第17章 治疗充血性心力衰竭药物 Drugs for Congestive Heart Failure

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 syndrome 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, peripheral 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。

Pathophysiology 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。

心力衰竭时机体的代偿机制: Augmented sympathetic activity Sodium and water retention Myocardial hypertrophy Ventricular dilatation 1．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。

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-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.

心衰的分级（NYHA标准） Ⅰ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； Ⅱ级：轻度代偿不全，活动轻度受限，休息时无症状； Ⅲ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； Ⅳ级：严重代偿不全，休息时亦有症状，不能从事任何体力活动。

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

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 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β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 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 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 beta-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 severe heart failure

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 modulate autonomic nervous system activity, and it is likely 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 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 inhibitors), 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 imidazolone derivatives- enoximone and piroximone

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 concentrations (hypotension and renal insufficiency) and increasing concentrations of kinins (cough and angioneurotic edema)

ARBs - angiotensin receptor blockers angiotensin receptor antagonists (AT1 Receptor Antagonists) losartan, candesartan, valsartan are as effective as ACE inhibitors in treating heart failure, but it appears that therapeutic efficacy may be comparable

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 patients (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

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 bradycardia

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 diuretics Thiazide diuretics act on the distal loop and are less effective than loop diuretics 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 therapy is potassium depletion which can be prevented by use of supplemental potassium, an ACE inhibitor, or a potassium-sparing diuretic (spironolactone or amiloride) Aldosterone Antagonists Recent clinical trials indicate that adding spironolactone (螺内酯)to standard treatment can significantly decrease mortality in patients with severe heart failure

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. 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 in humans indicate possible beneficial effects on systemic and pulmonary hemodynamics

________________________________________ Steps in the treatment of chronic heart failure. ________________________________________ 1. Reduce workload of the heart a. Limit activity level b. Reduce weight c. Control hypertension 2. Restrict sodium 3. Restrict water (rarely required) 4. Give diuretics 5. Give ACE inhibitor and digitalis1 6. Give b-blockers to patients with stable class II-III heart failure 7. Give vasodilators __________________________________________ 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 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