钙通道阻滞药物精选课件.ppt

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1、关于钙通道阻滞药物第一页，本课件共有33页 一类通过干扰细胞膜上钙离子通道的活性，阻断钙离子内流，从而降低细胞胞浆中钙离子浓度的药物。Calcium channel blockers(Calcium antagonist,钙拮抗剂钙拮抗剂)第二页，本课件共有33页Physiological roles of Ca2+l血管平滑肌张力维持（maintenance of vascular smooth muscle tone）l心肌收缩（myocardial contraction）l维持心脏自律性和传导性（maintenance of cardiac automaticity and propa

2、gation）l其他:细胞增殖、腺体分泌、细胞移行、递质释放、凝血等。第三页，本课件共有33页Sources of intracellular free calciuml胞外内流（胞外内流（influx from outside）:through calcium channels l肌浆网和线粒体释放（肌浆网和线粒体释放（sarcoplasmic reticulum and mitochondria release）+第四页，本课件共有33页Classification of calcium channels1.Voltage-dependent Ca2+channel(VDC):l膜去极化时

3、开放；l lSix subtypes:T,L,N,P,Q,RSix subtypes:T,L,N,P,Q,R2.Receptor-operated Ca2+channel(ROC):l激动剂如catecholamines(儿茶酚胺)可激动可激动l l对膜去极化不敏感对膜去极化不敏感第五页，本课件共有33页L-type calcium channel and mechanism of drug action1.L-type calcium channel组成与结构：组成与结构：n组成组成:1、2、和和 亚单位亚单位n功能亚单位功能亚单位:1第六页，本课件共有33页Channel structur

4、e and 1 subunitMenbraneOutsideInsideDHP:Dihydropyridine;PAA:Phenylalkylamines第七页，本课件共有33页2.Channel status and drug actionOIRCa2+i=Ca n pCa2+i:总钙离子内流总钙离子内流Ca:单一钙离子通道钙内流单一钙离子通道钙内流n:通道数目通道数目p:开放概率开放概率+Calcium channel blockersCalcium channelBlockers-第八页，本课件共有33页II.Pharmacological actions1.负性肌力作用（负性肌力作用（

5、negative inotropic effect）Decrease slow calcium influx during phase 2Decrease slow calcium influx during phase 2 contractility contractility 引起反射性心肌收缩力增强引起反射性心肌收缩力增强 BP BP baroreceptor sense sympathetic activity contractilitycontractility A.对心脏的作用对心脏的作用第九页，本课件共有33页钙通道阻滞药对心脏及对血管作钙通道阻滞药对心脏及对血管作用的选择性用的

6、选择性l维拉帕米 heart vascular SMCl硝苯地平 heart vascular SMCl地尔硫卓 heart vascular SMC第十页，本课件共有33页2.负性频率作用及负性传导作用（负性频率作用及负性传导作用（negative chronotropic and negative conductive action）l l Slow Ca2+influx in sinoatrial node(窦房结)automaticity(自律性)l l Slow Ca2+influx in atrioventricular node(房室结)conduction velocity引起

7、反射性心率加快引起反射性心率加快Nifedipine Diltiazem Verapamil第十一页，本课件共有33页B.对血管平滑肌（对血管平滑肌（vascular smooth muscle cells，VSMCs)的作用的作用1.Relax VSMCs,BP ,arterioles more sensitive than veins2.Most potent in dilation the coronary arterial1.treatment for variant anginavariant angina3.Nimodipine(尼莫地平)、Nicardipine(尼卡地平)具有脑

8、血管选择性具有脑血管选择性C.Other smooth muscle cells Relax bronchiolar,uterine and gastrointestinal SMCs第十二页，本课件共有33页III.Therapeutic uses1.心绞痛（心绞痛（angina）变异型心绞痛（variant angina）:舒张大的冠状动脉，首选；劳力型心绞痛（angina of effort）:BP,afterload,oxygen demand第十三页，本课件共有33页2.Supraventricular arhythmia(室上性室上性心动过速心动过速)n快速型室上性心动过速u维拉帕

