Management of heart failure Prevention of initial causative Pharmacological treatment
increase contractility Treatment – Conventional drugs Diuretic Digitalis vasodilators Progressive remodeling with impaired myocardial performance Treatment – Conventional drugs – Decreasing the process of cardiac remodeling (ACEI, -blocker, nitrate) – Neurohormone blockers ACEI (RAAS) Spironolactone (aldosterone) -blocker (renin) Digoxin (renin) Hemodynamic model (1950-1980) Neurohormone model (1980-2000)
Treatment of CHF 1. Control salt and water retention (diuretic) 2. Increase myocardial contractility (inotropic drugs) 3. Reduce work load of heart by Preload: Diuretic, Nitrate, ACEI Afterload: Direct vasodilator Decrease activation of neurohormone: ACEI, -blocker, spironolactone Goal: to relief symptom
Heart failure Decreased cardiac output Increased venous volume and pressure Congestion and edema Dysnea and orthopnea Decreased tissue perfusion Neuroendocri ne system activation Sympath etic activatio n RAS vasoconstri ction Na retenti on Increased afterload Positive inotropic vasodila tor
Positive inotropic effect (cont) Binding with Na + /K + ATPase thus inhibit Na + pump – 20-40 % inhibitiontherapeutic – >50 % inhibitiontoxic Increase the force of contraction of both normal and failure heart. Improvement hemodynamic in failure heart.
4. Other effects Muscle – Slightly increase Ca 2+ in muscle GI – N/V, stimulate CTZ (vomiting center) CNS – Disorientation, hallucination, convulsion
Pharmacokinetics Absorption Variable oral bioavailability depend on dosage form – 70% tablet – 85% elixir – 95% capsule 10% of pts. metabolism by Eubacterium lentum
V d 7-8 L/kg Little 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. Distribution
Excretion Renal route T 1/2 1.6 day Pts with renal disease increase T 1/2 3.5-4.5 d.
Therapeutic concentration Drug has narrow therapeutic index. Therapeutic range 0.5-2 ng/ml (after 4-5 T 1,/2 ) Dose adjustment when drug reach to steady State. (equilibrium between heart and serum)
ADR GI N/V, vomiting, diarrhea, abdominal pain, constipation Neurologic Headache, fatigue, insomnia, vertigo Visual Color vision (green or yellow), colored halos around the subject Miscellenoues Allergic, thrombocytopenia, necrosis
ADR (cont) Heart SA and AV node suppression AV block Atrial arrhythmia Ventricular arrhythmia
Risk of treatment Serum digoxin level > 2 ng/ml – Cardiac arrhythmia – GI symptom – Neurogenic compliant Lower digoxin level is toxic if hypokalemia, hypomagnesemia and hypercalcemia. Comcomittent use of quinidine, verapamil, flecainide and amiodarone which increase digoxin level.
Clinical Use To improve clinical status of the patient Combination with -blocker, diuretic, ACEI
1.catecholamine 2. PDEI
Catecholamine Dopamine 1, 1 DA receptor Increase NE… tachycardia Dobutamine synthetic analoge of dopamine Stimulate 1 > 2 receptor and > receptor (not DA receptor) positive inotropic Use in refractory HF, sever acute MI, cardiotonic shock
Vasodilators Reduce preload/afterload Venodilator…Isosorbide, nitroglycerine Vasodilator….hydralazine, minoxidil, Ca 2+ channel blocker Both Venodilator and Vasodilator……ACEI, prazosin
ACEI ACEI in CHF – Report that reduce remodeling – Reduce aldosterone from the compensatory mechanism – Vasodilate (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
ACEI in CHF Contraindicated in Angioedma Anuric renal failure Pregnancy Use with caution in pts with Serum K + > 5.5 mmole/L