Adrenergic neurotransmission

adrenergic transmission .
sympathomimetics

1. Adrenergic Transmission and Adrenergic Drugs

2. INTRODUCTION ADRENERGIC TRANSMISSION ADRENERGIC RECEPTORS ADRENERGIC DRUGS ( SYMPATHOMIMETICS )

3. Adrenergic Transmission Endogenous Catecholamines: Noradrenaline Adrenaline Dopamine

4. SYNTHESIS ,STORAGE ,RELEASE & METABOLISM OF CAs

5. Steps in the enzymatic synthesis of dopamine, norepinephrine and epinephrine .

6. Enzyme Cofactor requirement Tyrosine hydroxylase Tetrahydro biopterin, O 2 , Fe2 ++ Aromatic L –a.a decarboxylase (non-selective) Pyridoxal phosphate Dopamine β hydroxylase Ascorbic acid, O 2 Cu ++ Phenyl ethanolamine N- methyl transferase S -Adenosyl Methionine (CH 3 donor)

7. Drugs modulating Release Release – α2 Agonists β2 blockers Adre. Neurone blockers Bretylium Guanethidine Guanadrel Release – β2 agonists α2 blockers Tyramine Amphetamine NE NE

8. Termination of action 1) Reuptake into nerve terminals by NET (Na+ dependent ) 2) Dilution by diffusion out of Jn: cleft followed by Extra-neuronal uptake (not Na+ dependent ) 3) Metabolic transformation by MAO & COMT

9. METABOLISM OF CATECHOLAMINES

10. Adrenergic Receptors α Receptors β Receptors Dopamine receptors

11. α Receptors - α 1 Receptors: α1 A, α1 B, α1 D : Gq CR α2 Receptors: α2 A, α2 B , α2 C : Gi/Go CR

12. Adrenoceptor types and subtypes

13. Receptor specificity Adr : α1 + α2 + β1 + β2 and weak β3 action • NA : α1 + α2 + β1 + β3 but no β2 action • Iso : β1 + β2 + β3 but no α action

14. Organ system effects of sympathomimetic drugs

15. Adrenergic drugs: overall actions Heart ( β 1 ) Increases HR Activates latent pacemakers – arrhythmia at higher doses Force of contraction, cardiac output and oxygen consumption- increased Increased conduction velocity – may overcome partial heart block

16. Blood P r essu r e NA: rise in systolic, diastolic and mean BP ( α ) Iso: rise in systolic BP, marked fall in diastolic BP ( β 1 & β 2 ) Adr : (slow i.v. ) rise in systolic, fall in diastolic, mean BP rises

17. ADERNALINE NA ISOPRENALINE HR ↑ ↓ ↑↑ CARDIAC OUTPUT ↑↑ - ↑↑ BP- SYSTOLIC DIASTOLIC MEAN ↑↑ ↓↑ ↑ ↑↑ ↑↑ ↑↑ ↑ ↓↓ ↓

18. Blood vessels Vasoconstriction ( α 1 and α 2 ): cutaneous, mucous membrane, renal beds Vasodilation ( β 2 ): skeletal muscles, liver, coronaries Action more marked in arterioles and precapillary sphincters

19. VASOMOTOR REVERSAL OF DALE ALPHA blocker only fall in B.P

20. BLOOD FLOW BLOOD FLOW ADRENALINE NA ISO SKIN AND MM SK.MUSCLE KIDNEY LIVER CORONARY ↓ ↑↑ ↓ ↑↑ ↑ ↓ -, ↓ ↓ - ↑ - ↑ - ↑ ↑

21. Adrenergic drugs: overall actions Respiration Adr & Iso: potent bronchodilator (β 2 ) Adr: Bronchial mucosa decongestant Toxic dose of Adr: pulmonary edema Eye Mydriasis (α 1 : radial muscle contraction; poor with Adr) Reduced aqueous formation and outflow facilitated

22. Adrenergic drugs: overall actions Metab o lic Causes glycogenolysis: hyperglycaemia, hyperlactacidemia Lipolysis: rise in plasma free fatty acids, calorigenesis Transient hyperkalemia followed by hypokalemia