9、米为首选药物n折返引起的快速型室上性心动过速 维拉帕米为首选药物 80%恢复窦性节律 Use-dependence:channels being used frequently are more susceptible to block第十四页，本课件共有33页n房扑（atrial flutter）和房颤（fibrillation）u 房室结（atriaventricular node）conduction 心室率 n室性心动过速（Ventricular tachycardia）u 冠状动脉痉挛所致u对其他室性心律失常无效第十五页，本课件共有33页3.Hypertension(高血压高血压)l

10、降压效果与基础 BP相关，不影响正常人血压 lAdvantages:1.Do not affect cardiac output 2.Dilate renal vessels water and salt excretion without water/salt retention3.Uric acid excretion4.Risk of shock5.Prevent and reverse cardiovascular hypertrophy or remodeling第十六页，本课件共有33页4.心肌梗死（心肌梗死（myocardium infarction,MI）Ischemia Is

11、chemia membrane stability ,depolarization calcium influx ,overload activation of ATP consuming enzymes energy tores susceptibility to damage +动物实验动物实验:心律失常发生心律失常发生,MI梗死面积梗死面积人类人类:不能阻止不能阻止MI的发展，也不可降低其死亡率的发展，也不可降低其死亡率MI时存在钙超载时存在钙超载:energy stores Ischemia第十七页，本课件共有33页5.充血性心力衰竭（充血性心力衰竭（congestive heart

12、failure）l l临床应用存在争议临床应用存在争议l lIndications:CHF accompanied by angina or Indications:CHF accompanied by angina or hypertensionhypertensionl lEfficacy in ventricular diastolic dysfunction Efficacy in ventricular diastolic dysfunction ventricular systolic dysfunction ventricular systolic dysfunction 6.肥

13、厚型心肌病（肥厚型心肌病（hypertrophic myocardiopathy）Contraindications(禁忌证):left heart failure,sick sinus syndrome(病窦综合症),atrioventricular block（房室传导阻滞）第十八页，本课件共有33页7.动脉粥样硬化动脉粥样硬化（atherosclerosis,AS）：）：Prevent or attenuate the development of ASl lDecrease Ca2+in cytoplasml lInhibit platelet aggregationl lDilate

14、 vasculaturel lInhibit proliferation of vascular SMC第十九页，本课件共有33页8.血管性疾病（血管性疾病（vascular disease）l l脑血管痉挛（脑血管痉挛（cerebral vascular spasm）和脑缺血（cerebral ischemiacerebral ischemia）:nimodipine(尼莫地平)、nicardipine(nicardipine(尼卡地平尼卡地平)l l朱网膜下腔出血（朱网膜下腔出血（subarachnoid hemorrhagesubarachnoid hemorrhage）:nimodip

15、ine(尼莫地平尼莫地平)、flunarizin(氟桂嗪)l l偏头痛（migraine）:nimodipine(尼莫地平尼莫地平)l l原发性肺动脉高压原发性肺动脉高压:nifedipine nifedipine、diltiazem diltiazem CO CO ,relieve hypoxemiarelieve hypoxemial l外周血管疾病:雷诺病（Raynauds phenomenon）第二十页，本课件共有33页IV.Pharmacokineticsn n口服易吸收(90%)n n首关消除明显n n肝脏CYP450s(CYP3A4)代谢n n多数半衰期短：38 hn n肝功能异

16、常注意调整剂量第二十一页，本课件共有33页Adverse reactions头痛、眩晕、乏力、心悸、便秘、踝关节水肿V.Adverse reaction and interactions of drugs药物相互作用（药物相互作用（drug interactions）:lPharmacokinetics:dioxin concentration;cimetidine t1/2,quinidine concentrationlPharmacodynamics:hypotensive effects of nitrates and prazosin,atrioventricular blockad

17、e with-AR blockers第二十二页，本课件共有33页VI.Classification of CCBs1.1.苯烷胺类（苯烷胺类（苯烷胺类（苯烷胺类（phenyalkylamines）:如维拉帕米如维拉帕米（verapamil）和 (),阿尼帕米（阿尼帕米（anipamilanipamil）2.2.二氢吡啶类（二氢吡啶类（二氢吡啶类（二氢吡啶类（dihydropyridinesdihydropyridines），如），如），如），如硝苯地平（NifedipineNifedipine）,尼莫地平（nomodipinenomodipine）,尼卡地平（nicardipine）,非洛地平

