Drugs for the Treatment of Congestive Heart Failure (CHF)

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Presentation transcript:

Drugs for the Treatment of Congestive Heart Failure (CHF) 浙江大学医学院药理学系 张世红 shzhang713@zju.edu.cn

Outlines CHF概述 CHF的治疗策略 治疗CHF的药物

概述-CHF的定义和症状 充血性心力衰竭是指在静脉回流正常的情况下,由于原发的 心脏损害引起心排血量减少,不能满足组织代谢需要的一种 综合征。导致心衰的疾病包括冠心病,缺血性心脏病,心肌 病,高血压,心瓣膜病,肾病等。 临床上以肺循环和(或)体循环淤血以及组织血液灌注不足为 主要特征,包括无力、水肿、咳嗽、喘鸣,咯血,头晕,心 律失常等。

概述-心力衰竭的类型 (1) 收缩功能衰竭: the mechanical pumping action (contractility) and the ejection fraction of the heart are reduced. (2) 舒张功能衰竭: stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejection fraction may be normal. e.g. Pericarditis (心包炎) (3) 高输出型衰竭: can result from hyperthyroidism (甲亢), beriberi (脚气病), anemia (贫血), and arteriovenous shunts (动静脉分流).

概述-心功能分级 根据症状对心功能分级: Class I: no limitation is experienced in any activities; no symptoms from ordinary activities. Class II: slight, mild limitation of activity; the patient is comfortable at rest or with mild exertion. Class III: marked limitation of any activity; the patient is comfortable only at rest. Class IV: any physical activity brings on discomfort and symptoms occur at rest.

概述-心衰的分级 根据疾病进程对CHF分级: Stage A: a high risk HF in the future but no structural heart disorder; Stage B: a structural heart disorder but no symptoms at any stage; Stage C: previous or current symptoms of heart failure in the context of an underlying structural heart problem, but managed with medical treatment; Stage D: advanced disease requiring hospital-based support, a heart transplant or palliative care At risk HF

Changes of hemodynamics in CHF Cardiac failure Cardiac output Blood pressure Venous pressure Renal blood flow Renin, angiotension II Venous hyperemia Aldosterone Pulmonary circulation (cough, emptysis, dyspnea) Systemic circulation (jugular vein distension, edema) Sodium and water retention Changes of hemodynamics in CHF

概述-CHF的病理生理学 心肌损害 心输出量减少 心脏毒性 心衰症状 SNS和RAAS 激活 ANP 血管收缩,血流动力学改变 BNP 心肌肥厚(hypertrophy) 心血管重构(remodeling) 左室功能进行性恶化 心衰症状 发病和死亡 Fonarow GC. Rev Cardiovasc Med..2001;2:7–12. References: Fonarow GC. Heart failure: recent advances in prevention and treatment. Rev Cardiovasc Med. 2000;1:25–33.

Actions of angiotensin II Constricts vessels, increases peripheral resistance and returned blood volume. Increases sympathetic tension, promotes release of sympathetic transmitter. Stimulates release of aldosterone (醛固酮). Induces expression of c-fos、c-myc、c-jun rapidly, promotes proliferation and remodeling. 9

Actions of Aldosterone McMahon EG 2001,

概述-CHF的病理生理学 CHF时 受体的信号传导变化 - 1 受体密度  - Gs 蛋白数量或/和活性 - GRKs(G蛋白偶联受体激酶)活性 交感神经系统的激活使心肌后负荷及耗氧量增加,促进心室肥厚,诱发心律失常甚至猝死。 G蛋白偶联受体激酶活化,beta受体被磷酸化

CHF的治疗策略 A 抑制RAAS:ACEIs, ARBs, 醛固酮拮抗剂 B 降低交感神经活性: ACEIs, β blockers D 增强心肌收缩力:强心苷类, PDE III 抑制剂, 其他正性肌力药物 E 扩血管药:血管扩张药

