1. Part 4 Drugs for Treatment of Congestive Heart Failure

2. Contents § Overview § ACE inhibitors § Diuretics §  receptor blockers § Cardiac glycoside § Others Heart (cardiac) failure is said to have occurred when the heart is no longer able to maintain the circulation to the tissues for normal metabolism.

3. 1. Pathophysiological changes of congestive heart failure (CHF) (1) Function and structure changes (2) Increased sympathetic activity and down-regulation of  receptor down-regulation of  receptor (3) Activated renin-angiotensin-aldosterone system (RAAS) A. Overview

4. Pathophysiological changes of CHF

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

7. A. Overview 2. Grades of CHF I (A): no symptoms II (B): physical activities were limited and symptoms could be induced by general activity II (B): physical activities were limited and symptoms could be induced by general activity III (C): physical activities were markedly limited III (C): physical activities were markedly limited IV (D): symptoms appear even at rest IV (D): symptoms appear even at rest

8. 3. Therapeutic strategies in CHF (1) Increasing contractility of the cardiac muscles (2) Inhibiting RAAS (3) Reducing sympathetic activity (4) Dilating vessels (5) Diuresis A. Overview  Cardiac remodeling Decreaseoverload

9. Drug therapy for CHF

10. ACEI: captopril 卡托普利 captopril 卡托普利 enalapril 依那普利 enalapril 依那普利 AT 1 receptor antagonists: losartan 氯沙坦 losartan 氯沙坦 irbesartan 伊白沙坦 irbesartan 伊白沙坦 B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

11. Cardiovascular remodeling vasodilatation Systemic and local

12. ACEI 1. Pharmacological effects §Inhibiting the production of Ang II § vasoconstriction  ; sodium retention  ; § cardiac remodeling (myocardial hypertrophy)  §Inhibiting the degradation of bradykinin § vasodilatation  §Increasing ANP and scavenging free radicals B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

13. Box Actions of angiotensin II through activating AT 1 receptors Constricting vessels, increase peripheral resistance and returned blood volume.Constricting vessels, increase peripheral resistance and returned blood volume. Increasing sympathetic tension, promote release of sympathetic transmitter.Increasing sympathetic tension, promote release of sympathetic transmitter. Stimulating release of aldosterone.Stimulating release of aldosterone. Rapidly inducing expression of c-fos, c-jun, Egr-1, c-myc, etc.Rapidly inducing expression of c-fos, c-jun, Egr-1, c-myc, etc.

14. §Cardiovascular effects § Decrease resistance of peripheral vessels § Dilate coronary artery, increase blood supply of heart and kidney, improve cardiac and renal function § Reverse myocardial hypertrophy and ventricular remodeling B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

15. 2. Clinical uses (1) CHF increase motor tolerance increase motor tolerance decrease mortality decrease mortality (2) Hypertension

16. 3. Adverse effects Hypotension Hypotension §Cough and angioedema §Hyperpotassemia §Rashes and altered tastes §Contraindications: pregnancy and stenosis of renal artery B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

17. AT 1 receptor antagonists Compared with ACEI: §Blocking actions of angiotensin II directly §Not affecting bradykinin metabolism §Protecting renal function §Used for CHF and hypertension B. Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists

18. 1. Pharmacological effects §Reduce blood volume by increasing Na + and water excretion §Reduce Na + -Ca 2+ exchange in vascular smooth muscle cells 2. Clinical uses §CHF: grand I – IV (mainly used in II –III), alone or combined with other drugs §Edema, hypertension, etc. 3. Adverse effects imbalance of electrolytes/acid-base; imbalance of electrolytes/acid-base; plasma level of renin  ; hypokalemia; hyperuricemia; hyperglycemia/hyperlipidemia plasma level of renin  ; hypokalemia; hyperuricemia; hyperglycemia/hyperlipidemia C. Diuretics

19. Therapeutic effects of diuretics in CHF

20. Commonly used: carvedilol 卡维地洛, bisoprolol 比索洛 尔, sustained-release metoprolol 缓释型美托洛尔 1. Pharmacological effects (1) Blocking effects of catecholamines on myocardium: decreasing heart rate and cardiac oxygen demand (2) Up-regulating  receptor (3) Inhibiting RAAS and VP (vosopressin, 加压素 ): anti- myocardial hypertrophy and remodeling (4) Reducing cardiac oxygen remand, vasodilatation (  receptor block) (5) Anti-arrhythmic and anti-hypertensive effects D.  receptor blockers

21. 2. Clinical uses (1) CHF: grand II - III decreasing mortality decreasing mortality (2) Other uses: hypertension, arrhythmias, angina, etc. hypertension, arrhythmias, angina, etc. D.  receptor blockers

22. Therapeutic effects of  receptor antagonists on cardiac function in CHF patients D.  receptor blockers

23. 3. Adverse effects §Inhibition of cardiac function §Contraindications: § severe heart failure severe A-V block severe A-V block hypotension hypotension worsening bronchial asthma worsening bronchial asthma D.  receptor blockers

24. E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis) Cardiac glycoside: It is a kind of glycoside compounds which can selectively act on cardiac muscle, and increase the force of myocardial contraction. Cardiac glycoside : It is a kind of glycoside compounds which can selectively act on cardiac muscle, and increase the force of myocardial contraction.

