药物效应动力学机理讲解

药物效应动力学机理讲解Pharmacodynamics1学习目标o在本次课结束时，各位同学能n说出药物作用和药理效应的区别，药物特异性和选择性的关系；n列举药物常见的不良反应，并分析临床药物不良反应的类型；n指出药物量反应和质反应的量效曲线反映的参数及其含义；n解释药物与受体相互作用的规律及其参数的含义；说出作用于受体的药物的分类及竞争性与非竞争性拮抗剂的特点；n列举受体的主要类型；n分析受体调节的两种类型的临床意义。药物的基本作用药物的基本作用(Basic Effects of Drugs)Section 1药物作用的法则o药物不能产生新作用，只能调节已有的功能.o药物是双刃剑.n既有治疗作用，又有毒副作用.o药物的同一作用，在某些情况下是治疗作用，在另外一些情况下是不良反应.o药物的效应是通过与机体的生理过程相互作用而产生的.药物作用(action)&药理效应(effect)o药物作用：对靶点的初始作用，动因n特异性(specificity)：药物的构型、电荷、分子大小o药理效应：引起的机体反应，结果n兴奋 抑制o衰竭：过度兴奋导致 n直接作用 间接作用n局部作用 全身作用（吸收作用）n选择性(selectivity)：效应的专一性，与药物分布、组织细胞的结构及生化机能等差异有关n特异性作用和非特异性作用Example:阿司匹林(Aspirin)作用作用效应效应抑制环氧化酶抑制环氧化酶(COX)而而阻断前列腺素的合成阻断前列腺素的合成解热、镇痛解热、镇痛选择性选择性药物药物特异性特异性 范围范围敏感性敏感性特异性(specificity)选择性(selectivity)o问题：如果一个如果一个药具有很高的特异性，是否就有很好具有很高的特异性，是否就有很好的的选择性？性？特异性和选择性的关系o特异性弱 选择性低.o特异性强 选择性高.n e.g.:阿托品o药物的选择性作用是相对的，与剂量也有关。氯丙嗪氯丙嗪阿托品阿托品选择性(selectivity)o高选择性：药理作用强.n靶向药物(targeted medicine)o低选择性：药理作用广泛，可能副作用更多.n阿托品：低选择性，作用广泛，更多副作用o多病因或诊断不明，广谱药有其方便性.ne.g.：广谱抗菌素 治疗作用不良反应药物作用药物作用治疗作用治疗作用不良反应不良反应l对因治疗l对症治疗l补充治疗u副作用u毒性反应u后遗效应u停药反应u过敏反应u特异质反应急则治其标，缓则治其本；标本兼治，是其道也。不良反应(Adverse Drug Reaction,ADR)o与用药目的无关.o多数ADR是药物固有的效应，可预知，但不一定能避免.o药源性疾病(Drug-induced disease)：少数较严重的ADR，较难恢复.neg,庆大霉素导致神经性耳聋.1.副作用(Side Reaction)o治疗剂量o低选择性o轻而可逆氯丙嗪氯丙嗪阿托品阿托品口干唾液分泌扩瞳抑制瞳孔括约肌心率解除迷走神经对心脏的抑制 解痉内脏平滑肌松弛Atropine阿托品M-R blocker2.毒性反应(Toxic Reaction,Toxicity)o过量或因敏感性过高导致相对过量o药理作用的延伸o严重的病理变化o急性毒性急性毒性(Acute toxicity)：LD50n多损害循环、呼吸及神经系统功能o慢性毒性慢性毒性(Chronic toxicity)n多损害肝、肾、骨髓、内分泌功能n致畸胎(Teratogenesis）n致癌(Carcinogenesis)n致突变(Mutagenesis)3.后遗效应(After Effect,Residual Effect)o停药后血药浓度已降至阈浓度以下时残存的药理效应o巴比妥类 次晨宿醉4.停药反应(Withdrawal Reaction)o突然停药后原有疾病加剧回跃反应(Rebound Reaction).o长期服用可乐定停药次日血压即急剧升高5.过敏反应（变态反应）(Allergy,Hypersensitive Reaction)o过敏体质1.反应与药物效应无关2.程度与剂量无关3.预先敏化过程D +Protein DP(半抗原)(抗原)药物不同药物不同反应相同反应相同Adverse drug effect:allergic reaction6.特异质反应(Idiosyncrasy)o基因变异nG-6-PD 服用奎宁(quinine)出现急性溶血nRYR1 基因突变 服用全麻药或去极化肌松药如琥珀酰胆碱，引起恶性高热(malignant hyperthermia)1.反应与药物作用一致2.程度与剂量相关3.无需敏化过程药物即毒物，利弊并存，物即毒物，利弊并存，必必须权衡，正确衡，正确应用用药物剂量与效应关系药物剂量与效应关系(Dose-effect Relationship)Section 2量效关系(Dose-effect curve)分类o药理效应按性质分：n量反应量反应(Graded response)：o效应呈连续变化，可用具体数量或最大反应的百分率表示.n质反应质反应(All or none response,quantal response)：o效应表现为反应性质的变化，以阳性反应百分率或频率表示.量反应(Graded response)在一定剂量范围内，在一定剂量范围内，效应与剂量成正比效应与剂量成正比最大效应最大效应(maximum effect,Emax)增加剂量，可产生最大效应增加剂量，可产生最大效应达最大效应后增加剂量不再增强效应达最大效应后增加剂量不再增强效应变异性变异性(variability)半最大效应量或浓度半最大效应量或浓度(EC50):引起引起 50%50%最大最大效应的量效应的量最小有效剂量最小有效剂量或浓度（阈剂或浓度（阈剂量或阈浓度）量或阈浓度）o最小有效剂量 or 最低有效浓度(阈剂量 or 阈浓度)o最大效应(Emax)：效能(efficacy)o半最大效应浓度(EC50)o效价强度(Potency)n引起等效反应（一般采用50效应量）的相对浓度或剂量，其值越小则强度越大；n反映曲线与y轴接近程度o适用条件：曲线不相交o斜率(Slop)n反映药物效应剧烈或温和Potency:ABCEfficacy:ABCSlop:BA=CCCAABBResponseResponseLog concentrationLog concentrationCCAABBResponseResponseLog concentrationLog concentrationPotency:lAClBClAB?