ACEIs and ARBs ACEIs Captopril (卡托普利), enalapril (依那普利), lisinopril (赖诺普利), benazepril (贝那普利), fosinopril (福辛普利), etc. ARBs Losartan (氯沙坦), valsartan (缬沙坦), erbesartan (厄贝沙坦), candesartan (坎地沙坦), telmisartan (替米沙坦), etc

anti-proliferation, anti-hypertrophy ACEIs and ARBs 血管紧张素原 激肽原 激肽释放酶 and NO Chymase 黑人肾素途径往往较弱。 Vasodilation, anti-proliferation, anti-hypertrophy

ACEIs and ARBs ACEIs Actions 抑制Ang II合成 (dilate vessels, decrease sympathetic activity, protect renal and cardiac function, inhibit release of aldosterone, anti-hypertrophy) 抑制缓激肽降解 (vasodilation, anti-hypertrophy, myocardial protection, improvement of insulin receptor sensitivity)

ACEIs and ARBs ACEIs Clinical uses: CHF - 低剂量即延缓/逆转肥厚和重构 - 增加运动耐量 - 降低病死率 高血压

ACEIs and ARBs Adverse reactions ACEIs 低血压 (首剂现象) 肾脏损害 (肾动脉硬化患者) 干咳和血管性水肿(缓激肽刺激作用) 高钾血症 (醛固酮抑制) 皮疹和味觉改变 (-SH相关) 胎毒性 (妊娠中后期,pregnancy category D) CNS 和 GI 系统的不良反应

ACEIs and ARBs ACEIs Contraindications 肾动脉硬化(pressure-dependent kidney perfusion in these patients) 孕妇和哺乳期妇女

ACEIs and ARBs ARBS Compared with ACEIs: Block actions of angiotensin II directly No influence on bradykinin metabolism Protect renal function Used for CHF and hypertension Less adverse effects

CV Risk: reduction in future cardiovascular events; DN: diabetic nephropathy; H: hypertension; HF: heart failure; Post MI: reduction in heart failure or other cardiac events following myocardial infarction.

ACEIs and ARBs 醛固酮逃逸现象 醛固酮拮抗药: Spironolactone (螺内酯) and Eplerenone (依普利酮) get additional function to decrease morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy.

RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF Added (25 mg) to top key, per Dr Conti Added RR arrow, per Dr Fonarow Added asterisk footnote for title, per Dr Conti RALES:The Randomized Aldactone Evaluation Study HR = hazard ratio; RR = risk reduction. *Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months. Pitt B et al. N Engl J Med. 1999;341:709-717.

EPHESUS Co-Primary Endpoint: Total Mortality Added % values, per Dr Conti Added RR arrow, per Dr Fonarow Epleronone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) HR = hazard ratio. Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.

美托洛尔metoprolol, 比索洛尔bisoprolol, 卡维地洛carvedilol  blockers 美托洛尔metoprolol, 比索洛尔bisoprolol, 卡维地洛carvedilol Actions 阻断儿茶酚胺的心脏毒性作用 抑制RAAS和VP (vosopressin, 加压素) 降低心率和心肌耗氧量 抗心律失常,抗高血压,抗心绞痛效应 阻断受体及抗自由基作用(carvedilol)

 blockers Clinical uses: CHF -Ⅱ ~ Ⅲ, 特别是对伴扩张性心肌病的患者 - 降低病死率 高血压,心律失常,心绞痛等

The Use of Beta Adrenergic Blocking Agents in Heart Failure Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF)

US Carvedilol Heart Failure Trials Program 1094 Class II-IV CHF pts on triple therapy (ACEI, digoxin, diuretics) Carvedilol 6.25 bid test 2 weeks, then 12.5 bid, then 25 bid vs placebo Packer NEJM 1996;334:1349-55

Effect of Metoprolol CR/XL in Heart Failure MERIT-HF controlled release/extended release (CR/XL) 3991 pts with CHF Class II-IV, ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd, target dose 200 mg qd Lancet 1999;353:2001-07

-Blockers Differ in Their Long-Term Effects on Mortality in HF 比索洛尔 布新洛尔 卡维地洛 美托洛尔 那必洛尔 扎莫特罗 普萘洛尔 Bisoprolol1 Bucindolol2 Carvedilol3-5 Metoprolol tartrate6 Metoprolol succinate7 Nebivolol8 Xamoterol9 Propranolol10 Beneficial No effect Not well studied Minor effect Harmful Harmful+Beneficial Tartrate:酒石酸盐;succinate:琥珀酸盐 1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6. 10 BHAT study Group. Circulation. 1986;73(3):503-10.

