朱亮《药学导论》2药效学-zhuliang.ppt

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1、药物效应动力学Pharmacodynamics,朱亮上海交通大学医学院药理学及化学生物学学科,药物的药效学特征,选择性两重性剂量/浓度-效应关系药物-药靶作用、受体理论,选择性,选择性（selectivity）：药物对不同组织器官（作用对象）效应的差异性原因The tissue-specific expression of the receptor/target(s)Receptor/target specificityDrug access to target tissues and drug concentration in different tissues 意义Usually,more

2、 selective,less side effectsBroad specificity/selectivity might enhance the clinical utility of a drug,but also contribute to a spectrum of adverse side effects due to off-target interactions,药物作用和药理学效应,药物作用:对机体细胞的初始作用是动因对应“特异性,specificity”特异性由“药物化学结构药靶”决定药理效应：作用的结果，引起的机体反应兴奋(Excitation)：功能增强 抑制(Inh

3、ibition)：功能降低对应“选择性,selectivity”一般“特异性”是“选择性”的必要但非充分条件,血管收缩心率加快 血压升高,去甲肾上腺素,-R,ACh MR,Glands EyeSmooth muscle Heart Blood vessel CNS,阿托品,选择性和特异性并不一定平行,治疗作用和不良反应(Therapeutic Effects and Adverse Reactions),治疗作用（therapeutic effect)对因治疗对症治疗补充（替代）疗法不良反应（adverse drug reaction,ADR）副反应毒性反应后遗效应停药反应继发反应变态反应特异

4、质反应依赖性,A型，剂量相关,B型,副反应(Side reaction),治疗剂量出现的与用药目的无关的作用原因：药物作用的选择性低是药物的固有作用多数较轻微且可预料,毒性反应(Toxic reaction,Toxicity)用量过大或过久对机体功能、形态产生损害。药理作用延伸,急性毒性(Acute toxicity)，LD50慢性毒性(Chronic toxicity)致畸胎(Teratogenesis)致癌(Carcinogenesis)致突变(Mutagenesis),苯巴比妥催眠 次晨头晕、困倦,长期用糖皮质激素肾上腺皮质功能低下，持续数月,后遗效应（After effect）停药后残

5、留药物引起的生物效应,停药反应(Withdrawal reaction)突然停药后原有疾病加重 也称反跳(Rebound reaction),长期服用可乐定停药次日血压即急剧升高,继发反应（secondary rection）,继发于药物治疗之后的不良反应广谱抗菌药致二重感染心脏复律后心栓脱落镇痛后依赖性产生,变态反应（Allergic rection）,仅见于少数病人，很小量即可引起。,与药物药理效应无关反应程度相差很大与剂量无明显关系,特异质反应（idiosyncrasy）,a qualitatively abnormal reaction that occurs in only a fe

6、w exposed individuals a non-immunological hypersensitivity to a substance特异质病人对某种药物反应异常增高药物的药理作用在特异质病人身上的延伸、与剂量相关药理性拮抗有效例如磺胺致遗传性 G6PD缺乏者溶血、肼苯哒嗪致乙酰化酶缺乏者狼疮样反应、RyaR突变致琥珀胆碱吸入性麻醉药镇静药用药者恶性高热,idio-独有的 特异的sync-同时发生 共同krasis mixture,依赖性/成瘾性（dependence/addiction）,用药后机体产生的强迫性渴望连续定期使用该药的行为反应，目的是感受药物的精神效应或避免由于停药

7、所致的身体不适生理（躯体）性依赖心理（精神）性依赖,If something is not a poison,it is not a drugThe dose makes the poison,Della(2015).On the role of concentration-effect relationships in safety pharmacology:only the dose makes a drug not to be poison!Br J Clin Pharmacol,药物即毒物，利弊并存，必须权衡，正确应用,药物的量效关系 Dose-effect Relationship,

8、量效曲线（Dose response curve）,相关概念,最大效应 Emax(效能 efficacy)剂量相关最小有效量半最大效应浓度EC50/剂量ED50效价强度(potency)极量最小中毒量最小致死量,Potency:a measure of the amount of drug necessary to produce an effect of a given magnitude.The concentration of drug producing an effect that is 50 percent of the maximum is used to determine p

9、otency and is commonly designated as the EC50,Efficacy:Emax,the ability of a drug to elicit a response,23,半数中毒量（TD50或TC50）使50%受试者出现毒性反应时的药物剂量,半数致死量（LD50或LC50）使50%受试者死亡的药物剂量,Some Acute Oral LD50 ValuesCategoryDoseSpecies Chemical(mg/kg body weight)Practically nontoxic 15 000 Slightly toxic10 000Mouse

10、 乙醇 5 000 Moderately toxic 4 900Rat 氯化钠 750Rat 阿托品 500 Highly toxic 250Rat 胺甲萘(杀虫药)50 Extremely toxic 13Rat 对硫磷 三氧化二砷 5 Supertoxic 3Rat 华法林 0.4Duck 黄曲霉素B1,治疗指数(Therapeutic Index)LD50/ED50安全范围LD5/ED95表示药物安全性,Therapeutic window,is the range of steady-state concentrations of drug that provides therapeu

