朱亮藥學(xué)導(dǎo)論2藥效學(xué)-zhuliang

1、藥物效應(yīng)動(dòng)力學(xué)Pharmacodynamics,朱亮上海交通大學(xué)醫(yī)學(xué)院藥理學(xué)及化學(xué)生物學(xué)學(xué)科,藥物的藥效學(xué)特征,選擇性?xún)芍匦詣┝?濃度-效應(yīng)關(guān)系藥物-藥靶作用、受體理論,選擇性,選擇性（selectivity）：藥物對(duì)不同組織器官（作用對(duì)象）效應(yīng)的差異性原因The tissue-specific expression of the receptor/target(s)Receptor/target specificit

2、yDrug access to target tissues and drug concentration in different tissues 意義Usually, more selective, less side effectsBroad specificity/selectivity might enhance the clinical utility of a drug, but also contribute t

3、o a spectrum of adverse side effects due to off-target interactions,藥物作用和藥理學(xué)效應(yīng),藥物作用: 對(duì)機(jī)體細(xì)胞的初始作用是動(dòng)因?qū)?yīng)“特異性, specificity”特異性由“藥物化學(xué)結(jié)構(gòu)——藥靶”決定藥理效應(yīng)：作用的結(jié)果，引起的機(jī)體反應(yīng)興奮 (Excitation)：功能增強(qiáng) 抑制 (Inhibition)：功能降低對(duì)應(yīng)“選擇性, selectivit

4、y”一般“特異性”是“選擇性”的必要但非充分條件,,血管收縮心率加快 血壓升高,去甲腎上腺素,?-R,ACh MR,Glands EyeSmooth muscle Heart Blood vessel CNS,阿托品,,,選擇性和特異性并不一定平行,,治療作用和不良反應(yīng)(Therapeutic Effects and Adverse Reactions),治療作用（therapeutic effect)對(duì)因

5、治療對(duì)癥治療補(bǔ)充（替代）療法不良反應(yīng)（adverse drug reaction, ADR）副反應(yīng)毒性反應(yīng)后遺效應(yīng)停藥反應(yīng)繼發(fā)反應(yīng)變態(tài)反應(yīng)特異質(zhì)反應(yīng)依賴(lài)性,A型，劑量相關(guān),B型,,副反應(yīng) (Side reaction),治療劑量出現(xiàn)的與用藥目的無(wú)關(guān)的作用原因：藥物作用的選擇性低是藥物的固有作用多數(shù)較輕微且可預(yù)料,毒性反應(yīng) (Toxic reaction, Toxicity)用量過(guò)大或

6、過(guò)久對(duì)機(jī)體功能、形態(tài)產(chǎn)生損害。 藥理作用延伸,急性毒性 (Acute toxicity)，LD50慢性毒性 (Chronic toxicity) 致畸胎 (Teratogenesis) 致癌 (Carcinogenesis) 致突變 (Mutagenesis),苯巴比妥催眠 ? 次晨頭暈、困倦,長(zhǎng)期用糖皮質(zhì)激素?腎上腺皮質(zhì)功能低下，持續(xù)數(shù)月,后遺效應(yīng)（After effect）停藥后殘留藥物引起的生物效應(yīng),停藥反應(yīng)

7、 (Withdrawal reaction) 突然停藥后原有疾病加重 也稱(chēng)反跳 (Rebound reaction),長(zhǎng)期服用可樂(lè)定停藥次日血壓即急劇升高,繼發(fā)反應(yīng)（secondary rection）,繼發(fā)于藥物治療之后的不良反應(yīng)廣譜抗菌藥致二重感染心臟復(fù)律后心栓脫落鎮(zhèn)痛后依賴(lài)性產(chǎn)生,變態(tài)反應(yīng)（Allergic rection）,僅見(jiàn)于少數(shù)病人，很小量即可引起。,與藥物藥理效應(yīng)無(wú)關(guān)反應(yīng)程度相差很大與劑量無(wú)明顯關(guān)系,

8、特異質(zhì)反應(yīng) （idiosyncrasy）,a qualitatively abnormal reaction that occurs in only a few exposed individuals a non-immunological hypersensitivity to a substance特異質(zhì)病人對(duì)某種藥物反應(yīng)異常增高藥物的藥理作用在特異質(zhì)病人身上的延伸、與劑量相關(guān)藥理性拮抗有效例如磺胺致遺傳性

9、 G6PD缺乏者溶血、肼苯噠嗪致乙?；溉狈φ呃钳彉臃磻?yīng)、RyaR突變致琥珀膽堿吸入性麻醉藥鎮(zhèn)靜藥用藥者惡性高熱,idio- 獨(dú)有的 特異的sync- 同時(shí)發(fā)生 共同krasis mixture,依賴(lài)性/成癮性（dependence/addiction）,用藥后機(jī)體產(chǎn)生的強(qiáng)迫性渴望連續(xù)定期使用該藥的行為反應(yīng)，目的是感受藥物的精神效應(yīng)或避免由于停藥所致的身體不適生理（軀體）性依賴(lài)心理（精神）性依賴(lài),If something

