TRO

1. SYMPATHETIC NERVOUS SYSTEM DR. K.C.SWAIN PROF. & HEAD DEPT. OF PHARMACOLOGY TRO

2. 8. METABOLIC EFFECTS OF ADRENALINE. : • It causes Hyperglycaemia, Hyperlactacidemia & Hyperlipidemia. • Adrenaline causes glycolysis [ break down of glucose ] in sk. Muscle & heart leading to increase in production of lactic acids & hence, causes Hyperlactacidemia [ B-2receptor effect ].

3. B-2 stimulation in liver catalyzes phosphorylase enzyme & enhances glycogenolysis [ synthesis of glucose from glycogen ] & gluconeogenesis [ synthesis of glucose from lactate & amino acids ] leading to increase in blood glucose level.

4. Cont. • It inhibits utilization of glucose by peripheral tissues due to decrease in insulin secretion [ Alpha-2 receptors of pancreatic BETA islets cells inhibit release of insulin ]. There is also increased glucagon secretion from pancreatic A- islets cells by activation of B-2 receptors. All these foregoing mechanisms result in Hyperglycemia.

5. There is also efflux of K+ ions from liver [ along with glucose ] leading initially to hyperkalemia but subsequently hypokalemia results due to uptake of K+ especially by the sk. Muscle cells.

6. Cont. • Concentrations of plasma free fatty acids are increased due to stimulation of Beta-3 receptors in Adipocytes of adipose tissues leading to activation of triglyceride lipase which causes breakdown of triglycerides to form free fatty acids & glycerol resulting in Hyperlipidemia.

7. Calorigenic effects : Rise in BMR & increased CVS effects lead to rise in body temperature.

8. 9. C.N.S. EFFECTS. : Epinephrine has very poor penetration into the brain [ being a polar • Compound] in therapeutic doses , hence, in higher doses, it may produce restlessness, • , apprehension, headache & tremor.

9. 10.: EYE : It causes active mydriasis [ more light] by contraction of radial muscles of iris [ alpha-1 receptor] , no cycloplegia, no loss of light reflex, no photophobia, decreases I.O.P. both in normal & wide-angle glaucoma by facilitating outflow of aqueous humor &

10. Also by reducing formation of aqueous humor due to vasoconstriction of ciliary blood vessels by alpha-1 receptor • & decreasing secretion of cilliary epithelium [of ciliary body] by alpha-2 receptor.

11. 11. MISCELLANEOUS EFFECTS. • It causes piloerection , enhances sweating of palms & soles & decreases plasma volume, increases concentrations of erythrocytes, leukocytes & plasma proteins. • It causes eosinopenia & contractions of splenic capsule, it also contracts nictitating membrane [3rd eye lid] in lower animals.

12. Epinephrine enhances neuromuscular transmission by releasing Ach from somatic motor nerve endings by alpha-2 receptor. • It accelerates blood coagulation by activation of factor V of coagulation & also promotes fibrinolysis.

13. Epinephrine & selective B-2 agonists increase physiological tremor due to enhancement of discharge of muscle spindles. • It decreases plasma K+ conc. by enhancing K+ uptake into cells, especially skeletal muscle

14. by action of β-2 receptors, • hence, renal excretion of K+ decreases for which β2 AGONISTS are very useful for • management of hyperkalemic familial periodic paralysis characterized by episodic flaccid paralysis, hyperkalemia & depolarization of skeletal muscle.

15. It enhances thick-viscid salivary secretion, induces platelet aggregation by alpha-2 receptor activity. • Ejaculation is facilitated by activation of Alpha-1 receptor in vas deferens, seminal vesicles & prostate.

16. FORMULATIONS OF EPINEPHRINE. • It is unstable in alkaline solution; on exposure to air or light, it turns pink being oxidized to toxic substance Adrenochrome & then becomes brown due to formation of polymers. • Discard the solution even if it is slightly discolored.

17. Adrenaline solution is kept in amber colored bottle with addition of sodium metabisulphite or ascorbic acid to prevent its oxidation. • It is available for therapeutic use as injection, inhaler & solution {topical}. • Injection is available in 1:1,ooo, 1:10,000, & 1:1000,000 solutions. It is not used orally.