11、tic efficacy with minimal toxicity,药物作用机制 Mechanism of Drug Action,非特异改变理化条件 影响细胞物质代谢 影响生理物质转运、递质释放、激素分泌 改变酶的活性 影响细胞膜离子通透 影响核酸代谢 影响免疫功能 改变遗传物质 作用于受体,药物发挥作用的方式（作用机制）,非特异性药物作用机制:与药物的理化性质有关.渗透压作用:如甘露醇的脱水作用.脂溶作用:如全身麻醉药对中枢神经系统的麻醉作用.影响pH:如抗酸药中和胃酸.络合作用:如二巯基丙醇络合汞,砷等重金属离子而解毒.,药物作用靶点,A druggable target is a p

12、rotein,peptide or nucleic acid with activity that can be modulated by a drug,which can consist of a small molecular weight chemical compound(SMOL)or a biologic(BIOL),such as an antibody or a recombinant proteinIn 2006,a consensus number of 324 drug targets had been proposed分类受体酶离子通道转运体核酸,H+-K+ATP酶抑制

13、剂作用模式,血管紧张素转换酶抑制剂,作用于钠通道的药物,局部麻醉药抗癫痫药I 类抗心律失常药,作用于钾通道的药物,钾通道阻断药无机离子 Cs+Ba2+；小分子化合物 TEA、4-AP生物毒素 某些蝎毒、蜂毒、蛇毒临床药物 磺酰脲类、III类抗心律失常药钾通道开放药目前主要为作用于KATP者：尼克地尓（nicorandil）、吡那地尔（pinacidil）药理作用：细胞膜超极化主要用于心血管疾病：高血压、心衰、心肌缺血,作用于离子转运体的药物,作用于神经递质转运体的药物,药物与受体 Interaction of Drug and Receptor,狭义：The sensing elements

14、in the system of chemical communications that coordinates the function of all the different cells in the body.广义：Any large molecule in a cell to which a drug binds to produce its effect.,受体receptor,Model of Substrate-Enzyme Binding,Drug binding to receptor,D+R,D-R Complex,Response,内源性配体,受体的特性,药物和特异性

15、受体结合方式:(1)离子键（ionic bonds）(2)氢键（hydrogen bonds）(3)范德瓦尔斯力（Van der Waals forces）(4)共价键（covalent bonds）,Receptor,药物,高敏感性（Sensitivity）：受体含量极微(10fmol/1mg组织)高特异性（Specificity）：高亲和力(Affinity)：0.001-1nM配体即可引起效应 可饱和性(Saturable):与受体数量有限有关 可逆性(Reversible)：结合后可解离；可置换多样性(multiple-variation)竞争性(competition),受体的特征,

16、三、受体与药物的相互作用 受体结合量与效应的关系：D+R DR E,受体相对结合量（DR/RT）决定效应的相对强弱（E/Emax）,DR,RT,D,KDD,E DR D Emax RT KD+D,=,=,E DR D Emax RT KD+D,=,=,KD值为EC50时的药物浓度值,D=0,效应为,0,D,K,D,DR/R,T,=100%,达最大效应,DR/R,T,=50%,即,EC,50,时，,K,D,=D,亲和力(Affinity),100%0,内在活性(Intrinsic activity,),作用于受体的药物分类,An inverse agonist is an agent that

17、binds to the same receptor as an endogenous agonist but induces a pharmacological response opposite to that agonist.Nelson(2007).Phenotypic pharmacology:the influence of cellular environment on G protein-coupled receptor antagonist and inverse agonist pharmacology.Biochem Pharmacol,患者，男，20岁，xx年xx月xx

18、日xx时在YY会所昏迷，送急诊抢救。入院时意识丧失，口唇发绀，体格检查显示四肢外周静脉遍布注射针眼，呼吸每分钟6-7次，脉搏52次/min，血压55/25mmHg，瞳孔呈针尖样大小，心肺听诊未发现异常，生理反射存在，病理反射未引出，血常规、血糖、电解质检查及心电图未发现异常，初步诊断为急性阿片类药物中毒，经某特异性拮抗剂并对症和支持治疗，患者苏醒并逐渐恢复。,问题：药物有哪些不良反应类型，各有何特点？本例属于何种不良反应？作用于受体的药物如何分类，各有何特点？本例中“特异性”抢救药物最有可能是什么？其作用机制为何？,翻转式miniPBL试题,Regulation of the activity

19、 of a receptor with conformation-selective drugs,Bylund et al.Quantitative versus qualitative data:The numerical dimensions of drug action.Biochemical Pharmacology 2014,Inverse agonists,Typically,unbound receptors are inactive and require interaction with an agonist to assume an active conformation.