 blockers 不良反应: 心功能抑制 禁忌症: 严重心力衰竭,严重AV阻滞,低血压,支气管哮喘

Cardiac glycosides (强心苷, digitalis, 洋地黄) 毛地黄

Digitalis Digoxin (地高辛) Actions Positive inotropic action (正性肌力作用): - induces rapid and prompt contraction, prolongs diastolic period, no change or decease in oxygen consumption - Na+- K+ATPase 抑制剂

Mechanism of digitalis 2 K+ 3 Na+ Na+-K+-ATPase Digitalis NKA AP [Na+]i [K+]i [Ca2+]i 治疗剂量时,增加工作细胞收缩力,迷走神经兴奋。 慢反应细胞:迷走神经支配占主导,迷走神经兴奋,钾离子外流增加,窦房结自律性下降、房室结传导性减慢 心房肌快反应工作细胞:钾离子外流增加,ERP缩短,最大复极电位加大,动作电位幅度加大,传导加速 过量时 心动过缓,房室传导阻滞; 浦肯野纤维:过度抑制钠钾ATP酶,胞内失钾,外流减少,最大复极电位变小,ERP缩短,钙超载,自律性增加,出现室性心律失常 NCE Na+-Ca2+ exchange

Digitalis Digoxin Actions: Negative chronotropic action负性频率作用 - inhibits sympathetic activities - improves vagal activities (Ach accelerates K+ efflux)

Digitalis Actions Actions on cardiac electrophysiology Digoxin - decreases automaticity of sinoatrial node (vagal stimulation) - slows conduction (vagal stimulation) - increases automaticity of Pukinje fibres (at large doses, [K+]i, diastolic potential) - shortens ERP of fast reaction cells (at large doses, SNS activation, K+ efflux, ERP, [Ca2+]i) 治疗量时因迷走兴奋,心房肌钾离子外流增加,动作电位时程缩短,缩短ERP,浦肯野纤维和心室肌ERP轻微缩短。治疗心房扑动和心房颤动。 中毒剂量时,胞内大量失钾,外流减少,最大舒张电位变小,动作电位振幅及时程都缩短,ERP进一步缩短。同时兴奋交感神经,以及胞内钙离子浓度升高,诱发快速型心律失常。

Digitalis Digoxin Actions - autonomic nervous system Actions on the nervous system - autonomic nervous system - CNS (D2 receptor, emetic effect) Actions on neuroendocrine system - inhibits RAAS - increases ANP (心房钠尿肽) 对自主神经作用:兴奋迷走神经,抑制交感活性;中毒剂量增强交感活性 中枢神经系统作用:呕吐

Digitalis Digoxin Actions - increases blood supply of the kidney Actions on kidney (diuretic effect) - increases blood supply of the kidney - decreases Na+ resorption (inhibition of Na+-K+ ATP ase)

Digitalis Digoxin Clinical uses: CHF (systolic CHF) Especially suitable for systolic CHF with atrial fibrillation and ventricular tachycardia in sinus rhythm. Not used for diastolic CHF, CHF with dilated cardiomyopathy扩张性心肌病 and myocardial hypertrophy心肌肥厚. 对外周阻力增高的慢性心衰效果较好。对肺源性心脏病,活动性心肌炎或严重心肌损伤疗效较差,对扩张性心肌病、心肌肥厚、舒张性心力衰竭不应选用

Digitalis Digoxin Clinical uses: Some arrhythmias - atrial fibrillation: inhibits A-V conduction, decreases ventricular beats. - atrial flutter - paroxysmal surpraventricular tachycardia

Digitalis Digoxin Directions: Loading method: No-loading method: loading dose (digitalization)+maintaining dose No-loading method: maintaining dose everyday 洋地黄化概念:心率控制在70~80次/分,尿量明显增加,呼吸困难减轻,紫绀消失,浮肿消退,肿大的肝脏缩小等

Effect of Digoxin on Mortality in Heart Failure DIG (Digitalis Investigation Group): 6,800 patients with LVEF 45% randomized to digoxin (n=3,403) or placebo (n=3,397) in addition to therapy with diuretics and ACEI followed for 37 months. The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532.

