Catecholamines & noncatecholamines

brief description of Autonomic drugs & detailed note on catecholamines & noncatecholamines

1. CATECHOLAMINES & NON CATECHOLAMINES . . presented by Dr sindhu k mvsC scholar, Dept of vpt , covas .

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3. Autonomic drugs Drugs that exerts pharmacological effects simulating activation, intensification or inhibition of either the sympathetic/parasympathetic nervous system have been historically referred to as autonomic drugs. classification sympathomimetic sympatholytic parasympathomimetic parasympatholytic

4. Classifications sympathomimetic  adrenergic  adrenomimetic sympatholytic  receptor blocking effects  neuronal blocking effects parasympathomimetic  cholinergic  cholinomimetic parasympatholytic  receptor blocking effects  neuronal blocking effects

5. CATECHOLAMINES Norepinephrine – alpha agonist property Epinephrine – mixed acting (alpha & beta agonist) Isoproterenol – selective beta agonist Dopamine – immediate precursor of NE

6. ADRENERGIC/SYMPATHOMIMETIC DRUGS Amine substances that causes physiologic response similar to those evoked by the endogenous adrenergic mediators viz Epinephrine & Norepinephrine are known as ADRENERGIC DRUGS SYMPATHOMIMETIC = pharmacologic effect mimic sympathetic nervous system clinically relevant adrenergic agonist pharmacological action. receptor activation.

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8. Adrenoceptors / adrenergic receptors adrenoceptors are macro molecular structure localized on/within the surface membrane of cells innervated by adrenergic neurons basic physiological function is to recognize & interact with endogenous adrenergic mediators viz : Adr , Noradr . adrenergic receptors are membrane bound G protein coupled receptors which functions primarily by increasing / decreasing the intracellular production of secondary messengers cAMP , IP3, DAG.

9. Organs Alpha action Beta action Arterioles & veins Vasoconstriction = rise in BP Vasodilation = fall in BP Heart Arrhythmia @ higher dose Positive inotropic, positive chronotropic Radial muscle of iris Mydriasis aqueous secretion Relaxation of ciliary muscles aqueous secretion Urinary bladder contraction relaxation Uterus contraction Relaxation Splenic capsule Contraction Relaxation Insulin Secretion inhibited Augumented insulin Glucagon Secretion

10. Epinephrine secreted by adrenal medulla & neuro -effector transmitter of adrenergic drugs.

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12. Pharmacological effect cardiovascular system vascular smooth muscle : alpha = vasoconstriction -> mesenteric arteries -> mucus membrane -> renal beds -> cutaneous : beta = vasodilation -> skeletal muscle -> coronary blood vessel -> liver

13. Blood pressure Norepinephrine -> dose related increase in systolic & diastolic BP Epinephrine -> potent vasopressor agent

14. Heart Iso >>> Epi > Norepi

15. Smooth muscles & uterus Alpha receptors causes contraction -> release of intracellular Ca ++ activation of IP3 Contraction Beta receptors -> Relaxation

16. Metabolic effects Carbohydrate metabolism glycogenolysis in liver release of glucagon & release of insulin Lipid metabolism -> raises concentration of free fatty acids in blood -> stimulates beta receptors of adipose tissues -> activates adenylate cyclase -> cAMP stimulates lipase for hydrolysis of triacylglycerols -> free fatty acids & glycerol

17. Pharmacokinetics orally not effective -> rapid metabolism by MAO & COMT rapidly absorbed after IM injection for immediate effects I/V on inhalation action restricted to respiratory tract (local action)

18. Clinical indications Drug of choice for treatment of Type 1 hypersensitivity reaction In critical conditions = drowning, suffocation, shock, electrocution Bcoz of vasoconstriction property used in combination with local anesthetics Severe respiratory distress like acute asthma & anaphylactic shock ( B.dilator ) In opthalmology as 2% epinephrine solution

19. Doses for hypersensitivity reaction Small animals @ 5-20 microg /kg, IV, SC, IM @ 50 microg /kg endotracheally (feline asthma) Large animals @ 20 micrig /kg IM & 5-10 microg /kg IV for cardiac resucscitation ( asystole /cardiac arrest) Small animals @ 10-20 microg /kg IV @ 100 – 200 microg /kg endotracheally Large animals @ 20 microg /kg SC, IV, I/ tracheally .

