Ionotropes and vasopressors

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1. DR RIYAS A DR S M C S I,karakonam Vasopressors and Inotropic Agents

2. Objectives Understand the vasopressor and inotropic agent receptor physiology Understand appropriate clinical application of vasopressors and inotropic agents

3. Background Vasopressors are class of drugs that elevate Mean Arterial Pressure (MAP) by inducing vasoconstriction. Inotropes increase cardiac contractility. Many drugs have both vasopressor and inotropic effects. Vasopressors are indicated for a decrease of >30 mmHg from baseline systolic blood pressure or MAP <60 mmHg, when either condition results in end-organ dysfunction secondary to hypoperfusion .

4. Receptor Physiology Main categories of adrenergic receptors relevant to vasopressor activity: Alpha-1adrenergic receptor Beta-1, Beta-2 adrenergic receptors Dopamine receptors

5. Receptor Physiology Receptor   Location Effect Alpha-1 Adrenergic   Vascular wall Vasoconstriction     Heart Increase duration of contraction without       increased chronotropy Beta Adrenergic Beta-1 Heart ↑ Inotropy and chronotropy   Beta-2 Blood vessels Vasodilation Dopamine   Renal Vasodilation     Splanchnic (mesenteric)       Coronary       Cerebral     Subtype   Vasoconstriction

6. PHARMACOLOGICAL ACTIONS Cardiac effects Positive chronotropic effect An action that increases heart rate Positive dromotropic effect An action that speeds conduction of electrical impulses ( ↑ conduction velocity through AV node) Positive inotropic effect An action that increases the force of contraction of cardiac muscle

7. Cardiac effects of epinephrine Cardiac output is determined by heart rate and stroke volume Epi → β 1 receptors at SA node→↑HR Epi→ β 1 receptors on ventricular myocytes→ ↑ force of contraction CO = HR x SV

8. vascular smooth muscle In blood vessels supplying skin, mucous membranes, viscera and kidneys, vascular smooth muscle has almost exclusively alpha 1 -adrenergic receptors Also biphasic response α 1

9. α 1+ β 1 effect β 2 effect (at low doses) Mainly α -action β Blocker β 2 effect α Blocker E E (A) (B) Biphasic Response

10. vascular smooth muscle In blood vessels supplying skeletal muscle, vascular smooth muscle has both alpha 1 and beta 2 adrenergic receptors α 1 β 2 α 1 stimulation β 2 stimulation

11. Effects of epinephrine on blood vessel caliber Blood vessels to skin, mucous membranes, viscera and kidneys Stimulation of α 1 -adrenergic receptors causes constriction of vascular smooth muscle α 1

12. Effects of epinephrine on blood vessel caliber: skeletal muscle At low plasma concentrations of Epi, β 2 effect predominates→ vasodilation At high plasma concentrations of Epi, α 1 effect predominates→ vasoconstriction α 1 β 2

13. Effects of Epi on arterial blood pressure Arterial BP = CO x PVR Epinephrine: ↑ CO Low doses ↓ PVR (arteriolar dilation in skeletal muscle) High doses ↑PVR

14. Effects of epinephrine on airways Epi → β 2 -adrenergic receptors on airway smooth muscle→ rapid, powerful relaxation→ bronchodilation

15. Effects of epinephrine in the eye Epi at α 1 -adrenergic receptors on radial smooth muscle → contraction→ mydriasis Epi at B2-adrenergic receptors→ relaxation of ciliary muscle α 1 β 2

16. OTHER SYSTEMS GIT : Peristalsis is reduced, sphincters are contracted. Bladder : Detrusors relaxed, trigone contracted Splenic capsule : Contracts (alpha action), RBCs are poured Skeletal muscle : Neuromuscular transmission is facilitated. (Tremors due to beta 2 actions) CNS : Restlessness , tremors , fall in BP and bradycardia Metabolic : Hyperglycemia, lipolysis