18. Cont. • 1 ml of local anesthetic [ xylocaine] contains 5 mcg of adrenaline which when given by s. c. route, delays absorption of local anesthetic

19. by producing vasoconstriction of blood vessels & thereby, increases its “contact time” with nerve facilitating minor surgical procedures, moreover, the decreased absorption results in decreased systemic toxicity,

20. Usual adult dose for sc & I .m.-- 0.3 - 0.5 mg [1 mg/ml amp]. It must be adequately diluted & injected iv very slowly ; • usual dose 0.25 mg iv except cardiac arrest where larger doses may be required to be given by intracardiac route. A 1% { 1:100} preparation is available for inhalation .

21. TOXICITY, ADR,CONTRAINDICATION . • Initially it may cause restlessness, tremor, & palpitation. In higher doses it causes angina, hypertension, ventricular arrhythmias & cerebral haemorrhage. • It is contraindicated in pts taking non selective B blockers or MAOIs& pts. having CAD, ischaemic heart diseases, thyrotoxicosis & Hypertension. • It should not be given to pts. under halothane & chloroform general anesthetics which sensitize the myocardium to the arrhythomogenic effects of adrenaline.

22. THERAPEUTIC USES. • Hypersensitivity reactions type- I to drugs & other allergens including ACUTE ANAPHYLACTIC REACTION / SHOCK. It is not only life- saving drug but also drug of first- choice in this emergency. The Ig E antibody is involved in this AG:AB reaction, Adrenaline acts as a physiological antagonist to histamine, bradykinin & other inflammatory agents released from mast cell during such reaction.

23. Cont. 3.Acute bronchial asthma & status asthmaticus., because it is one of the most powerful bronhodilator 4.As a topical haemostatic agent on bleeding surfaces to prevent capillary oozing in conditions such as in mouth [ during tooth extraction], nose [ epistaxis ] or in bleeding Peptic ulcers during endoscopy of stomach /duodenum [by vasoconstriction].

24. 5. Along with local anesthetics to prolong their duration of actions by decreasing absorption.

25. 6. When given topically, it is not well absorbed in eyes, hence, its prodrug, Dipivefrin [ which is converted by esterase to adrenaline in eye] is used in chronic wide- angle glaucoma.

26. Norepinephrine{levarterenol} It is a major/ main physiological sympathetic neurotransmitter which normally amounts about 10% to 20% of catecholamines contents of adrenal medulla but about 97% in its tumor like pheochromocytoma. It has Alpha-1+ Alpha-2+ B-1+ B-3 [weak] receptor activity but no B-2 receptor.

27. It is equipotent with epinephrine in stimulating β1 receptors but has relatively very less effects on β3 receptors in comparison to epinephrine.

28. It has no B-2 receptor activity. Both systolic & diastolic BP, mean arterial BP& total peripheral resistance are increased. Heart rate is decreased [bradycardia ] due to compensatory vagal reflex activity.

29. Norepinephrine Contd…. • It constricts all the blood vessels except coronary. • Total coronary blood flow is increased by complex mechanisms just like epinephrine.

30. It is available as injection—4 mg / 2ml amp & to be dissolved in one liter of 5% glucose solution & given as I. V. INFUSION at the rate of 0.5 to 1.0 ml/ min. to increase BP in cardiogenic shock [acute MI] & other hypotensive states.

31. ISOPRENALINE[ ISOPROPYLARTERENOL] • It is a synthetic drug having both β1 & β2 receptor activity, it produces +ve Inotropic & +ve chronotropic effects on the heart. It causes hypertension, arrhythmia, angina & even MI when used for prolonged period for treatment of bronchial asthma, hence, it is no more used in asthma, now selective B-2 agonists are used

32. It causes vasodilatation in all the blood vessels leading to fall of both diastolic BP & mean arterial pressure [ due to decrease in t.p.r.] . • Systolic pressure may remain unchanged or slightly rise due to B-1 receptor effect on heart.

33. Cont. • It causes palpitation, sinus tachycardia & serious arrhythmias. • It may be used in pts with sinus bradycardia or heart block • & ventricular arrhythmia like torsade’s de pointes [atypical rapid ventricular tachycardia which may progress to ventricular fibrillation].

