临床药理--治疗充血性心力衰竭药物课件

1、临床药理-治疗充血性心力衰竭药 物 1 治疗充血性心力衰竭药物治疗充血性心力衰竭药物 Drugs for Congestive Heart FailureDrugs for Congestive Heart Failure 心力衰竭（心力衰竭（heart failure）是各种原因引起的心肌）是各种原因引起的心肌 舒缩障碍，导致心输出量不能满足机体需求的一组舒缩障碍，导致心输出量不能满足机体需求的一组 临床综合征。充血性心衰是其中最主要的一种。临床综合征。充血性心衰是其中最主要的一种。 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）是各种病因所引起的多种心脏疾病）是各种病因所引起的多种心脏疾病 （冠心、高心、肺心、风心、心肌病等）的终末阶（冠心、高心、肺心、风心、心肌病等）的终末阶 段，当静脉回流足够的情况下，心脏排出量绝对或段，当静脉回流足够的情况下，心脏排出量绝对或 相对减少，不能满足机体组织需求的相对减少，不能满足机体组织需求的一种临床或病一种临床或病 理综合征理综合征。 心衰病人运动耐量下降，寿命缩短。心衰病人运动耐量下降，寿命缩短。 临床药理-治疗充血性心力衰竭药 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 临床药理-治疗充血性心力衰竭药 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. 动脉系统缺血动脉系统缺血- - 乏力，气短，头晕乏力，气短，头晕 静脉系统淤血静脉系统淤血- - 水肿，颈静脉怒张，肝脾水肿，颈静脉怒张，肝脾 肿大，呼吸困难肿大，呼吸困难 静脉淤血所致的症状为主。静脉淤血所致的症状为主。 临床药理-治疗充血性心力衰竭药 物 4 心衰的分级（心衰的分级（NYHA标准）标准） 级：心功能代偿完全，体力活动不受限，级：心功能代偿完全，体力活动不

6、受限， 日常活动无乏力，心悸，呼吸困难等症状；日常活动无乏力，心悸，呼吸困难等症状； 级：轻度代偿不全，活动轻度受限，休息级：轻度代偿不全，活动轻度受限，休息 时无症状；时无症状； 级：中度代偿不全，体力活动明显受限，级：中度代偿不全，体力活动明显受限， 日常活动即可产生症状。限于室内活动；日常活动即可产生症状。限于室内活动； 级：严重代偿不全，休息时亦有症状，不级：严重代偿不全，休息时亦有症状，不 能从事任何体力活动。能从事任何体力活动。 临床药理-治疗充血性心力衰竭药 物 5 心力衰竭不是一种独立的疾病，而是由多心力衰竭不是一种独立的疾病，而是由多 种原因引起的心肌收缩和种原因引起的心肌收

7、缩和/或舒张功能障碍或舒张功能障碍 的综合征。近年来的研究发现，心力衰竭的综合征。近年来的研究发现，心力衰竭 虽然主要表现为心肌收缩和舒张功能障碍虽然主要表现为心肌收缩和舒张功能障碍 ，但神经内分泌的改变对其恶性循环的形，但神经内分泌的改变对其恶性循环的形 成和维持有重要的作用。这些变化导致心成和维持有重要的作用。这些变化导致心 脏出现不可逆的重构脏出现不可逆的重构(remodeling)，使衰竭，使衰竭 的心脏一步步恶化。的心脏一步步恶化。 Pathophysiology 临床药理-治疗充血性心力衰竭药 物 6 心力衰竭时机体的代偿机制心力衰竭时机体的代偿机制: Augmented symp

8、athetic activity Augmented sympathetic activity Sodium and water retention Sodium and water retention Myocardial hypertrophy Myocardial hypertrophy Ventricular dilatationVentricular dilatation 1心脏本身的代偿心脏本身的代偿 心率加快、心肌收缩加强心率加快、心肌收缩加强-快速发生快速发生 心脏扩大和肥大心脏扩大和肥大缓慢发生缓慢发生 是心脏本身储备功能的动员。是心脏本身储备功能的动员。 2 心脏外的代偿心

9、脏外的代偿 血容量增加血容量增加 血液重分配及红细胞增多血液重分配及红细胞增多 等几方面的心脏外代偿作用。等几方面的心脏外代偿作用。 临床药理-治疗充血性心力衰竭药 物 7 机体的代偿机制虽然有助于维持机体所需的心机体的代偿机制虽然有助于维持机体所需的心 输出量要求，但长时间代偿机制的激活可加重输出量要求，但长时间代偿机制的激活可加重 心脏的负担。心脏的负担。 在在CHF的长期发病过程中，各种代偿机制对心的长期发病过程中，各种代偿机制对心 脏和动脉血管等的影响可产生恶性循环，加重脏和动脉血管等的影响可产生恶性循环，加重 心脏负担，最终加重心力衰竭。心脏负担，最终加重心力衰竭。 实际上慢性心衰的

