Vasoactive agents

Vasoactive agents

1. VASOACTIVE AGENTS Presenter- Dr. Suresh Pradhan Resident, Department of Anaesthesiology , NGMC Moderator- Dr. Battu Kumar Shrestha

2. Outline Introduction Classification Receptor Physiology Individual Agents Pharmacology Actions Clinical Uses, Dosing and Adverse Effects

3. Introduction a  vasoactive  substance is an endogenous  agent  or pharmaceutical  drug  that has the effect of either increasing or decreasing blood pressure and/or heart rate through its vasoactivity , that is, vascular activity (effect on blood vessels) drugs that has effect on heart & circulatory system use is based on cost, availability, interpretation of physiology and personal/ institutional preference

4. Classification of Vasoactive Agents vasopressors are the agents that cause vasoconstriction leading to increased systemic and/or pulmonary vascular inotropes increase cardiac contractility vasodilators dilate blood vessels many drugs have both vasopressor and inotropic effects inodilators are agents with inotropic effects that also cause vasodilation leading to decreased systemic and/or pulmonary vascular resistance

5. Classification of Vasoactive Agents Vasopressors Inotropes Vasodilators Adrenaline Noradrenaline Phenylepherine Vasopressin Ephedrine Dopamine Dobutamine Amrinone Milrinone Adrenaline Digoxin Calcium Na Nitroprusside Nitroglycerine Hydralazine

6. CLASSIFICATION Catecholamines Non-Catecholamines natural: adrenaline, noradrenaline, dopamine, synthetic: dobutamine, isoprenaline phosphodiestrase enzyme inhibitors (PDE III) milrinone calcium sensitizer ( levosemindan ) antidieuretic hormone vasopressin

7. Receptor Physiology main categories of receptors relevant to vasoactive agents’ activity: Alpha-1 & Alpha-2 adrenergic receptors Beta-1 & Beta-2 adrenergic receptors Dopamine receptors Vasopressin receptors

8. ALPHA 1 ( α 1) present in- vascular smooth muscle in the myocardium- mediate positive inotropic and negative chronotropic effects activation increases intracellular calcium ion concentration, which leads to contraction of smooth muscles- leads to vasoconstriction

9. ALPHA 2 ( α 2) located primarily on sympathetic presynaptic nerve endings and control the release of norepinephrine causes feedback inhibition and inhibits further release of norepinephrine from the stimulated adrenergic neuron vascular smooth muscle contains postsynaptic α2- receptors that produce vasoconstriction

10. BETA 1 ( β 1) located on the postsynaptic membranes in the heart stimulation activates adenylate cyclase, which converts adenosine triphosphate to cyclic adenosine monophosphate and initiates a kinase phosphorylation cascade initiation of the cascade has positive chronotropic (increased heart rate) dromotropic (increased conduction), and inotropic (increased contractility) effects

11. BETA 2 ( β 2) primarily postsynaptic adrenoceptors located in smooth muscle and gland cells share a common mechanism of action with β1-receptors: adenylate cyclase activation β2 stimulation relaxes smooth muscle, resulting in bronchodilation, vasodilation, and relaxation of the uterus, bladder, and gut

12. DOPAMINE RECEPTORS group of adrenergic receptors that are activated by dopamine are classified as D1 and D2 receptors activation of D1 receptors mediates vasodilation in the kidney, intestine, and heart D2 receptors are believed to play a role in the antiemetic action of droperidol

13. VASOPRESSIN RECEPTORS actions of vasopressin are mediated by stimulation of tissue-specific  G protein-coupled receptors   are classified into the V 1  (V 1A & V 1B ) and V 2 receptor subtypes these three subtypes differ in localization, function and signal transduction mechanisms

14. Individual Agents

15. Epinephrine/ Adrenaline endogenous catecholamine that is released by the adrenal medulla in response to physiological stress normally produced in the adrenal medulla by methylation of nor-adrenaline the most potent natural β-agonist

16. Actions: stimulates both α-adrenergic and β-adrenergic receptors (β1 and β2 subtypes), and produces dose-dependent increase in heart rate, stroke volume, and blood pressure Low doses (0.05 – 0.3 mcg/kg/min)- β activation Increase HR, contractility, decrease SVR Higher doses (0.3- 1 mcg/kg/min) -  activation Increased SVR and MAP Increased myocardial O 2 demand