20. Norepinephrine Noradrenaline released by the mammalian post ganglionic sympathetic NS NA constitutes 10-20% of catecholamine content adrenal medulla NA affects large area of brain -> mainly Alertness & Arosal . Levo form >> dextro form NE differs from Epi only by lacking the methyl substitution in amino group chemically 1-B (3,4 – dihydroxy phenyl) alpha - aminoethanol

21. Pharmacological effects B lood vessel -> Vasoconstriction BP -> dose related increase in systolic & diastolic BP heart -> potent myocardial stimulant Smooth Muscles -> Relaxation of intestinal SM = retention of ingesta Metabolic effect -> hyperglycemia

22. Pharmacokinetics Ineffective when given orally poorly absorbed from S/C site inactivated by MAO & COMT 4-16 % administered drug excreted in urine

23. Clinical indications NE has limited use but therapeutically important in INTENSIVE CARE UNIT in patients with critical hypotension ( vasodilatory shock viz septic shock & neurogenic shock ) in the treatment of BP, NE is administered by I/V infusion dose titrated to pressor response. Major limitation in clinical application = NE reduces blood supply to kidneys

24. Doses All species @ 0.1 – 0.2 microgram/kg/min IV infusion in 5% dextrose or 5% dextrose saline solution but never use NS solution alone. infusion of NE should be reduced gradually, avoiding abrupt withdrawl .

25. Isoprenaline /isoproterenol Direct acting synthetic CA’s with chemical name d, 1- B(3,4-dihydroxyphenyl)-alpha-isopropyl aminoethanol Hcl . It was commonly used to treat ASTHMA before the clinical applications of beta receptors were discovered. Iso predominantly stimulates B1 & B2 adrenoceptors and has no alpha activity @ therapeutic levels.

26. Pharmacological effects 1. CARDIOVASCULAR SYSTEM >decreased pheripheral resistance (relaxation of skeletal muscles) >markedly decreases diastolic pressure with moderately increase in systolic pressure >most potent cardiac stimulant +++ chronotropic +++inotropic

27. GIT Potent INHIBITORY effect RESPIRATORY EFFECTS > potent BRONCHODILATOR. >inhibits the antigen mediated release of histamine & other mediators of inflammation. >often used clinically to dilate bronchiolar airways during episode of allergic reactions.

28. Clinical indications + Doses for S inoatrial arrest, Sinus Bradycardia, Complete AV block Dogs & Cats @ 0.4 mg (total dose) in 250 ml of 5% dextrose slow IV infusion. for bronchoconstriction/feline asthma Dogs @ 0.1 – 0.2 mg (total dose) IM or SC 4 times a day. Cats @ 0.2mg (total dose) in 100 ml of 5% dextrose slow IV infusion to effect, TID Horses @ 0.4 microgram/kg in normal saline, slow IV.

29. DOPAMINE 3,4-dihydroxy phenyl ethylamine Endogenous CA’s = immediate precursor of NE as central NT in the basal ganglia & the adrenal medulla. PERIPHERY -> synthesized in renal epithelium  diuretic/natriuretic. is an important adrenergic & dopaminergic agonist used in ICU = maintain HR/BP

30. Pharmacological effect MOA  mixed adrenergic action -> direct (alpha & beta) -> indirect (release of NE)  dopaminergic actions (D1, D2 receptors)

31. Cardiovascular system @ low I/V dose = 0.5 – 2 microgram/kg/min  RENAL DOSE acts on vascular D1 dopaminergic receptors & dilates renal, mesenteric, coronary vascular bed. @ intermediate dose = 2 – 10 microgram/kg/min  RENAL&CARDIAC DOSE Stimulates renal D1 receptors + activates beta adrenergic receptors on heart -> release of NE  ++inotropic effect, systolic BP @ high dose = > 10 microgram/kg/min  PRESSOR DOSE Activates vascular alpa1 adrenoceptors  VC, elevated BP negate the dopaminergic effect.