质反应36oMedian effective dose(ED50)oMedian toxic dose(TD50)oMedian lethal dose(LD50)37Some Acute Oral LD50 ValuesCategoryDose(mg/kg body weight)SpeciesChemicalPractically nontoxic15000Slightly toxicMouse乙醇5000Moderately toxicRat氯化钠Rat阿托品500Highly toxic250Rat胺甲萘(杀虫药)50Extremely toxic13Rat对硫磷(杀虫药)5Supertoxic3Rat华法林0.4Duck黄曲霉素B1Therapeutic index(TI):LD50/ED50(平行时)A and B:to have A and B:to have same TI,difference same TI,difference slopeslopeoSafety Range(安全范围):nthe distance between ED95 and LD5.oTherapeutic Window(治疗窗):nthe concentration range of drug producing therapeutic effect.4142安全性o治疗指数(Therapeutic Index,TI)n动物：TI=LD50/ED50n临床：TI=TD50/ED50o安全范围(Safety Margin,SM)n动物：SM ED95 LD5 的距离n临床：SM ED95 TD5 的距离o可靠安全系数(Certain Safety Factor,CSF)n动物：CSF LD1/ED99n临床：CSF TD1/ED99o安全界限n动物：CSF (LD1-ED99)/ED99 100%n临床：CSF (TD1-ED99)/ED99 100%o有效率中毒率有效率-中毒率oTI：nAB=CoSM：nABCED95LD95ED95LD95ED95LD95构效关系构效关系(Structure Activity Relationship)Section 3构效关系构效关系oThe property of drug action is firstly based on the chemical structure of drugnbasic frameworknactivity groupnlength of side chainnstereoisomerism(立体异构;chirality,手性药物)ngeometrical isomerism(几何异构,顺式或反式)netc.46Cartoon illustrating the nonsuperimposibility of the two stereoisomers of carvedilol on the receptor.oThe effects of enantiomer(光学异构体,镜像体)may be not same.oMost left-oriented(左旋体)of drug have the pharmacological activity.e.g.levo-chloramphenicol(氯霉素),levamisole(左旋咪唑),etc.o a few dextro-drugs possess higher pharmacological activity.e.g.quinidine(奎尼丁),ethambutol(乙胺丁醇),etc.49oRational Drug Design:nQSAR(定量的构效关系)n3D-QSAR(三维定量构效关系)51药物的作用机制药物的作用机制(Mechanisms of Drug Action)Section 4药物的作用机制药物的作用机制o非特异性作用(Nonspecific action)nPhysical or chemical reaction:e.g.antacid nOsmotic pressure(渗透压):e.g.bulk laxatives(容积性泻药)nSolubility(溶解度):nSurface tension(表面张力):o特异性作用(Specific action)结构特异性药物，作用于特定靶点1.Taking part in or interfering metabolism of cell 2.Affecting transport of physiological substance 3.Acting on enzyme:20%4.Acting on ion channel 5.Affecting metabolism of nucleic aid 6.Affecting immune mechanism 7.Gene therapy and genetic engineering drug8.Receptor:50%药物与受体的相互作用药物与受体的相互作用(Interaction of Drug and Receptor)Section 51.受体oA kind of functional protein which mediates signal transduction of cell.信息放大系统生理、药理学反应l功能蛋白,细胞膜或细胞内l可识别微量化学物质l介导细胞信号传导Receptor 内源性配体药物2.