《心力衰竭知識》ppt課件

1、Chapter 26Anti-congestive heart failure drugsLNMU PharmacologyChronic or Congestive Heart Failure，CHF CHF occurs when the cardiac output is inadequate to provide the oxygen needed by the body. The key defect in CHF is a decrease in cardiac contractility, resulting in inadequate cardiac outputThe Cau

2、ses of Heart Failure Population-attributable risk,%010203040506070MaleFemale60393410115864475Hyper-Myo- Angina Diabetes LV heart Valvulartensioncardial hyper- heartinfarction trophy diseaseThe characterizations of CHFDecrease in cardiac contractility, inadequate cardiac output.Intravascular volume e

3、xpansion and ventricular filling pressures, systemic and pulmonary hypertentension, dyspnea呼吸困難.Activation of sympathetic nervous and RASMyocardial dysfunction.Ventricular remodeling.Ventricular remodeling after acute infarctionVentricular remodeling in diastolic舒張 and systolic收縮 heart failureInitia

4、l infarctExpansion of infarct(hours to days)Global remodeling(days to months)Normal heartHypertrophied heart(diastolic heart failure)Dilated heart(systolic heart failure)Myocardial remodeling in Calcineurin transgenic hearts(Cell, Vol 93, 215-228,1998)Heart failureReduced cardiac outputSympathetic n

5、ervous system activationVasoconstrictionElevated cardiac filling pressureSodium and water retentionAngiotensin ReninCardiac remodelingAldosteroneAngiotensinPathophysiological mechanisms of heart failure and major sites of drug actiondigoxin -blockers, digoxinVasodilatorsACE inhibitorsAngiotensin-R b

6、lockersDiureticsSpironolactoneClassification of drugs used in CHF1. Renin-angiotensin-aldosterone system inhibitors (1) ACEI captopril(2) ang receptor blocker (AT1 antagonist) losartan(3) aldosterone antagonist spironolacton2. Diuretics thiazides, furosemide3. -receptor blocker Metoprolol, carvedilo

7、l4. positive inotropic agents(1)Cardiac glycosides digoxin, digitoxin(2)non-glycoside positive inotropic agents milrinone5.vasodilators nitroprusside sodium6.calcium sensitizer and calcium channel blockers amlodipineSection IIInhibitors of renin-angiotensin-aldosterone system (RAAS)Renin-Angiotensin

8、System(RAS) angiotensinogenreninAngiotensin糜酶旁路ACEAngiotensin AT1receptor1. vasoconstriction, aldosterone：BP2. hypertrophyandproliferation cardiovascularremodeling Kallikrein-KininSystem(KKS) kininogenase Bradykinin 降解產(chǎn)物AT2receptorNO , part fight AT1receptorVasodilation, BPACEI()The composition and

9、physiologicalrole of RASAT1 Blockerspironolactone angiotensin-converting enzyme inhibitor，ACEI: captopril, enalapril angiotensin receptor (AT1) blocker, ARB: losartan氯沙坦 antagonist for the aldosterone receptor: spironolactoneThe classification of Inhibitors RAAS1. ACEI卡托普利captopril開搏通依那普利enalapril悅寧

10、定賴諾普利lisinopril 帝益洛苯那普利benazepril 洛丁新 /諾華福辛普利fosinopril 蒙諾/施貴寶喹那普利quinapril益恒雷米普利ramipril 瑞泰培哚普利perindopril雅施達(dá)西拉普利cilazapril 一平蘇藥 物起始劑量目標(biāo)劑量卡托普利6. 25 mg，tid50 mg，tid依那普利2. 5 mg，bid1020 mg，bid福辛普利510 mg/d 40 mg/d賴諾普利2. 55 mg/d 3035 mg/d培哚普利2 mg/d48 mg/d喹那普利5 mg，bid20 mg，bid雷米普利2. 5 mg/d5 mg，bid 或10 mg