32. Clinical indication + doses Adjunctive therapy of acute cardiac failure All species @ 1 – 10 microgram/kg/min, IV infusion in NS Adjunctive therapy for oliguric renal failure All species @ 2 – 5 microgram/kg/min, IV infusion with diuretics Treatment of severe hypotension/shock All species @ 1 – 20 microgram/kg/min, IV infusion

33. NONCATECHOLAMINES 3-4 DIHYDROXYBENZENE  max potency many drugs without catechol nucleus exerts similar effect = noncatecholamines Ephedrine Amfetamine Methyl phenidate Pseudoephedrine Phenyl Propanol Amine oxymetazoline

34. EPHEDRINE mixed acting alkaloid isolated from Chinese shrub Ma huang levo isomer = more active used as stimulant, nasal decongestant, bronchodilator, to promote urinary incontenance in small animals.

35. MOA sympathomimetic action = direct activation of alpha/beta receptors = release of endogenous NE action in CNS limited bcoz crosses BBB weakly & not very efficiently. repeated doses causes TACHYPHYLAXIS (depletes the neuronal pool of NE)

36. Doses 1. For bronchoconstriction Dogs @ 1-2 mg/kg, PO, BID Cats @ 2-5 mg/kg, PO, BID 2. Urinary incontinence Dogs & Cats @ 2-4mg/kg PO TID 3. As Pressor agent Dogs @ 0.5-0.75 mg/kg, IV,IM, SC 4. As decongestant 1-1.5% solution.

37. PSEUDO EPHIDRINE stereo-isomer of ephedrine pharmacological effect = Ephedrine in veterinary medicine it is used orally as decongestant  symptomatic relief in URT inf cats  allergic rhinitis Dogs @ 15-50 mg (total) PO TID Cats @ 2-4 mg/kg PO BID

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39. AMPHETAMINE synthetic sympathomimetic  powerful CNS stimulant action + alpha/beta adrenergic action powerful psycho stimulant drug + potent drug of abuse & drug dependency.

40. Pharmacological effects Release of several NT’S = NE, Dopamine, serotonin from storage vesicle @ their respective nerve terminals. Peripheral effects Central effects {stimulates entire CS axis, cortex, brain stem, medulla  high alertness, decreasd fatigue, mood elevation, euphoria, decreased appetite } CNS stimulant = drug of abuse = athletics & race horses  improve physical performance

41. METAMPHETAMINE I n humans causes amphetamine psychosis resembles paranoid schizophrenic attacks like hallucinations & paranoid delusions, loss of weight tolerance to central action  toxic effects of amphetamine pharmacokinetic+pharmacodynamics recovery = rapid after withdrawal of drug but chronic conditions precipitate as psychosis in veterinary medicine limited use

42. METHYL PHENIDATE R acemic mixture of a psychostimulant drug with structural resemblance to amphetamine MOA - dopamine level & NE in brain through reuptake inhibition of MAO transporters. approved clinically for Rx of attention deficient hyper activity syndrome, psychiatric disorder, obsessive compulsive disorders in humans

43. PHENYL PROPANOL AMINE Non catecholamine sympathomimetic agent Pharmacological action = Ephedrine In veterinary medicine used as decongestant, mild bronchodilator For the treatment of urethral sphincter hypotonus . Dogs & cats @ 1-2 mg/kg PO TIB

44. OXYMETAZOLINE Direct acting noncatecholamine MOA : non selectively agonizes alpha1 & alpha2 adrenergic receptors : vascular alpha1 adrenergic receptors  VasoConstriction . : local application  stimulation of endothelial post synaptic alpha2 receptors  VC (on systemic circulation) : In contrast ~ centrally mediated inhibition of sympathetic tone via pre-synaptic alpha2 receptors  vasodilation.

45. Clinical indications Topically as decongestant  Rhinitis & conjunctivitis

46. Discussion

47. Thank you References GOODMAN & GILMAN`S The pharmacological basis of therapeutics, 11th edition HS SANDHU Essentials of veterinary pharmacology and toxicology, 2nd edition. H RICHARD ADAMS Veterinary pharmacology and therapeutics, 8th edition. Jim E Riviere & Mark G Papich , Veterinary Pharmacology and Therapeutics, 9th edition google images