Δακτυλίτιδα και Ινότροπα Φάρμακα στην Καρδιακή Ανεπάρκεια Ι.Κανονίδης
Cardiac Glycosides
Chronic Congestive Heart Failure DIGOXIN Na-K ATPase Na + K + Na-Ca Exchange Na + Ca ++ Ca ++ K + Na + Myofilaments Ca ++ CONTRACTILITY
Chronic Congestive Heart Failure DIGOXIN PHARMACOKINETIC PROPERTIES Oral absorption (%) 60-75 Protein binding (%) 25 Volume of distribution (l/kg) 6 (3-9) Half life 36 (26-46) h Elimination Renal Onset (min) i.v. 5-30 oral 30-90 Maximal effect (h) i.v. 2-4 oral 3-6 Duration 2-6 days Therapeutic level (ng/ml) 0.5-2
Chronic Congestive Heart Failure DIGOXIN DIGITALIZATION STRATEGIES Loading dose (mg) Maintenance Dose i.v oral 12-24 h oral 2-5 d (mg) 0.5 + 0.25 / 4 h 0.75 + 0.25 / 6 h 0.25 / 6-12 h 0.125-0.5 / d ILD: 0.75-1 1.25-1.5 1.5-1.75 0.25 / d ILD = average INITIAL dose required for digoxin loading
Chronic Congestive Heart Failure DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation
Chronic Congestive Heart Failure DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors
Effect of digoxin on plasma norepinephrine
Digitalis trials
Digoxin in heart failure
Chronic Congestive Heart Failure DIGOXIN EFFECT ON CHF PROGRESSION % WORSENING OF CHF 30 20 DIGOXIN: 0.125-0.5 mg /d (0.7-2.0 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 = 0.001 DIGOXIN n=85 RADIANCE N Engl J Med 1993;329:1 0 20 40 60 Days 80 100
The DIG trial design
Chronic Congestive Heart Failure OVERALL MORTALITY 50 40 % 30 20 Placebo n=3403 p = 0.8 DIG 10 DIGOXIN n=3397 0 0 12 24 36 Months N Engl J Med 1997;336:525 48
The DIG trial MORBIDITY N Engl J Med 1997;336:525
The DIG trial
Chronic Congestive Heart Failure DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions
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
Chronic Congestive Heart Failure POSITIVE INOTROPES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists Dopamine Dobutamine Xamoterol PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Milrinone Piroximone CALCIUM SENSITISERS Pimobentan Levosimendan
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 1 ++ + + + ± > 5 ß 1 + ++ ++ ++ ± ++ Dobutamine ß 1 ++ ± ++ + ±
INOTROPES In Chronic Congestive Heart Failure (oral administration)
The PROMISE Trial
Xamoterol Study
The Enoximone Trial
The Enoximone Trial
INOTROPES In Acute Heart Failure (intravenous administration)
Dobutamine or high dose Dopamine versus Placebo Mortality
Dobutamine or high dose Dopamine versus Placebo Effect on NYHA Class
PDE Inhibitors versus Dobutamine or high dose Dopamine Mortality
Chronic Congestive Heart Failure Heart Failure Score OPTIM-CHF ( Milrinone versus Placebo )
Chronic Congestive Heart Failure Adverse Events OPTIM-CHF ( Milrinone versus Placebo )
Chronic Congestive Heart Failure OPTIM-CHF ( Milrinone versus Placebo ) End Points
Sensitizers
Levosimendan Δοσολογία 0,05-0,2 μg/kg/min
Levosimendan Hemodynamic Effects
Levosimendan Hemodynamic Effects
LEVOSIMENDAN BNP Changes
LIDO
RUSLAND
RUSLAND
SURVIVE Trial Levosimendan versus Dobutamine
SURVIVE Trial Levosimendan versus Dobutamine
SURVIVE Trial Levosimendan versus Dobutamine
SURVIVE Trial Levosimendan versus Dobutamine
SURVIVE Trial Levosimendan versus Dobutamine BNP-Mean Change From Baseline
SURVIVE Trial Levosimendan versus Dobutamine Mortality
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
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)
Chronic Congestive Heart Failure
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