1、Definition and Clinical Features慢性心力衰竭(充血性心力衰竭)o 心脏在正常充盈压时无法提供有效的前向射血，心脏收缩心脏在正常充盈压时无法提供有效的前向射血，心脏收缩功能下降，同时心室舒张末压增加，心腔残余血液增加，功能下降，同时心室舒张末压增加，心腔残余血液增加，导致肺循环和体循环淤血导致肺循环和体循环淤血o Congestive heart failure(chronic heart failure,CHF)is a complex of symptoms-shortness of breath,tachycardia,fatigue,and congest
2、ion-that are related to the inadequate perfusion of tissue during exertion and to the retention of fluid.慢性心衰的呼吸困难、心率增加、乏力、淤血等缘于组织慢性心衰的呼吸困难、心率增加、乏力、淤血等缘于组织灌注不足及体液潴留灌注不足及体液潴留1治疗慢性心衰的药物10/14/2022Definition and Clinical Features慢性心力衰竭(充血性心力衰竭)oCongestive heart failure(chronic heart failure,CHF)is the p
3、athophysiologic state in which the heart is unable to pump blood at a rate commensurate with相称 the tissue requirements,or can do so only from an elevated filling pressure.心输出量不能满足组织代谢需求心输出量不能满足组织代谢需求,或需通过升高充盈压代偿或需通过升高充盈压代偿oIts primary cause is that the heart fails to provide adequate output at norma
4、l filling pressures,which is associated with a syndrome of reduced contraction capacity as well as pulmonary and systemic venous congestion.主要原因是心脏在心脏在正常充盈压时无法提供有效的前向射血，导致心脏收缩功能功能下降正常充盈压时无法提供有效的前向射血，导致心脏收缩功能功能下降以及肺循环和体循环淤血以及肺循环和体循环淤血2治疗慢性心衰的药物10/14/2022Systemic and Pulmonary Circulation3治疗慢性心衰的药物10/
5、14/2022When left ventricle failsLeft ventricular end-diastolic pressure左室舒张末压左室舒张末压LAPLAP左房压左房压Pulmonary cap wedge pressure肺毛细血管锲压肺毛细血管锲压Left ventricle contraction左室射血左室射血4治疗慢性心衰的药物10/14/2022Thickening of the respiratory membrane reduces O2 exchange5治疗慢性心衰的药物10/14/2022Enlarged heart(ContractionLVEDP
6、)and pulmonary congestion(O2 Exchange)6治疗慢性心衰的药物10/14/2022Clinical FeaturesOrthopnea特征与鉴别oExertional dyspnea,nocturnal paroxysmal dyspnea and orthopneapulmonary congestion 早期运动性呼吸困难、夜间运动性呼吸困难、夜间阵发性呼吸困难，阵发性呼吸困难，急性加重呈端坐呼吸端坐呼吸-肺淤血肺淤血 为左心衰特征为左心衰特征7治疗慢性心衰的药物10/14/2022Hypertension,Myocardial Hypertrophy a
7、nd Diastole Dysfunction心肌肥厚与舒张功能障碍Normal Hypertension 8治疗慢性心衰的药物10/14/2022Diastolic and Systolic Heart Failure舒张性心衰与收缩性心衰均表现为呼吸困难(肺淤血)78 yo Woman Recurrent Pul Edema50 yo Man HCM9治疗慢性心衰的药物10/14/2022颈静脉怒张颈静脉怒张肝脾肿大肝脾肿大下肢浮肿下肢浮肿肺淤血肺淤血运动性及运动性及夜间阵发性夜间阵发性呼吸困难呼吸困难肺水肿肺水肿端坐呼吸端坐呼吸心源性哮喘心源性哮喘心肌收缩力下降心肌收缩力下降 心心腔残余
8、血增加腔残余血增加 左室左室舒张末压增高舒张末压增高肾灌注下降肾灌注下降尿量减少尿量减少 水钠潴留水钠潴留头昏、乏力、运动耐力下降头昏、乏力、运动耐力下降反射性反射性SNSSNS及及RAASRAAS兴奋，血管兴奋，血管痉挛、心率加快、回心血量痉挛、心率加快、回心血量10治疗慢性心衰的药物10/14/2022oWhen the heart fails,arterial pressure reduces which causes the baroreceptor response and excitation of sympathetic nervous system(SNS)and renin-