20、However,some receptors show a spontaneous conversion from R to R*in the absence of agonist(that is,they can be active without the presence of agonist).These receptors,thus,show a constitutive activity that is part of the baseline response measured in the absence of drug.Inverse agonists,unlike full

21、agonists,stabilize the inactive R form.All of the constitutively active receptors are forced into the inactive state by the inverse agonist.This decreases the number of activated receptors to below that observed in the absence of drug.Thus,inverse agonists reverse the constitutive activity of recept

22、ors and exert the opposite pharmacological effect of receptor agonists.,The effect of a so-called“pure”antagonist on a cell or in a patient depends entirely on its preventing the binding of agonist molecules and blocking their biologic actions.An antagonist has no effect if an agonist is not present

23、.Antagonists have no intrinsic activity and,therefore,produce no effect by themselves.Although antagonists have no intrinsic activity,they are able to bind avidly to target receptors because they possess strong affinity.,竞争性和非竞争性拮抗,降低其亲和力，而不改变内在活性 增加激动药剂量后量效曲线平行右移,竞争性拮抗药(Competitive antagonist),与激动药

24、竞争同一受体，可逆性结合,剂量比(Dose ratio),增加后的激动药剂量（D）原激动药剂量（D）,剂量比为2时（D/D=2）竞争性拮抗药浓度的负对数 反映拮抗药的拮抗强度，pA2越大，所需拮抗药浓度越小，拮抗作用越强,拮抗参数(antagonist parameter,pA2,)p for logarithm,like pH;A for antagonist,激动药 递增剂量的竞争性拮抗药,激动药,剂量比,对数浓度（激动药）,最大效应（%）,非竞争性拮抗药(Noncompetitive antagonist,Irreversible antagonist)在拮抗药作用下，激动药的亲和力和内

25、在活性均降低，增加剂量也不能恢复到无拮抗药时的Emax,激动药,药物的对数浓度,最大效应（%）,机制：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 拮抗药阻断了受体结合后的某一中介反应环节，受体的结合未受影响,脱敏(desensitization)长期用激动药后反应性下降,受体的调节 维持机体内环境稳定,非特异性脱敏：对某类激动药 脱敏后，对其它受体激动药 也反应性下降 机制 受体有共同反馈调节机制 信号传导通路某共同环节被调节,特异性脱敏：仅对某类激动药 脱敏 机制 受体磷酸化；受体内移,增敏（hypersensitization）长期用拮抗药后反应性增强,Accep

26、tor,Many drugs also interact with acceptors(e.g.,serum albumin)within the body.Acceptors are entities that do not directly cause any change in biochemical or physiological response.However,interactions of drugs with acceptors such as serum albumin can alter the pharmacokinetics of a drugs actions.,受

27、体类型,Ligand gated ion channels(ionotropic)G-protein-coupled receptors(metabotropic)Receptors with tyrosine kinase activityIntracellular receptors,1.门控离子通道型受体（离子通道型受体，Ligand-Gated Channels）配体：N-ACh、GABA、兴奋性氨基酸（甘氨酸、谷氨酸、天门冬氨酸）,5个亚单位组成反复4次穿过细胞膜,受体活化 离子通道开放 膜去极化或超极化,2.G-蛋白偶联受体(G protein-coupled receptor)最

28、多，其作用需G-蛋白参与,Receptors make up the largest group of drug targets with 193 proteins accounting for 44%of human drug targets.G-protein-coupled receptors(GPCRs)have been commonly targeted by antihypertensive and antiallergy drugs,and represent about 36%of drug targets.,The 2012 Nobel Prize Laureates fo

29、r Chemistry,Robert LefkowitzProfessor of Howard Hughes Medical Institute and Duke University,Brian KobikaProfessor of Stanford University School of Medicine,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,GPCR classification,G-蛋白(鸟苷酸结合调节蛋白)：细胞膜内侧，由、亚单位组成 Gs：激活AC cAMP Gi：抑制AC cAMP,3.具酪氨酸激酶活性的受体（Receptors

30、with tyrosine kinase activity）细胞外段，与配体结合区 中间段，穿透细胞膜 细胞内段，酪氨酸激酶,配体：胰岛素、胰岛素样生长因子、上皮生长因子、血小板生长因子、淋巴因子,配体与细胞外段结合 构型改变 酪氨酸激酶活化 残基磷酸化 激活细胞内蛋白激酶 DNA、RNA合成加速 蛋白合成加速 产生生物学效应,4.细胞内受体（Intracellular Receptor）,配体 皮质激素、性激素、甲状腺激素、Vit.D,Intracellular Mechanism:Steroid,Effect,第二信使(Second Messengers)细胞外信号如何进入细胞内？,通过膜上的信号系统，增加细胞内第二信使的浓度而发挥作用,1.cAMP,3.Calcium&Phosphoinositides（磷酸肌醇),Well-Established Second Messengers,2.cGMP,促滤泡素,黄体生成素,促甲状腺素,甲状旁腺素,thyrotropin-releasing-hormone,酶,