Treatment of congestive heart failure

1. Treatment of congestive heart failure Overview of congestive heart failure Congestive heart failure (CHF) is a condition in which the heart is unable to pump sufficient blood to meet the needs of body. CHF can be increased workload imposed on the heart. CHF is accompanied by abnormal increases in blood volume and interstitial fluid; the heart, veins, and capillaries are therefore generally dilated with blood. Hence the term “congestive(充血性)” heart failure, since the symptoms include pulmonary congestion with life heart failure, and peripheral edema with right heart failure. Underlying causes of CHF include arteriosclerotic heart disease, hypertensive heart disease, valvular heart disease(心瓣膜病), dilated cardiomyopathy(扩张性心肌病), and congenital heart disease(先天性心脏病). Left systolic dysfunction secondary to coronaryartery disease is the most common cause of heart failure.

2. Heart Failure • Final common pathway for many cardiovascular diseases whose natural history results in symptomatic or asymptomatic left ventricular dysfunction • Cardinal manifestations of heart failure include dyspnea, fatigue and fluid retention • Risk of death is 5-10% annually in patients with mild symptoms and increases to as high as 30-40% annually in patients with advanced disease

3. Main causes • Coronary artery disease • Hypertension • Valvular heart disease (心瓣膜病) • Cardiomyopathy (心肌病) • Cor pulmonale

4. Compensatory changes in heart failure • Activation of SNS • Activation of RAS • Increased heart rate • Release of ADH • Release of atrial natriuretic peptide心钠素 • Chamber enlargement 心室腔扩大 • Myocardial hypertrophy 心室肥厚

5. Classification of heart failure • Class I: No limitation of physical activity • Class II: Slight limitation of physical activity • Class III: Marked limitation of physical activity • Class IV: Unable to carry out physical activity without discomfort

6. New classification of heart failure • Stage A: Asymptomatic with no heart damage but have risk factors for heart failure • Stage B: Asymptomatic but have signs of structural heart damage • Stage C: Have symptoms and heart damage • Stage D: End stage disease ACC/AHA guidelines, 2001

7. CHF的病理生理过程及可能治疗的环节 心功能障碍 收缩功能 舒张功能 正性肌力药 改善舒张功能药 输出量 心率 受体阻断药 长期病情 血管收缩 神经激素 心肌1受体 RAA CA 心缩力顺应性 阻抗顺应性后负荷 抗RAA系统药 钠水潴留 减后负荷药 心肌肥大、重构 利尿药 血管肥厚、重构 血容量 前负荷 恢复心血管病理形态的药 静脉淤血 减前负荷药

8. Strategy of treatment of CHF The therapeutic goal for CHF is to increase cardiac output. • Inotropic agents that increase the strength of contraction of cardiac muscle • PDEI (phosphodiesterase inhibitors) agents that increase cAMP to induce systoles and vasodilatation • Calcium sensitizers extracellular fluid volume • b adrenergic agonist • b adrenergic antagonist • Vasodilators: Calcium channel blocker • Decreasing RAS activity: ACEI and AT1 antagonist • Diuretic agents

9. Treatment of congestive heart failure Classification 1 Positive inotropic drugs Cardiac glycosides β-adrenergic agonists (New dopamine receptor agonist) phosphodiesterase inhibitors Calcium sensitizers 2 Diuretics 3 Vasodilators Calcium channel blocker Nitryl-vasodilators Hydralazine 4 RAAS inhibitors: antiotensin converting enzyme inhibitor and AT1 antagonist 5 β-receptor blocker

10. Classification1 Positive inotropic drugsCardiac glycosides/强心苷类 structure-activity relationship A cardiac glycoside molecule consists of an aglycone苷元 or genin配基, which possesses the same pharmacologic activity as the whole molecule combined chemically with one or more sugars.

11. CH3 12 17 O D C CH3 OH O A B 3 O H C18 H31O9 Cardiac glycosides Aglycones 苷元 Digitoxin Digoxin = H at 12 C = OH at 12 C Unsaturated lactone 不饱和内酯环 Convey cardiotonic activity steroid nucleus 甾核 Convey the pharmacological activity Sugars- 3 mols. of digitoxose 3分子洋地黄毒糖 Modulate potency and pharmacokinetic distribution

12. CH3 12 17 O D C CH3 OH O A B 3 O H C18 H31O9 1. The relationship between structure and effects C C14 C The Indispensable parts of activity The number of -OH and glycose will decide water-solubility and lipid-solubility • 活性基团activity：C17 不饱和内酯环Unsaturated lactone 、C14羟基OH、C3 洋地黄毒糖digitoxose • 脂溶性lipid-solubility： C3 洋地黄毒糖；水溶性water-solubility：C12及其他位点的羟基数