9、angiotensin-aldosterone system(RAAS).心输出量下降导致反射性交感神经系心输出量下降导致反射性交感神经系统及肾素血管紧张素醛固酮系统兴奋统及肾素血管紧张素醛固酮系统兴奋Compensation mechanisms during chronic heart failure心衰代偿机制及其作用AT1Renin-Angiotensin-Aldosterone System11治疗慢性心衰的药物10/14/2022Compensation mechanisms during chronic heart failure心衰代偿机制的不利影响oThe epinephri
10、ne/norepinephrine(SNS)and angiotensin/aldosterone(RAAS)enhance heart performance and contract peripheral vessel with water/sodium retention to compensate for reduced cardiac output and redistribution of blood to important organs such as the CNS.肾上腺素、肾上腺素、去甲肾上腺素、血管紧张素使心肌收缩增强、心率加快、外周血管去甲肾上腺素、血管紧张素使心肌收
11、缩增强、心率加快、外周血管收缩、水钠潴留，血流重新分配以保证重要脏器血流收缩、水钠潴留，血流重新分配以保证重要脏器血流oIn addition,the vasoconstrictive effectors of the SNS and RAAS lead to an increase in systemic vascular resistance,which contributes to an increased impedance阻抗 to left ventricular ejection(increased afterload)and therefore myocardial oxyge
12、n consumption.交感神经及肾素血管紧张素交感神经及肾素血管紧张素醛固酮系统兴奋增加外周阻力，进而导致心脏后负荷增加，心肌耗醛固酮系统兴奋增加外周阻力，进而导致心脏后负荷增加，心肌耗氧增加氧增加12治疗慢性心衰的药物10/14/2022颈静脉怒张颈静脉怒张 肝脾肿大肝脾肿大下肢浮肿下肢浮肿肺淤血肺淤血运动性及运动性及夜间阵发性夜间阵发性呼吸困难呼吸困难肺水肿肺水肿端坐呼吸端坐呼吸心源性哮喘心源性哮喘心肌收缩力下降心肌收缩力下降左室舒张末压增高左室舒张末压增高肾灌注下降肾灌注下降尿量减少尿量减少 水钠潴留水钠潴留头昏、乏力、运动耐力下降头昏、乏力、运动耐力下降反射性反射性SNSSNS及
13、及RAASRAAS兴奋兴奋，血管，血管痉挛、心率加快、回心血量痉挛、心率加快、回心血量强心强心 Digitalis洋地黄类洋地黄类降低心脏负荷与氧耗降低心脏负荷与氧耗-blocker ACEI降低前后负荷降低前后负荷Vasodilator扩血管药扩血管药利尿利尿Diuretics 减轻水钠潴留减轻水钠潴留Diuretics 利尿剂利尿剂减轻肺淤血减轻肺淤血利用哪些途径和药物治疗慢性心力衰竭？13治疗慢性心衰的药物10/14/2022Pharmacotherapy of CHF治疗慢性心衰的药物o Positive inotropic agents 正性肌力药o Digitalis 洋地黄o D
14、iuretics 利尿药o 氢氯噻嗪 呋塞米o Vasodilators 扩血管药o 酚妥拉明o-adrenergic receptor blockers 肾上腺素能受体阻断药o Inhibitors of Renin-Angiotensin System 肾素血管紧张素系统抑制药14治疗慢性心衰的药物10/14/2022Therapeutic Aims of CHFoCHF is a major contributor to morbidity and mortality worldwide.Mortality in patients with advanced heart failure
15、exceeds 50%at 1 year.现代社会中慢性心衰高发病率现代社会中慢性心衰高发病率和高死亡率和高死亡率oWhile palliation of symptoms缓解症状 and improvement in the quality of life 改善生活质量 remain important goals,it is possible to approach therapy with the expectation that disease progression can be attenuated,减缓病情进展 and,in many instances,survival pro
16、longed.延长生存期 治疗目标：缓解症状、降低死亡率，缓解病情进展、改善生存质量治疗目标：缓解症状、降低死亡率，缓解病情进展、改善生存质量15治疗慢性心衰的药物10/14/2022Clinical conditions that precipitate deterioration of CHFo Elevated blood pressure 血压升高o Arrhythmia 心律失常o Myocardial ischemia 心肌缺血o Mental and physical stress 心理与躯体应激o Valve lesion and regurgitation先心或瓣膜病变所致的
17、分流与反流o Infection,esp.lung infection 各类感染尤其是肺部感染o High salt intake 高盐饮食慢性心衰治疗慢性心衰治疗同时纠正诱因同时纠正诱因同样重要同样重要16治疗慢性心衰的药物10/14/2022Pharmacotherapy of CHF治疗慢性心衰的药物o Positive inotropic agents 正性肌力药o Diuretics 利尿药o Vasodilators 扩血管药o-adrenergic receptor blockers 肾上腺素能受体阻断药o Inhibitors of Renin-Angiotensin Syst
