臨床藥理--治療充血性心力衰竭藥物課件

1、臨床藥理-治療充血性心力衰竭藥 物 1 治療充血性心力衰竭藥物治療充血性心力衰竭藥物 Drugs for Congestive Heart FailureDrugs for Congestive Heart Failure 心力衰竭（心力衰竭（heart failure）是各種原因引起的心?。┦歉鞣N原因引起的心肌 舒縮障礙，導致心輸出量不能滿足機體需求的一組舒縮障礙，導致心輸出量不能滿足機體需求的一組 臨床綜合征。充血性心衰是其中最主要的一種。臨床綜合征。充血性心衰是其中最主要的一種。 慢性或充血性心力衰竭（慢性或充血性心力衰竭（congestive heart congestive hear

2、t failure, CHFfailure, CHF）是各種病因所引起的多種心臟疾?。┦歉鞣N病因所引起的多種心臟疾病 （冠心、高心、肺心、風心、心肌病等）的終末階（冠心、高心、肺心、風心、心肌病等）的終末階 段，當靜脈回流足夠的情況下，心臟排出量絕對或段，當靜脈回流足夠的情況下，心臟排出量絕對或 相對減少，不能滿足機體組織需求的相對減少，不能滿足機體組織需求的一種臨床或病一種臨床或病 理綜合征理綜合征。 心衰病人運動耐量下降，壽命縮短。心衰病人運動耐量下降，壽命縮短。 臨床藥理-治療充血性心力衰竭藥 物 2 Concept:Concept: CHF is a complex clinical

3、syndrome CHF is a complex clinical syndrome characterized by impaired ventricular characterized by impaired ventricular performance, exercise intolerance, a performance, exercise intolerance, a high incidence of ventricular high incidence of ventricular arrhythmias, and shortened life arrhythmias, a

4、nd shortened life expectancy expectancy 臨床藥理-治療充血性心力衰竭藥 物 3 The signs and symptoms The signs and symptoms of heart The signs and symptoms of heart failure include tachycardia, decreased failure include tachycardia, decreased exercise tolerance and shortness of exercise tolerance and shortness of bre

5、ath, peripheral and pulmonary breath, peripheral and pulmonary edema, and cardiomegaly.edema, and cardiomegaly. 動脈系統缺血動脈系統缺血- - 乏力，氣短，頭暈乏力，氣短，頭暈 靜脈系統淤血靜脈系統淤血- - 水腫，頸靜脈怒張，肝脾水腫，頸靜脈怒張，肝脾 腫大，呼吸困難腫大，呼吸困難 靜脈淤血所致的癥狀為主。靜脈淤血所致的癥狀為主。 臨床藥理-治療充血性心力衰竭藥 物 4 心衰的分級（心衰的分級（NYHA標準）標準） 級：心功能代償完全，體力活動不受限，級：心功能代償完全，體力活動不

6、受限， 日?；顒訜o乏力，心悸，呼吸困難等癥狀；日常活動無乏力，心悸，呼吸困難等癥狀； 級：輕度代償不全，活動輕度受限，休息級：輕度代償不全，活動輕度受限，休息 時無癥狀；時無癥狀； 級：中度代償不全，體力活動明顯受限，級：中度代償不全，體力活動明顯受限， 日?；顒蛹纯僧a生癥狀。限于室內活動；日?；顒蛹纯僧a生癥狀。限于室內活動； 級：嚴重代償不全，休息時亦有癥狀，不級：嚴重代償不全，休息時亦有癥狀，不 能從事任何體力活動。能從事任何體力活動。 臨床藥理-治療充血性心力衰竭藥 物 5 心力衰竭不是一種獨立的疾病，而是由多心力衰竭不是一種獨立的疾病，而是由多 種原因引起的心肌收縮和種原因引起的心肌收

7、縮和/或舒張功能障礙或舒張功能障礙 的綜合征。近年來的研究發(fā)現，心力衰竭的綜合征。近年來的研究發(fā)現，心力衰竭 雖然主要表現為心肌收縮和舒張功能障礙雖然主要表現為心肌收縮和舒張功能障礙 ，但神經內分泌的改變對其惡性循環(huán)的形，但神經內分泌的改變對其惡性循環(huán)的形 成和維持有重要的作用。這些變化導致心成和維持有重要的作用。這些變化導致心 臟出現不可逆的重構臟出現不可逆的重構(remodeling)，使衰竭，使衰竭 的心臟一步步惡化。的心臟一步步惡化。 Pathophysiology 臨床藥理-治療充血性心力衰竭藥 物 6 心力衰竭時機體的代償機制心力衰竭時機體的代償機制: Augmented symp

