Weiping Zhang, MD, Ph.D., Department of Pharmacology Zhejiang University School of Medicine

1. Pharmacology for cardiovascular system Part 6 Drugs for Treatment of Congestive Heart Failure Weiping Zhang, MD, Ph.D., Department of Pharmacology Zhejiang University School of Medicine 2010.6.28

7. Contents I. Introduction II. Basic Pharmacology of Drugs Used in Heart Failure III. Clinical Pharmacology of Drugs Used in Heart Failure Cardiac glycoside Diuretics and vasodilators ACE inhibitors  receptor blockers Others

8. I. Introduction 1.Heart Failure: (1) Systolic failure: the mechanical pumping action (contractility) and the ejection fraction of the heart are reduced. (2)Diastolic failure: stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejection fraction may be normal. e.g. Pericarditis  铁甲心 (3) High-output failure: can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts.

9. Stage Patient Description A High risk for developing heart failure (HF) • Hypertension • CAD • Diabetes mellitus • Family history of cardiomyopathy B Asymptomatic HF • Previous MI • LV systolic dysfunction • Asymptomatic valvular disease C Symptomatic HF • Known structural heart disease • Shortness of breath and fatigue • Reduced exercise tolerance D Refractory end-stage HF • Marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) 2. New Approach to the Classification of Heart Failure At Risk Heart Failure Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

10. 3. Pathophysiology of Heart Failure: Fall in cardiac output Myocardial injury Activation of RAAS, SNS and others ANP BNP Peripheral vasoconstriction Hemodynamic alterations Myocardial toxicity Remodeling and progressive worsening of LV function Heart failure symptoms Morbidity and mortality Fonarow GC. Rev Cardiovasc Med..2001;2:7–12.

11. 3. Pathophysiology of Heart Failure: intrinsic compensatory: myocardial hypertrophy: helps maintain cardiac performance at the beginning but can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling: proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes.

12. Pathophysiologic Effects of Angiotensin II and Epinephrine/Norepinephrine Cardiac Myocyte Fibroblast Peripheral Artery Coronary Artery Vasoconstriction Vasoconstriction Hypertrophy Hyperplasia Endothelial Dysfunction Endothelial Dysfunction Apoptosis Collagen Synthesis Atherosclerosis Hypertrophy Cell Sliding Fibrosis Restenosis Decreased Compliance Increased Wall Stress Thrombosis Increased O2 Consumption Impaired Relaxation

13. Cardiac failure Cardiac output Blood supply Venous pressure Renal blood flow Renin - angiotension Ⅱ Venous hyperemia Aldosterone Pulmonary circulation: cough, emptysis, dyspnea Systemic circulationhyperemia: jugular vein distension, edema Sodium and water retention Changes of hemodynamics in CHF

14. 3. Pathophysiology of Heart Failure: • extrinsic compensatory: • Sympathetic nervous system • RAAs  Cardiac output  Carotid sinus firing  Renal blood flow  Sympathetic discharge  Renin release  force  Rate  Angiotensin II  Preload  Afterload Remodeling • Cardiac output (via compensation)

15. II. Basic Pharmacology of Drugs Used in Heart Failure

16. II. Basic Pharmacology of Drugs Used in Heart Failure Positive inotropic agents, very helpful in acute failure and reduce symptoms in chronic failure. ---act on myocardia. ACEI, -blockers, spironolactone (an aldosterone receptor antagonist) and hydralazine + isosorbide can actually prolong life in patients with chronic heart failure. ---act both cardiac and non-cardiac target, such as kidney, adrenergic system, RAA system. To improve the life qualitity, decrease hospitalization and the mortality.

17. II. Basic Pharmacology of Drugs Used in Heart Failure • 1. Positive Inotropic Drugs • Digitalis • Beta Adrenoceptor Stimulants • Dopamine • 2. Diuretics • 3. RAAS inhibitors • ACEI • ARB • Adolsterone antagonists • 4. Vasodilators • 5. Beta blockers • 6. rhBNP Whether they can decrease the mortality ?

18. Stage C patients Stage D patients 2009 guideline

19. II. Basic Pharmacology of Drugs Used in Heart Failure • 1. Positive Inotropic Drugs • Digitalis •  Adrenoceptor Stimulants • Dopamine • 2. Diuretics • 3. RAAS inhibitors • ACEI • ARB • Adolsterone antagonists • 4. Vasodilators • 5. Beta blockers • 6. rhBNP

20. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis: Digitalis is the genus name for the family of plants that provide most of the medically useful cardiac glycosides, eg, digoxin. Aglycone (genin)

21. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Pharmacokinetics • Absorption and Distribution 1Ouabain and digitoxin are no longer in use in the USA.

22. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Pharmacokinetics • Metabolism and Excretion Almost 2/3 of digoxin is excreted unchanged by the kidneys. Digitoxin is metabolized in the liver and excreted into the gut via the bile. The enterohepatic circulation of digitoxincontributes to the very long half-life. Ouabain must be given parenterally and is excreted, mostly unchanged, in the urine.

23. II. Basic Pharmacology of Drugs Used in Heart Failure X 1. Digitalis  Pharmacoligical mechanism Hypokalemia Hyperkalemia

24. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Pharmacoligical mechanism ACTIONS （1）Positive inotropic action - inhibitor of Na+-K+ATPase （2）Negative chronotropic action - inhibits sympathetic activities - improves vagal activities （3）Actions on cardiac electrophysiology - decreases automaticity of sinoatrial node slow conduction - increases automaticity of Pukinje fibres - shortens ERP of fast reaction cells

25. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Pharmacoligical mechanism ACTIONS （4） Actions on nervous system - autonomic nervous system - central nervous system（D2 receptor） （5）Actions on neuroendocrine system - inhibits RAAS - increases ANP（心房钠尿肽） （6）Actions on kidney（diuretic effect） - increases blood supply of kidney - decreases Na+ resorption (inhibition of Na+-K+ ATP ase)

26. Digoxin Cardiac failure Cardiac output Blood supply Venous pressure Renal blood flow Renin - angiotension Ⅱ Venous hyperemia Aldosterone Pulmonary circulation: cough, emptysis, dyspnea Systemic circulationhyperemia: jugular vein distension, edema Sodium and water retention Changes of hemodynamics in CHF

27. Cardiac output

28. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Clinical usage and toxicity Therapeutic uses： （1）CHF Especially associated with atrial fibrillation and ventricular tachycardia （2）Some arrhythmias - atrial fibrillation - atrial flutter - paroxysmal surpraventricular tachycardia

29. II. Basic Pharmacology of Drugs Used in Heart Failure Administration & Dosage 1. Digitalis  Clinical usage and toxicity

30. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Toxicity and prevention • Cardiac toxicity • Tachyarrhythmia：various • Bradyarrhythmia：atrial ventricular block, sinus bradycardia. Atropine, isoprenaline,. • Digoxin immune fab

31. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Toxicity and prevention • 2) GI response • Anorexia, nausea, vomit, diarrhea. Should be distinguish with heart failure. • 3) CNS response and visual disturbance • Dizzy, headache, fatigue, xanthopsia, chloropsia etc • 4) The symptoms to stop digitalis administration： • Severe vomit、chromatopsia, Ventricular premature, Heart rate < 60 times/min

32. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Toxicity and prevention • Serum digitalis and K+ levels and the ECG should be monitored during therapy of significant digitalis toxicity. Of the available antiarrhythmic agents, lidocaine is favored. • Digitalis antibodies (digoxin immune fab) are clinically used for severe toxic patients.

33. II. Basic Pharmacology of Drugs Used in Heart Failure 1. Digitalis  Toxicity and prevention Interactions • Hypokalemia increase the risk of serious digitalis-induced cardiac arrhythmias • Quinidine displaces digoxin from tissue binding sites (a minor effect) and depresses renal digoxin clearance (a major effect) . • Antibiotics that alter gastrointestinal flora may increase digoxin bioavailability. • Agents that release catecholamines may sensitize the myocardium to digitalis induced arrhythmias.

34. 50 Relative Risk 0.99 95% CI 0.91–1.07 P=.80 Placebo 40 Digoxin 30 Mortality From Any Cause (%) 20 10 All-cause mortality rates: Placebo 35.1%; Digoxin 34.8% 0 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Months Number of patients at risk: Placebo 3,403 3,239 3,105 2,976 2,868 2,758 2,652 2,551 2,205 1,881 1,506 1,168 734 339 Digoxin 3,397 3,269 3,144 3,019 2,882 2,759 2,644 2,531 2,184 1,840 1,475 1,156 737 335 Effect of Digoxin on Mortality in Heart Failure: The Digitalis Investigation Group CV Mortality 0% HF Hospitalizations 28% Total Hospitalizations 6% DIG (Digitalis Investigation Group): 6,800 patients with LVEF 45% randomized to digoxin (n=3,403) or placebo (n=3,397) in addition to therapy with diuretics and ACEI followed for 37 months. The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532.

35. II. Basic Pharmacology of Drugs Used in Heart Failure 2. Other Positive Inotropic Drugs Used in Heart Failure （略）  Adrenoceptor Stimulants, e.g. dobutamine Result in  cardiac output and  ventricular filling pressure. There is potential for producing angina or arrhythmias in patients with coronary artery disease. Side effects: angina, arrhythmias and tachyphylaxis etc

36. II. Basic Pharmacology of Drugs Used in Heart Failure 2. Other Positive Inotropic Drugs Used in Heart Failure （略） Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure.

