Drugs for Congestive Heart Failure

1. Required reading: Katzung, 9thed. pp. 201-215, 281-290 Drugs for Congestive Heart Failure Digitalis Lanata Cardiovascular System Course William B. Jeffries, Ph.D. Room 570A Criss III, 280-4092 Email: wbjeff@creighton.edu flap.creighton.edu

2. Compensatory Mechanisms in Heart Failure • Mechanisms designed for acute loss in cardiac output • Chronic activation of these mechanisms worsens heart failure

3. Potential Therapeutic Targets in Heart Failure • Preload • Afterload • Contractility • Remodeling

4. Positive Inotropic Agents • Cardiac Glycosides • Phosphodiesterase inhibitors • b-adrenoceptor agonists

5. Cardiac Glycosides • digoxin • digitoxin • deslanoside • ouabain

6. Mechanism of Digitalis Action: Molecular • Inhibition of Na/K ATPase • blunting of Ca2+ extrusion • ­ Ca2+i • ­ sarcomere shortening

7. Effects on Cardiac Function Three Types of Effects: • Mechanical Effects: Positive inotropy • Caused by increased Ca2+ Availability • Direct Electrophysiological Effects • Altered cellular action potential • Afterdepolarizations • Indirect Electrophysiological Effects: • Mediated through increased vagal tone and withdrawal of sympathetic tone

8. Direct Electrophysiological Effects:Cellular Action Potential

9. Afterdepolarizations

10. Parasympathomimetic Effects • Vagus-mediated hyperpolarization of AV node. Leads to: • Decreased conduction velocity in the AV node • Increased effective refractory period in the AV node • AV block (toxic concentrations)

11. Therapeutic Uses of Digitalis • Congestive Heart Failure • Atrial fibrillation

12. Overall Benefit of Digitalis to Myocardial Function • ­ cardiac output • ­ cardiac efficiency • ¯ heart rate • ¯ cardiac size NO survival benefit

13. 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

14. Adverse Effects • Cardiac • AV block • Bradycardia • Ventricular extrasystole • Arrhythmias • CNS • GI Therapeutic index is ~ 2!

15. Serum Electrolytes Affect Toxicity • K+ • Digitalis competes for K binding at Na/K ATPase • Hypokalemia: increase toxicity • Hyperkalemia: decrease toxicity • Ca2+ • Hypercalcemia: increases toxicity

16. Phosphodiesterase Inhibitors • amrinone • milrinone • Mechanism of Action • inhibition of type III phosphodiesterase • ­ intracellular cAMP • ­ activation of protein kinase A • Ca2+ entry through L type Ca channels • increased Ca2+ sequestration by SR • Phosphorylation of MLCK • ­ cardiac output • ¯ peripheral vascular resistance • “Inamrinone”

17. Phosphodiesterase Inhibitors: Therapeutic Use • short term support in advanced decompensated cardiac failure • long term use not possible

18. Adverse Effects of Phosphodiesterase Inhibitors • Cardiac arrhythmias • GI: Nausea and vomiting • Sudden death

19. b-Adrenoceptor and Dopamine Receptor Agonists • Dobutamine • Dopamine

20. Mechanism of Action:Dobutamine • Stimulation of cardiac b1-adrenoceptors: ­ inotropy > ­ chronotropy • peripheral vasodilatation • ­ myocardial oxygen demand

21. Mechanism of Action: Dopamine • Stimulation of peripheral postjunctional D1 and prejunctional D2 receptors • Splanchnic and renal vasodilatation

22. Therapeutic Use • Dobutamine:management of acute decompensated failure only • Dopamine:restore renal blood in acute failure

23. Adverse Effects • Dobutamine • Tolerance • Tachycardia • Dopamine • Tachycardia • Arrhythmias • Peripheral vasoconstriction

24. ACE Inhibitors in Heart Failure Therapeutic targets in heart failure

25. Mechanism of Action • Afterload reduction • Preload reduction • Reduction of cardiac remodeling (hypertrophy) • Withdrawal of sympathetic tone

26. ACE Inhibitors: Therapeutic Uses • Drugs of choice in heart failure (with diuretics) • Acute myocardial infarction • ATII antagonists

27. 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

28. Vasodilators • Mechanism of action: reduce preload and afterload • Drugs used • Isosorbide dinitrate + Hydralazine • Demonstrated survival benefit • Inferior to ACE inhibition • Ca2+ channel blockers • No benefit in systolic failure • Use in diastolic failure? • Alpha-1 adrenergic antagonists: • no proven benefit • Neseritide

29. Nesiritide • Recombinant B-type natriuretic peptide • Mechanism of Action • Activates smooth muscle guanylyl cyclase • Dilatation of venous and arterial beds • Natriuresis/diuresis (but not in decompensated heart failure) • Preload and afterload reduction • Reduced pulmonary capillary wedge pressure • Reduced dyspnia

30. See: Topol, NEJM 353:2 113-116, 2005 Nesiritide • Approved in acute decompensated failure • Off Label Use: Ambulatory heart failure • Effects similar to nitrates • Adverse effects: • hypotension (NO arrhythmias) • Increased renal failure? • Increased death rate?

31. -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

32. Aldosterone Antagonists • Rationale: • Aldosterone promotes increased plasma volume, Increased serum K, and (possibly) hypertrophic effects on the heart • Aldosterone inappropriately elevated in CHF (even after ACE inhibition) • Thus, positive outcome if aldosterone effects on heart and kidney are prevented • Evidence: Aldosterone antagonists have been shown to reduce mortality in CHF • Available aldosterone antagonists • Spironolactone • Eplerenone

33. Spironolactone and Eplerenone • Aldosterone antagonists, K-sparing diuretics • Effects in Heart Failure • Potassium Sparing Diuretics • Mobilize edema fluid in heart failure • Prevent K loss caused by other diuretics (protection against digitalis toxicity?) • Reduction of cardiovascular remodeling • Potential side effects • Hyperkalemia • Androgenic effects (spironolactone) • Gynecomastia (spironolactone)

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