受体的结构o结合位点合位点o催化部位：催化部位：some haveo非特异非特异结合位点合位点o抗原域抗原域563.受体的特性o敏感性敏感性o特异性特异性o饱和性和性n竞争争o可你行可你行o多多样性性 n亚型型4.受体学说o占领学说(Occupation theory):n1926 Clark,1937 Gaddum put forward respectively.n1954 Ariens revises:intrinsic activityn1956 Stephenson:spare receptor,silent receptoro速率学说(Rate theory):n1961 Paton:frequency of the collision between molecular of drug and receprot.o二态模型学说(Two model theory):5.受体与药物的相互作用o受体结合量与效应的关系：直方双曲线半指数曲线（S型）1.量效关系式2.Michaelis-Menten公式3.Langmuir等温吸附公式4.Henderson-Hasselbach方程式 以上公式的相似性，正说明了分子间相互作用具有普遍性的定量规律，药物与靶体、酶与底物、抗原-抗体、氧-血红蛋白。D=0D=0效应为效应为效应为效应为 00D D KKDDDR/RDR/RTT=100%,=100%,达最大效应达最大效应达最大效应达最大效应DR/RDR/RTT=50%=50%即即即即ECEC5050时时时时,K,KDD=D=D K KDD值为值为值为值为ECEC5050时的药物浓度值时的药物浓度值时的药物浓度值时的药物浓度值ParametesoKD&affinity(亲和力亲和力):nKD与亲和力成反比与亲和力成反比nKD=EC50npD2=-logKD,与亲和力成正比与亲和力成正比ResponseResponseLog concentrationLog concentrationCCAABB只有作用于同一受体，才能比较亲和力大小A、B平行，表明作用于同一受体，亲和力:A BB与C不平行，表明作用于不同受体，不能比较ParametesoEmax&intrinsic activity(内在内在活性活性,)n100%0nEmax represents the efficacy(效效能能)of drugsnEmax reflects the intrinsic activity of drugs6.Principles of Drug-Receptor BindingoAffinity:strength of attraction between drug and receptoroPotency:amount of drug needed to produce an effectnaffinity influences potencyand vis versa6.Principles of Drug-Receptor BindingoSelectivity:degree to drug dose produces desired effect vs.adverse effects ndependent on specificity of drugoSpecificity:degree to which drug binds to single receptor type.7.作用于受体的药物分类o激激动剂(Agonist)n完全激完全激动剂(Full agonist)=100n部分激部分激动剂(Partial agonist)0%100%o拮抗拮抗剂(Antagonist)=0n竞争性拮抗争性拮抗剂(Competitive antagonist)n非非竞争性拮抗争性拮抗剂(Noncompetitive antagonist)Partial agonist(部分激动剂)o具有激动剂和拮抗剂的双重特性n单用时表现为激动作用，与完全激动剂联合应用又表现为拮抗作用。A:The percentage of receptor occupancy resulting from full agonist(present at a single concentration)binding to receptors in the presence of increasing concentrations of a partial agonist.Because the full agonist and the partial agonist compete to bind to the same receptor sites,when occupancy by the partial agonist increases,binding of the full agonist decreases.B:When each of the two drugs is used alone and response is measured,occupancy of all the receptors by the partial agonist produces a lower maximal response than does similar occupancy by the full agonist.C:Simultaneous treatment with a single concentration of full agonist and increasing concentrations of the partial agonist produces the response patterns.The fractional response caused by a single high concentration of the full agonist decreases as increasing concentrations