11Management of heart failure Prevention of initial causativePharmacological treatment
12Neurohormone model (1980-2000) Hemodynamic model( )increase contractilityTreatmentConventional drugsDiureticDigitalisvasodilatorsProgressive remodeling with impaired myocardial performanceTreatmentConventional drugsDecreasing the process of cardiac remodeling(ACEI, -blocker, nitrate)Neurohormone blockersACEI (RAAS)Spironolactone (aldosterone)-blocker (renin)Digoxin (renin)
13Treatment of CHF 1. Control salt and water retention (diuretic) Goal: to relief symptom1. Control salt and water retention (diuretic)2. Increase myocardial contractility(inotropic drugs)3. Reduce work load of heart byPreload: Diuretic, Nitrate, ACEIAfterload: Direct vasodilatorDecrease activation of neurohormone: ACEI, -blocker, spironolactone
14Heart failurePositive inotropicvasodilatorDecreased cardiac outputIncreased venous volume and pressureDecreased tissue perfusionNeuroendocrine system activationCongestion and edemaDysnea and orthopneaSympathetic activationRASvasoconstrictionNa retentionIncreased afterload
21Positive inotropic effect (cont) Binding with Na+/K+ ATPase thus inhibit Na+ pump20-40 % inhibition therapeutic>50 % inhibition toxicIncrease the force of contraction of both normal and failure heart.Improvement hemodynamic in failure heart.
244. Other effects Muscle GI CNS Slightly increase Ca2+ in muscle N/V, stimulate CTZ (vomiting center)CNSDisorientation, hallucination, convulsion
25Pharmacokinetics Absorption Variable oral bioavailability depend on dosage form70% tablet85% elixir95% capsule10% of pts. metabolism by Eubacterium lentum
26DistributionVd 7-8 L/kgLittle affinity for distribution into fat (dosing should base on ideal body weight)Myocardial/serum digoxin concentration ratio are approximately 30:1.Hypokalemia increase the binding of digoxin to heart.
28Excretion Renal route T1/2 1.6 day Pts with renal disease increase T1/ d.
29Therapeutic concentration Drug has narrow therapeutic index.Therapeutic range ng/ml(after 4-5 T1,/2)Dose adjustment when drug reach to steady State. (equilibrium between heart and serum)
30ADR GI N/V, vomiting, diarrhea, abdominal pain, constipation NeurologicHeadache, fatigue, insomnia, vertigoVisualColor vision (green or yellow), colored halos around the subjectMiscellenouesAllergic, thrombocytopenia, necrosis
31ADR (cont) Heart SA and AV node suppression AV block Atrial arrhythmia Ventricular arrhythmia
32Risk of treatment Serum digoxin level > 2 ng/ml Cardiac arrhythmiaGI symptomNeurogenic compliantLower digoxin level is toxic if hypokalemia, hypomagnesemia and hypercalcemia.Comcomittent use of quinidine, verapamil, flecainide and amiodarone which increase digoxin level.
33Clinical Use To improve clinical status of the patient Combination with -blocker, diuretic, ACEI
42ACEIACEI in CHFReport that reduce remodelingReduce aldosterone from the compensatory mechanismVasodilate (Preload/after load)Improve symptoms and clinical status and decrease the risk of death and hospitalization in mild, moderate, severe heart failure.Decrease risk of HF in pts with LV-dysfunction
43ACEI in CHF Contraindicated in Angioedma Anuric renal failure PregnancyUse with caution in pts withSerum K+> 5.5 mmole/L
49beta-blockers Effect in CHF Improve symptoms and clinical status Block SNS effectsBlock reninImprove symptoms and clinical statusCombination with diuretic, ACEI, digoxin, vasodilatorsBisoprolol, metoprolol, Carvedilol
50Risk of treatment Hypotension Fluid retention & worsening CHF Bradycardia & heart blockContraindication in pts with CHF exacerbation
51Aldosterone antagonist SpironolactoneResearch study indicate that spironolactone reduce mortality and morbidity in CHF.Monitor K+ level.