8、athetic activity Augmented sympathetic activity Sodium and water retention Sodium and water retention Myocardial hypertrophy Myocardial hypertrophy Ventricular dilatationVentricular dilatation 1心臟本身的代償心臟本身的代償 心率加快、心肌收縮加強心率加快、心肌收縮加強-快速發(fā)生快速發(fā)生 心臟擴大和肥大心臟擴大和肥大緩慢發(fā)生緩慢發(fā)生 是心臟本身儲備功能的動員。是心臟本身儲備功能的動員。 2 心臟外的代償心

9、臟外的代償 血容量增加血容量增加 血液重分配及紅細胞增多血液重分配及紅細胞增多 等幾方面的心臟外代償作用。等幾方面的心臟外代償作用。 臨床藥理-治療充血性心力衰竭藥 物 7 機體的代償機制雖然有助于維持機體所需的心機體的代償機制雖然有助于維持機體所需的心 輸出量要求，但長時間代償機制的激活可加重輸出量要求，但長時間代償機制的激活可加重 心臟的負擔。心臟的負擔。 在在CHF的長期發(fā)病過程中，各種代償機制對心的長期發(fā)病過程中，各種代償機制對心 臟和動脈血管等的影響可產生惡性循環(huán)，加重臟和動脈血管等的影響可產生惡性循環(huán)，加重 心臟負擔，最終加重心力衰竭。心臟負擔，最終加重心力衰竭。 實際上慢性心衰的

10、發(fā)展過程就是在實際上慢性心衰的發(fā)展過程就是在心肌氧供不心肌氧供不 足和維持機體循環(huán)血供需求之間不斷平衡的矛足和維持機體循環(huán)血供需求之間不斷平衡的矛 盾發(fā)展過程盾發(fā)展過程。 臨床藥理-治療充血性心力衰竭藥 物 8 神經體液系統主要改變神經體液系統主要改變 Increased sympathetic nervous system sympathetic nervous system activityactivity (and increased plasma catecholamines, b-receptor down regulation ) Increased activity of the

11、 renin-renin- angiotensin-aldosterone systemangiotensin-aldosterone system Increased release of arginine-arginine- vasopressinvasopressin 臨床藥理-治療充血性心力衰竭藥 物 9 心衰的一些代償機制 In addition to the effects shown, angiotensin II increases sympathetic effects by facilitating norepinephrine release. 臨床藥理-治療充血性心力衰

12、竭藥 物 10 慢性心衰的藥物治療： 應減輕負荷，降低能耗，保護心臟應減輕負荷，降低能耗，保護心臟。達 到改善血流動力學；改善運動耐量；延改善血流動力學；改善運動耐量；延 長生命。長生命。 而不是病馬加鞭，只增強心肌收縮力 心衰的血流動力學指標： 壓力指標：LVEDP，dP/dtmax； 容積指標：SV，CO，CI，EF（正常0.67, 心衰 0.45, 嚴重心衰0.3 ） 時間指標：PEP，LVET，T-dP/dtmax 臨床藥理-治療充血性心力衰竭藥 物 11 抗心衰藥物的發(fā)展和演變抗心衰藥物的發(fā)展和演變 洋地黃時代（從民間的治療水腫藥物而 來） 利尿藥（噻嗪類、汞撒利） 非苷類強心藥（兒

13、茶酚胺類，磷酸二酯 酶抑制劑-氨力農、米力農） 擴血管藥物 血管緊張素轉化酶抑制劑 ACEIs，ARBs 受體阻斷劑 醛固酮受體阻斷劑 臨床藥理-治療充血性心力衰竭藥 物 12 使用抗心衰藥物后心功能曲線的改變使用抗心衰藥物后心功能曲線的改變 (I) 正性肌力藥 物 positive inotropic agents (V) 舒血管藥 Vasodilators (D) 利尿藥 Diuretics 臨床藥理-治療充血性心力衰竭藥 物 13 pharmacologic intervention pharmacologic intervention in CHFin CHF 抗心衰藥物是主要用于治療

