1、心力衰竭与治疗慢性心衰的药物Pharmacotherapy of Congestive Heart Failure充血性心力衰竭的药物治疗充血性心力衰竭的药物治疗Definition and Clinical Features慢性心力衰竭(充血性心力衰竭)Congestive heart failure(chronic heart failure,CHF)is the pathophysiologic state in which the heart is unable to pump blood at a rate commensurate相称的 with the tissue requir
2、ements,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,或需通过升高充或需通过升高充盈压代偿盈压代偿Its primary cause is that the heart fails to provide adequate output at normal filling pressures,which is associated with a syndrome of reduced functional capacity and pulmonary and systemic
3、 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，导致心功能功能下降以及肺循正常充盈压时无法提供有效的前向射血，导致心功能功能下降以及肺循环和体循环淤血环和体循环淤血Definition and Clinical Features慢性心力衰竭(充血性心力衰竭)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，心脏收缩功能功能下降，同时心室舒张末压增加，心腔残余血液增功能功能下降，同时心室舒张末压增加，心腔残余血液增加，肺循环和体循环淤血加，肺循环和体循环淤血 CHF is a complex of symp
4、toms-fatigue,shortness of breath,and congestion-that are related to the inadequate perfusion of tissue during exertion and to the retention of fluid.其乏力、呼乏力、呼吸困难、充血、浮肿等缘于组织灌注不足及体液潴留吸困难、充血、浮肿等缘于组织灌注不足及体液潴留Systemic and Pulmonary CirculationWhen left ventricle failsLeft ventricular end-diastolic pressu
5、re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Thickening of the respiratory membrane reduces O2 exchangeEnlarged heart(ContractionLVEDP)and pulmonary congestion(O2 Exchange)Definition and Clinical Features慢性心力衰竭(充血性心力衰竭)心脏在正常充盈压时无法提供有效的前向射血，心脏收
6、缩心脏在正常充盈压时无法提供有效的前向射血，心脏收缩功能功能下降，同时心室舒张末压增加，心腔残余血液增功能功能下降，同时心室舒张末压增加，心腔残余血液增加，肺循环和体循环淤血加，肺循环和体循环淤血 CHF is a complex of symptoms-fatigue,shortness of breath,and congestion-that are related to the inadequate perfusion of tissue during exertion and to the retention of fluid.其乏力、呼乏力、呼吸困难、充血、浮肿等缘于组织灌注不足及
7、体液潴留吸困难、充血、浮肿等缘于组织灌注不足及体液潴留Clinical Features-OrthopneaExertion dyspnea,nocturnal paroxysmal dyspnea and orthopneapulmonary congestion 运动性呼吸困难、夜间阵发性呼吸困难与端坐呼运动性呼吸困难、夜间阵发性呼吸困难与端坐呼吸吸-肺淤血肺淤血 为左心衰特征为左心衰特征Hypertension and Myocardial HypertrophyNormal Hypertension Diastolic and Systolic Heart Failure78 yo W
8、oman Recurrent Pul Edema50 yo Man HCM76 yo W,Hx MI,CABG Dyspnea,Edema78 yo Woman Labile Systolic HT Acute DyspneaEF=0.15EF=0.68Basis for compensation during chronic heart failureThe principal function of the circulatory system is to deliver oxygenated blood to the periphery.心脏主要功能是作为一个强有力的泵向组织输送氧合的血
9、液心脏主要功能是作为一个强有力的泵向组织输送氧合的血液当心脏不能有效泵出血液当心脏不能有效泵出血液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、回心血量心（泵）功能的调节心（泵）功能
10、的调节Cardiac output(CO)心输出量及其影响因素：心输出量及其影响因素：stroke volume heart rate 每搏量每搏量心率心率 Myocardial contraction 心肌收缩力的自身调节心肌收缩力的自身调节：Frank-Starling Law-Force-length relationships of cardiac muscle Heart rate 心率心率 在一定范围内增加心率可增加在一定范围内增加心率可增加CO Preload 前负荷前负荷：ventricular diastolic volume and blood volume 血容量血容量(
11、回心血量回心血量)增加即前负荷增加则心室充盈增加，心肌初长度增加使心增加即前负荷增加则心室充盈增加，心肌初长度增加使心肌收缩力增加肌收缩力增加 Afterload 后负荷后负荷：blood pressure and vessel constriction 后负荷增加心后负荷增加心脏射血负荷增加脏射血负荷增加 Blood supply 心肌的血液供应心肌的血液供应Myocardial Blood SupplyMyocardial Blood Supply心脏血液灌心脏血液灌注注Basis for compensation during chronic heart failureThe princ
12、ipal function of the circulatory system is to deliver oxygenated blood to the periphery.心脏主要功能是作为一个强有力的泵向组织心脏主要功能是作为一个强有力的泵向组织输送氧合的血液输送氧合的血液The systemic circulation consists of a number of parallel regional circulatory beds,each of which offers an intrinsic vasular resistance to flow.The vascular re