11、/d西拉普利0. 5 mg/d12. 5 mg/d苯那普利2. 5 mg/d510 mg，bid治療慢性心衰的ACEI及其劑量The mechanism for anti-congestive heart failure effect1. peripheral vascular resistance, cardiac afterload 2. aldosterone 3. myocardial and ventricular remodeling4. changes of hemodynamics 5. the activity of sympathetic nervous systemACE

12、I1.peripheral vascular resistance, cardiac afterloadACEI內(nèi)皮衍生超極化因子(Endothelium Derived Hyperpolarizing Factor) 5. antisympathetic effectAT1 receptor in presynaptic membrane of sympathetic nerve NA AT1 receptor in adrenal medella NA AT1 receptor in CNScentral sympathetic impulse transmission heart loa

13、d and damageACEI1) The salt and water retention 2) The preload and afterload3) The long-term remodeling of the heart and vessels Mortality and morbidityTherapeutic applicationsCHFHypertensionClinical using:ACEI AT1 blocker, ARB 氯沙坦(losartan)纈沙坦(valsartan)厄貝沙坦(irbesartan)坎地沙坦(candesartan)依普沙坦(eprosar

14、tan)替米沙坦(telmisartan)Renin-AngiotensinSystem(RAS) angiotensinogenreninAngiotensin糜酶旁路ACEAngiotensin AT1receptor1. vasoconstriction, aldosterone：BP2. hypertrophyandproliferation cardiovascularremodeling Kallikrein-KininSystem(KKS) kininogenase Bradykinin 降解產(chǎn)物AT2receptorNO , part fight AT1receptorVaso

15、dilation, BPThe composition and physiologicalrole of RASARBSection III Diuretics High-efficacy diuretics (loop diuretics)Furosemide Moderate-efficacy diuretics Thiazides; Low-efficacy diureticsSpironolactone；They can promote the loss of sodium and water from the body and provide a reduction in prelo

16、ad and afterload.Cardiogenic edema relieve the symptoms mild CHF Thiazides moderate CHFThiazides + SpironolactoneIf it fails or for the serious CHFloop diuretics；But Cautions: A large dose diureticscardiac output; sympathetic nerve activityaldosterone and hypokalemia. Coadministration with spironola

17、ctone Diuretics Section IV -receptor blocker 1. Drugs acting on -receptor (1) Carvedilol , -receptor blocker . (2) Metoprolol1-receptor blockerPharmacological effectsInhibition of sympathetic activity catecholaminesCa2+ infux myocardial necrosismyocardial remodelingreninangiotensinup-regulating R se

18、nsitivity of R to catecholaminesAnti-arrhythmic and anti-ischemic effects-R blockerTherapeutic applications Mild and moderate CHF Dilated cardiomyopathy心肌病 CHF, ischemic CHF Improve symptoms and decrease mortality Combination with diuretics and ACEI The medication should be initiated with low doses.

19、-R blockerBronchospasm, bradycardia and hypotensionOthers: depression, nightmares, fatigue, and sexual dysfunction; asthma; masking hypoglycemic symptoms Adverse Effects-R blockerClassification of drugs used in CHF1. Renin-angiotensin-aldosterone system inhibitors (1) ACEI captopril(2) ang receptor

20、blocker (AT1 antagonist) losartan(3) aldosterone antagonist spironolacton2. Diuretics thiazides, furosemide3. -receptor blocker Metoprolol, carvedilol4. positive inotropic agents(1)Cardiac glycosides digoxin, digitoxin(2)non-glycoside positive inotropic agents milrinone5.vasodilators nitroprusside s

21、odium6.calcium sensitizer and calcium channel blockers amlodipineHeart failureReduced cardiac outputSympathetic nervous system activationVasoconstrictionElevated cardiac filling pressureSodium and water retentionAngiotensin ReninCardiac remodelingAldosteroneAngiotensinPathophysiological mechanisms o