13. Classification of cardiac glycosides 1. grade 1: in plant, cedilanide 2. grade 2: extract of digitalis Digitoxin（洋地黄毒苷）, Digoxin（地高辛）, Deslanoside （旋花毛地黄苷）, Strophanthin K（毒毛旋花子苷K) 3.地高辛和洋地黄毒苷C3位均联结3个洋地黄毒糖，地高辛C12位多一个羟基，毒毛花苷K的甾核上有多个羟基，所以脂溶性：洋地黄毒苷>地高辛>毒毛花苷K。

14. Process of drug through body

15. Pharmacologic action I. Action of cardiac glycosides on the heart • Positive inotropic action：Increasing contractility of cardiac muscle in heart failure. • (1) characteristic: • myocardiac quick contraction, Q-T period↓ ①rate of force ↑ • ②time to peak tension ↓

16. B. no increase oxygen consumption： the increase in output is not accompanied by an equivalent increase in oxygen consumption Factors of oxygen consumption： 1）Myocardia contractility 2）Heart rate 3）Myocadiac fiber length and tone

17. Factors affect consumption of oxygen • The force of cardiac contraction • Heart rate • Volume of ventricular

18. C. Effect of positive inotropic act ① cardiac output is increased ② compensatory sympathetic tone is reduced ③ cardiac preload and afterload is decreased ④ heart rate is reduced ⑤ myocardiac fiber tone and oxygen consumption is decreased ⑥ increasing stroke volume causes a decrease in end-systolic volume

19. (2) Machanism of cardiac glycoside on positive inotropic action A. Inhibiting Na+-K+-ATPase in therapeutic dose: B. Increasing of calcium inward and induce the releasing of calcium from sarcoplasmic reticulum ( internal stores, by CICR)

20. Na+-K+-ATPase is a recetor of glycoside ↓ ↓ glycoside → α β ↓ Structure changes ↓ Enzyme activity ↓ ↓ Na+↑,K+↓ in cell ↓ Ca2+Na+exchange↓ in cell) Mechanism of pharmacological act

21. →  Na+  i Na+-K+-ATPase is the receptor of cardiac glycosides , so cardiac glycosides act byinhibitingthe membrane Na+-K+-ATPase pump→  Na+ i

22. →by Na＋/Ca 2+exchanger → Ca2+ i↑ Bidirectional exchange ①Na+ enter↓ →Ca2+ ↓ outer ②Na+ outer↑→Ca2+ ↑ enter

23. → Ca 2+ i↑ Sarcoplasmic reticulum Ca2+ -induced Ca2+ release Sarcoplasmic reticulum release Ca 2+ Enhance the increased cytosolic calcium concentration

24. 2.Negative chronotropic action A. Continuous effect of positive inotropic action decreasing sinus rate heart rate is decreased

25. B. Increasing sensibility of myocardia to vagus nerve (increasing of potassium outward and resting potential,reducing of automaticity). Heart rate is decreased, Atropine can antagonize (block)

26. 3. Affects of glycosides to conductive tissues A. Increasing conduction of the atrial muscle fibers, because increasing excitation of vagus nerve (increasing of potassium outward). Increasing resting potential. Elevating rate of phase-0 depolarization. Acceleration rate of depolarization phase-0 and atrial fibers conduction.

27. B. Slowing (depress) conduction at the atrioventricular (A-V) node (inhibiting Na-K-ATPase, reducing resting potential), and increase effctive refractory period atrial fibrillation, atrial flutter, paroxymal (and) or supraventricular tachycardia C. Increasing automaticity of Purkinjie fibres： toxicity

28. Mechanism of toxicity act • If Na+-K+-ATPase was inhibited more than 30%, cardiac glycosides would induce toxicity by the overload of intercellular free calcium concentration in myocardiac. (decreasing inotropic action) • If intercellular potassium concentration was lower level, cardiac glycosides would easily induce toxicityin myocardiac. (arrhythmia)

29. 4. Affects of cardiac glycasides to ECG (electrocardiography) A. Therapeutic dose: T-wave can become low, flat, isoelectric or inverted S-T segment falls below the isoelectric line P-R interval is lengthened, which is associated with slower or delayed A-V conduction Q-T interval is shortened, ERP and APD is shortened in Purkenje fibers B. Higher dose: arrhythmias

30. The affects on ECG T wave It is characterized by an descend ST segment on the ECG P-R Q-T P-P

31. II. Action of cardiac glycosides on neural and hormone • Directly inhibit or reflected decrease sympathetic activity • Exciting increase the vagal activity • Inhibit RAAS system, promote the excrete of ANP • cause arrhythmias (toxic doses) II. Action of cardiac glycosides on vascular and kidney • Vasoconstriction, increase in peripheral vascular resistance • Diuretic，increase the blood flow through kidney and inhibit Na+-K+-ATPase → Na＋decreased re-absorb new

32. Clinical uses • Cardiac glycosides are given for CHF • Effects： Best go with atrial fibrillation • Better hypertension congenital heart disease • not good anaemia lack of vitamin B1 • not useful pericarditis 心包炎 • Some kinds of arrhythmias • Atrial fibrillation • Atrial flutter • Supraventricular Tachycardia