18、em 肾素血管紧张素系统抑制药17治疗慢性心衰的药物10/14/2022化学结构化学结构基本骨架基本骨架NoImageNoImageWilliam Withering17411799Positive inotropic agents正性肌力药Cardiac glycosides 强心苷 Digitalis 洋地黄类洋地黄类 abstracts from plant digitalis Digoxin 地高辛地高辛 cidellannid 西地兰西地兰18治疗慢性心衰的药物10/14/2022Positive inotropic agents正性肌力药Cardiac glycosides 强心苷
19、 Digoxin 地高辛地高辛po cidellannid 西地兰西地兰 ivoActions and usagesoThe cardiac effects are:a)increasing force of contraction 增强心肌收缩力增强心肌收缩力 positive inotropic action 正性肌力作用正性肌力作用b)cardiac slowing(negative chronotropic action)负性频率作用负性频率作用 and reduced rate of conduction through the AV node 负性负性传导作用传导作用c)distu
20、rbances of rhythm,对心肌电生理的影响对心肌电生理的影响 especially -block of AV conduction 抑制房室传导抑制房室传导 -increased ectopic pacemaker activity尤其是蒲氏纤维尤其是蒲氏纤维oUsed in chronic heart failure and for controlling ventricular rate in atrial fibrillation19治疗慢性心衰的药物10/14/2022MechanismCardiac glycosides 强心苷pMechanisms of positiv
21、e inotropic action Inhibition of Na+,K+-ATPase.Cardiac glycosides are potent and highly selective inhibitors of the active transport of Na+&K+across cardiac cell membranes.They binds to a subunit of Na+,K+-ATPase,increasing cytosolic Na+,which in turn through Na+-Ca2+exchange increases the level of
22、cytosolic Ca2+available to interact with the contractile proteins,thereby increasing the force of contraction.抑制钠钾抑制钠钾ATP酶，增加细胞内游离钙水平酶，增加细胞内游离钙水平NoImage20治疗慢性心衰的药物10/14/2022洋地黄体内过程与给药特点o 地高辛口服生物利用度60%-80%，但个体差异及不同厂家产品生物利用度差异很大o 地高辛以原型主要经肾脏排泄，易蓄积中毒，应随时根据患者尿量调整药物剂量o 地高辛小剂量口服，西地兰静脉给药起效快o 奎尼丁、胺碘酮、维拉帕米等均
23、可升高地高辛血药浓度o 利尿药疗效显著时可能导致患者血容量不足、血液浓缩 使地高辛血药浓度升高NoImageNoImage21治疗慢性心衰的药物10/14/2022Adverse Effects of Cardiac glycosides 强心苷的不良反应强心苷安全范围小强心苷安全范围小 过量易中毒过量易中毒 小剂量个体化用药小剂量个体化用药oAdverse effectsoOne of the main drawbacks of glycosides is the narrow margin between effectiveness and toxicity.Adverse effects
24、 are common and can be severe.容易导致中毒容易导致中毒a)Cardiac adverse effects:AV blockade,ventricular premature contraction(PVC)and even ventricular fibrillationlidocaine and potassium should be given for室性心律失常与传导阻滞b)Extracardiac adverse effects:nausea,vomiting,diarrhea,blurred vision,and confusionc)The recog
25、nition of digoxin toxicity is important in the differential diagnosis of arrhythmias and neurological and gastrointestinal symptoms.NoImageNoImage22治疗慢性心衰的药物10/14/2022Positive inotropic agents正性肌力药Cardiac glycosides 强心苷pRegulation of Sympathetic Nervous System Activity.洋洋地黄对交感神经活性的影响地黄对交感神经活性的影响 Whe
