1、,第三章 受體理論 there are no spare receptors,50,d,Here there are a total of 20 receptors only 10 are required to produce a maximal response,10 receptors produce maximal response,Half-maximal,5 receptors produce,half-maximal response,response,EC = 5 - concentration that produces half-maximal response,50,K

2、= 10 - concentration that occupies 50% of receptors,d,When EC K ; it suggests existence of spare receptors,50,d,When all receptors need to be occupied for a full response: then EC = K i.e. the concentration of a,50,d,drug which produces half-maximal response (EC ) will,50,Spare receptors,equal the c

3、oncentration that occupies half the number,allow maximal response without total receptor occupancy ,of total receptors (K ),increase sensitivity of the system,d,spare receptors can bind (and internalize) extra ligand preventing an exaggerated response if too much ligand is present,Type of receptors,

4、1. Channel linked receptors :,Example: the ACh receptor, signal is neurotransmitter, depolarization is signal, Na+ channel is target.,Type of receptors,2. G-protein coupled receptors:,Signal through trimeric G proteins.,The proteins can alter the function,of many proteins.,Type of receptors,3. Enzym

5、e linked receptors:,Usually signal through protein kinases,or protein phosphatases. Protein modification then alters intracellular enzyme activity.,結(jié) 合 區(qū),Type of receptors,4. Intracellular receptors,Hormone receptors,Signal binds directly to an intracellular protein which then activates transcriptio

6、n.,第二信使,Primitive signal,Receptor,binds with receptor and then trigger second messenger,Intracellular effect,First messengers,Second messengers,Small, nonprotein, water-soluble molecules or ions Readily spread throughout the cell by diffusion Two most widely used second messengers are: 1. Cycle AMP,

7、 ,2. Calcium ions Ca2+ （ cAMP,IP3,DG,),Signal amplification,Phosphates tranferred to target proteins,Adenylyl cyclase,Cyclic cAMP,Protein kinases,Receptor,G-protein,10-10M Adr in bl ood blood glu cose levels by 50%,No amplification,No amplification,Amplification,Amplification,Amplification,Results i

8、n a tremendous increase in the potency of the initial s ignal permits precise control of cell behavior,受體調(diào)節(jié)：與配體作用過(guò)程中,相關(guān)數(shù)目和親和力變化稱受體調(diào)節(jié),下調(diào)（衰減性調(diào)節(jié)、耐受）和 上調(diào)（上增性調(diào)節(jié)、反跳） 同種調(diào)節(jié)：配體使自身受體變 化 異種調(diào)節(jié)：配體對(duì)其他受體進(jìn) 行調(diào)節(jié), ,效能與效價(jià)強(qiáng)度的關(guān)系,200 150,B,C,D,A,100 50,0,0.1 0.3,1,3,10 30 100 300 1000,劑量( mg),。,100 50,A,B,100 50,D,治療指數(shù) =C

9、, B 安全范圍 C, B,100 50,C,治療指數(shù) =A, B 安全范圍 =B, A,有效量的量效關(guān)系 中毒量的量效關(guān)系,量效關(guān)系,Dose-effect Relationship,量效曲線,質(zhì)反應(yīng) (Qualitative effect) Immeasurable,， alive or di,Positive or negative, all or none e ， effective or ineffective,N=100,Produce a same efficacy,Quantal dose response curve different doses of a drug are

10、 given to a group of people and a given response is noted e.g. induction of sleep,9498 100,100 80 60 40 20 0,100 80 60 40 20 0,88,80,65,44 29,21,15 15,16,13,9,8,7,5,6,4,2,2,2,50,100,200,50,100,200,Dose of drug,Dose of drug,Frequency distribution,Cumulative frequency ,Each bar shows the number of peo

11、ple responding to that dose at 100 mg 21 people respond, excludes people responding to lower doses,each bar shows the number of people responding to that dose and to lower doses at 200 mg all 100 people respond,Quantal (Cumulative) Dose-Response curves,ED effective dose in 50% of people,Quantificati

12、on of drug safety Here two effects have been recorded hypnosis and death,50,TD toxic dose in 50% of people,50,LD lethal dose in 50% of people,50,Therapeutic Index = TD50/ED50 (higher the ratio, safer the drug) Therapeutic Window = TD1 - ED80 (the wider the safer),Therapeutic window,The range of conc

13、entration over which a dru g is therapeutically beneficial and safe.,Therapeutic window may vary from patient to patient,Minimum toxic concentration window,Drugs w/ narrow the,Therapeutics,rapeutic windows re quire smaller & mor e frequent doses or a different method o,Minimum effective concentratio

14、n,f administration,作 用,常用量,0,無(wú) 最 效 小 量 有 效,極 最 量 小 中,最 小 致 死 量,劑量,毒 量,量,劑量與藥物作用的關(guān)系示意圖,量效曲線,量反應(yīng) (Quantitative response),Measurable, Blood pressure, heart rate, blood glucose, enz,yme activity,Quantitative dose response curve,效能,強(qiáng)度,效能 vs 強(qiáng)度,Efficacy:,Maximal response a drug can produce,Potency:,Measur

15、e of dose required to produce a response,A is more _ than B., ,A and B are more _ than C.,藥物作用機(jī)制,Mechanisms of Drug Action,非特異性藥物作用機(jī)制,與藥物理化性質(zhì)相關(guān) 解 離度、溶解度、表面張力， 滲透壓、脂溶性、絡(luò)合作 用等,與藥物（立體）化構(gòu)關(guān)系不 大,特異性藥物作用機(jī)制,藥物生物活性與化構(gòu)密切相關(guān),藥物作用蛋白靶點(diǎn)：受體、離子通道、 酶、載體分子 其他有：結(jié)構(gòu)蛋白、細(xì)胞內(nèi)蛋白、 DNA 、細(xì)胞壁組分等 作用舉例： 1. 激動(dòng)或拮抗受體 2. 影響 遞質(zhì)釋放或激素分泌 3

16、. 影響自身活性 物質(zhì) 4. 影響酶活性 5. 影響離子通道,選擇題,甲藥的 LD50 和 ED50 分別為 30mg/kg 與 3mg/kg, 而乙藥分別為 10mg/kg 與 2mg/k g, 下述那種評(píng)價(jià)是正確的, ,A. B. C. D. E.,甲藥的毒性更大，但療效更強(qiáng) 甲藥的毒性較低，而療效更強(qiáng) 甲藥的毒性較低，且安全性也較大 甲藥的療效較強(qiáng)，且毒性較低,甲藥的療效較弱，且安全性也較小,小結(jié),藥物的基本作用 : 興奮、抑制 藥動(dòng)學(xué) :ADME, ,藥效學(xué)：兩重性 ( 治療作用 + 不良反 應(yīng) ),量效關(guān)系 : 劑量、效能與效價(jià)、 LD 與 ED ， TI,50,50,作用原理：受體原理（親和力、內(nèi)在 活性、激動(dòng)劑、阻斷劑、部分激動(dòng) 劑）,Summary, ,most drugs act through receptors,there are 4 common signal transduction methods the interaction between drug and receptor can be,described mathematically and graphical