25. Digoxin 地高辛 E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

26. 1. Pharmacological effects (1) Positive inotropic effects inhibiting Na + -K + -ATPase  free Ca 2+   excitation- contraction coupling  inhibiting Na + -K + -ATPase  free Ca 2+   excitation- contraction coupling  cardiac output   organ blood supply  cardiac output   organ blood supply  Vmax   diastolic duration   venous return  Vmax   diastolic duration   venous return   coronary blood supply   coronary blood supply  cardiac oxygen consumption  cardiac oxygen consumption  E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

27. Inhibition of Na + -K + -ATPase by digitalis and potentiation of cardiac muscle contraction

29. (2) Negative chronotropic effects Reflex inhibition of sympathetic activity cardiac output   Sympathetic activity   HR  cardiac output   Sympathetic activity   HR  Increasing vagal activitydirectly Increasing vagal activity directly Reducing AV conduction: ventricular rate  E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

30. (3) Electrophysiological effects decreasing automaticity of sinoatrial node slow conduction, especially AV conduction slow conduction, especially AV conduction increasing automaticity of Purkinje fibres increasing automaticity of Purkinje fibres shortening ERP of fast response cells shortening ERP of fast response cellsMechanisms: intracellular Na + , K + , Ca 2+   intracellular Na + , K + , Ca 2+   MDP , afterdepolarization MDP , afterdepolarization E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

31. Overdose: Na + , K + , Ca 2+    MDP   afterdepolarization Electrophysiological basis for digitalis overdose

32. ECG: P-R  ; S-T/T wave  ; various arrhythmias P-R  S-T/T wave  prematural ventricular beat

33. (4) Other effects Vessels: vasoconstriction Central nervous system: CTZ dopamine D 2 receptor CTZ dopamine D 2 receptor mental and vision disorders mental and vision disordersKidney: increase blood supply of kidney increase blood supply of kidney diuretic effect: decrease Na + reabsorption diuretic effect: decrease Na + reabsorption E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

34. 2. Clinical uses (1) Congestive heart failure (CHF) especially associated with atrial fibrillation and sinus tachycardia especially associated with atrial fibrillation and sinus tachycardia (2) Arrhythmias atrial fibrillation / atrial flutter: paroxysmal surpraventricular tachycardia paroxysmal surpraventricular tachycardia E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

35. 3. Adverse effects (1) Gastrointestinal effects nausea, vomiting, etc. nausea, vomiting, etc. (2) CNS effects alteration of color perception （ 色视, such as yellow vision 黄视 ） ; headache, fatigue, confusion, etc. E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

36. (3) Cardiac toxicity arrhythmias ： prematural beats, tachycardia ， atrioventricular block, sinus bradycardia, etc. Prevention ： Dose individualization Avoiding provocation factors: plasma K + , and drug interactions, etc. Avoiding provocation factors: plasma K + , and drug interactions, etc. Treatment ： KCl, phenytoin or lidocaine, i.v. Atropine: A-V block, sinus bradycardia Atropine: A-V block, sinus bradycardia Fab segment of digoxin antibody, i.v. Fab segment of digoxin antibody, i.v. E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

37. Drug interactions that probably induce digitalis cardiotoxicity

38. 4. Administration (1) Loading + maintaining doses §full dose (digitalization) + maintaining doses §for severe patients (2) Maintaining dose given daily reaching steady state of plasma concentration with 1 week (digoxin) reaching steady state of plasma concentration with 1 week (digoxin) for stable patients for stable patients E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

39. 5. ADME and properties of different digitalis drugs (1) Moderate-acting: digoxin 地高辛 (2) Long-acting ： digitoxin 洋地黄毒苷 digitalization + maintaining doses digitalization + maintaining doses (3) Short-acting ： deslanoside 西地兰, 去乙酰毛花苷 acute attack of CHF acute attack of CHF E. Cardiac glycoside(digitalis) E. Cardiac glycoside (digitalis)

41. 1.  receptor agonists dobutamine 多巴酚丁胺 dobutamine 多巴酚丁胺 §Positive inotropic drugs §Arrhythmias, etc. 2. PDE-III inhibitors milrinone 米力农, vesnarinone 维司力农 ， amrinone 安力农 amrinone 安力农 §Positive inotropic drugs §Hypotension, thrombocytopenia, etc. F. Other drugs

42. 3. Vasodilators cardiac preload and afterload , output  cardiac preload and afterload , output  4. Calcium channel blocker 5. Calcium sensitizers F. Other drugs

43. Action modes of positive inotropic drugs

44. Therapeutic strategies of CHF