14、CHF的藥物，主 要有強心苷、非甙類正性肌力藥、利尿藥、強心苷、非甙類正性肌力藥、利尿藥、 ACEI和和受體阻斷藥受體阻斷藥等。 Improving hemodynamics with inotropic drugs does not decrease mortality; （病馬 加鞭） long-term treatment directed towards neurohormonal factors with ACE inhibitors and beta-blockers can decrease mortality 臨床藥理-治療充血性心力衰竭藥 物 14 Consensus rec

15、ommendations for the management of CHF Patients with heart failure should first be evaluated to assess LV ejection fraction. Patients with systolic dysfunction (EF 40%) should then undergo the following treatment: 水鈉潴留：利尿藥 ACEIs，ARBs 和/或 beta-blocker 室率快的房顫：強心苷（地高辛） 重癥患者延長壽命：醛固酮受體拮抗劑 臨床藥理-治療充血性心力衰竭藥

16、 物 15 fluid retention - a fluid retention - a diureticdiuretic. . ACE inhibitorACE inhibitor and and beta-blockerbeta-blocker should be should be initiated and maintained unless specifically initiated and maintained unless specifically contraindicated. contraindicated. （Patients with severe heart Pa

17、tients with severe heart failure should probably not receive a failure should probably not receive a beta-beta- blockerblocker） DigoxinDigoxin - in patients with rapid atrial fibrillation. - in patients with rapid atrial fibrillation. Spironolactone, an aldosterone antagonist, may reduce mortality i

18、n patients with severe heart failure 臨床藥理-治療充血性心力衰竭藥 物 16 ACE inhibitors first-line therapy in all patients with heart failure improve symptoms, slow progression of the disease, reduce mortality, and decrease the incidence of hospitalization The most common adverse effects of ACE inhibitors are dire

19、ctly related to lowering angiotensin II concentrations (hypotension and renal insufficiency) and increasing concentrations of kinins (cough and angioneurotic edema) 臨床藥理-治療充血性心力衰竭藥 物 17 血管緊張素原血管緊張素原 Angiotensin 收縮血管 腎素 激肽原激肽原 緩激肽緩激肽 降解失活 Ang ACE ACEIs Ang 分泌醛固酮 NO PGI ( - ) ACE和ACEIs作用示意圖 舒張血管 臨床藥理-

20、治療充血性心力衰竭藥 物 18 Captopril 第1個在臨床上廣泛應用的ACEI。含巰 基，可致味覺異常。 Enalapril 前體藥，不含巰基。藥效和作用時間比 cartopril強。 臨床藥理-治療充血性心力衰竭藥 物 19 ARBs - angiotensin receptor blockersangiotensin receptor blockers angiotensin receptor antagonists (angiotensin receptor antagonists (AT1 Receptor Antagonists) are as effective ) are

21、as effective as ACE inhibitors in treating heart as ACE inhibitors in treating heart failure, but it appears that therapeutic failure, but it appears that therapeutic efficacy may be comparable efficacy may be comparable losartan, candesartan, valsartan losartan, candesartan, valsartan 臨床藥理-治療充血性心力衰

22、竭藥 物 20 Inotropic Drugs- digitalis The beneficial effects of cardiac glycosides in the treatment of heart failure have been attributed to a positive inotropic effect on failing myocardium and efficacy in controlling the ventricular rate response to atrial fibrillation. The cardiac glycosides also mo

23、dulate autonomic nervous system activity, and it is likely that this mechanism contributes substantially to their efficacy in the management of heart failure. 臨床藥理-治療充血性心力衰竭藥 物 21 Positive Inotropic Effect （抑制Na+,K+- ATPase ） Electrophysiological Actions （加上增強迷 走） Regulation of Sympathetic Nervous S

24、ystem Activity There is evidence that digitalis may act directly to sensitization of baroreceptor response and thereby exert some of its beneficial effects through reduction of sympathetic tone 臨床藥理-治療充血性心力衰竭藥 物 22 The recent Digitalis Investigation Group The recent Digitalis Investigation Group (DI

25、G) clinical trial indicated digoxin did (DIG) clinical trial indicated digoxin did not reduce overall mortality in patients not reduce overall mortality in patients with heart failure (who were receiving with heart failure (who were receiving diuretics and ACE inhibitors), but did diuretics and ACE

