Drugs for Treatment of Congestive Heart Failure （ CHF ）

1. Drugs for Treatment of Congestive Heart Failure （CHF）

2. 病 例 回 顾 患者×××，男，61岁。因反复胸闷、气促3年，再发伴加重半月入院。 现病史：患者3年前无明显诱因出现胸闷、气促，好高枕卧位。无胸骨后疼痛，无畏寒发热，无咳嗽，无头晕黑蒙，无晕厥及视物模糊。前往某医院就诊，诊断为“扩张型心肌病，急性左心衰”，给予“地高辛”、“双克”、“氨苯蝶啶”、“鲁南欣康”、“参麦”、“葛根素”等治疗，症状好转后出院。此后上述症状反复发作，曾多次入院治疗。半个月前患者因感冒、咳嗽、咳痰导致上述症状再次发作，静息时即感到胸闷、气促，稍作体力活动后症状加重。夜间睡眠不能平卧，有时端坐呼吸。无发热、畏寒，有咳嗽，咳大量白色粘痰，为求进一步诊治，以“扩张型心肌病”、“肺部感染”、“心功能不全III度”收住入院。 入院体检：T 36.5℃，P 90次/分，R 20次/分，BP 125/95mmHg， 呼吸音粗，左下肺有湿罗音，心浊音界扩大，双下肢轻度水肿

3. 病 例 回 顾 入院医嘱： 第一天2pm： 心内科护理常规、I级护理、低盐普食、吸氧必要时 速尿（呋塞米） 20mg qd 安体舒通（螺内酯）20mg qd 欣康（单硝酸异山梨酯） 40mg qd FDP(果糖二磷酸钠) 10g qd 来立信（左氧氟沙星）0.3g，静滴，bid ……(各种检查)

4. 病 例 回 顾 第三天…………….（利尿药） 第七天 达力全（卡维洛尔）3.125mg qd 倍他乐克（美托洛尔）120mg bid 第二天1am： 计24小时尿量 米力农10mg，静滴，qd 地高辛0.125g qd 洛汀新（贝那普利）10mg qd 吉诺通（粘痰溶解药）1 tid

5. OVERVIEW---Types of 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 (心包炎) (3) High-output failure: can result from hyperthyroidism (甲亢), beriberi(脚气病), anemia(贫血), and arteriovenous shunts (动静脉分流).

6. OVERVIEW---Grades Grades of CHF according to symptoms: Class I: no limitation is experienced in any activities; no symptoms from ordinary activities. Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion. Class III: marked limitation of any activity; the patient is comfortable only at rest. Class IV: any physical activity brings on discomfort and symptoms occur at rest.

7. OVERVIEW---Grades Grades of CHF according to progress: Stage A: a high risk HF in the future but no structural heart disorder; Stage B: a structural heart disorder but no symptoms at any stage; Stage C: previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment; Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care At risk HF

8. 1. OVERVIEW--Pathophysiological changes of CHF Fall in cardiac output Myocardial injury Activation ofSNS, RAAS 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.

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

10. Actions of angiotensin II • Constricts vessels, increases peripheral resistance and returned blood volume. • Increases sympathetic tension, promotes release of sympathetic transmitter. • Stimulates release of aldosterone (醛固酮). • Induces expression of c-fos、c-myc、c-jun rapidly, promotes proliferation and remodeling.

11. Changes of  receptor signal transduction in CHF ---Uncoupling of 1receptors and Gs protein ---Density of 1 receptors  ---Amount and/or activity of Gs protein 

12. OVERVIEW--- Therapeutic strategies in CHF A To inhibit RAAS: ACEIs, ARBs B To decrease sympathetic activity: ACEIs, β blockers C To increase contractility of the cardiac muscle: glycosides, PDE III inhibitors, other positive inotropes (正性肌力药物) D To dilate vessels: vasodilators E To decrease circulation volume: diuretics F To retard or reverse remodeling: ACEIs, amlodipine

13. ACEIs and ARBs ACEIs (captopril, enalapril) Actions • Inhibit the production of Ang II • Inhibit the degradation of bradykinin

14. PGI2 NO Actions of ACEIs Inactive peptide Angiotensin II Brandykinin Angiotensin I ACEIs (—) B2 receptor ACEIs ACE Circulation and local tissues (—) ACE Circulation and local tissues Vasodilatation Anti-proliferation, anti-hypertrophy

15. ACEIs and ARBs ACEIs Actions • 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 as well as vascular remodeling • Increase ANP and anti-free radical effect

16. ACEIs and ARBs ACEIs Clinical uses: • CHF - increase motor tolerance - decrease mortality • Hypertension

17. ACEIs and ARBs ACEIs Adverse effects: • Hypotension • Cough and angioedema • Hyperpotassemia: aldosterone inhibition • Contraindication: Pregnant or lactation women, stenosis of renal artery

18. ACEIs and ARBs ARBS Compared with ACEIs: • Block actions of angiotensin II directly • No influence on bradykinin metabolism • Protect renal function • Used for CHF and hypertension

19. 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.

20. ACEIs and ARBs Additional: Aldosterone antagonists Spironolactone (螺内酯) and Eplerenone (依普利酮) get additional function to decrease morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy.

21. 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.

22. 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.