26、n CO declines to a level that is inadequate to meet the tissue demands,increased SNS activity occurs as a compensatory response.This is due in part to a reduction in the sensitivity of the baroreflex response to BP,resulting in a decline in baroreflex-mediated tonic suppression of CNS-directed sympa
27、thetic activity。pA direct effect of digitalis on carotid baroreflex response to changes in carotid sinus pressure has been demonstrated in isolated preparations from heart failure animals.In patients with moderate-to-advanced heart failure,infusion of a digitalis increased forearm blood flow and car
28、diac index and decreased HR;skeletal muscle sympathetic nerve activity,an indicator of the CNS tone,was markedly reduced.洋地黄降低心衰时的代偿性交感兴奋23治疗慢性心衰的药物10/14/2022地高辛的应用与血药浓度监测pUse of Digoxin in Clinical Practice and Monitoring of Serum Levels.It is recommended that digoxin be reserved for patients with
29、heart failure with atrial fibrillation,or for patients in sinus rhythm who remain symptomatic despite maximal therapy with ACE inhibitors and antagonists.Digoxin may be unique among inotropic drugs by virtue of its neurohumoral effects,including attenuation of sympathetic activation and renin releas
30、e.pMost studies suggest that the maximal increase in contractility is apparent at serum levels of digoxin around 1.4 to 1.8 nmol.The neurohormonal benefits of digoxin may occur at lower serum levels of 0.5-1 ng/ml;higher concentrations are not associated with further clinical benefit.24治疗慢性心衰的药物10/1
31、4/2022Use of Sympathomimetics in CHF交感激动药在慢性心衰中的应用与争议pThe use of sympathomimetic drugs 拟交感药拟交感药 such as dobutamine多巴酚丁胺多巴酚丁胺 and dopamine 多巴胺多巴胺 was found to provide short-term relief of heart failure symptoms in patients with advanced ventricular dysfunction.It was presumed that the development of
32、oral congeners of these sympathomimetic agents would represent a major advance in the pharmacotherapy of heart failure.pThis mechanistic hypothesis has been discredited by the results of a number of trials that have addressed the longer-term use of positive inotropic agents.These trials have been co
33、ncordant in demonstrating increased mortality in CHF patients treated with drugs that amplify the receptor/cyclic AMP-modulated Ca2+signaling that underlies myocardial contraction and relaxation.拟交感强心药治疗急性心功能障碍效果尚好，拟交感强心药治疗急性心功能障碍效果尚好，但治疗慢性心衰仅暂时缓解缓解症状仍增加其死亡率但治疗慢性心衰仅暂时缓解缓解症状仍增加其死亡率25治疗慢性心衰的药物10/14/20