13、sistance can be modulated to increase or decrease perfusion based on local and/or whole body demand for oxygen.心输出量向外心输出量向外周血管床的分配取决于局部血管床阻力周血管床的分配取决于局部血管床阻力When the heart fails,arterial pressure reduces which causes the baroreceptor response and excitation of sympathetic nervous system(SNS)and reni
14、n-angiotensin-aldosterone system(RAAS).心输出量下降导致反射性交感神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经系统及肾素血管紧张素醛固酮系统兴奋Compensation mechanisms during chronic heart failureAT1Renin-Angiotensin-Aldosterone SystemCompensation mechanisms during chronic heart failureThe epinephrine/norepinephrine(SNS)and angiotensin/ald
15、osterone(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
16、潴留，血流重新分配以保证重要脏器血流In addition,the vasoconstrictive effectors of the SNS and RAAS lead to an increase in systemic vascular resistance,which contributes to an increased impedance to left ventricular ejection(increased afterload).交感神经及肾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增
17、加Compensation mechanisms during chronic heart failureA dynamic reduction of venous capacitance that results in“centralization”of peripheral blood volume and enhanced venous return,thereby increasing left ventricular end-diastolic volume,leading to an increase in the length of left ventricular muscle
18、 fibers,thereby producing greater contractile force and increased stroke volume(Frank-Starling relationship).静脉回心血量静脉回心血量增加，通过增加，通过Frank-Starling机制增强左心收缩力使左室每搏量增加，机制增强左心收缩力使左室每搏量增加，心输出量增加心输出量增加In the setting of contractile dysfunction,the increase in LVEDV results in higher left atrial pressure,alte
19、ring Starling forces in the pulmonary capillaries to favor transudation of fluid into the extravascular spaces of the pulmonary interstitium,producing interstitial and alveolar edema.LVEDV增加致使肺毛细血管压增高增加致使肺毛细血管压增高间质及肺泡水肿间质及肺泡水肿 Compensation mechanisms during chronic heart failureThese compensation me
20、chanisms increase myocardial oxygen consumption as well as preload and afterload,rendering the heart more vulnerable to ischemia and finally decompensation.这些代偿同时也增加心脏前负荷及这些代偿同时也增加心脏前负荷及后负荷，增加心肌耗氧，最后导致失代偿后负荷，增加心肌耗氧，最后导致失代偿 The consequent reduction of cardiac output serves as an iterative反复的 stimulus
21、 to continued activation of the neurohumoral systems that stimulate the failing heart and constrict the vessels.心输出量下降导致的前后负荷心输出量下降导致的前后负荷增加不断激活神经体液系统以刺激衰竭的心脏收缩，导致血管过度痉增加不断激活神经体液系统以刺激衰竭的心脏收缩，导致血管过度痉挛，形成恶性循环挛，形成恶性循环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
22、缩力下降左室心肌收缩力下降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、回心血量强心强心 Digitalis洋地黄类降低氧耗降低氧耗-blocker ACEI降低心肌耗氧 降低前后负荷降低前后负荷Vasodilator扩血管药利尿利尿Diuretics 减轻水钠潴留Diuretics 利尿剂减轻肺淤血利用哪些途径和药物治疗慢性心力衰竭？Therapeutic Aims of CHFCHF is a major
23、 contributor to morbidity and mortality worldwide.Mortality in patients with advanced heart failure exceeds 50%at 1 year.现现代社会中慢性心衰高发病率和高死亡率代社会中慢性心衰高发病率和高死亡率While 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 t
24、he expectation that disease progression can be attenuated,减缓病情进展 and,in many instances,survival prolonged.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Clinical conditions that precipitate deterioration of CHF Myocardial ischemia 心肌缺血 Elevated blood pressure 血压升高 Mental and physica