23. ADRENERGIC DRUGS Direct -adrenaline , NA , Isoprenaline Indirect - act on adrenergic neurons to release NA - tyramine ,amphetamine Mixed -ephedrine, mephentermine

24. Therapeutic Classification: Adrenergic Drugs Therapeutic Class Examples Pressor agents Noradrenaline, Phenylephrine, Ephedrine, Methoxamine, Dopamine, Mephentermine Cardiac stimulants Adrenaline, Dobutamine, Isoprenaline Bronchodilators Isoprenaline, Salmeterol, Salbutamol, Formeterol, Bambuterol, Terbutaline Nasal decongestants Phenylephrine, Naphazoline, Xylometazoline, Pseudoephedrine, Oxymetazoline, Phenylpropanolamine CNS stimulants Amphetamine, Methamphetamine, Dexamphetamine , Methyl phenidate Anorectics Fenfluramine, Sibutramine, Dexfenfluramine Uterine relaxant Ritodrine, salbutamol, Isosuxprine, Terubtaline

25. Specific sympathomimetic drugs

26. Endogenous catecholamines Epinephrine Norepinephrine Dopamine

27. EPINEPHRINE agonist at both α and β receptors Potent Vasoconstrictor & Cardiac stimulant ↑ systolic BP and ↓ DBP

28. PK/PREP/DOSE/ROUTE Not effective orally Solution unstable in alkaline P H - turns pink on exposure to air Inj. Adrenaline- 1/1000 (1mg/ml) 1/10000 (0.1mg/ml) 1/20000 (0.5mg/ml)

29. CONT…… Usually 0.2-0.5 ml of a 1/1000 ,given S/C In shock (IM) & cardiac arrest (I/T, IV) Other routes- Endotracheal, I/Osseous

30. CONTRA-INDICATIONS Hypertension Ischemic heart diseases Cardiac arrhythmias Hyperthyroidism Patients receiving Halothane, MAOI nonselective β blockers

31. ADVERSE REACTIONS Cold clammy skin, Tachycardia, palpitation, Anxiety, tremor etc. I/V – HTN- Cerebral Hemorrhage , Angina, Arrhythmia , Pulmonary edema DRUG INTERACTIONS GA- Halothane, Cyclopropane – Arrythmia

32. USES 1) Acute Bronchial Asthma 0.3-0.5 ml of a 1/1000,given S/C, 1/100 (N) 2) Cardiac arrest, resuscitation 0.2-0.5 ml of a 1/1000,given I/T 3) Anaphylactic shock – DOC 0.2-0.5 ml of a 1/1000,given IM

33. 4) Local Haemostatic - after tonsillectomy, Tooth extraction etc. Epinephrine pack dipped in 1/10000,1/20000 solution 5) Along with LA- 1/20000,1/100000 solution (prolongs action, decreases toxicity) 6) Glaucoma- Prodrug –Dipivefrine after absorption converted into Epinephrine AH formation

34. NOREPINEPHRINE LEVARTERENOL L-norEpinephrine (α 1 , α 2 , β 1 , β 3 ) Constitute 10-20% of CA content of adrenal medulla up to 97% in some pheochromocytoma as they do not express PNMT

35. COMPARATIVE EFFECTS OF INFUSIONS OF EPINEPHRINE AND NOREPINEPHRINE IN HUMAN BEINGS

36. COMPARATIVE EFFECTS OF INFUSIONS OF EPINEPHRINE AND NOREPINEPHRINE IN HUMAN BEINGS

37. ADR Headache Anxiety Tremor Angina Ischemic necrosis if extravasated High doses- hyperglycemia

38. USE Treatment of refractory Hypotension (neurogenic) Effect disappear 1-2’ after stopping infusion So taper it off gradually.

39. DOPAMINE (3,4 di OH phenyl ethylamine) MIXED ACTING D 1 , β 1 , α 1 , Indirect Action ACTIONS Central - neurotransmitter involved in the regulation of movement Periphery - synthesized in the PCT ( local diuretic & natriuretic effect) On BP - ↑ SBP & PP, no effect on DBP.