34、22Diuretics 利尿剂pDiuretics retain a central role in the pharmacological management of the“congestive”symptoms in patients with heart failure.慢性心衰通常伴有水钠潴留，肺淤血与外周循慢性心衰通常伴有水钠潴留，肺淤血与外周循环受阻，利尿药始终是治疗心衰最重要的药物之一。环受阻，利尿药始终是治疗心衰最重要的药物之一。pDiuretics reduce blood volume through diuresis利尿,leading to lowered prelo
35、ad and blood pressure.利尿剂通过利尿剂通过利尿作用降低血容量，亦可降低血压，同时降低心脏前后负荷。利尿作用降低血容量，亦可降低血压，同时降低心脏前后负荷。pThey are useful in relieving the pulmonary and peripheral edema as well as hypertension.利尿剂对肺水肿及外周水肿缓利尿剂对肺水肿及外周水肿缓解作用显著，同时也能有效地治疗高血压。解作用显著，同时也能有效地治疗高血压。急性左心衰发生肺水肿用药举例急性左心衰发生肺水肿用药举例26治疗慢性心衰的药物10/14/2022Diuretics
36、利尿剂p利尿剂通常分为强效、中效和弱效三类，常用的强效利尿药为呋塞米利尿剂通常分为强效、中效和弱效三类，常用的强效利尿药为呋塞米又称袢利尿剂又称袢利尿剂(loop diuretics)，中效为氢氯噻嗪，弱效利尿剂也为，中效为氢氯噻嗪，弱效利尿剂也为保钾保钾(K+-Sparing)利尿剂，如螺内酯，可根据病情选用或联合应用利尿剂，如螺内酯，可根据病情选用或联合应用pUsage:Furosemide is injected to relieve the pulmonary edema quickly and efficiently,while hydrochlorothiazide is the
37、most choices for oral administration.呋塞米为强效利尿呋塞米为强效利尿剂，可静脉给药有效缓解水肿包括肺水肿，口服通常选用氢氯噻嗪剂，可静脉给药有效缓解水肿包括肺水肿，口服通常选用氢氯噻嗪pAdverse effects:Diuretics could cause depletion of blood volume and reflex SNS activation,low serum potassium,which are detrimental to heart failure and may lead to severe arrhythmias.过度利尿
38、可导致水电解质平衡紊乱，低血容过度利尿可导致水电解质平衡紊乱，低血容量可致反射性交感兴奋，低血钾、低血镁等易致心律失常，应注意避量可致反射性交感兴奋，低血钾、低血镁等易致心律失常，应注意避免过度利尿，及时补充钾，或与保钾利尿药合用。免过度利尿，及时补充钾，或与保钾利尿药合用。27治疗慢性心衰的药物10/14/2022Vasodilators 扩血管药 -adrenergic blocker 酚妥拉明（酚妥拉明（受体阻断药）受体阻断药）sodium nitroprusside 硝普钠硝普钠(NO donor)oUsage:used for short-term release of sympto
39、ms,by reducing preload and afterload 酚妥拉明用药举例酚妥拉明用药举例oAdverse effects:tachycardia(reflex SNS activation),avoid long-term and large doses use 硝普钠须避光使用，过量可致氰化物中毒硝普钠须避光使用，过量可致氰化物中毒NoImage28治疗慢性心衰的药物10/14/2022Use of-blocker in CHF受体阻断药在慢性心衰中的应用pHeart failure is characterized by sympathetic hyperactivati
40、on,a neurohumoral state that reflects biological responses that can be both compensatory and maladaptive.既是代偿又有适应不良 增加心肌耗氧pWhile many of sympathomimetics increased mortality in CHF patients,an unexpected mortality benefit was seen with the administration of adrenergic blocking drugs.p adrenergic blo
41、ckers reduce the heart work load and catecholamines myocardial toxicity,producing long-term benefits in patients with CHF.pStart blocker at lose dose and with digitalis or diuretics.小剂量开始启用逐渐增加至最大耐受剂量，常常需合用强心苷和小剂量开始启用逐渐增加至最大耐受剂量，常常需合用强心苷和/或或利尿剂利尿剂29治疗慢性心衰的药物10/14/2022Heart function changes with the
42、use of-blocker in CHFpThe direct hemodynamic effect of a antagonist in patients with heart failure is to depress contractile function.An increase in left ventricular systolic function between 2 and 4 months after initiation of therapy is seen consistently.NoImage30治疗慢性心衰的药物10/14/2022Inhibitors of Re