22、f heart failure and major sites of drug actiondigoxin -blockers, digoxinVasodilatorsACE inhibitorsAngiotensin-R blockersDiureticsSpironolactoneDigitoxin 洋地黃毒苷Digoxin 地高辛 Deslanoside 毛花苷丙Strophantin K 毒毛花苷KSection V Cardiac glycosides甾核Steroid 不飽和內(nèi)酯環(huán)Lactone ring三分子洋地黃毒糖 tri-digitoxose (苷元的作用強(qiáng)度和時(shí)間Chem

23、ical structure of Digoxin 苷元aglycone(正性肌力)C3 、C14) OH；C17具構(gòu)型。否那么苷元失去強(qiáng)心作用。OOOOHOHCH3HCH3HC18H31O531417BACDEffects of cardiac glycosides on heart(a highly selective for heart) 1. Positive inotropic action(1) Cardiac glycosides the maximum force the contractility of cardiac muscle the velocity of cardi

24、ac muscle contraction diastole relative extension 強(qiáng) 心 苷Anti-congestive heart failure drugsCHF patients: Cardiac glycosides cardiac output cardiac filling pressures heart size and venous and capillary pressures. (2) Cardiac output 強(qiáng) 心 苷Anti-congestive heart failure drugsIn normal individuals: contrac

25、tility myocardial minute oxygen consumption (MVO2) .b. In patients with CHF: ventricular volume MVO2.(3) Myocardial oxygen consumption 強(qiáng) 心 苷Anti-congestive heart failure drugsMyocardial oxygen consumptionventricular pressure(afterload)ventricular volume(preload) contractility heart rate ventricular

26、wall tension O2 demand 強(qiáng) 心 苷Anti-congestive heart failure drugsInhibit the membrane-bound Na+-K+-ATPase .Inhibition of Na+-K+-ATPase results in intracellular accumulation of Na+(and loss of intracellular K+).Accumulation of intracellular Na+ slight movement of extracellular Ca2+ into the cell second

27、ary to activation of a membrane Na+-Ca2+ carrier.The mechanism for positive inotropic effect Digoxin may interfere with the ability of the sarcoplasmic reticulum to bind Ca2+ making more Ca2+ available for interaction with contractile proteins Ca2+ positive inotropic effect說教學(xué)過程N(yùn)a+Ca2+K+intracellula

28、rextracellularNKANCE 強(qiáng) 心 苷 Anti-congestive heart failure drugsNKA: Na+-K+-ATPaseNCE: Na+-Ca2+ exchangerThe mechanism for positive inotropic effect說教學(xué)過程 強(qiáng) 心 苷Anti-congestive heart failure drugsCICR: Calcium induced calcium releaseCa2+Ca2+i與AP和心肌收縮的關(guān)系The mechanism for positive inotropic effectThe mech

29、anism for positive inotropic effectCardiac glycosidesMLCK: Myosin light chain kinase肌球蛋白輕鏈激酶SERCA: Sarco-endoplasmic Reticulum Calcium Atpase肌漿網(wǎng)鈣泵SOCE: store-operated calcium entry channels鈣池支配鈣離子通道RYR: Ryanodine receptor蘭尼堿受體 強(qiáng) 心 苷Anti-congestive heart failure drugs 強(qiáng)心苷 Na+-K+ -ATPase Na+-K+ 交換Cell

30、內(nèi)Na+短暫 C內(nèi)Na+ 超負(fù)荷， 失K+ 影響Na+ - Ca2+ 交換機(jī)制 Ca2+超負(fù)荷 異位節(jié)律點(diǎn) 自律性 Na+ 外流，Ca2+內(nèi)流 遲后去極 Na+ 內(nèi)流，Ca2+外流 C內(nèi) Ca2+ i 心律失常 正性肌力治療量中毒量CICRCICR: Calcium induced calcium release說教法HRMechanism：A：COactivating vagus nerve B：sensitivity of vagusSignificance：負(fù)性頻率心動周期舒張期 心室充盈好 心肌本身供血 心肌獲充分休憩心功能改善Effects of cardiac glycosides

