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Drugs for Congestive Heart Failure

  1. Drugs for Congestive Heart Failure Dr Lokendra Sharma Sr. Professor, Pharmacology SMS Medical College, Jaipur
  2. Basic Definition Heart failure is a medical term that describes an inability of the heart to keep up its work load of pumping blood to the lungs and to the rest of the body.
  3. Classification I) Drugs with positive inotropic effects- a) Cardiac glycosides- Digoxin, Digitoxin, Ouabain b) Phosphodiesterase inhibitors- Inamrinone, Milrinone, Levosimendan c) Beta adrenergic agonist- Dopamine, Dobutamine, Dobuxamine
  4. II) Drugs without positive inotropic effects- a) Diuretics- Bumetanide, Furosemide, Hydrochlorothiazide, Spironolactone b) ACEIs- Enalapril, Lisinopril, Ramipril c) Beta-1 adrenoceptor antagonist- Bisoprolol, Carvedilol, Metoprolol
  5. A, B, C, D, Es of Heart Failure Therapy A Angiotensin converting enzyme inhibitors anticoagulants, amiodarone, AICD, assist devices B Beta blocking drugs C Calcium channel blocking drugs, coronary revascularization, cardiac transplant, cardiomyoplasty, cardiac reduction surgery D Diet, diuretics, digitalis, dobutamine E Exercise
  6. CHF ClassificationNew York Heart Association Class I - Asymptomatic Class II - Symptomatic with moderate exertion Class III - Symptomatic with mild exertion Class IV - Symptomatic with no exertion/or at rest
  7. CHF: Clinical Assessment Left or right sided History – Left sided • Orthopnea • Dyspnea – Right sided • Anorexia • Abdominal distension • Ankle edema Exam – Left sided • Rales • Narrow pulse pressure • Increasing S3 – Right sided • Elevated JVP • Hepato-jugular reflex • Loud P2
  8. CHF: Pharmacotherapy  Relief of symptoms Diuretics Digoxin  Reduction in mortality/hospitalizations ACE Inhibitors Beta blockers Spironolactone  Rescue in advanced failure Inotropic infusions (dobutamine) Vasodilators
  9. Principles in selecting appropriate medications Reduction in Pre-load: Diuretics After-load: ACE Inhibitors Filling pressures: Nitrates Restoring perfusion Inotropic agents Beta adrenergic receptor agents: Dobutamine Phosphodiesterase inhibitors: Milrinone
  10. Compensatory Mechanisms in Heart Failure Mechanisms designed for acute loss in cardiac output Chronic activation of these mechanisms worsens heart failure
  11. Potential Therapeutic Targets in Heart Failure Preload Afterload Contractility
  12. Positive Inotropic Agents Cardiac Glycosides Phosphodiesterase inhibitors  b-adrenoceptor agonists and dopamine receptor agonists
  13. Cardiac Glycosides Digoxin Digitoxin Deslanoside Ouabain
  14. Mechanism of Digitalis Action: Molecular Inhibition of Na/K ATPase Blunting of Ca2+ extrusion  Ca2+ i  Sarcomere shortening
  15. Effects on Cardiac Function Positive inotropy Direct electrophysiological effects Effects mediated through increased vagal tone
  16. Direct Electrophysiological Effects: Cellular Action Potential
  17. Summary Direct Electrophysiological Effects Less negative membrane potential: decreased conduction velocity Decreased action potential duration: decreased refractory period in ventricles Enhanced automaticity due to Steeper phase 4 After depolarizations
  18. Parasympathomimetic Effects Decreased conduction velocity in the AV node increased effective refractory period in the AV Heart block (toxic concentrations)
  19. EKG Effects of Digitalis Decrease in R-T interval Inversion of T wave Uncoupled P waves (Toxic concentrations) Bigeminy (toxic concentrations)
  20. Summary of Pharmacokinetic profile of cardiac glycosides
  21. Therapeutic Uses of Digitalis Congestive Heart Failure Atrial fibrillation
  22. Overall Benefit of Digitalis to Myocardial Function  cardiac output  cardiac efficiency   heart rate   cardiac size NO survival benefit
  23. Other Beneficial Effects Restoration of baroreceptor sensitivity Reduction in sympathetic activity Increased renal perfusion, with  edema formation
  24. Administration Digoxin has a long enough half life (24-36 hr.) and high enough bioavailability to allow once daily dosing Digoxin has a large volume of distribution and dose must be based on lean body mass Increased cardiac performance can increase renal function and clearance of digoxin Eubacterium lentum