40. ACTIONS Low doses (0.5 -2 µg/kg/mt) D 1 - ↑ renal, mesenteric & coronary blood flow ↑ RBF, ↑ GFR, & ↑ excretion of Na & H 2 O – Diuretic action.

41. Moderate doses (2-10µg/kg/mt) D 1 + β 1 & release NE (contribute -effect on the heart) ↑β 1 : + ve inotropic action ↑ in BP due to + inotropic action. Also ↑ blood flow to vital organs little chronotropic & ↓ arrhythmogenic . High doses (10-20 µg/kg/mt) α 1 ↑ BP by VC & ↓ blood flow to vital organs

42. PREPARATION & DOSE – Dopamine hydrochloride - 200 mg in 200ml of 5% dextrose : 8-16 drops/min ADVERSE EFFECTS N,V, tachycardia, angina, arrhythmia, HTN, peripheral VC (high doses) Extravasation – ischemic necrosis & sloughing

43. USES Severe CCF in patients with oliguria & low or normal PR Improves physiological parameters in the Rx of cardiogenic & septic shock Improve cardiac & renal function in severely ill patients with chronic heart d/s or renal failure

44. DIRECT ACTING SYMAPTHOMIMETICS

45. Phenylephrine Action - α 1 stimulation ↑ BP, reflex bradycardia Uses Nasal decongestant- Topically, orally Eye Mydriatic when cycloplegia is not required- fundoscopy Wide angle glaucoma-↓IOP

46. MIDODRINE Prodrug Desglymidodrine Alpha 1 agonist action Use – orthostatic hypertension

47. Methoxamine Direct-acting α 1 -receptor agonist Blood pressure vasoconstriction Also causes a vagally mediated bradycardia. Clinical application – hypotensive states

48. α 2 AGONISTS Sympatholytic action CLONIDINE α METHYL DOPA GUANABENZ GUANFACINE

49. Clonidine Imidazoline derivative Rapid I/V infusion - acute rise in BP ( activation of post synaptic α 2 in vascular smooth muscles ) Mechanism of action - (1) activation of α 2 receptors in the VMC. (2) Imidazoline receptors (GPCR) I 1,2,3 (3) activates presynaptic α 2 to ↓ NE release

50. Clonidine Pharmacokinetics - well absorbed orally - t ½- 8-12 hour - max. hypotensive effect after 2-4 hrs. Preparations - oral - i /v - Epidural - TD patch

51. ADR Dry mouth & sedation Bradycardia Impotence Clonidine withdrawal syndrome Constipation Interaction TCA ,CHLORPROMAZINE

52. USES Antihypertensive ( moderate HTN ) – 100 µg BD opioid & nicotine withdrawal symptoms (↓ craving ) Prophylaxis of Migraine Along with anesthetics ↓ Pain in severe painful conditions like cancer, post –op, labor etc

53. CLONIDINE- T/D - Menopausal syndrome for ↓ hot flashes Miscellaneous uses of clonidine Atrial Fibrillation Attention Deficit Hyperactivity Disorder Hyperhidrosis Mania Post Herpetic Neuralgia Ulcerative Colitis, etc

54. α Methyl DOPA central action - similar to clonidine in action Peripheral - “ false transmitter” ( α methyl NE) Not as potent as NE Used in PIH

55. ISOPRENALINE (Isoproterenol, Isopropyl arterenol) Nonselective β agonist β 1 similar to Epinephrine- ↑ HR & AV conduction, ↑ contractility β 2 – relax vascular & non-vascular smooth muscle ↓ Mediator release. Metabolic Effect- ↑ glycogenolysis (β 2 )

56. Kinetics – inefficient orally – COMT ADR Tachycardia, palpitation, angina, arrhythmia - β 1 Headache, flushing, dizziness, tremor - β 2 Combined administration with E- Fatal

57. Uses 1. A/c Bronchial asthma 2. Complete AV block- to stimulate HR 3. Syncope attack a/w AV block. 4. Bacteremic shock

58. Xylometazoline and oxymetazoline Direct-acting α agonists Use : topical decongestants S/E: hypotension

59. Dobutamine Derivative of Dopamine Selective β 1 agonist Uses- As an inotropic agent in pump failure accompanying: Myocardial Infarction Cardiac surgery Short term management of severe congestive heart failure