17. indications : resuscitation of non shockable cardiac arrest (asystole & electromechanical dissociation) anaphylaxis acute asthmatic attacks sever hypotension due to any cause post arrest as infusion unless sever tachycardia or hypertension occurs

18. indications for its use as a continuous infusion are: low cardiac output state beta effects will improve cardiac function alpha effects may increase afterload and decrease cardiac output septic shock useful for both inotropy and vasoconstriction

19. Aqueous Epinephrine Solutions and Their Clinical Uses

20. adverse effects: anxiety, tremors, palpitations tachycardia and tachyarrhythmias increased myocardial oxygen requirements and potential to cause ischemia decreased splanchnic and hepatic circulation (elevation of AST and ALT) anti-Insulin effects: lactic acidosis, hyperglycemia

21. Caution in known cases of: hypersensitivity to sympathomimetic amines coronary insufficiency (ISHD) arrhythmias hypertension cerebral arteriosclerosis hyperthyroidism

22. Norepinephrine/Noradrenaline is an endogenous catecholamine that normally functions as an excitatory neurotransmitter when used as an exogenous drug, norepinephrine functions as a vasopressor used primarily for alpha agonist effect - increases SVR without significantly increasing CO differs from epinephrine in that the vasoconstriction outweighs any increase in cardiac output i.e. norepinephrine usually increases blood pressure and SVR, often without increasing cardiac output

23. Indications: First choice vasopressor, mainly used in distributive shock with marked vasodilatation as: septic shock post high spinal injury associated with tachycardia pheochromocytoma surgery after tumor excision total spinal after spinal anethesia massive haemorrage with tachycardia till blood products are available

24. infusion rates titrated between 0.05 to 1mcg/kg/min effective dose rate in septic shock varies widely in individual patients, but is usually below 40 µg/min hypotension that is refractory to norepinephrine usually prompts the addition of dopamine or vasopressin, but there is no evidence that this practice improves outcomes

25. Adverse Effects: similar to those of Epinephrine can compromise perfusion in extremities more profound effect on splanchnic circulation and myocardial oxygen consumption

26. Caution in patients with: mesenteric vascular occlusion intestinal or renal infarctions peripheral vascular insufficiency

27. Dopamine intermediate product in the enzymatic pathway leading to the production of norepinephrine; thus, it indirectly acts by releasing norepinephrine directly has  ,  and dopaminergic actions which are dose-dependent indications are based on the adrenergic actions desired

28. at a low dose (0.5 – 3 µg/kg/min) it activates the Dopaminergic receptors in the splanchnic and renal vasculature leading to vasodilation and increased GFR at intermediate dose (3 – 10 µg/kg/min) activation of the cardiac β 1 receptors occurs with + ve inotropic, chronotropic effects

29. at high doses (10 – 20 µg/kg/min) activation of α 1 receptors with increased peripheral vascular resistance and afterload at very high doses > 20 µg/kg/min the vasoconstrictor action overwhelms the dopaminergic vasodilator action and may compromise the blood flow to the limbs, kidney & mesentery

30. used mainly as a second line inotrope and vasopressor and as a diuretic agent to increase renal blood flow and urine output in cases where the oliguria is due to low systemic blood pressure or marked renal vasoconstriction

31. Adverse Effects: extravasation tachyphylaxis immunosuppression and endocrine disturbances increased myocardial O 2 demand tachycardia and arrhythmia

32. Dobutamine a synthetic catecholamine with marked β 1 and very little α and β 2 actions primary cardiovascular effect is a rise in cardiac output as a result of increased myocardial contractility a decline in peripheral vascular resistance caused by β2-activation usually prevents rise in arterial blood pressure

33. considered the first choice inotrope in cardiogenic shock especially in acute cases with maintained blood pressure c hronic cases of heart failure show down regulation of beta receptors which may render the dobutamine infusion ineffective also, non specific activation of β 2 receptors however small can cause marked pressure drop and accentuate the shock state especially in hypovolemic patients

34. Dosage :  2 to 20 mcg/kg/minute. Maximum: 40 mcg/kg/min. Titrate to desired response Side effects: tachycardia & tachyarrythmias increased myocardial oxygen consumption

35. Isoproterenol/ Isoprenaline synthetic catecholamine which stimulates both β 1 & β 2 adrenoceptors producing an increase in cardiac output by increasing myocardial contractility and heart rate it’s vasodilator action surpasses the increase in the CO caused by it’s + ve inotropic action so the net result is decreased MAP

36. Indications: bradycardia decreased cardiac output bronchospasm (bronchodilator) Occasionally used to maintain heart rate following heart transplantation.