23.  blockers metoprolol, carvedilol, bisoprolol Actions • Block effects of catecholamine on myocardium • Inhibit RAAS and VP (vosopressin, 加压素) • Decrease heart rate and cardiac oxygen demand • Antiarrhythmias, antihypertenstion and antianginal effects • Anti- myocardial hypertrophy and remodeling • Block -receptor and anti- free radical

24.  blockers Clinical uses: • CHF -Ⅱ ~ Ⅲ - decrease mortality • Hypertension, arrhythmias, angina, etc

25. The Use of Beta Adrenergic Blocking Agents in Heart Failure 15 10 5 LVEF % change 0 -5 -10 0 6 12 18 24 Time (weeks) Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF)

26. US Carvedilol Heart Failure Trials Program P<0.001 1094 Class II-IV CHF pts on triple therapy (ACEI, digoxin, diuretics) Carvedilol 6.25 bid test 2 weeks, then 12.5 bid, then 25 bid vs placebo Packer NEJM 1996;334:1349-55

27. Effect of Metoprolol CR/XL in Heart Failure MERIT-HF 3991 pts with CHF Class II-IV, ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd, target dose 200 mg qd Lancet 1999;353:2001-07

28. -Blockers Differ in Their Long-Term Effects on Mortality in HF Bisoprolol1 Bucindolol2 Carvedilol3-5 Metoprolol tartrate6 Metoprolol succinate7 Nebivolol8 Xamoterol9 Propranolol10 Beneficial No effect Beneficial Not well studied Beneficial Minor effect Harmful Harmful+Beneficial 1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6. 10 BHAT study Group. Circulation. 1986;73(3):503-10.

29.  blockers Adverse effects: • Inhibition of cardiac function • Contraindications: severe heart failure severe AV block hypotension bronchial asthma

30. Digitalis 毛地黄

31. Digitalis Digoxin(地高辛) Actions • Positive inotropic action- induces rapid and prompt contraction, prolongs diastolic period, no change or decease in oxygen consumption - Inhibitor of Na+- K+ATPase

32. 3 Na+ 2K+ Na+-K+-ATPase AP [Na+]i [Ca2+]i NCE Na+-Ca2+ exchange Mechanism of digitalis Digitalis NKA [K+]i

33. Digitalis Digoxin Actions: • Negative chronotropic action - inhibits sympathetic activities - improves vagal activities(accelerate K+ efflux)

34. Digitalis Digoxin Actions • Actions on cardiac electrophysiology -decreases automaticity of sinoatrial node - slows conduction - increases automaticity of Pukinje fibres - shortens ERP of fast reaction cells

35. Digitalis Digoxin Actions • Actions on the nervous system -autonomic nervous system - central nervous system (D2 receptor） • Actions on neuroendocrine system - inhibits RAAS - increases ANP (心房钠尿肽)

36. Digitalis Digoxin Actions • Actions on kidney (diuretic effect） -increases blood supply of the kidney - decreases Na+ resorption (inhibition of Na+-K+ ATP ase)

37. Digitalis Digoxin Clinical uses： • CHF Especially associated with atrial fibrillation and ventricular tachycardia

38. Digitalis Digoxin Clinical uses： • Some arrhythmias - atrial fibrillation - atrial flutter - paroxysmal surpraventricular tachycardia

39. Digitalis Digoxin Directions： • Typical method: full dose(digitalization)+maintaining dose • No-loading method： maintaining dose everyday

40. Effect of Digoxin on Mortality in Heart Failure 50 CV Mortality  0% Relative Risk 0.99 95% CI 0.91–1.07 P=.80 Placebo 40 Hospitalizations  28% Digoxin 30 Mortality From Any Cause (%) Total Hospitalizations  6% 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 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.

41. Digitalis Digoxin Adverse effects： • Gastrointestinal responses -severe nausea, vomit, diarrhea • Symptoms of the central nervous system： -alteration of color perception (chromatopsia，色视) - headache, fatigue, confusion

42. Digitalis Digoxin Adverse effects： • Cardiac effects - arrhythmias：tachycardia atrioventricular block sinus bradycardia

43. Symptoms to stop digitalis administration： - Severe vomit - Chromatopsia - Ventricular premature - Heart rate < 60 /min

44. Digitalis Digoxin Adverse effects： • Treatments： - KCl, phenytoin sodium or lidocaine, iv. - Bradycardia：Atropine, isoprenaline (NO supplement of K+) - Fab segment of digoxin antibody, iv.

45. Digitalis Digitoxin (洋地黄毒苷)： long-term actions digitalization + maintaining dose Deslanoside (Cedilanid，西地兰，毛花苷C（丙）） i.v.,acute attack of CHF

47. Diuretics Actions: • Reduce plasma volume • Reduce Na+-Ca2+ exchange in vascular smooth muscle cells

48. Diuretics Clinical uses: • CHF - CHF - used alone or combined with other drugs • Edema, hypertension, etc

49. Diuretics Adverse effects: plasma level of renin  (combined with ACEIs to minimize) hypokalemia (低钾血症) hyperuricemia (高尿酸血症) hyperglycemia (高血糖) hyperlipidemia (高脂血症)

50. Vasodilators Reduction in preload (through venous dilation), or reduction in afterload (through arteriolar dilation), or both. Long-term use of hydralazineand isosorbide dinitratecan also reduce damaging remodeling of the heart.