17. Mnemonic for therapeutic uses of adrenaline ABCDEG A - Anaphylactic shock B - Bronchial asthma C - Cardiac arrest D - Delay absorption of local anesthetics E - Epistaxis , Elevate BP G - Glaucoma Others : Reduce nasal congestion, Induces mydriasis

18. Epinephrine (contd..) Adverse effects of epinephrine Hypertensive crisis Dysrhythmias Angina pectoris Necrosis following extravasation Hyperglycemia

19. Dose( ng /kg/min Receptor SVR 10-30 Beta May decrease 30-50 Beta,alpha variable >150 Alpha and beta increased

20. NE Primary physiological postganglionicsympathetic Actions alpha 1&2 adrenergic action and beta agonist

21. HR Variable Contractility Increased CO Increasde or decreased BP increased SVR Increased PVR increased

22. advantage Redistibutiob of blood Direct adrenergic agonist Elicit intense alpha one and two adrenergic agonism

23. disadvantage Reduce organ perfusion MI Pulmonary vasoconstriction Arrhythmias Skin necrosis

24. Septic shock Vasoplegia after CPB Condition in which SVR rise needed with cardiac stimulation

25. Use through central line only

26. Dose 15-30ng/kg/min iv 30-300ng/kg/min Minimize duration of use Watch for oliguria and metabolic acidosis Can use along with vasodilators to counter act alpha stimulation RVF—FOR stimulatinf Left atriumplus inhaled nitric oxide

27. Dopamine (DA) Dopaminergic neurons in brain, enteric nervous system and kidney Dopaminergic receptors in brain, mesenteric and renal vascular beds

28. Dopamine Moderate doses DA: Stimulate DA receptors in mesenteric and renal vascular beds → vasodilation Stimulate β 1 receptors in heart → ↑HR and ↑force of contraction High doses DA: Stimulate α 1 receptors → vasoconstriction

29. Receptor activation 1-3 mcg/kg/min DA Increaesed renal and mesentric blood flow 3-10mcg/kg/min beta1+beta 2+dopa Increases HR,CO,contractility Decreses SVR >10 alpha Increases SVR,decreases renal blood flow,increases HR,

30. advantages At low dose renal blood flow increases BP response easy to titrate

31. disadvantage Indirect action get deminished Skin necrosis Pulmonary vasoconstriction Tachycardia and arrythmia MVO2 increases ,MI can occur if coronory flow doesn’t increase

32. Therapeutic uses Shock (moderate doses) ↑ blood flow to kidney and mesentery ↑ cardiac output Refractory congestive heart failure Moderate doses ↑ cardiac output without ↑PVR

33. administration Cental line only Correct hypovolemia before use At 5-10mcg/kg/min the response is not adequate add epinephrine or milrinone

34. Synthetic Catecholamines : Dobutamine It’s a derivative of DA but not a D1 or D2 receptor agonist Stimulates β 1 - and β 2 -adrenergic receptors, but at therapeutic doses, β 1 -effects predominate Increases force of contraction more than increases heart rate ↑CO = ↑HR x ↑ ↑ SV

35. Heart rate Increased Contractility Increased CO Increased BP Increased SVR Decresed LVEDP Decreased PVR Decreased LAP Decreased

36. advantages After load reduction—improve LV &RV fn Renal blood flow may increase

37. disavantages Tachycardia and arrhythmias Tachyphylaxis more than 72hrs Coronary steal Nonselective vasodilator Mild hypokalemia

38. Dobutamine : Therapeutic uses Cardiogenic Shock MI Cardiac surgery Refractory congestive heart failure

39. Administration…through i /v central line only

40. Clinical uses Dose…2-20mcg/kg/min Increases CO with lesser increment in MVO2 and higher coronary blood flow Beta blocked patients SVR may incease

41. Major toxic effects of catecholamines All are potentially arrhythmogenic Epi and isoproterenol more arrhythmogenic than dopamine and dobutamine Some can cause hypertension Epinephrine, in particular, can cause CNS effects – fear, anxiety, restlessness Dobutamine can cause vomiting and seizures in cats – must be used at very low doses