of the partial agonist compete to bind to the receptor with increasing success;at the same time the portion of the response caused by the partial agonist increases,while the total responseie,the sum of responses to the two drugsgradually decreases,eventually reaching the value produced by partial agonist alone(compare with B).Partial antagonist(部分拮抗剂)o以拮抗作用为主，兼有微弱的内在活性n具有内在拟交感活性的-受体阻断药，吲哚洛尔(Pindolol)、醋丁洛尔(acebutolol)。n先用利血平耗竭内源性儿茶酚胺，可表现为-受体激动作用。Competitive antagonistocompete for same binding site oreversible bindingCompetitive Antagonist激动剂DD +RDREARKD竞争性拮抗剂AKA+AAgonist aloneAgonist+antagonistIncreased agonist+antagonist 当A0，上式即Clark基本公式。A越大，则E/Emax越小，在加用拮抗剂浓度为A时，要产生不加A的药效，势必增加D的用量，设由Do增加到DA，则：Antagonistic Index(pA2)当DA比 DO大一倍时，将A的浓度称为半拮抗浓度A2。反映拮抗反映拮抗药的拮抗的拮抗强度，度，pA2越大，所需越大，所需拮抗拮抗药浓度越小，拮抗作用越度越小，拮抗作用越强.Noncompetitive antagonist1.bind to alternative cellular site and alter action of ligand相当于乘了一个相当于乘了一个（1 1），内在活性），内在活性变小，激小，激动剂的的E Emaxmax显然减弱，称然减弱，称为“减活作用减活作用”；但并不改；但并不改变激激动剂的的K KD D值，亲和力不和力不变。激动剂D非竞争性拮抗剂 IDED +RDRDR-IKDKI+IIRKD+KI+INoncompetitive antagonist2.Irreversible antagonistn拮抗药与受体成强键结合，如共价键，解离速率=0，相当于灭活了部分受体3.拮抗拮抗药阻断了受体阻断了受体结合后的某一中介反合后的某一中介反应环节，受体的，受体的结合未受影响合未受影响100%50%00Log DLog DpDpD22EECompetitive antagonist Irreversible antagonistIn the presence of a competitive antagonist,higher concentrations of agonist are required to produce a given effect;thus the agonist concentration(C)required for a given effect in the presence of concentration I of an antagonist is shifted to the right.High agonist concentrations can overcome inhibition by a competitive antagonist.This is not the case with an irreversible(or noncompetitive)antagonist,which reduces the maximal effect the agonist can achieve,although it may not change its EC50.Mechanisms of receptor antagonismMechanisms of receptor antagonism8.储备受体(Spare Receptors)o通常全部受体被占通常全部受体被占领才才产生生EmaxEmaxo高活性高活性药物激活部分受体即物激活部分受体即产生生EmaxEmax，剩余的，剩余的未被激活受体称未被激活受体称储备受体受体n酪氨酸蛋白激酶受体仅需少数被激活即能维持大量底物蛋白的磷酸化反应o意意义：n提高激动药的敏感性。n拮抗药必须在完全占领储备受体后才能发挥其拮抗效应。n非可逆性结合或其它原因丧失一部分受体时，并不总会立即影响最大效应。Spare receptors(receptor reserve)MAXMagnitude of response IS NOT proportional to receptor occupancy9.沉默受体(Silent Receptor)oreceptors which are below than the threshold receptor agonist bound to produce effects.Silent receptors(receptor reserve)no effectReceptor which produce effects have a THRESHOLD effect10.