第二章藥效學(xué) 3

1、Chapter 2 Pharmacodynamics,Department of Pharmacology, Medical school of Nankai University Jingling Zhang Tel:(office) E-mail: jlzhang,Pharmacodynamics,教學(xué)目的 掌握藥效學(xué)的基本概念和藥理作用的基本規(guī)律，為各論藥物的學(xué)習(xí)提供理論基礎(chǔ)。,2,Pharmacodynamics,教學(xué)內(nèi)容 藥物的基本作用和效應(yīng)；器官功能的升高或降低，即興奮和抑制。藥物作用的選擇性和可逆性。 藥物作用的臨床效果，即治療作用和不良反應(yīng)。 藥物作

2、用原理；藥物作用原理的多樣性； 受體和配體的概念，受體在藥物作用中的意義；,3,Pharmacodynamics,親和力（pD2），內(nèi)在活性（），受體激活至效應(yīng)器反應(yīng)的中間過程；反饋的生理意義。 激動藥，部分激動藥，對抗藥的共性與個性，拮抗參數(shù)pA2， 藥物的構(gòu)效關(guān)系。 藥物作用的量效關(guān)系：質(zhì)反應(yīng)與量反應(yīng)。量效關(guān)系曲線，作用強度與最大效應(yīng)，半數(shù)效應(yīng)量，閾劑量，治療量，極量，中毒量及致死量。,4,Pharmacodynamics,Concept of pharmacodynamics It is the study of drug effects and their mechanisms of

3、action.,5,Pharmacodynamics,Drug action The therapeutic effect of drug and adverse drug reaction (ADR) Dose-effect relationship Structure-activity relationship Targets for drug action Theory about interaction of drug and receptor,6,Drug action,Drug action Types of drug action Selectivity of drug acti

4、on Pharmacological effect,excitation inhibition,7,The therapeutic effect of drug,Etiological treatment Symptomatic treatment Supplementary therapy or replacement therapy,complementary the loss of nutrition Quantal response ( All-or-none response ) Significance,10,11,12,Special points：,Slope Minimum

5、effective concentration，threshold concentration Maximum effect or Efficacy Median effective dose, ED50 TD50 LD50 Potency Effective dose；Toxic dose；Lethal dose；Maximum dose,the effect cannot increase with the addition of the drug.,the equivalent dose among the different drugs which produce the same t

6、herapeutic effect.,13,14,Safety,Therapeutic index： TI=LD50/ED50； Margin of safety： ED95TD5； Structure-activity relationship,15,16,Dose-effect curve of the effects and toxicity of Phenobarbital(Ph)、drugA and drugB. (*LD50/ED50 of Ph and A both are 2.6, that of B is 3.0; #A: ED80=LD10, B: ED80=LD15。),

7、Ph is safer than A and B, A is safer than B,ED50,LD50,17,Targets for drug action,Receptors Enzymes Ion channels Carrier molecules (transporters) Gene,18,Mechanism of drug action,Nonspecific mechanism of drug action Specific Mechanisms of drug action,19,Nonspecific mechanism of drug action,Other pH c

8、hange Osmosis Liposoluble action Oxidation-reduction Complex action or sorption.,20,Specific mechanism of drug action,Interfere or Incorporate into metabolic process of cells Influence physiological transmitters and hormones secretion Influence function of the biological membrane Interaction between

9、 drug and receptor,penetration, barrier, protection; enzyme, ion channels, carrier, molecule, receptor,21,Interaction between drug and receptor,Concept of the receptor The term receptor is used in different ways. In pharmacology, it describes protein molecules whose function is to recognise and resp

10、ond to endogenous chemical signals.,22,Interaction between drug and receptor,The concept of receptors is central to pharmacology, and the term is most often used to describe the target molecules through which soluble physiological mediators-hormones, neurotransmitters, inflammatory mediators, etc.-p

11、roduce their effects.,23,Interaction between drug and receptor,Property of receptor Sensitivity Specificity Saturability Reversibility Multiple-variation Affinity Competition,Type of receptor G proteins-coupled receptor Ligand gated ion channel receptor Tyrosine kinase receptor Intracellular recepto

12、rs,24,25,26,27,28,Interaction between drug and receptor,Ligand Concept Type,Receptor theory: Occupation theory; Rate theory; Two model theory;,Exterior ligand Drug, Toxin, Ag; Inner ligand Transmitters, Hormones, Autacoids;,The term “l(fā)igand” denotes the chemical agents that recognize and bind to rec

13、eptors.,29,Fig. 2-7 The two-state model. The receptor is shown in two conformational states, resting (R) and activated R*, which exist in equilibrium.,30,Occupation theory,When receptors are occupied, the pharmacological effects will occur. The effects of drug are directly proportional to the number

14、s of receptors occupied.,31,Development of occupation theory,令 KD = K2 / K1；,Clark（1926）,32,Development of occupation theory,整理后得：AR(KD+A)=A RT,因為: RT=R+AR，R=RT-AR；,代入R得：,33,Development of occupation theory,When AR/RT=0, E=0. When AKD, AR/RT=1, AR=RT , E=Emax. When AR/RT=1/2, E=50%Emax, KD = A.,34,I

15、nteraction between drug and receptor,pD2 (affinity index),35,Development of occupation theory,Ariens(1954)：intrinsic activity (內(nèi)在活性) pD2affinity index (親和力指數(shù)) Stephenson(1956)：spare receptor (儲備受體) silent receptor (沉默受體),( 0C,Affinity index (pD2) : XYZ intrinsic activity (): X=Y=Z,37,Classification

16、of the drug,Drug can be divided into different group according to the receptor theory: Agonist Absolute agonist Partial agonist Inverse agonists,Partial agonist can evoke weak agonist effects but may also displace full agonists from the binding sites and reduce their biologic effect.,38,Classificati

17、on of the drug,Antagonist Competitive antagonist pA2=-log(I)2 Noncompetitive antagonist pA2= -log(I)2,Antagonist binds to a receptor without producing any of the effects associated with agonist binding.,39,40,KD = A,THE END!,41,42,測試題 1. 下列關(guān)于競爭性拮抗藥拮抗參數(shù)（pA2）的描述中不對的是： A、 pA2值是表示拮抗相應(yīng)激動藥的強度； B、 pA2大表示拮抗

18、藥與相應(yīng)受體的親和力大； C、 pA2值越大對相應(yīng)激動藥拮抗力越強； D、不同亞型受體 pA2值不盡相同； E、 pA2是拮抗藥摩爾濃度的對數(shù)值。,43,2、pD2值可以反映藥物與受體親和力，pD2值大說明： A、藥物與受體親和力大，用藥劑量?。?B、 藥物與受體親和力大，用藥劑量大； C、 藥物與受體親和力小，用藥劑量小； D、 藥物與受體親和力小，用藥劑量大； E、以上均不對。,44,50,100,E %,lg C,A,N,A+C,藥物A、N及A+C 的對數(shù)-效應(yīng)曲線,3、已知藥物均作用于同一種受體，指出下列正確的敘述： A、A藥和N藥有同等的效能； B、N藥是一種完全激動藥； C、N藥是A藥的一種競爭性拮抗藥； D、C藥是A藥的一種競爭性拮抗藥； E、N藥作用效價高于A藥。,45,Interaction between drug and receptor,IR=IR/Ki (1),AR=AR/KD (2) R/AR=KD/A (3),46,Interaction between drug and receptor,因為：RT=R+AR+IR； 所以：R=