25、l stress 心理与躯体应激 Arrhythmia 心律失常 Valve lesion and regurgitation先心或瓣膜病变所致的分流与反流 Infection,esp.lung infection 各类感染尤其是肺部感染 High salt intake 高盐饮食Case-1一70岁老年男性患者，高血压三十余年，因呼吸困难不能平卧入院治疗。入院体检BP164/100mmHg,心率110次/分，双肺可闻及较多细小水泡音，双下肢凹陷性浮肿。入院后给予地高辛(洋地黄类)强心、复方降压片（含利血平及利尿剂氢氯噻嗪）等治疗，患者尿量增加、呼吸困难减轻，可平卧休息。血压控制在130-14
26、0/80-90mmHg,心率70-80次/分，双肺底深吸气时偶可闻及细湿罗音。一日晚间忽听患者病房患者疾呼值班医生。查见该老年患者端坐呼吸，吸气及呼气均十分费力。病友述其儿前来来探视时二人发生争执，儿子离去后患者出现显著的呼吸困难。患者神志清楚，两肺满布湿罗音及高调哮鸣音，心音被罗音掩盖，即测血压180/106mmHg。急查心电图示窦性心动过速。Case-1用何种药物治疗？即予呋塞米（强效利尿剂）20mg稀释后缓慢静脉推注，患者很快出现尿意，血压逐渐下降，半小时后呼吸困难缓解，取半卧位休息。主要诊断：高血压病，慢性心力衰竭，急性肺水肿Case-2一60岁男性患者，因呼吸困难入急诊治疗。急诊医生
27、先后两次以西地兰（洋地黄类）及呋塞米静脉推注治疗均未奏效。心电图示窦性心动过速、偶发室性早搏。急诊值班医生呼救。急诊留观室外即可闻患者高调哮鸣音。入室查见患者端坐呼吸，神志清楚，鼻腔给氧，皮肤湿冷，血压190/70mmHg，双肺满布湿罗音及哮鸣音，第一心音显著增强第二心音减弱，坐位前倾心前区可闻及舒张期水音。立即予以立其丁（苄胺唑啉，受体阻断药，扩血管药）5mg稀释后缓慢静脉推注，血压迅速下降，患者呼吸困难显著缓解，哮鸣音及湿罗音减轻。主要诊断：主动脉瓣关闭不全，心源性哮喘Case-3一68岁女性患者，因神志不清被家人送入急诊治疗。急诊医生检查心电图示窦性心动过速，初步诊断为心力衰竭，给予西地
28、兰静脉注射一次后无效，建议收入心内科进一步诊治。查见患者平卧位，神志淡漠，鼻腔给氧，呼吸平稳，呼吸频率16次/分，血压150/88mmHg，心率120次/分，律齐。皮肤温暖干燥，双肺未闻及干湿罗音，颈前略隆起，仔细听诊甲状腺区可闻及轻微吹风样杂音。立即抽血送T3、T3检查并安排收入内分泌科诊治。主要诊断：淡漠型甲状腺功能亢进症该患者可以使用何种药物治疗？Pharmacotherapy of CHF治疗慢性心衰的药物 Positive inotropic agents 正性肌力药 Diuretics 利尿药 Vasodilators 扩血管药-adrenergic receptor blocke
29、rs 肾上腺素能受体阻断药 Inhibitors of Renin-Angiotensin System 肾素血管紧张素系统抑制药化学结构化学结构基本骨架基本骨架William 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Positive inotropic agents正性肌力药Cardiac glycosides 强心苷 Digox
30、in 地高辛地高辛po cidellannid 西地兰西地兰 ivActions The 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 and reduced rate of conduction through the AV node 负性负性频率频率(negative chronotropic action)与负性传导作用与负性传导作用c)disturbances of rhythm,es
31、pecially 对心肌电生理的影响对心肌电生理的影响 -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Positive inotropic agents正性肌力药Cardiac glycosides 强心苷p Mechanisms of positive inotropic action Inhibition of Na+,K+-ATPase.Cardiac glycosides are potent and highly selective inhibitors
32、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 cytosolic Ca2+available to interact with the contractile proteins,thereby increasing the force of contraction
33、.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Positive inotropic agents正性肌力药Cardiac glycosides 强心苷 Adverse effects One of the main drawbacks of glycosides is the narrow margin between effectiveness and toxicity.Adverse effects are common and can be severe.安安全范围小，过量容易导致中毒全范围小，过量容易导致中毒a)Cardiac adverse effects:
34、AV blockade,ventricular premature contraction(PVC)and even ventricular fibrillationlidocaine and potassium should be given forb)Extracardiac adverse effects:nausea,vomiting,diarrhea,blurred vision,and confusionc)The recognition of digoxin toxicity is important in the differential diagnosis of arrhyt
35、hmias and neurological and gastrointestinal symptoms.一位风湿性心瓣膜病慢性心衰门诊强心利尿治疗无效的女性Positive inotropic agents正性肌力药Cardiac glycosides 强心苷p Regulation of Sympathetic Nervous System Activity.洋地黄对交感神经洋地黄对交感神经活性的影响活性的影响 When CO declines to a level that is inadequate to meet the tissue demands,increased SNS ac
36、tivity 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 sympathetic activity。p A direct effect of digitalis on carotid baroreflex response to change