43、nin-Angiotensin System抑制肾素血管紧张素系统的药物抑制肾素血管紧张素系统的药物pAngiotensin converting enzyme(ACE)Inhibitors:ACE inhibitors suppress Ang II and aldosterone production,decrease sympathetic nervous system activity,and potentiate the effects of diuretics in heart failure.pHowever,Ang II levels frequently return to
44、baseline values following chronic treatment with ACE inhibitors,due in part to production of Ang II through ACE-independent enzymes such as chymase,a tissue protease.31治疗慢性心衰的药物10/14/2022Pharmacotherapy of CHF治疗慢性心衰的药物oPositive inotropic agents 正性肌力药oDigitalis 洋地黄类:Digoxin地高辛o-adrenergic agonists:do
45、pamine多巴胺 dobutamine多巴酚丁胺oDiuretics 利尿药oLoop diuretics 袢利尿药 强效利尿药：furosemide呋塞米oThiazide diuretics 中效利尿药：hydrochlorothiazide氢氯噻嗪oVasodilators 扩血管药 o-adrenergic blocker酚妥拉明osodium nitroprusside硝普钠o-adrenergic receptor blockers 肾上腺素能受体阻断药oCarvedilol卡维地洛(兼有受体阻断作用)bisoprolol比索洛尔oACEIs and ARB 血管紧张素转化酶抑制
46、剂及AT1受体阻断剂oCaptopril卡托普利,losartan洛沙坦32治疗慢性心衰的药物10/14/2022Pharmacotherapy of CHF治疗慢性心衰的药物oPositive inotropic agents 正性肌力药oCardiac glycosides(强心苷类,digitalis洋地黄类):Digoxin地高辛Phosphodiesterase III(PDE)inhibitors 磷酸二酯酶峰抑制剂 and-adrenergic agonists：dopamine多巴胺 dobutamine多巴酚丁胺Diuretics 利尿药Loop Diuretics 袢利尿药
47、，强效利尿药 furosemide呋塞米Thiazide Diuretics 噻嗪类利尿药，中效利尿药：hydrochlorothiazideK+-Sparing diuretics and aldosterone antagonists 保钾利尿药及醛固酮拮抗剂，弱效利尿Vasodilators 扩血管药-adrenergic blockers酚妥拉明,sodium nitroprusside硝普钠(Mixed)-adrenergic receptor blockers 肾上腺素能受体阻断药、Carvedilol卡维地洛 bisoprolol比索洛尔Inhibitors of Renin-A
48、ngiotensin System:ACE Inhibitors and AT1 Receptor Antagonists 血管紧张素转化酶抑制剂及AT1受体阻断剂Captopril卡托普利,losartan洛沙坦(沙坦类)33治疗慢性心衰的药物10/14/2022US guidelines for adult CHF美国成人慢性心力衰竭治疗指南解读l NYHANYHA心功能分类方法心功能分类方法 传统传统 1 1级级 日常活动无明显受限，心功能代偿期日常活动无明显受限，心功能代偿期 2 2级级 日常活动水平时出现心衰症状日常活动水平时出现心衰症状 3 3级级 稍活动出现心衰症状稍活动出现心衰
49、症状 4 4级级 静息状态下有心衰症状静息状态下有心衰症状 心力衰竭新的分类方法：一个对疾病过程进行客观评价的心力衰竭新的分类方法：一个对疾病过程进行客观评价的分期系统分期系统 对对NYHANYHA功能分级的补充功能分级的补充 A A期期 心衰高危但没有器质性心脏病或心力衰竭症状心衰高危但没有器质性心脏病或心力衰竭症状 B B期期 器质性心脏病但没有心衰症状器质性心脏病但没有心衰症状 C C期期 器质性心脏病并且既往或目前有心衰症状器质性心脏病并且既往或目前有心衰症状 D D期期 需要特殊干预治疗的难治性心力衰竭需要特殊干预治疗的难治性心力衰竭34治疗慢性心衰的药物10/14/2022NoIm
50、ageNoImageUS guidelines for adult CHF美国成人慢性心力衰竭治疗指南解读35治疗慢性心衰的药物10/14/2022 心力衰竭新的分类方法心力衰竭新的分类方法 图示图示NoImageNoImage36治疗慢性心衰的药物10/14/2022Try mild exercise therapy for your CHF patients after symptom reliefNoImagePlants in my hometown Nanping,FujianProvinceNoImage37治疗慢性心衰的药物10/14/2022补充幻灯38治疗慢性心衰的药物10/