二态模型学说oConformation of receptor:nactivate(Ra)inactive(Ri)othe effect of drug lies on the affinity of drug to the two conformation.11.Category of ReceptoroG protein-coupled receptorsoLigand-gated ion channel receptorsoTyrosine-kinase receptorsoIntracellular receptorsnreceptors in cytoplasm:steroid hormonenreceptors in nucleus:thyroxine oOther receptors92Ligand-gated ion channel receptorso配体：配体：nN-AchN-AchnGABAGABAn兴奋性氨基酸（甘氨兴奋性氨基酸（甘氨酸、谷氨酸、天门冬酸、谷氨酸、天门冬氨酸氨酸)G protein-coupled receptoro最多=肽链，7个-螺旋反复穿过细胞膜=氨基酸组成不同导致配体特异性=细胞内部分有GP结合区G protein(鸟苷酸结合调节蛋白鸟苷酸结合调节蛋白)99G protein(鸟苷酸结合调节蛋白)o膜内侧o由由、亚单位组成亚单位组成o许多类型：许多类型：nGs:激活激活ACcAMP nGi:抑制抑制ACcAMP nGp:PI-PLCnGtnGo1023.具酪氨酸激酶活性的受体具酪氨酸激酶活性的受体（Receptors with tyrosine kinase activity）l 细胞外段，与配体结合区细胞外段，与配体结合区l 中间段，穿透细胞膜中间段，穿透细胞膜l 细胞内段，酪氨酸激酶细胞内段，酪氨酸激酶配体：胰岛素、胰岛素样生长因子、上皮生配体：胰岛素、胰岛素样生长因子、上皮生长因子、血小板生长因子、淋巴因子长因子、血小板生长因子、淋巴因子Tyrosine-kinase receptorso细胞外段，与配体结合区o中间段，穿透细胞膜o细胞内段，酪氨酸激酶配体：胰配体：胰岛素、胰素、胰岛素素样生生长因子、上皮生因子、上皮生长因子、血小板生因子、血小板生长因子、淋巴因子因子、淋巴因子104配体与细胞外段结合配体与细胞外段结合 构型改变构型改变酪氨酸激酶活化酪氨酸激酶活化 残基磷酸化残基磷酸化 激活细胞内蛋白激酶激活细胞内蛋白激酶 DNA、RNA合成加速合成加速 蛋白合成加速蛋白合成加速产生生物学效应产生生物学效应Intracellular receptorsoreceptors in cytoplasm:steroid hormoneoreceptors in nucleus:thyroxinencellnuclear hormone receptors:transcription factors12.Signal transduction in celloFirst messenger:extracellular messengeroSecond messenger:1.cAMP2.cGMP3.Phosphatidylinositol4.Ca2+oThird messenger:Second messenger109The cAMP second messenger pathwayThe Ca2+-phosphoinositide signaling pathway112thyrotropin-releasing-hormone酶13.受体的调节(Receptor Regulation)oReceptor desensitization：nAgonist-specific desensitization:ophosphorylation or shift inward of receptor nAgonist-nonspecific desensitization:o受体有共同的反馈调节机制o信号转导通路上的某个共同环节受到调节oReceptor hypersensitization:nwithdrawal reactionodown-regulation&up-regulationnkinds of de-and hypersensitization when only involving change of the density of receptor.11313.受体的调节(Regulation of Receptor)o受许多因素调控和内环境稳态的控制n受体的合成和降解；n共价修饰；nAssociation with other regulatory proteinsnRelocalization within the cell反馈调节(Feedback regulation)o受体脱敏(Receptor desensitization,also referred to as adaptation,refractoriness,or down-regulation)：nRapid desensitization-快速耐受(tachyphylaxis)o受体的磷酸化nSlow desensitization-慢速耐受(bradyphylaxis)o受体合成下降nHomologous desensitization:oReceptor molecule phosphorylation,internalization and proteolysis,decreased synthesis,etc.nHeterologous desensitization:oInhibition or loss of one or more downstream proteins that participate in signaling from other receptors as well.o受体脱敏(Receptor hypersensitization,also referred to as up-regulation)：nwithdrawal reaction同种调节o配体作用于其特异性受体，使自身的受体发生变化。n乙酰胆碱受体、胰岛素受体异种调节o配体作用于其特异性受体，对另一种配体的受体产生调节作用。n-氨基丁酸受体可被苯二氮卓类调节n-肾上腺素受体可被甲状腺素、糖皮质激素和性激素调节118