  25. Adverse Effects Cardiac AV block Bradycardia Ventricular extra systole Arrhythmias CNS GI Therapeutic index is ~ 2!
  26. Serum Electrolytes Affect Toxicity K+ Digitalis competes for K binding at Na/K ATPase Hypokalemia: increase toxicity Hyperkalemia: decrease toxicity Mg2+ Hypomagnesemia: increases toxicity Ca2+ Hypercalcemia: increases toxicity
  27. Treatment of Digitalis Toxicity Reduce dose: 1st degree heart block, ectopic beats Atropine: advanced heart block KCl: increased automaticity Antiarrhythmic: ventricular arrhythmias Fab antibodies: toxic serum concentration; acute toxicity
  28. Phosphodiesterase Inhibitors  Amrinone  Milrinone  levosimendan Mechanism of Action  Inhibition of type III phosphodiesterase  intracellular cAMP  activation of protein kinase A  Ca2+ entry through L type Ca2+ channels  inhibition of Ca2+ sequestration by SR  cardiac output   peripheral vascular resistance
  29. Mechanism of action of beta agonists and PDE isozyme-3 inhibitors in heart failure
  30. Phosphodiesterase Inhibitors: Therapeutic Use Short term support in advanced cardiac failure Long term use not possible
  31. Adverse Effects of Phosphodiesterase Inhibitors Cardiac arrhythmias GI: Nausea and vomiting Dose dependent thrombocytopenia Sudden death
  32. b-Adrenoceptor and Dopamine Receptor Agonists Dobutamine Dopamine
  33. Mechanism of Action: Dobutamine Stimulation of cardiac b1- adrenoceptors: inotropy > chronotropy Peripheral vasodilatation  myocardial oxygen demand
  34. Mechanism of Action: Dopamine Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors Splanchnic and renal vasodilatation
  35. Therapeutic Use Dobutamine: management of acute failure only Dopamine: restore renal blood in acute failure
  36. Dobutamine  ß-1 receptor agonist  Low-dose dobutamine (2-3 ug/kg/min)   myocardial contractility and cardiac output, arteriovenous dilatation  High-dose dobutamine (5-15 ug/kg/min) tachycardia, arrhythmia, splanchnic and renal vasoconstriction associated with symptomatic benefit  Continuous home pump infusion  T .half life 2 minute
  37. Adverse Effects Dobutamine Tolerance Tachycardia Dopamine tachycardia arrhythmias peripheral vasoconstriction
  38. Mechanism of Action Afterload reduction Preload reduction Reduction of facilitation of sympathetic nervous system Reduction of cardiac hypertrophy
  39. ACE Inhibitors: Therapeutic Uses Drugs of choice in heart failure (with diuretics) Current investigational use: Acute myocardial infarction AT II antagonists
  40. Diuretics: Mechanism of Action in Heart Failure Preload reduction: reduction of excess plasma volume and edema fluid Afterload reduction: lowered blood pressure Reduction of facilitation of sympathetic nervous system
  41. Vasodilators Mechanism of action: reduce preload and afterload Drugs used Sodium nitroprusside Hydralazine Ca2+ channel blockers Prazosin
  42. b-Blockers in Heart Failure: Mechanism of Action Standard b-blockers: Reduction in damaging sympathetic influences in the heart (tachycardia, arrhythmias, remodeling) inhibition of renin release Carvedilol: Beta blockade effects peripheral vasodilatation via a1- adrenoceptor blockade (carvedilol)
  43. Spironolactone Aldosterone antagonist, K-sparing diuretic Prevention of aldosterone effects on: Kidney Heart? Aldosterone inappropriately elevated in CHF Mobilizes edema fluid in heart failure Prevention of hypokalemia induced by loop diuretics (protection against digitalis toxicity?) Prolongs life in CHF patients
  44. Take Home Message Diuretics of choice in acute CHF- Loop diuretic Short term management of acute CHF- Inotropic drugs Cardiac glycosides act by inhibiting Na+ K+ ATPase Digoxin is only inotropic drug, can be given orally Thrombocytopenia side effect of Inamrinone CCBs should not used in CHF – may increase mortality
  45. Aldosterone antagonist and beta blocker- reduce the mortality Widely used beta blocker- Carvedilol Beta blockers contraindicated in acute CHF.
  46. Thank You

Editor's Notes

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