37. II. Basic Pharmacology of Drugs Used in Heart Failure • 1. Positive Inotropic Drugs • Digitalis • Beta Adrenoceptor Stimulants • Dopamine • 2. Diuretics • 3. RAAS inhibitors • ACEI • ARB • Adolsterone antagonists • 4. Vasodilators • 5. Beta blockers • 6. rhBNP

38. II. Basic Pharmacology of Drugs Used in Heart Failure 3. Drugs Without Positive Inotropic Effects Used in Heart Failure Diuretics To reduce venous pressure and ventricular preload. The results are reduction of edema and its symptoms and reduction of cardiac size, which leads to improved pump efficiency.

39. Therapeutic effects of diuretics in CHF

40. II. Basic Pharmacology of Drugs Used in Heart Failure • 1. Positive Inotropic Drugs • Digitalis • Beta Adrenoceptor Stimulants • Dopamine • 2. Diuretics • 3. RAAS inhibitors • ACEI • ARB • Adolsterone antagonists • 4. Vascular dilators • 5. Beta inhibitors • 6. rhBNP

41. Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20 reabsorption RAAS Angiotensinogen t-PA Cathepsin G Tonin Renin A I Bradykinin ACE CAGE Cathepsin G Chymase Degradation products A II AT1 receptor AT2 receptor • Hypertrophy/proliferation • Vasoconstriction • Sympathetic stimulation • Aldosterone release • Vasopressin • Antiproliferation • Antifibrotic • NO Release • Differentiation • Vasodilation

42. II. Basic Pharmacology of Drugs Used in Heart Failure 3. Drugs Without Positive Inotropic Effects Used in Heart Failure RAAS inhibitors Reduce peripheral resistance and thereby reduce afterload; Reduce salt and water retention (by reducing aldosterone secretion) and in that way reduce preload. Reduces sympathetic activity. Reduce the long-term remodeling of the heart and vessels.

43. ACEI Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20 reabsorption RAAS Angiotensinogen t-PA Cathepsin G Tonin Renin X A I Bradykinin ACE CAGE Cathepsin G Chymase X Degradation products A II AT1 receptor AT2 receptor • Hypertrophy/proliferation • Vasoconstriction • Sympathetic stimulation • Aldosterone release • Vasopressin • Antiproliferation • Antifibrotic • NO Release • Differentiation • Vasodilation X X

44. II. Basic Pharmacology of Drugs Used in Heart Failure 3. Drugs Without Positive Inotropic Effects Used in Heart Failure CV Risk, reduction in future cardiovascular events; DN, diabetic nephropathy; H, hypertension; HF, heart failure; Post MI, reduction in heart failure or other cardiac events following myocardial infarction.

45. x ARB Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20 reabsorption RAAS Angiotensinogen t-PA Cathepsin G Tonin Renin A I Bradykinin ACE CAGE Cathepsin G Chymase Degradation products A II ARB x AT1 receptor AT2 receptor x • Hypertrophy/proliferation • Vasoconstriction • Sympathetic stimulation • Aldosterone release • Vasopressin • Antiproliferation • Antifibrotic • NO Release • Differentiation • Vasodilation

46. II. Basic Pharmacology of Drugs Used in Heart Failure 3. Drugs Without Positive Inotropic Effects Used in Heart Failure CV Risk, reduction in future cardiovascular events; DN, diabetic nephropathy; H, hypertension; HF, heart failure; Post MI, reduction in heart failure or other cardiac events following myocardial infarction.

47. II. Basic Pharmacology of Drugs Used in Heart Failure 3. Drugs Without Positive Inotropic Effects Used in Heart Failure Aldosterone antagonists Spironolactone and Eplerenone get additional function to decrease morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy.

48. Effects of Aldosterone Cardiac Myocyte Fibroblast Peripheral Artery Kidney Vasoconstriction Potassium Loss Hypertrophy Hyperplasia Endothelial Dysfunction Sodium Retention Collagen Synthesis Norepinephrine Release Hypertrophy Fibrosis Decreased Compliance

49. RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF 1.00 Spironolactone (25 mg) + standard care (n = 822) 0.95 Placebo + standard care (n = 841) 0.90 0.85 0.80 HR = 0.70 (95% CI, 0.60 to 0.82) 0.75 0.70 Probability of Survival (%) 0.65 0.60 0.55 P<.001 0.50 0.45 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months HR = hazard ratio; RR = risk reduction. *Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months. Pitt B et al. N Engl J Med. 1999;341:709-717.

50. 22 20 18 16 14 12 Cumulative Incidence (%) 10 8 6 HR = 0.85 (95% CI, 0.75 to 0.96)P = .008 4 2 0 0 3 6 9 12 15 18 21 24 27 Months Since Randomization EPHESUS Co-Primary Endpoint:Total Mortality Eplerenone + standard care (n = 3319) (16.7%) (14.4%) Placebo + standard care (n = 3313) HR = hazard ratio. Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.