37、s 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 cardiac index and decreased HR;skeletal muscle sympathetic nerve activity,an indicator of
38、 the CNS tone,was markedly reduced.洋地黄降低心衰时代偿性交感兴奋地高辛的应用与血药浓度监测p Use of Digoxin in Clinical Practice and Monitoring of Serum Levels.It is recommended that digoxin be reserved for patients with heart failure with atrial fibrillation,or for patients in sinus rhythm who remain symptomatic despite maxim
39、al 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 release.p Most studies suggest that the maximal increase in contractility is apparent at serum levels of digoxin
40、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.Use of Sympathomimetics in CHF交感激动药在慢性心衰中的应用与争议p The use of sympathomimetic drugs such as dobutamine多巴酚丁胺多巴酚丁胺 and dopami
41、ne 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 oral congeners of these sympathomimetic agents would represent a major advance in the pharmacotherapy of heart failure.p This mechanist
42、ic 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 concordant in demonstrating increased mortality in CHF patients treated with drugs that amplify the receptor/cyclic AMP-modulated Ca2+si
43、gnaling 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，但治疗慢性心衰可增加死亡率但治疗慢性心衰可增加死亡率Diuretics 利尿剂p Diuretics retain a central role in the pharmacological management of the“congestive”symptoms in patients with heart failure.慢性心衰通常慢性心衰通常 伴有伴有水钠潴留，肺淤血与外周循环受阻，利
44、尿药始终是治疗心衰最重要的水钠潴留，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。药物之一。p Diuretics reduce blood volume through diuresis,leading to lowered preload and blood pressure.利尿剂通过利尿作用降低血容量，同时亦可降低血利尿剂通过利尿作用降低血容量，同时亦可降低血压，同时降低前后负荷。压，同时降低前后负荷。p They are useful in relieving the pulmonary and peripheral edema as well as hypertens
45、ion.利尿剂对肺水肿及外周水肿缓解作用显著，同时也能有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。效地治疗高血压。Diuretics 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，弱效利尿剂也为保钾，中效为氢氯噻嗪，弱效利尿剂也为保钾(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p Usage:Furosemide is injected to relie
46、ve the pulmonary edema quickly and efficiently,while hydrochlorothiazide is the most choices for oral administration.呋塞米为强效利尿剂，可静脉给药有效缓解水肿包括肺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。水肿，口服通常选用氢氯噻嗪。p Adverse effects:Diuretics could cause depletion of blood volume and reflex SNS activation,low serum potas
47、sium,which are detrimental to heart failure and may lead to severe arrhythmias.过度利尿可导致水电解质平衡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，应注意避免过度利尿，及时补充钾，或与保钾利尿药合用。常，应注意避免过度利尿，及时补充钾，或与保钾利尿药合用。Use of-blocker in CHF受体阻断药在慢性心衰中的应用p Heart failure is characterized by sympathe
48、tic hyperactivation,a neurohumoral state that reflects biological responses that can be both compensatory and maladaptive.p While many of sympathomimetics increased mortality in CHF patients,an unexpected mortality benefit was seen with the administration of adrenergic blocking drugs.p adrenergic bl
49、ockers reduce the heart work load and catecholamines myocardial toxicity,producing long-term benefits in patients with CHF.p Start 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/或利或利尿剂尿剂Heart function changes with the use of-blocker in C
50、HFp The 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.Inhibitors of Renin-Angiotensin System抑抑制肾素血管紧张素系统的药物制肾素血管紧张素系
