钙通道阻滞药物.ppt

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1、关于钙通道阻滞药物现在学习的是第1页，共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)现在学习的是第2页，共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 p

2、ropagation）l其他:细胞增殖、腺体分泌、细胞移行、递质释放、凝血等。现在学习的是第3页，共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）+现在学习的是第4页，共33页Classification of calcium channels1.Voltage-dependent Ca2+channel(VDC

3、):l膜去极化时开放；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现在学习的是第5页，共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现在学习的是第6页，共33页

4、Channel structure and 1 subunitMenbraneOutsideInsideDHP:Dihydropyridine;PAA:Phenylalkylamines现在学习的是第7页，共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-现在学习的是第8页，共33页II.Pharmacological act

5、ions1.负性肌力作用（负性肌力作用（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 sensebaroreceptor sense sympathetic activity sympathetic activity contractility A.对心脏的作用对心脏的作用现

6、在学习的是第9页，共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现在学习的是第10页，共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

7、 in atrioventricular node(房室结)conduction velocity引起反射性心率加快引起反射性心率加快Nifedipine Diltiazem Verapamil现在学习的是第11页，共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,Relax VSMCs,BP BP,arterioles more sensitive than veins2.Most potent in dilation the coronary arterial1.treatment for

8、treatment for variant angina3.Nimodipine(尼莫地平)、Nicardipine(尼卡地平)具具有脑血管选择性有脑血管选择性C.Other smooth muscle cells Relax bronchiolar,uterine and gastrointestinal SMCs现在学习的是第12页，共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现在学

9、习的是第13页，共33页2.Supraventricular arhythmia(室上性心室上性心动过速动过速)n快速型室上性心动过速u维拉帕米为首选药物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现在学习的是第14页，共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（Ventricul

10、ar tachycardia）u 冠状动脉痉挛所致u对其他室性心律失常无效现在学习的是第15页，共33页3.Hypertension(高血压高血压)l l降压效果与基础 BP相关，不影响正常人血压 l 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 hypertr

11、ophy or remodeling现在学习的是第16页，共33页4.心肌梗死（心肌梗死（myocardium infarction,MI）Ischemia Ischemia 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

12、在钙超载时存在钙超载:energy stores Ischemia现在学习的是第17页，共33页5.充血性心力衰竭（充血性心力衰竭（congestive heart failure）l临床应用存在争议lIndications:CHF accompanied by angina or hypertensionlEfficacy in ventricular diastolic dysfunction Efficacy in ventricular diastolic dysfunction ventricular systolic dysfunction ventricular systolic

13、 dysfunction 6.肥厚型心肌病（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）现在学习的是第18页，共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 cytoplasmlInhibit platelet aggr

14、egationlDilate vasculaturel lInhibit proliferation of vascular SMC现在学习的是第19页，共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）和脑缺血（cerebral ischemiacerebral ischemia）:nimodipine(尼莫地平尼莫地平)、nicardipine(nicardipine(尼卡地平尼卡地平)l l朱网膜下腔出血（subarachnoid hemorrhagesubarachnoid he

15、morrhage）:nimodipine(nimodipine(尼莫地平)、flunarizin(flunarizin(氟桂嗪)l l偏头痛（migrainemigraine）:nimodipine(尼莫地平)l l原发性肺动脉高压原发性肺动脉高压:nifedipine、diltiazem CO CO,relieve hypoxemial l外周血管疾病:雷诺病（Raynauds phenomenon）现在学习的是第20页，共33页IV.Pharmacokineticsn n口服易吸收(90%)n首关消除明显n肝脏CYP450s(CYP3A4)代谢n多数半衰期短：38 hn n肝功能异常注意调

16、整剂量现在学习的是第21页，共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 blockade w

17、ith-AR blockers现在学习的是第22页，共33页VI.Classification of CCBs1.苯烷胺类（苯烷胺类（苯烷胺类（苯烷胺类（phenyalkylaminesphenyalkylamines）:如维拉帕米如维拉帕米（verapamilverapamil）和）和 (),(),阿尼帕米（anipamil）2.二氢吡啶类（二氢吡啶类（dihydropyridinesdihydropyridines），如），如硝苯地平（NifedipineNifedipine）,尼莫地平（nomodipinenomodipine）,尼卡地平尼卡地平（nicardipinenicardipi

18、ne）,非洛地平（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（diltiazemdiltiazem）卓卓卓卓现在学习的是第23页，共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

19、activity myocardium contractility 现在学习的是第24页，共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)现在学习的是第25页，共33页C.Adverse reactions：Headache,hypotension,flush

20、,peripheral edema,Headache,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 现在学习的是第26页，共33页Nitrendipine(尼群地平尼群地平)lVasodilation activity 6-fold higher than nifedipinel lInhibit secretion of al

21、dosteroneInhibit secretion of aldosterone lLong-acting,tLong-acting,t1/21/2=7 8 hourslTherapeutic use:hypertension and anginaTherapeutic use:hypertension and anginaNisodipine(尼索地平尼索地平)l lThe strongest CCBThe strongest CCBlHighly selective for coronary arterylRapidly absorbed with low bioavailability

22、l lTherapeutic use:hypertension and anginaTherapeutic use:hypertension and angina现在学习的是第27页，共33页Nicardipine(尼卡地平尼卡地平)nSelective for cerebral vessels and coronary arterynInhibits phosphodiesterase(磷酸二酯酶磷酸二酯酶磷酸二酯酶磷酸二酯酶)nTherapeutic use:hypertension,angina,cerebral Therapeutic use:hypertension,angina,c

23、erebral vasospasm and ischemiavasospasm and ischemiaNimodipine(尼莫地平尼莫地平)lHighly selective for cerebral vesselslPreserves and promotes memoryl lTherapeutic use:cerebral vasospasm and ischemia,Therapeutic use:cerebral vasospasm and ischemia,subarachnoid hemorrhagesubarachnoid hemorrhage现在学习的是第28页，共33页

24、Amlodipine(氨氯地平氨氯地平)lAct slowly but lasting,t1/2=35 50 hoursl lBioavailability:60%65%Bioavailability:60%65%lTherapeutic use:hypertension and angina现在学习的是第29页，共33页Verapamil(维拉帕米维拉帕米/Isoptin,异博定异博定)l Negative inotropic effect(负性肌力作用负性肌力作用)Blocks calcium channel;activates phosphodiesterase;inhibits the

25、 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.Actions：现在学习的是第30页，共33页B.Therapeutics uses1.Supraventricular tachycardia2.Angia(variant)3.Hyp

26、ertension4.Hypertrophic myocardiopathyC.Adverse reaction1.Constipation,flush,headache,itch2.Large doses:atrioventricular blockade3.Most serious:hypotension(i.v)现在学习的是第31页，共33页A.A.Actions1.1.Negative inotropic effectNegative inotropic effect2.2.Negative chronotropic effect3.3.Vasodilation of coronary artery and its branches,Vasodilation of coronary artery and its branches,and peripheral resistant vesselsand peripheral resistant vessels4.4.Ameliorates myocardial metabolism and protects the function of mitochondriaDiltiazem(地尔硫地尔硫 )卓卓现在学习的是第32页，共33页感感谢谢大大家家观观看看现在学习的是第33页，共33页