37. dose starts at 0.01 mcg/kg/min and is increased to 2.0 mcg/kg/min for desired effect avoid in patients with subaortic stenosis hypertrophic cardiomyopathy TOF lesions

38. Milrinone has non-receptor mediated activity based on selective inhibition of Phosphodiesterase Type III enzyme resulting in cAMP accumulation in myocardium cAMP increases force and rate of contraction and extent of relaxation of myocardium inotropic, vasodilator and lusitropic effect and hence also labelled as inodilator

39. Advantage over catecholamines: independent action from -receptor activation, particularly when these receptors are downregulated Dose: Load with 50 mcg/kg over 30 mins followed by 0.25 to 0.75 mcg/kg/min causes no increase in myocardial O 2 requirement

40. indications: catecholamine refractory cold shock with normal BP cardiogenic shock with normal BP pulmonary hypertension

41. Adverse Effects: hypotension toxicity in renal failure long half life thrombocytopenia

42. Vasopressin a peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure possesses antidiuretic and vasopressor properties deficiency of this hormone results in diabetes insipidus also raises blood pressure by inducing moderate vasoconstriction by stimulating V 1 receptors and reducing NO activity in the vascular smooth muscles

43. Administration intravenous, intramuscular, or intranasal routes IV is route for vasopressor activity half-life of circulating ADH is approximately 20 minutes has renal and hepatic catabolism

44. interacts with vasopressin receptors: V 1 receptors are found on vascular smooth muscle cells and mediate vasoconstriction V 2 receptors are found on renal tubule cells and mediate anti-diuresis through increased water permeability and water resorption in the collecting tubules

45. infusion rates of 0.01 to 0.03 units/min can be used with other vasopressor in shock state in GI bleeding the dose is increased to 0.2 – 0.4 unit/min used in refractory septic shock

46. Ephedrine a noncatecholamine sympathomimetic cardiovascular effects are similar to those of epinephrine: increase in blood pressure, heart rate, contractility, and cardiac output also a bronchodilator

47. important differences between ephedrine & epinephrine has a longer duration of action much less potent has indirect and direct actions stimulates the central nervous system (it raises minimum alveolar concentration)

48. commonly used as a vasopressor during anesthesia however, its administration should be viewed as a temporizing measure while the cause of hypotension is determined and remedied

49. in adults, ephedrine is administered as a bolus of 2.5–10 mg in children, it is given as a bolus of 0.1 mg/kg subsequent doses are increased to offset the development of tachyphylaxis, which is probably due to depletion of norepinephrine stores

50. Phenylephrine a selective α 1 -adrenergic receptor agonist of the phenethylamine class commonly used as a vasopressor to increase the blood pressure in unstable patients with hypotension, especially resulting from septic shock

51. commonly used in anesthesia or critical-care practices; especially in counteracting the hypotensive effect of epidural and subarachnoid anesthetics counteracting the vasodilating effect of bacterial toxins and the inflammatory response in sepsis and systemic inflammatory response syndrome dose: 50–100 μ g (0.5–1 mcg/kg) IV

52. Levosimendan calcium sensitizer: enhanced contractility of myocardial cell by amplifying trigger for contraction with no change in total intracellular Ca 2+ binds to troponin C and change configuration of tropomyosin and increases contractility opens potassium channels-reduced SVR and coronary vasodilation

53. does not increase myocardial O 2 demand SV/CO/HR increases pulmonary arterial pressure and MAP decreases atrial arrhythmias common half life-1.5-2 hours

54. loading dose of 12mic/kg over 10 minutes continuous infusion of 0.1-0.2 mic/kg/min

55. Methylene Blue heterocyclic aromatic molecule medication and dye it is typically given by IV route acts as an inhibitor of nitric oxide synthase and guanylate cyclase

56. indications: methaemoglobinaemia vasoplegic shock post cardiopulmonary bypass other possible roles in critical illness: hepatopulmonary syndrome, septic shock

57. dose: Methaemoglobinaemia 1-2mg/kg IV over 5 minutes followed by saline flush; repeat at 30-60 min if MetHb levels not falling repeat dose every 6-8h when MetHb continues for days, e.g. dapsone toxicity Vasoplegia 1.5-2 mg/kg IV over 30-60min

