1、治疗充血性心力衰竭药物 Drugs for Congestive Heart Failure,心力衰竭（heart failure）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（congestive heart failure, CHF）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一种临床或病理综合征。 心衰病人运动耐量下降，寿命缩短。,Concept:CHF is a complex clinical sy
2、ndrome characterized by impaired ventricular performance, exercise intolerance, a high incidence of ventricular arrhythmias, and shortened life expectancy,The signs and symptoms,The signs and symptoms of heart failure include tachycardia, decreased exercise tolerance and shortness of breath, periphe
3、ral and pulmonary edema, and cardiomegaly. 动脉系统缺血- 乏力，气短，头晕静脉系统淤血- 水肿，颈静脉怒张，肝脾肿大，呼吸困难静脉淤血所致的症状为主。,心衰的分级（NYHA标准）级：心功能代偿完全，体力活动不受限，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，休息时无症状；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；级：严重代偿不全，休息时亦有症状，不能从事任何体力活动。,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/或舒张功能障碍的综合征。近年来的研究发现，心力衰竭虽然主要表现为心肌
4、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(remodeling)，使衰竭的心脏一步步恶化。,Pathophysiology,心力衰竭时机体的代偿机制:Augmented sympathetic activity Sodium and water retention Myocardial hypertrophy Ventricular dilatation1心脏本身的代偿心率加快、心肌收缩加强-快速发生心脏扩大和肥大缓慢发生是心脏本身储备功能的动员。2 心脏外的代偿血容量增加血液重分配及红细胞增多等几方面的心脏外代偿作用。,机体
5、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心脏的负担。在CHF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，加重心脏负担，最终加重心力衰竭。实际上慢性心衰的发展过程就是在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盾发展过程。,神经体液系统主要改变Increased sympathetic nervous system activity (and increased plasma catecholamines, b-receptor down regulation ) Increased activity of the renin
6、-angiotensin-aldosterone system Increased release of arginine-vasopressin,心衰的一些代偿机制In addition to the effects shown, angiotensin II increases sympathetic effects by facilitating norepinephrine release.,慢性心衰的药物治疗：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
7、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,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,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,pharmacologic intervention in
8、 CHF,抗心衰药物是主要用于治疗CHF的药物，主要有强心苷、非甙类正性肌力药、利尿药、ACEI和受体阻断药等。 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,Consensus recommendations for the management
9、 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,fluid retention - a diuretic. ACE inhibitor and b
10、eta-blocker should be initiated and maintained unless specifically contraindicated. （Patients with severe heart failure should probably not receive a beta-blocker） Digoxin - in patients with rapid atrial fibrillation.Spironolactone, an aldosterone antagonist, may reduce mortality in patients with se
11、vere heart failure,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 directly related to lowering angiotensin II
12、 concentrations (hypotension and renal insufficiency) and increasing concentrations of kinins (cough and angioneurotic edema),血管紧张素原,Angiotensin,收缩血管,肾素,激肽原,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,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。,
13、ARBs - angiotensin receptor blockers,angiotensin receptor antagonists (AT1 Receptor Antagonists) are as effective as ACE inhibitors in treating heart failure, but it appears that therapeutic efficacy may be comparable losartan, candesartan, valsartan,Inotropic Drugs- digitalis,The beneficial effects
14、 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 modulate autonomic nervous system activity, and it is likel
15、y that this mechanism contributes substantially to their efficacy in the management of heart failure.,Positive Inotropic Effect （抑制Na+,K+-ATPase ）Electrophysiological Actions （加上增强迷走）Regulation of Sympathetic Nervous System Activity There is evidence that digitalis may act directly to sensitization
16、of baroreceptor response and thereby exert some of its beneficial effects through reduction of sympathetic tone,The recent Digitalis Investigation Group (DIG) clinical trial indicated digoxin did not reduce overall mortality in patients with heart failure (who were receiving diuretics and ACE inhibi
17、tors), but did reduce the rate of hospitalization,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-inhibitable PDE) Inhibitors Bipyridines- amrinone and milrinone im
18、idazolone derivatives- enoximone and piroximone,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 to severe heart failure, and may slow the progression of heart failure in some patien
19、ts (reviewed in Bristow, Circulation 101:558 (2000),Though beta-blockers were widely considered to be contraindicated for patients with heart failure only a decade ago, they are now considered first-line therapy for patients with mild to moderate heart failure 现认为脂溶性的效果更好。metoprololcarvedilolbisopro
20、lol,The adverse effects : worsening of symptoms, hypotension, and bradycardia These 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 bradyca
21、rdia,Diuretics,Most pateints with heart failure require treatment 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 diureti
22、cs 多用于严重水钠潴留和肾功能不全时。Thiazide diuretics act 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,The most common adverse effect of diuretic ther
23、apy is potassium depletion which can be prevented by use of supplemental potassium, an ACE inhibitor, or a potassium-sparing diuretic (spironolactone or amiloride) Aldosterone AntagonistsRecent clinical trials indicate that adding spironolactone (螺内酯)to standard treatment can significantly decrease
24、mortality in patients with severe heart failure,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 morbidity and mortality in p
25、atients with severe heart failure. N Engl J Med 1999;341:709,醛固酮受体拮抗剂螺内酯降低充血性心衰病人死亡率,Other Agents with Therapaeutic Potential,Endothelin-1 Antagonists The vasoconstrictor peptide, endothelin-1, is known to be elevated in heart failure and is a predictor of mortality in patients with heart failure. A
26、nimal 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 in humans indicate possible beneficial effects on systemic and pulmonary hemodynamics,xanthine
27、 oxidase inhibitorBackground: High serum uric acid (SUA) levels are a strong, independent marker of impaired prognosis in patients with moderate to severe CHF. Results and conclusion: Oxypurinol did not produce clinical improvements in unselected patients with moderate-to-severe heart failure.Howeve
28、r, 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.,Steps in the treatment of chr
29、onic heart failure._1. Reduce workload of the hearta. Limit activity levelb. Reduce weightc. Control hypertension2. Restrict sodium3. Restrict water (rarely required)4. Give diuretics5. Give ACE inhibitor and digitalis16. Give b-blockers to patients with stable class II-III heart failure7. Give vaso
30、dilators_1Many clinicians use angiotensin-converting enzyme inhibitors before digitalis.,Summary,On the basis of several recent large-scale clinical trials it appears that reduction in ventricular volume and perhaps a reduction in the risk of lethal ventricular arrhythmias are the keys to long-term
31、improvement and survival of patients with CHF Emphasis on therapy for heart failure has shifted in the past several years from acute interventions to improve hemodynamics and inotropic state to long-term therapies that might slow or halt the progression of the disease,Future therapies will most likely involve therapeutic strategies that prevent or minimize the remodeling processes in the heart and vasculature, and thereby arrest the syndrome at early stages of cardiac dysfunction,