33. Toxic effects • Responses of stomach-intestines : • Anorexia 厌食, nausea，vomiting , • Abdominal pain and diarrhoea • CNS: visual disturbaces • Arrhythmia: • 1) Tachycardia • 2)AV block • 3)Bradycardia <60 beat/min

34. Prophylaxis and treatment of the toxicity • Clear the signal of toxic and the indication of withdraw • Inspect the concentration of digoxin (3ng/ml), digitoxin(45ng/ml) • If necessary ,potassium supplements and antiarrhythmic drugs ( phenytoin ,lidocaine,atropine )administered • For severe intoxication ,antibodies specific to cardiac glycosides are available

35. Method of administration • Classical ：whole effect dose • quick or slow (have use digoxin within two weeks) • The suitable dose to the patients • Maintain ：4～5 t ½ • Digoxin 0.25mg/day , 6～7 day ( t ½ 33～36 hours)

36. Classification1 Positive inotropic drugs  -Adrenoceptor agonists They are used intravenously in CHF emergencies Example of  -Adrenoceptor agonists : • Dobutamine (多巴酚丁胺) • Exciting β1 Adrenoceptor → positive inotropic action →the volume of output↑ • Exciting β2 Adrenoceptor→dilate the vascular → afterload↓ • have benefits within short time

37. Classification1 Positive inotropic drugs Phosphodiesterase-Ⅲ inhibitors Inodilator / inodilating drugs Inhibiting the activity of PDE Ⅲ → cAMP↑→ causes an increase in myocardial contractility and vasodilatation →total peripheral resistance →cardiac output ↑ Examples: Armirinone（氨力农）: Inhibits the excess product of NO, TNF and affects the neurohormone, anti-the forming of thrombus milrinone（米力农）: stronger20 time vesnarinone（维司力农）: myocardial contract element’s the sensitivity to calcium

38. Classification1 Positive inotropic drugs Calcium sensitizers Pimobendan 匹莫苯: Inhibit PDE Ⅲ ; increase TnC’s sensitivity to calcium Tn troponin—肌钙蛋白；myosin－肌球蛋白；tropomyosin－原 ；Actin 肌动蛋白

39. Classification 2Diuretics Diuretics inhibit sodium and water retention, →reduce the volume of blood, →venous pressure and the thus cardiac preload are reduced↓, increasing the efficiency of the heart as a pump→ cardiac output ↑, so reduce oedema due to heart failure • Heart failure • Low-grade : Thiazides hydrochlorothiazide 氢氯噻嗪 • Higher-grade : Acute left heart failure • loop diuretics --- furosemide 呋塞米（速尿） • Spironolacton 螺内酯 • （anti-aldosterone ,keep potassium and diuretics)

40. Classification 3Vasodilators • Antiotensin converting enzyme inhibitor (ACEI) and AT1 antagonist • Calcium channel blocker • Nitryl-vasodilators • Hydralazine

41. ACEI and AT blocker bradykinin aldosterone

42. Classification 3Vasodilators Angiotensin-converting-enzyme inhibitor (ACEI ) Captopril Enalapril • Methanism of anti-CHF: • Humour: Inhibit ACE→angiotensin Ⅱ and aldosterone levels↓, reduce sodium retention, increase bradykinin levels , ANP、 NO、PGI2↑, reduce the release of NA ET and renew the expression of βreceptor • This therefore causes vasodilatation (include coronary artery) →reduction in peripheral resistance→ increase the cardiac output, Increase the blood flow of kidney so Improve the function of kidney • 3) Prevent the remodel of the heart

43. AT1 antiagonists Losartan （氯沙坦） The function just like ACEⅠ It dosen’t influence bradykinin levels • Clinical utilize: • CHF • Protection of kidney

44. Calcium-channel blockers Amlodipine 氨氯地平 Vessel Dilate artery Dilate the coronary Alleviate the LV Wall Tension

45. Others --- Vasodilators mechanism Dilatation of the veins→ decreases preload Dilatation of the artery→ decreases afterload Decrease the oxygen demand of the heart Nitrate esters: nitroglycerin , nitroprusside sodium硝普纳 Hydralazine 肼屈嗪 direct dilate the vascular Prazosin 哌唑嗪 ɑ- receptor blocker

46. Classification 4 receptor blocker Carvedilol 卡维地洛 labetalol 拉贝洛尔 Bisoprolol 比索洛尔 • Carvedilol 卡维地洛 • mechanism • Anti RAAS system • Anti-arrthymias • Anti-myocardial ischemia Cardiomyopathy心肌病

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48. 二 other action of cardiac gylcosides • Nerve system Toxic concentration:enhancing sympathetic activity increasing sympathetic impulse of preganglial and afterganglial fibers, can cause atrial fibrillation and ventricular tachycardia.

49. Therapeutic dose: increasing parasympathetic center in brain stem excitation------slowing rate of heart,inhibiting conduction

50. 2. Effect of cardiac glycosides to kidney ①increasing renal blood flow and filtering rate of glomerulus ②competitive antagonism with aldosterone in proximal tubule