58. contraindications G6PD deficiency (lack of NADPH prevents methylene blue from working and may lead to hemolysis) renal impairment methaemoglobin reductase deficiency nitrite-induced methaemoglobinaemia due to cyanide poisoning hypersenstitivity

59. Methylene blue in catecholamine Refractory Vasoplegia Vasoplegic syndrome is generally defined as an arterial pressure <50 mm Hg cardiac index >2.5 L /min/m right atrial pressure <5 mm Hg left atrial pressure <10 mm Hg and low systemic vascular resistance <800 dyne/sec/cm

60. Risk factors for vasoplegia : recent studies have established various risk factors for postoperative vasoplegia preoperative use of heparin ACE inhibitors congestive heart failure

61. poor left ventricular function duration of cardiopulmonary bypass (CPB) re-operation age of the patient opiod anesthesia

62. Mechanism of action of methylene blue in vasoplegia : refractory vasoplegia may reflect a dysregulation of nitric oxide synthesis and vascular smooth cell guanylate cyclase activation soluble intracellular enzyme guanylate cyclase is activated to produce cyclic guanosine monophosphate (C-GMP) presumably under the influence of several mediators including nitric oxide Methylene Blue acts by inhibiting guanylate cyclase, thus decreasing cGMP and vascular smooth muscle relaxation

63. Actions of Catecholamines

64. Guide to infusion

65. Vasodilators Classified by site of action Venodilators : reduce preload - Nitroglycerin Arteriolar dilators: reduce afterload Minoxidil and Hydralazine Combined: act on both arterial and venous beds and reduce both preload and afterload-Sodium Nitroprusside

66. Nitroprusside acts directly on arterial and venous vascular smooth muscle indicated in hypertension and low cardiac output states with increased SVR also used in post-operative cardiac surgery to decrease afterload on an injured heart action is immediate; half-life is short; titratable action

67. dose starts at 0.5 mcg/kg/min and titrate to 5 mcg/kg/min to desired effect may go higher (up to 10 mcg/kg/min) for short periods of time

68. Adverse Effects: cyanide toxicity- severe, unexplained metabolic acidosis might suggest cyanide toxicity should be suspected in any patient requiring an increasing dose especially more than 2 µg/kg/min or in a previously responsive patient who becomes less or unresponsive to the drug

69. Early Signs: mixed venous P0 2 is increased metabolic acidosis (plasma lactate conc. of > 10 mM ) cardiac arrhythmias increased cerebral venous oxygen content in awake patients, CNS dysfunction (mental status changes, seizures) may occur

70. Treatment: administration 100% oxygen sodium bicarbonate is administered to correct metabolic acidosis administration sodium thiosulfate (150 mg/kg over 15 min)- Thiosulfate acts as a sulfur donor to convert cyanide to thiocyanate

71. if cyanide toxicity is severe, with deteriorating hemodynamics and metabolic acidosis, the recommended treatment is slow IV administration of 3% sodium nitrate (5 mg/kg over 5 min), which oxidizes hemoglobin to methemoglobin which acts as an antidote by converting cyanide to cyanomethemoglobin administration of methylene blue (1–2 mg/kg of a 1% solution over 5 min) -reduces methemoglobin to hemoglobin

72. Clinical Uses: Hypertensive emergencies Controlled hypotension Cardiac diseases Cardiac surgery Aortic surgery

73. Nitroglycerine direct vasodilator as well, but the major effect is as a venodilator with lesser effect on arterioles not as effective as nitroprusside in lowering blood pressure potential benefit is relaxation of the coronary arteries, thus improving myocardial regional blood flow and myocardial oxygen demand

74. used to improve myocardial perfusion following cardiac surgery dose ranges from 0.5 to 8 mcg/kg/min typical dose is 2 mcg/kg/min for 24 to 48 hours post-operatively

75. Adverse Effects: tachycardia hypotension perspiration headache meth emoglobinemia

76. Vasoactive Inotrope Score Wernovsky et al modified by Skippen and Krahn

77. .... after controlling for diagnosis, high maximum vasoactive–inotropic score was strongly associated with a poor outcome with an adjusted odds ratio of 8.1 (95% confidence interval, 3.4–19.2; p < .001) compared with patients with a low maximum vasoactive– inotropic score. High vasoactive–inotropic score was also associated with prolonged cardiothoracic intensive care unit stay, duration of mechanical ventilation, and time to negative fluid balance …..

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