60. Prenalterol Moderate inotropic action (sympathetic – low) Marked inotropic action ( symp activity high) – during exercise Use – for short term control of mild to moderate heart failure ( i /v infusion)

61. Selective β 2 STIMULANTS Uses Bronchodilators Vasodilators Uterine relaxants.

62. β 2 AGONISTS USED IN ASTHMA SALBUTAMOL TERBUTALINE SALMETEROL FORMOTEROL BAMBUTEROL longestacting

63. I SOXSUPRINE Ut.relaxant&V.D RITODRINE Uterine relaxant IV infusion – treatment of preterm labour .

64. INDIRECTLY ACTING AMPHETAMINE Catecholamine Reuptake Inhibitors

65. AMPHETAMINE D -isomer- dex amphetamine- CNS action (Most potent sympathomimetic amine in stimulating CNS) L -isomer – meth amphetamine- CVS action

66. AMPHETAMINE AMPHETAMINE

67. Mech. of CNS action Release of NE (alerting & anorectic actions) Dopamine ( locomotor activity & stereotype behavior) 5HT (disturbance of perception & overt psychotic behavior)

68. ACTIONS CNS - Produces alertness, initiative, ↑ concentration & self confidence. delays onset of fatigue Improves physical performance, ( due to cortical action) Produce wakefulness by ↑ RAS CVS - Cardiac stimulation, ↑ BP - β 1 Smooth muscle- contract sphincters – α 1 Others - Respiratory stimulant, suppress appetite

69. ADR Anxiety, restlessness, tremor, irritability, delirium, psychosis, tachycardia, palpitation, angina, arrhythmia Dry mouth , metallic taste, N,V, D, Urine retension Fatal doses- convulsions, coma & cerebral H’ages Use – seldom used due to addiction liability & risk of psychosis Narcolepsy, obesity, ADHD,

70. Tyramine By product of tyrosine metabolism Metabolized by MAO ( liver ) High first-pass effect Spectrum of action is similar to that of norepinephrine Patients taking MAO inhibitors must be very careful to avoid tyramine-containing foods

71. Catecholamine Reuptake Inhibitors Atomoxetine ( norepinephrine reuptake transporter) Reboxetine Sibutramine - NE & 5 HT reuptake (-) - appetite suppressant for long-term treatment of obesity

72. Catecholamine Reuptake Inhibitors Duloxetine serotonin and norepinephrine transporter Milnacipran Cocaine - produces an amphetamine-like psychological effect - inhibit dopamine reuptake into neurons in the “pleasure centers

73. MIXED ACTING EPHEDRINE Pseudoephedrine

74. EPHEDRINE Alkaloid - Ephedra Vulgaris Actions - MIXED ACTING –mainly indirectly + direct action on α & β CNS- Anxiety, restlessness, tremor, insomnia α 1 – VC-↑ BP, Mydriatic β 1 - + ve inotropic β 2 - VD, Uterine relaxation

75. PK - Effective orally -Resistant to MAO cross BBB & potent CNS stimulant. Tolerance develops rapidly. Uses mild chronic Bronchial asthma Hypotension due to spinal injuries, spinal anesthesia

76. Pseudoephedrine Enantiomer of ephedrine Vasoconstriction Fewer CNS and CVS effects

77. TACHYPHYLAXIS acute tolerance With drugs like Ephedrine, Tyramine, Amphetamine, 5HT, Isoprenaline when administered repeatedly , at very short intervals , the pharmacological response elicited decreases progressively.

78. Therapeutic uses

79. VASCULAR Hypotensive states - ( adrenaline in anaphylactic shock) Along with local anaesthetics Control of local bleeding Nasal decongestant Peripheral vascular disease

80. CARDIAC Cardiac arrest Partial A-V block CCF   Bronchial asthma   Allergic disorders Mydriatic / open angle glaucoma  

81.   CENTRAL USES Hyperkinetic children Obesity Nocturnal enuresis in children Uterine relaxant

82. SUMMARY Adrenergic transmission Receptors Endogenous CAs Organ specific effects of NE Sympathomimetic drugs and use

83. THANK YOU