34. DOPAMINE{ DA} • It is an immediate METABOLIC precursor of NE . It is a mixed acting drug. • It is a major central neurotransmitter in basal ganglia, limbic system, CTZ & anterior pituitary, it regulating movements of body. • It has alpha-1, alpha-2, B-1 receptors along with specific dopaminergic receptors such as D1,D2,D3, D4,D5 but has not B-2 receptor. Its duration of action is only one minute.

35. METABOLISM OF DOPAMINE. • Dopamine is metabolized by both the enzymes MAO & COMT to HOMOVANILLIC ACID [ HVA ]. DOPAMINE MAO COMT 3,4-Dihydroxyphenylacetic acid (DOPAC) 3-Methoxy Tyramine COMT MAO Homovanillic Acid (HVA)

36. DOSE DEPENDENT RESPONSES • At low conc.{ 2- 5 mcg/kg/min.} iv infusion, it interacts with vascular D1 receptors, especially present in the renal, mesenteric, & coronary beds leading to vasodilatation resulting in increased GFR,

37. renal blood flow, diuresis & Na+ excretion for which dopamine has appropriately been used in the management of states of low cardiac output associated with compromised renal function like severe CCF.

38. RESPONSES OF DOPAMINE [cont.] 2. In an intermediate doses of 5 to 10 mcg/kg/min. DA stimulates both D1 receptor& cardiac β1 Receptor resulting in increased force of contraction of heart [ +ve inotropic effect ] , increased Cardiac output but total peripheral resistance & mean arterial BP remain unchanged due to simultaneous vasodilatation of renal, mesenteric, coronary & splanchnic blood vessels by D1 Receptors.

39. 3. In high doses > 10 mc g/kg/min, it stimulates vascular alpha-1 & Cardiac β1 receptors leading to tachycardia, increased tpr & increased BP, hence, beneficial effects of low & intermediate doses are lost.

40. Therapeutic uses It is used in • severe & refractory CCF with oliguria, • cardiogenic shock due to acute MI, surgery & trauma, • septic Shock (endotoxic shock) • acute threatened renal failure.

41. It is given only by iv infusion. The contents of one ampoule {40 mg/ml} are diluted in 100 ml of 5% dextrose solution or normal saline. It is given initially at a rate of 2 to 5 mcg/kg/min & gradually increased maximum up to 10 mcg /kg/Min.

42. ADRs & Contraindications of DOPAMINE. • In higher doses, DA causes nausea, vomiting, angina , tachycardia, arrhythmia & hypertension . • It should be avoided or doses to be adjusted in pts. taking MAOIs & tricyclic anti depressants.

43. Precaution : In pts. with shock, the hypovolemiashould be first corrected by transfusion of whole blood, plasma & other appropriate fluids before starting iv infusion of dopamine.

44. FENOLODOPAM &DOPEXAMINE. Fenolodopam: It is a selective D1 receptor agonist & lowers BP in hypertensive crisis. It decreases peripheral resistance.

45. DOPEXAMINE : It is an inotropic agent. • It dilates coronary, renal { both afferent & efferent arterioles } & mesenteric arteries . • It has effects both on cardiac DA receptor & peripheral B-2 receptors. It is given in heart failure due to surgery, CCF & septic shock.

46. DOBUTAMINE.{ CARDIAC INOTROPIC AGENT}. • Dobutamine structurally resembles to dopamine. But it has direct β & alpha receptor activity. • It is available as racemic product. The l- isomer is a potent alpha-1 receptor agonist But d- isomer is a potent alpha-1 antagonist.

47. But both l- & d- isomers are β receptor agonist. • The d-isomer is about ten times more potent than l-isomer on heart. • Dobutamine has more potent inotropic effect than chronotropic effect on the heart.

48. Cont….. • It has a half-life of 2 mins. • Onset of action is rapid, initial loading dose is not required, steady-state conc. is achieved within 10 mints. by iv infusion.

49. It is used for short-term treatment & management of cardiac decompensatation due to cardiac surgery, CCF & acute M.I. • It increases cardiac output & stroke volume in such pts. Rate of i.v. infusion: 2.5 to10 mcg /min