18、（非洛地平（felodipine）和氨氯地平）和氨氯地平（amlodipine）3.地尔硫地尔硫 类（类（benzothiazepines）:如地尔硫（diltiazem）卓卓卓卓第二十三页，本课件共有33页A.Actions1.扩张血管（扩张血管（vasodilation）t tPeripheral and lung resistant vessel beds t tCoronary arteryNifedipine(硝苯地平硝苯地平)2.正性肌力作用（正性肌力作用（positive inotropic effect）Reflex sympathetic activity myocardiu

19、m contractility 第二十四页，本课件共有33页B.Therapeutics uses1.Hypertension2.Variant angina3.Heart failure:acute left ventricular failure caused by ischemia or hypertension4.Others:pulmonary hypertension(肺动脉高压),Raynauds disease(雷诺病)第二十五页，本课件共有33页C.Adverse reactions：Headache,hypotension,flush,peripheral edema,He

20、adache,hypotension,flush,peripheral edema,tachycardiatachycardiaD.Contraindications低血压、肥厚性梗阻性心肌病、严重的主动脉狭低血压、肥厚性梗阻性心肌病、严重的主动脉狭窄窄Be Cautious in HF and unstable angina 第二十六页，本课件共有33页Nitrendipine(尼群地平尼群地平)l lVasodilation activity 6-fold higher than Vasodilation activity 6-fold higher than nifedipinenife

21、dipinel lInhibit secretion of aldosteroneInhibit secretion of aldosterone l lLong-acting,tLong-acting,t1/21/2=7 8 hours=7 8 hoursl lTherapeutic use:hypertension and anginaTherapeutic use:hypertension and anginaNisodipine(尼索地平尼索地平)lThe strongest CCBl lHighly selective for coronary arteryHighly select

22、ive for coronary arteryl lRapidly absorbed with low bioavailabilityRapidly absorbed with low bioavailabilityl lTherapeutic use:hypertension and anginaTherapeutic use:hypertension and angina第二十七页，本课件共有33页Nicardipine(尼卡地平尼卡地平)nSelective for cerebral vessels and coronary arteryn nInhibits phosphodieste

23、rase(Inhibits phosphodiesterase(磷酸二酯酶磷酸二酯酶)nTherapeutic use:hypertension,angina,cerebral vasospasm and ischemiaNimodipine(尼莫地平尼莫地平)l lHighly selective for cerebral vesselsHighly selective for cerebral vesselsl lPreserves and promotes memoryPreserves and promotes memorylTherapeutic use:cerebral vasos

24、pasm and ischemia,subarachnoid hemorrhage第二十八页，本课件共有33页Amlodipine(氨氯地平氨氯地平)l lAct slowly but lasting,tAct slowly but lasting,t1/2=35 50 hours=35 50 hoursl lBioavailability:60%65%Bioavailability:60%65%lTherapeutic use:hypertension and angina第二十九页，本课件共有33页Verapamil(维拉帕米维拉帕米/Isoptin,异博定异博定)l Negative i

25、notropic effect(负性肌力作用负性肌力作用)Blocks calcium channel;activates phosphodiesterase;inhibits the function of systolic proteinsl Negative chronotropic effect(负性频率作用负性频率作用)l P-R interval(间期间期)dose dependentl Vasodilation(血管扩张血管扩张)Resistant vessels and coronary artery Reflex sympathetic activity is mildA.A

26、ctions：第三十页，本课件共有33页B.Therapeutics uses1.Supraventricular tachycardia2.Angia(variant)3.Hypertension4.Hypertrophic myocardiopathyC.Adverse reaction1.Constipation,flush,headache,itch2.Large doses:atrioventricular blockade3.Most serious:hypotension(i.v)第三十一页，本课件共有33页A.A.Actions1.1.Negative inotropic ef

27、fectNegative inotropic effect2.2.Negative chronotropic effectNegative chronotropic effect3.3.Vasodilation of coronary artery and its branches,and peripheral resistant vessels4.4.Ameliorates myocardial metabolism and protects the function of mitochondriaDiltiazem(地尔硫地尔硫 )卓卓第三十二页，本课件共有33页感感谢谢大大家家观观看看第三十三页，本课件共有33页