药理学精品教学（汕头大学）药物效应动力学课件

1、药物效应动力学Pharmacodynamics,学习目标,在本次课结束时，各位同学能 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； 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； 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； 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； 分析受体调节的两种类型的临床意义,药物的基本作用(Basic Effects of Drugs,Section 1,药物作用的法则,药物不能产生新作用，只能调节已有的功能. 药物是双刃剑. 既有治疗作用，又有毒副作用. 药物的同一作用，在某些

2、情况下是治疗作用，在另外一些情况下是不良反应. 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) chirality,手性药物) geometrical isomerism (几何异构,顺式或反式) etc,药物的作用机制(Mechanisms of Drug Action,Section 4,药物的作用机制,非特异性作用(Nonspecific action) Physical or chemical reaction: e.g. antacid Osmotic pressure (渗透压): e.g. bulk laxatives (容积性泻药) 特异性作用(Sp

3、ecific action) 结构特异性药物，作用于特定靶点 Taking part in or interfering metabolism of cell Affecting transport of physiological substance Acting on enzyme: 20% Acting on ion channel Affecting metabolism of nucleic aid Affecting immune mechanism Gene therapy and genetic engineering drug Receptor: 50,药物与受体的相互作用(

4、Interaction of Drug and Receptor,Section 5,受体,A kind of functional protein which mediates signal transduction of cell,生理、药理学反应,受体的特性,敏感性 特异性 饱和性 竞争 可逆性 多样性 亚型,受体学说,占领学说(Occupation theory) : 1926 Clark , 1937 Gaddum put forward respectively. 1954 Ariens revises: intrinsic activity 1956 Stephenson: sp

5、are receptor, silent receptor 速率学说(Rate theory): 1961 Paton: frequency of the collision between molecular of drug and receptor. 二态模型学说(Two model theory,受体与药物的相互作用,受体结合量与效应的关系,直方双曲线,S型半指数曲线,D = 0效应为 0 D KDDR / RT = 100%, 达最大效应 DR / RT = 50%即EC50时, KD=D KD值为EC50时的药物浓度值,Parameters,KD & affinity(亲和力): K

6、D与亲和力成反比 KD = EC50 pD2 =-logKD, 与亲和力成正比,Response,Log concentration,Parameters,Emax & intrinsic activity (内在活性, ) 100% 0 Emax represents the efficacy(效能) of drugs Emax reflects the intrinsic activity of drugs,Principles of Drug-Receptor Binding,Affinity: strength of attraction between drug and recept

7、or Potency: amount of drug needed to produce an effect affinity influences potency and vis versa,作用于受体的药物分类,激动剂 (Agonist) 完全激动剂 (Full agonist) = 100 部分激动剂 (Partial agonist) 0% 100% 拮抗剂 (Antagonist) = 0 竞争性拮抗剂 (Competitive antagonist) 非竞争性拮抗剂 (Noncompetitive antagonist,Partial agonist (部分激动剂,具有激动剂和拮抗

8、剂的双重特性 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,Partial antagonist (部分拮抗剂,以拮抗作用为主，兼有微弱的内在活性 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) 。 先用利血平耗竭内源性儿茶酚胺，可表现为-受体激动作用,竞争性拮抗剂 （Competitive antagonist,compete for the same binding site reversible binding,Agonist + antagonist,Increased agonist + antagonist,当A0，上

9、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,反映拮抗药的拮抗强度，pA2越大，所需拮抗药浓度越小，拮抗作用越强,Noncompetitive antagonist,bind to alternative cellular site and alter action of ligand,Mechanisms of receptor antagonism,Mechanisms of receptor an

10、tagonism,储备受体(Spare Receptors,通常全部受体被占领才产生Emax 高活性药物激活部分受体即产生Emax，剩余的未被激活受体称储备受体 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 意义： 提高激动药的敏感性。 拮抗药必须在完全占领储备受体后才能发挥其拮抗效应。 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,20,10,30,10,20,30,Spare receptors (receptor reserve,MAX,Magnitude of response IS NOT proportional to receptor oc

11、cupancy,二态模型学说,Conformation of receptor: activate (Ra) inactive (Ri) the effect of drug lies on the affinity of drug to the two conformation,11. 受体类型,G protein-coupled receptors Ligand-gated ion channel receptors Tyrosine-kinase receptors Intracellular receptors receptors in cytoplasm: steroid hormo

12、ne receptors in nucleus: thyroxine Other receptors,反馈调节(Feedback regulation,受体脱敏(Receptor desensitization, also referred to as adaptation, refractoriness, or down-regulation)： Rapid desensitization-快速耐受(tachyphylaxis) 受体的磷酸化 Slow desensitization-慢速耐受(bradyphylaxis) 受体合成下降 Homologous desensitization: Receptor molecule phosphorylation, internalization and proteolysis, decreased synthesis, etc. Heterologous desensitization: Inhibition or loss of one or more downstream proteins that participate in signaling from other receptors as well. 受体增敏(R