31、 on heart2. Negative chronotropic action 強(qiáng) 心 苷Anti-congestive heart failure drugs竇房結(jié)自律性房室傳導(dǎo)心房ERP浦肯野纖維自律性，ERP、傳導(dǎo)與添加迷走神經(jīng)活性有關(guān)3. Electrophysiological effects抑制Na+-K+-ATP酶0 -50If , Ik and Na+-Ca2+ exchangeCa2+ channelK+ channel添加迷走神經(jīng)活性Ca2+內(nèi)流房室傳導(dǎo)房撲轉(zhuǎn)為房顫a. therapeutic dose3. Electrophysiological effects 強(qiáng) 心

32、 苷Anti-congestive heart failure竇房結(jié)細(xì)胞KAch開放頻率K+外流靜息期膜電位多負(fù)自律性竇性頻率K+外流心房ERP縮短0 -50If , Ik and Na+-Ca2+ exchangeCa2+ channelK+ channel 促K+外流 心房肌靜息電位加大 零相除極速度 心房傳導(dǎo)速度 ()Na+-K+-ATP酶K+i最大舒張電位少負(fù)接近閾電位自律性；c. toxic doseb. high dose提高普氏纖維自律性Central sympathetic activityCa2+i；ERP中毒時(shí)室速或室顫的機(jī)制 強(qiáng) 心 苷Anti-congestive he

33、art failure drugsK+外流ERP最大舒張電位除極發(fā)生在較小的膜電位 強(qiáng) 心 苷Anti-congestive heart failure drugs電生理 特性竇房結(jié)心房房室結(jié)浦肯野纖維自律性傳導(dǎo)性ERP與添加迷走神經(jīng)活性有關(guān)抑制Na+-K+-ATP酶是強(qiáng)心苷引起室早、室性心律失常的緣由之一治療房顫、房撲使房撲轉(zhuǎn)為房顫3. Electrophysiological effectsWith more toxic concentration, resting membrane potential is reduced as a result of inhibition of the

34、 sodium pump and reduced intracellular potassium.Glycosides toxicity: atrioventricular junctional rhythm, premature ventricular depolarization, bigeminal rhythm, and atrioventricular blockade.3. Electrophysiological effectsRegulation of neuroendocrine activity-Parasympathomimetic effectsAt lower dos

35、e: mainly affects atrial and atrioventricular nodal function.-Sympathomimetic effectsAt overdose, enhance the activity of sympathetic nervous centre.Anorexia厭食, nausea and vomiting, headache, fatigue, . -RAASrenin activity; Ag; aldosterone 強(qiáng) 心 苷Anti-congestive heart failure drugs1) Effects on vascul

36、ar In normal individuals: peripheral vascular resistance (direct action)In patients with CHF: peripheral vascular resistance (indirect action)2) Effects on kidney A diuretic effect.cardiac function improvementinhibition of kidney tubular Na+-K+-ATPaseExtracardiac effects 強(qiáng) 心 苷Anti-congestive heart f

37、ailure drugsPharmacokinetics Serum Principal Absorption Protein Therapeutic MetabolicDrugs (Per os) Binding T1/2 Concentration RouteDigoxin 6085% 25% 36h 0.52.0ng KidneyDigitoxin 90100% 97% 57d 1035ng/ml Liver 強(qiáng) 心 苷Anti-congestive heart failure drugsTherapeutic usesCHF 強(qiáng) 心 苷Anti-congestive heart fai

38、lure drugs2. Arrhythmias:1.心房纖顫：350-600次/分f波 強(qiáng)心苷迷走興奮房室傳導(dǎo) 房室結(jié)隱匿性傳導(dǎo)心室率 2.心房撲動：240-430次/分F波 強(qiáng)心苷心房ERP撲動變顫抖心室率；有些病人在停用強(qiáng)心苷后可恢復(fù)為竇性節(jié)律 3.陣發(fā)性室上性心動過速：迷走興奮現(xiàn)已少用)房撲房顫fff 強(qiáng) 心 苷Anti-congestive heart failure drugsDrug actions and doses 1. Action vs Effect or Response2. Pharmacological effects and doseslethaltoxic max. effectivemin. effective submedicalTherapeutic or medical doseUntowar