Digitalis Digoxin Adverse effects: Gastrointestinal responses - severe nausea, vomit, diarrhea Symptoms of the central nervous system: - alteration of color perception (chromatopsia,色视) - headache, dizziness, insomnia, fatigue, delirium谵妄

Digitalis Digoxin Adverse effects: Cardiac effects - arrhythmias:tachycardia atrioventricular block sinus bradycardia

Symptoms to stop digitalis administration: - Severe vomit - Chromatopsia - Ventricular premature - Heart rate < 60 /min

Digitalis Digoxin Adverse effects: Treatments: - KCl, phenytoin sodium or lidocaine, iv. - Bradycardia: atropine, isoprenaline (NO supplement of K+) - Fab segment of digoxin antibody, iv.

Digitalis Digoxin Drug interaction: With antiarrhythmic agents: quinidine, amiodarone, verapamil. With phenytoin With K+-eliminating diuretics

Digitalis long-term actions digitalization + maintaining dose Digitoxin (洋地黄毒苷): long-term actions digitalization + maintaining dose Deslanoside (Cedilanid,西地兰,毛花苷C(丙)) i.v., acute attack of CHF

Diuretics Loop diuretics: high-ceiling diuretics (high efficacy), act at thick ascending limb of Henle loop, inhibit Na+-K+-2Cl- symporter: furosemide (呋塞米) Thiazide diuretics: moderate efficacy, act at distal convoluted tubule, inhibit Na+-Cl- symporter: hydrochlorothiazide (氢氯噻嗪) K+-retaining (sparing) diuretics: low efficacy, act at late distal tubule and collecting duct, inhibit renal epithelial Na+ channels or aldosterone: spironolactone (螺内酯) Carbonic anhydrase inhibitors: acetazolamide (乙酰唑胺) 碳酸酐酶抑制剂 Osmotic diuretics渗透性利尿药: mannitol (甘露醇) 袢利尿药 噻嗪类利尿药 保钾利尿药

Diuretics Actions Reduce plasma volume (diuretic effect) Dilate vessels: promote renal synthesis of PG, decrease Na+-Ca2+ exchange in vascular smooth muscle cell (peripheral resistance  )

Diuretics Clinical uses: CHF - CHF - used alone or combined with other drugs Edema, hypertension, etc

Diuretics Adverse effects: - plasma level of renin  - hypokalemia (低钾血症): more excretion of K+ through distal tubules. - hyperuricemia (高尿酸血症): competitive secretion from the proximal tubules - hyperglycemia (高血糖): inhibition of  cells in the islets - hyperlipidemia (高脂血症): inhibition of PDE in the liver 噻嗪类利尿药抑制胰岛beta细胞功能(可能与低血钾有关),引起血糖升高;抑制肝脏磷酸二脂酶,引起高脂血症。

Vasodilators Reduction in preload (through venous dilation), or reduction in afterload (through arteriolar dilation), or both. Long-term use of hydralazine 肼屈嗪and isosorbide dinitrate硝酸异山梨酯 can also reduce damaging remodeling of the heart.

I/H: isosorbide dinitrate/hydralazine fixed-dose combination of isosorbide dinitrate and hydralazine (FDCI/H) I/H: isosorbide dinitrate/hydralazine J Cardiac Fail 2007;13:331-339

Other positive inotropic drugs PDE-III inhibitors (milrinone, vesnarinone)

Other positive inotropic drugs Catecholamines (dopamine, dobuamine) Calcium sensitizers (pimobendan匹莫苯, levosimendan左西孟坦, thiadizinone噻唑嗪酮)

Other positive inotropic drugs Limit activity Limit Na+ Low Na+ ACEIs strategies Digitalis  blockers thiazides Loop diuretics combined Dilator Other positive inotropic drugs Ⅱ Ⅲ Ⅳ grades