromocytoma headache sweating palpitations chest pain anxiety glucose intolerance increased metabolic rate classic triad

13. G s →  s → AC → cAMP↑ 　 G i →  i → AC → cAMP↓ 　 G q →  q → PLC → IP 3 + DAG 　 Classes of G protein

14. 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.

15. 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 β 1 , β 2 and β 3 . β 1 -Adrenergic receptors are located mainly in the heart. β 2 -Adrenergic receptors are located mainly in the lungs, gastrointestinal tract, liver, uterus, vascular smooth muscle, and skeletal muscle. β 3 -receptors are located in fat cells.

16. Receptors and signal transduction in the ANS Adrenergic Receptors a 1A a 1 b a 2 a 1B a 1D a 2A a 2B a 2C b 1 b 2 b 3

17. Direct acting adrenergic receptor agonists: a 1 receptors Phenylephrine (Neosynephrine) Methoxamine (Vasoxyl) Oxymetazoline (Visine) P h e n y l e p h r i n e H O C H C H 2 N H C H 3 O H NH 3 COOH G q Phospho - lipase C (+) PIP 2 IP 3 Diacylglycerol Increase Ca 2+ Activate Protein Kinase C Response

18. Direct acting adrenergic receptor agonists: a 2 receptors Clonidine (Catapres) Methyldopa (Aldomet) Guanabenz (Wytensin) Guanfacine (Tenex) Tizanidine (Zanaflex) C l o n i d i n e NH 3 COOH G I (-) ATP cAMP Reduce cAMP -Dependent Protein Kinase Activity Response X (+) K + Adenylate Cyclase

19. Direct acting adrenergic receptor agonists: b receptors G S (+) ATP cAMP Increase cAMP -Dependent Protein Kinase Activity Response NH 3 COOH Adenylate Cyclase

20. β3 adrenergic agonist Amibegron (SR-58,611A) It is the first orally active β3 agonist developed that is capable of entering the Central Nervous System, and has antidepressant and anxiolytic effects. Solabegron (GW-427,353) It is being developed for the treatment of overactive bladder and irritable bowel syndrome. It has been shown to produce visceral analgesia by releasing somatostatin from adipocytes .

21. Classification of Adrenergic Hormone Receptors Receptor Agonists Second Messenger G protein alpha 1 (  1 ) NE > E IP 3 /Ca 2+ ; DAG G q alpha 2 (  2 ) E > NE  cyclic AMP G i beta 1 (  1 ) E = NE  cyclic AMP G s beta 2 (  2 ) E >> NE  cyclic AMP G s E = epinephrine; NE = norepinephrine

22. Cardiovascular effects of adrenergic agonists in man (injected iv) A ( a + b ) NA ( a >> b ) Iso ( b )

23. Indications Ventricular fibrillation Asystole Cardiac Arrest

24. Indications Sever hypotension Anaphylaxis

25. In cardiac arrest 1 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). Precautions Can precipitate myocardial ischemia Avoid mixing with alkaline solutions Can induce myocardial ectopy Dosage

26. EpiPen EpiPen is a registered trademark for the most commonly used autoinjector of epinephrine (aka adrenaline), used in medicine to treat anaphylactic shock . http://www.epipen.com/howtouse_high.aspx

27. Anaphylaxis is a severe and rapid multi-system allergic reaction. The term comes from the Greek words ana (against) and phyllus (protection). Anaphylaxis occurs when a person is exposed to a trigger substance, called an allergen , to which they have already become sensitized. Minute amounts of allergens may cause a life-threatening anaphylactic reaction. Anaphylaxis may occur after ingestion, inhalation, skin contact or injection of an allergen. The most severe type of anaphylaxis — anaphylactic shock — will usually lead to death in minutes if left untreated. Most common presentation is sudden cardiovascular collapse. Anaphylaxis

28. Ephinephrine can be injected directly into the heart to stimulate it after 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 and maintain sufficient blood pressure and ensure adequate blood flow to vital organs. When local anesthetics are used to reduce or eliminate pain in a specific area, epinephrine is frequently used in conjunction with these agents to constrict the blood vessels at the area and prevent drug diffusion from that area.

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