26、inhibitors), but did reduce the rate of hospitalizationreduce the rate of hospitalization 臨床藥理-治療充血性心力衰竭藥 物 23 Other inotropic agents 只適用于急性心衰，長期應用于慢性心衰 后，病人死亡率增加。 Beta-Adrenergic Agonists dopamine, dobutamine, prenalterol Levodopa and ibopamine Cyclic Nucleotide Phosphodiesterase (PDE- III, cGMP-in

27、hibitable PDE) Inhibitors Bipyridines- amrinone and milrinone imidazolone derivatives- enoximone and piroximone 臨床藥理-治療充血性心力衰竭藥 物 24 Beta-Blockers and CHF A number of studies beginning in the 1970s have shown that beta-blockers can improve symptoms and ventricular function in patients with moderate

28、to severe heart failure, and may slow the progression of heart failure in some patients (reviewed in Bristow, Circulation 101:558 (2000) 臨床藥理-治療充血性心力衰竭藥 物 25 Though beta-blockers were widely considered to be contraindicated for patients with heart failure only a decade ago, they are now considered f

29、irst-line first-line therapy for patients with mild to moderate therapy for patients with mild to moderate heart failure heart failure 現認為脂溶性的效果更好。 metoprolol carvedilol bisoprolol 臨床藥理-治療充血性心力衰竭藥 物 26 The adverse effectsThe adverse effects : worsening of symptoms, hypotension, and bradycardia These

30、 symptoms can be minimized by initiating therapy with low doses and gradually increasing dosage until tolerable therapeutic doses are reached Beta-blockers are contraindicated in patients with asthma or severe bradycardia 臨床藥理-治療充血性心力衰竭藥 物 27 Diuretics Most pateints with heart failure require treatm

31、ent with diuretics to relieve symptoms of fluid retention (edema and congestion), but their is no evidence that diuretics slow the progression of the disease or decrease mortality. Loop diuretics (furosemide) are the most effective diuretics 多用于嚴重水鈉潴留和腎功能不全時。 Thiazide diureticsThiazide diuretics act

32、 on the distal loop and are less effective than loop diuretics 用于輕度水鈉潴留。 Concurrent use of two diuretics with different sites of action may be needed in patients who do not respond well to a single oral diuretic 臨床藥理-治療充血性心力衰竭藥 物 28 The most common adverse effect of diuretic therapy is potassium dep

33、letion which can be prevented by use of supplemental potassium, an ACE inhibitor, or a potassium-sparing diuretic (spironolactone or amiloride) Aldosterone AntagonistsAldosterone Antagonists Recent clinical trials indicate that adding spironolactone (螺內酯)to standard treatment can significantly decre

34、ase mortality in patients with severe heart failure 臨床藥理-治療充血性心力衰竭藥 物 29 Effect of spironolactone on survival in patients with moderate or severe congestive heart failure in a randomized double-blind clinical study. (Reproduced, with permission, from Pitt B et al: The effect of spironolactone on mor

35、bidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709 醛固酮受體拮抗劑螺內酯醛固酮受體拮抗劑螺內酯 降低充血性心衰病人死亡率降低充血性心衰病人死亡率 臨床藥理-治療充血性心力衰竭藥 物 30 Other Agents with Therapaeutic Potential Endothelin-1 AntagonistsEndothelin-1 Antagonists The vasoconstrictor peptide, endothelin-1, is known to

36、be elevated in heart failure and is a predictor of mortality in patients with heart failure. Animal models of heart failure indicate endothelin receptor antagonists such as bosentan may have long-term benefits in reversing myocardial remodeling and improving survival. Short-term, small-scale trials

37、in humans indicate possible beneficial effects on systemic and pulmonary hemodynamics 臨床藥理-治療充血性心力衰竭藥 物 31 xanthine oxidase inhibitor Background: High serum uric acid (SUA) levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. Results and conclusion:

38、Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure. However, post-hoc analysis suggests that benefits occur in patients with elevated SUA in a manner correlating with the degree of SUA reduction. Impact of oxypurinol in patients with symptomatic heart failure. Results of the OPT-CHF study. J Am Coll Cardiol 2008;51 (24):2301- 9. 臨床藥理-治療充血性心力衰竭藥 物 32 Steps