42. Adverse effects CNS: Restlessness Palpitation Anxiety, tremors CVS: Increase BP….cerebral haemmorrhage Ventricular tachycardia, fibrillation May precipitate angina or AMI

43. Non-catecholamine direct-acting adrenergic agonists Ephedrine Stimulates α 1 -, β 1 and β 2 -adrenergic receptors and ↑ NE release from noradrenergic fibers Repeated injections produce tachyphylaxis It is resistant MAO, orally Longer acting (4-6), cross BBB

44. Plant dervived Sympathomimetic

45. EFFECTS Heart rate Increased Contractility Increased CO Increased BP Increased SVR Slighltly incresed Pre load increased

46. advantages Easily titrated Short duration ( i /m can prolong ) Tachyphylaxis Safe in pregnancy Ideal to correct sympathectomy induced relative hypovolemia After spinal or epidural

47. Dis advantage Effect is decreased with NE stores get depleted Malignant hypertion with MAO inhibiors

48. routes i /v ,,, i / m,,,oral,,,s /c Dose 5-10mg i /v bolus,25-50mg i /m

49. phenylephrine Synthetic Acts on pre synaptic alpha 1 Vasoconstriction…mainly arteriolar Minimal venous Mb mainly by MAO

50. effects Heart rate Decreased Contractility -- CO Nad or decreased BP Increased SVR Incresed Pre load Minimal change

51. advantages Short Increses perf press with low SVR With hypotension increses CPP Useful in fixed out put lesions,CAD,TOF

52. disadvantages Inceases PVR Decreases SV secon to decrese in after load Rarely may induce coronary artery spasm or internal mammary,radial or gastro epiploiec

53. indication Hypotension due to pheripheral vasodilatation Temporay therapy R-L shunt SVT

54. dose 0.5-10mcg/kg/min i /v bolus 1-10mcg/kg bolus For TOF5-50mcg/kg

55. vasopressin Endogenous ADH Pheripheral vasoconstriction(v1) No action on beta More constriction on skin,adipose,intestine etc

56. advantage Acts independently of adrenergic When phenylephrine or NE ineffetive Without producingSE increases coronary perfussion after arrest

57. disadvantage Decreses splanchnic circulation Adverse effects of severe constriction Decreased platelet roduction Lactic acidosis is common

58. uses Alternative to epinephrine…>in countershock –refractory arrhythmias dose(40units i /v) Septic shock Vasoplegia after bypass In drug interaction related hypotension such as ACE or GA

59. milrinone Powerful ionotrope,vasodilatory property Increses cAMP ionotrophy,lusitrophy,chronotropy,dromotropy,increases automaticity

60. HR No change or slight increase CO Increased BP Variable SVR & PVR Decreased Preload Decreased MVO2 Unchnaged or incresed

61. advantage Favourable effect on myocardial oxygen supply and demand balance No tachyphylaxis No tachycardia or minimal

62. disadvantage Arrhythmia

63. use 25-75 mcg/kg/min over 1-10 min Maintanance 0.5mcg/kg/min Administer before changing the patient from pump

64. use Low CO Increased LVEDP Pulmonary hypotension RV failure Use as a bridge in cadiac transplatation to suppliment /potentiate beta receptors

65. Clinical Application     1st Line Agent 2nd Line Agent Septic Shock Norepinephrine ( Levophed ) Vasopressin     Phenylephrine ( Neosynephrine ) Epinephrine (Adrenalin) Heart Failure   Dopamine   Milrinone     Dobutamine   Cardiogenic Shock   Norepinephrine ( Levophed )     Dobutamine   Anaphylactic Shock   Epinephrine (Adrenalin) Vasopressin Neurogenic Shock   Phenylephrine ( Neosynephrine )   Hypotension Anesthesia-induced Phenylephrine ( Neosynephrine )   vasopressin   Following CABG Epinephrine (Adrenalin)