10、发展过程就是在实际上慢性心衰的发展过程就是在心肌氧供不心肌氧供不 足和维持机体循环血供需求之间不断平衡的矛足和维持机体循环血供需求之间不断平衡的矛 盾发展过程盾发展过程。 临床药理-治疗充血性心力衰竭药 物 8 神经体液系统主要改变神经体液系统主要改变 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 临床药理-治疗充血性心力衰竭药 物 9 心衰的一些代偿机制 In addition to the effects shown, angiotensin II increases sympathetic effects by facilitating norepinephrine release. 临床药理-治疗充血性心力衰

12、竭药 物 10 慢性心衰的药物治疗： 应减轻负荷，降低能耗，保护心脏应减轻负荷，降低能耗，保护心脏。达 到改善血流动力学；改善运动耐量；延改善血流动力学；改善运动耐量；延 长生命。长生命。 而不是病马加鞭，只增强心肌收缩力 心衰的血流动力学指标： 压力指标：LVEDP，dP/dtmax； 容积指标：SV，CO，CI，EF（正常0.67, 心衰 0.45, 严重心衰0.3 ） 时间指标：PEP，LVET，T-dP/dtmax 临床药理-治疗充血性心力衰竭药 物 11 抗心衰药物的发展和演变抗心衰药物的发展和演变 洋地黄时代（从民间的治疗水肿药物而 来） 利尿药（噻嗪类、汞撒利） 非苷类强心药（儿

13、茶酚胺类，磷酸二酯 酶抑制剂-氨力农、米力农） 扩血管药物 血管紧张素转化酶抑制剂 ACEIs，ARBs 受体阻断剂 醛固酮受体阻断剂 临床药理-治疗充血性心力衰竭药 物 12 使用抗心衰药物后心功能曲线的改变使用抗心衰药物后心功能曲线的改变 (I) 正性肌力药 物 positive inotropic agents (V) 舒血管药 Vasodilators (D) 利尿药 Diuretics 临床药理-治疗充血性心力衰竭药 物 13 pharmacologic intervention pharmacologic intervention in CHFin CHF 抗心衰药物是主要用于治疗

14、CHF的药物，主 要有强心苷、非甙类正性肌力药、利尿药、强心苷、非甙类正性肌力药、利尿药、 ACEI和和受体阻断药受体阻断药等。 Improving hemodynamics with inotropic drugs does not decrease mortality; （病马 加鞭） long-term treatment directed towards neurohormonal factors with ACE inhibitors and beta-blockers can decrease mortality 临床药理-治疗充血性心力衰竭药 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: 水钠潴留：利尿药 ACEIs，ARBs 和/或 beta-blocker 室率快的房颤：强心苷（地高辛） 重症患者延长寿命：醛固酮受体拮抗剂 临床药理-治疗充血性心力衰竭药

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 临床药理-治疗充血性心力衰竭药 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) 临床药理-治疗充血性心力衰竭药 物 17 血管紧张素原血管紧张素原 Angiotensin 收缩血管 肾素 激肽原激肽原 缓激肽缓激肽 降解失活 Ang ACE ACEIs Ang 分泌醛固酮 NO PGI ( - ) ACE和ACEIs作用示意图 舒张血管 临床药理-

20、治疗充血性心力衰竭药 物 18 Captopril 第1个在临床上广泛应用的ACEI。含巯 基，可致味觉异常。 Enalapril 前体药，不含巯基。药效和作用时间比 cartopril强。 临床药理-治疗充血性心力衰竭药 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 临床药理-治疗充血性心力衰

22、竭药 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. 临床药理-治疗充血性心力衰竭药 物 21 Positive Inotropic Effect （抑制Na+,K+- ATPase ） Electrophysiological Actions （加上增强迷 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 临床药理-治疗充血性心力衰竭药 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 临床药理-治疗充血性心力衰竭药 物 23 Other inotropic agents 只适用于急性心衰，长期应用于慢性心衰 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 临床药理-治疗充血性心力衰竭药 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) 临床药理-治疗充血性心力衰竭药 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 现认为脂溶性的效果更好。 metoprolol carvedilol bisoprolol 临床药理-治疗充血性心力衰竭药 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 临床药理-治疗充血性心力衰竭药 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 多用于严重水钠潴留和肾功能不全时。 Thiazide diureticsThiazide diuretics act

32、 on the distal loop and are less effective than loop diuretics 用于轻度水钠潴留。 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 临床药理-治疗充血性心力衰竭药 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 (螺内酯)to standard treatment can significantly decre

34、ase mortality in patients with severe heart failure 临床药理-治疗充血性心力衰竭药 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 醛固酮受体拮抗剂螺内酯醛固酮受体拮抗剂螺内酯 降低充血性心衰病人死亡率降低充血性心衰病人死亡率 临床药理-治疗充血性心力衰竭药 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 临床药理-治疗充血性心力衰竭药 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. 临床药理-治疗充血性心力衰竭药 物 32 Steps