Δακτυλίτιδα και Ινότροπα Φάρμακα στην Καρδιακή Ανεπάρκεια. Ι.Κανονίδης

Transcription

1 Δακτυλίτιδα και Ινότροπα Φάρμακα στην Καρδιακή Ανεπάρκεια Ι.Κανονίδης

2 Cardiac Glycosides

3 Chronic Congestive Heart Failure DIGOXIN Na-K ATPase Na + K + Na-Ca Exchange Na + Ca ++ Ca ++ K + Na + Myofilaments Ca ++ CONTRACTILITY

4 Chronic Congestive Heart Failure DIGOXIN PHARMACOKINETIC PROPERTIES Oral absorption (%) Protein binding (%) 25 Volume of distribution (l/kg) 6 (3-9) Half life 36 (26-46) h Elimination Renal Onset (min) i.v oral Maximal effect (h) i.v. 2-4 oral 3-6 Duration 2-6 days Therapeutic level (ng/ml) 0.5-2

5 Chronic Congestive Heart Failure DIGOXIN DIGITALIZATION STRATEGIES Loading dose (mg) Maintenance Dose i.v oral h oral 2-5 d (mg) / 4 h / 6 h 0.25 / 6-12 h / d ILD: / d ILD = average INITIAL dose required for digoxin loading

6 Chronic Congestive Heart Failure DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation

7 Chronic Congestive Heart Failure DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors

8 Effect of digoxin on plasma norepinephrine

9 Digitalis trials

10 Digoxin in heart failure

11 Chronic Congestive Heart Failure DIGOXIN EFFECT ON CHF PROGRESSION % WORSENING OF CHF DIGOXIN: mg /d ( ng/ml) 10 EF < 35% Class I-III (digoxin+diuretic+acei) Also significantly decreased exercise time and LVEF. 0 Placebo n=93 DIGOXIN Withdrawal p = DIGOXIN n=85 RADIANCE N Engl J Med 1993;329: Days

12 The DIG trial design

13 Chronic Congestive Heart Failure OVERALL MORTALITY % Placebo n=3403 p = 0.8 DIG 10 DIGOXIN n= Months N Engl J Med 1997;336:525 48

14 The DIG trial MORBIDITY N Engl J Med 1997;336:525

15 The DIG trial

16 Chronic Congestive Heart Failure DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions

17 Chronic Congestive Heart Failure DIGOXIN CLINICAL USES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs

18 Chronic Congestive Heart Failure POSITIVE INOTROPES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists Dopamine Dobutamine Xamoterol PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Milrinone Piroximone CALCIUM SENSITISERS Pimobentan Levosimendan

19

20 Chronic Congestive Heart Failure DOPAMINE AND DOBUTAMINE EFFECTS Receptors Contractility Heart Rate Arterial Press. Renal perfusion Arrhythmia < 2 DA 1 / DA 2 ± ± ± ++ - DA (µg / Kg / min) 2-5 ß ± > 5 ß ± ++ Dobutamine ß 1 ++ ± ++ + ±

21 INOTROPES In Chronic Congestive Heart Failure (oral administration)

22 The PROMISE Trial

23 Xamoterol Study

24 The Enoximone Trial

25 The Enoximone Trial

26 INOTROPES In Acute Heart Failure (intravenous administration)

27 Dobutamine or high dose Dopamine versus Placebo Mortality

28 Dobutamine or high dose Dopamine versus Placebo Effect on NYHA Class

29 PDE Inhibitors versus Dobutamine or high dose Dopamine Mortality

30 Chronic Congestive Heart Failure Heart Failure Score OPTIM-CHF ( Milrinone versus Placebo )

31 Chronic Congestive Heart Failure Adverse Events OPTIM-CHF ( Milrinone versus Placebo )

32 Chronic Congestive Heart Failure OPTIM-CHF ( Milrinone versus Placebo ) End Points

33 Sensitizers

34 Levosimendan Δοσολογία 0,05-0,2 μg/kg/min

35

36 Levosimendan Hemodynamic Effects

37 Levosimendan Hemodynamic Effects

38 LEVOSIMENDAN BNP Changes

39 LIDO

40 RUSLAND

41 RUSLAND

42

43

44

45

46

47

48 SURVIVE Trial Levosimendan versus Dobutamine

49 SURVIVE Trial Levosimendan versus Dobutamine

50 SURVIVE Trial Levosimendan versus Dobutamine

51 SURVIVE Trial Levosimendan versus Dobutamine

52 SURVIVE Trial Levosimendan versus Dobutamine BNP-Mean Change From Baseline

53 SURVIVE Trial Levosimendan versus Dobutamine Mortality

54

55 Chronic Congestive Heart Failure POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy

56 Chronic Congestive Heart Failure European Guide Lines Class IIa Level of Evidence B (levosimendan) C (dobutamine ) Acute heart failure in the presence of hypoperfusion with or without congestion or pulmonary edema refractory to diuretics and vasodilators (2005)

57 Chronic Congestive Heart Failure

58 Ευχαριστώ