1. PRINCIPIOS DE LA TERAPIA INOTRÓPICA Y VASOPRESORA JULIO CESAR GARCIA CASALLAS MEDICINA INTERNA FARMACOLOGIA CLINICA UNIVESIDAD DE LA SABANA UNIVERSIDAD EL BOSQUE

7. INOTRÓPICOS VASOACTIVOS

9. MECANISMO DE ACCION

11. Gs + AC Gi - Gs + Gq - PLC Nucleus transcription PKA PKC β1-AR β2-AR Sarcolemmal Ca 2+ pump Na + /H + exchanger Ca 2+ channel Na + /K + pump Na + /Ca 2+ exchanger P IP3R SERCA2 RYR FKBP P P PLB SR Sarcomers K + P MITO P P ATP cAMP P DAG IP3 Ca 2+ CaM CaMKs MLCV2 cTnl P Ras Raf MEK ERK P β-ADRENERGIC SIGNALLING CASCADES IN CARDIOMYOCYTES L L Ca 2+ Ca 2+ Ca 2+ Ca 2+ VDCC β-ARK GRK2/3

13. α β γ AC L α β γ AC ATP cAMP PKA CaM β - ARK GRK2/3 P P P Arrestin Clathrin Clathrin Clathrin endosome Receptor internalization Receptor resensitization Receptor degradation Ca 2+ β -1 Adrenergic receptor internalization, resensitization or degradation In healthy human cardiomyocytes, β 1 -ARs constitute approximately 70 to 80% of the β-ARs In case of elevated sympathetic drive (eg, cardiac insufficiency, shock states), β 1 -Ars are downregulated. Β 2 -ARs do not decrease but show some loss of contractile response to agonist stimulation as a result of the upregulation of β-ARK and G i proteins P

20. Meccanismo d’azione degli inotropi positivi Gs Gi beta-receptor Na + /Ca 2+ ex. Na + /K + exchanger ATP cAMP (active) AMP (inactive) PDE rise in intracellul a r calcium Ca 2+ Na + K + Dobutamine Milrinone PDE III inhibitor Digoxin INOTROPES MECHANISMS OF ACTION Na + rises Ca 2+

32. VASOPRESORES

43. Actividad adrenérgica de las aminas simpaticomiméticas A1 A2 ß 1 ß2 DOPA Dopamina 1-2 µg/kg/min 2-10 µg/kg/min 10-20 µg/kg/min 0 0 +++ 0 0 0 + ++++ ++++ 0 0 0 ++++ ++++ 0 Dobutamina 2-10 µg/kg/min >10 µg/kg/min + ++ 0 0 +++ ++++ ++ +++ 0 0 Epinefrina 0.01-0.05 µg/kg/min >0.05 µg/kg/min + +++ 0 +++ ++ +++ +++ +++ 0 0 Norepinefrina 0.5-3 µg/kg/min ++++ +++ ++ 0 0 Fenilefrina 10-50 µg/min ++++ 0 0 0 0 Isoproterenol 2-10 µg/min 0 0 ++++ +++ 0

44. VASODILATADORES

48. Il meccanismo contrattile: fase di rilasciamento Actin Tropomyosin TnI TnT Ca 2+ cTnC Myosin head (S1 fragment) ATP pocket RLC ELC MECHANISM OF CONTRACTION: relaxation phase LEVOSIMENDAN Calcium sensitisation for enhanced cardiac contractility

49. Il meccanismo contrattile: fase di contrazione Actin Actin TnT TnT cTnC TnI Tm Tm TnI cTnC cTnC TnI cTnC TnI Tm TnT Tm Actin Actin Tm Tm TnT Myosin head Myosin head Ca 2+ Ca 2+ Ca 2+ Ca 2+ Warber K.D. and Potter J.D., in The Heart and Cardiovascular System, H.A. Fozzard et al. , eds., Raven Press, New York, pp.779-788 , 1986 MECHANISM OF CONTRACTION: contraction phase LEVOSIMENDAN Calcium sensitisation for enhanced cardiac contractility Calcium sensitisation leads to enhanced systolic contraction of myofilaments, but allow normal diastolic relaxation (inotropic and lusitropic effect of Levosimendan)

50. Troponin C Calcium ion ACTIN MYOSIN Tropomyosin Tropomyosin Troponin C ACTIN MYOSIN Calcium ion LEVOSIMENDAN In contrast to the positive inotropes, calcium sensitisers such as Levosimendan increase the contractile force generated for a given amount of free calcium in the cytoplasm, binding to Troponin C and increasing the sensitivity of the contractile proteins to calcium without increasing the influx of calcium into the myocytes. Levosimendan binds during the first part of systole rather during diastole

51. K + K + K + K + K + K + K + Levosimendan has also been shown to increase Coronary and Systemic Vasodilatation. This effect is mediated by the opening of Adenosine Triphosphate Dependent Potassium (K ATP ) channels by the action of Levosimendan on muscle tissue, reducing the preload and afterload of the myocardium, improving oxygen supply to the myocardium and renal blood flow LEVOSIMENDAN Potassium VASODILATATION K ATP channel

57. Efficacy and safety of intravenous Levosimendan compared with Dobutamine in severe low output heart failure (the LIDO study): A randomized double blind trial F.Follath, JGF Cleland, H Just et al Lancet 2002; 360:196-202 MORTALITY 26% for levosimendan and 38% for dobutamine p=0.029

58. DAYS RISCHIO DI MORTALITA’ A 6 MESI Simdax: Studio RUSSLAN RUSSLAN STUDY: RISK OF MORTALITY 6 MONTHS SURVIVORS Patients with acute heart failure after an acute myocardial infarction Levosimendan significantly lowered death rates by 40% during the first 14 days after treatment (p=0.036) Moiseyev V.S. European Heart Journal 2002; 23:1422-1432

59. NO MEDICAL TREATMENT ACE INHIBITORS (AT1-RB) β-BLOCKERS DIURETICS SPIRONOLACTONE DIGITALIS ANTICOAGULANTS LEVOSIMENDAN HTx NYHA IV NYHA III NYHA II NYHA I

61. HEMODYNAMIC CHANGES IN SEVERE SEPSIS CO=SV x HR, SVR = (MAP-CVP)/CO x 79.92 DO2 = CI x arterial oxygen x 10, VO2 = CI x (arterial – venous oxygen) x 10 parameter Normal range Changes in severe sepsis Heart rate (HR) 72-88 beats/min Sinus tachycardia Mean arterial pressure (MAP) 70-105mmHg Hypotension <60mmHg Cardiac output (CO) 4-8l/min Increased but not enough to compensate for low SVR Systemic vascular resistance (SVR) 800-1500dynes/cm2 Reduced (<600 if no pressor agents) Oxygen delivery (DO2) 520-720ml/min/m2 Decreased Oxygen consumption (VO2) 100-180ml/min/m2 Typically increased

62. Sepsis or tissue hypoxia with lactic acidosis Nitric oxide synthase Nitric oxide cGMP Open K Ca ATP, H + , Lactate in vascular smooth muscle Open K ATP Cytoplasmic Ca 2+ Phosphorilated myosin VASODILATATION Vasopressin secretion Vasopressin stores Plasma vasopressin MECHANISMS OF VASODILATORY SHOCK N Engl J Med 2001,345:588-595

64. Gracias…