10、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 Pharm

11、acol,,藥物即毒物，利弊并存，必須權(quán)衡，正確應(yīng)用,藥物的量效關(guān)系 Dose-effect Relationship,量效曲線（Dose response curve）,相關(guān)概念,最大效應(yīng) Emax (效能 efficacy)劑量相關(guān)最小有效量半最大效應(yīng)濃度EC50/劑量ED50效價(jià)強(qiáng)度 (potency)極量最小中毒量最小致死量,Potency: a measure of the amount of drug

12、 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 potency and is commonly designated as the EC50,Efficacy: Emax, t

13、he ability of a drug to elicit a response,23,半數(shù)中毒量（TD50或TC50） 使50%受試者出現(xiàn)毒性反應(yīng)時(shí)的藥物劑量,半數(shù)致死量（LD50或LC50） 使50%受試者死亡的藥物劑量,Some Acute Oral LD50 ValuesCategoryDoseSpecies Chemical(mg/kg body weight)Practic

14、ally nontoxic 15 000 Slightly toxic10 000Mouse 乙醇 5 000 Moderately toxic 4 900Rat 氯化鈉 750Rat 阿托品 500 Highly toxic 250Rat 胺甲萘(殺蟲(chóng)藥) 50 Extremely t

15、oxic 13Rat 對(duì)硫磷 三氧化二砷 5 Supertoxic 3Rat 華法林 0.4Duck 黃曲霉素B1,,,,,,,,,,,,,,治療指數(shù) (Therapeutic Index) LD50/ED50安全范圍LD5/ED95表示藥物安全性,Therapeutic window, is the r

16、ange of steady-state concentrations of drug that provides therapeutic efficacy with minimal toxicity,藥物作用機(jī)制 Mechanism of Drug Action,非特異改變理化條件 影響細(xì)胞物質(zhì)代謝 影響生理物質(zhì)轉(zhuǎn)運(yùn)、遞質(zhì)釋放、激素分泌 改變酶的活性 影響細(xì)胞膜離子通透 影響核酸代謝 影響免疫功能 改變遺傳物質(zhì) 作用

17、于受體,藥物發(fā)揮作用的方式（作用機(jī)制）,非特異性藥物作用機(jī)制:與藥物的理化性質(zhì)有關(guān).滲透壓作用:如甘露醇的脫水作用.脂溶作用:如全身麻醉藥對(duì)中樞神經(jīng)系統(tǒng)的麻醉作用.影響pH:如抗酸藥中和胃酸.絡(luò)合作用:如二巰基丙醇絡(luò)合汞,砷等重金屬離子而解毒.,藥物作用靶點(diǎn),A ‘druggable’ target is a protein, peptide or nucleic acid with activity that can be

18、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 prop

19、osed分類(lèi)受體酶離子通道轉(zhuǎn)運(yùn)體核酸,H+-K+ATP酶抑制劑作用模式,血管緊張素轉(zhuǎn)換酶抑制劑,,作用于鈉通道的藥物,局部麻醉藥抗癲癇藥I 類(lèi)抗心律失常藥,作用于鉀通道的藥物,鉀通道阻斷藥無(wú)機(jī)離子 Cs+ Ba2+；小分子化合物 TEA、 4-AP生物毒素 某些蝎毒、蜂毒、蛇毒臨床藥物 磺酰脲類(lèi)、III類(lèi)抗心律失常藥鉀通道開(kāi)放藥目前主要為作用于KATP者：尼克地尓（nicorandil）、吡那地爾（pinac

20、idil）藥理作用：細(xì)胞膜超極化主要用于心血管疾病：高血壓、心衰、心肌缺血,,作用于離子轉(zhuǎn)運(yùn)體的藥物,,作用于神經(jīng)遞質(zhì)轉(zhuǎn)運(yùn)體的藥物,藥物與受體 Interaction of Drug and Receptor,狹義：The sensing elements in the system of chemical communications that coordinates the function of all the differ

21、ent cells in the body.廣義：Any large molecule in a cell to which a drug binds to produce its effect.,受體receptor,Model of Substrate-Enzyme Binding,Drug binding to receptor,D + R,D-R Complex,Response,,,,內(nèi)源性配體,受體的特性,藥物和特異性受體

22、結(jié)合方式: (1) 離子鍵（ ionic bonds ）(2) 氫鍵（ hydrogen bonds ） (3) 范德瓦爾斯力（ Van der Waals forces ） (4) 共價(jià)鍵（ covalent bonds ）,Receptor,藥物,高敏感性（Sensitivity）：受體含量極微 (10fmol/1mg組織) 高特異性（Specificity）：高親和力 (Affinity )：0.001-1nM配體即可

23、引起效應(yīng) 可飽和性 (Saturable): 與受體數(shù)量有限有關(guān) 可逆性 (Reversible)：結(jié)合后可解離；可置換多樣性 (multiple-variation) 競(jìng)爭(zhēng)性 (competition),受體的特征,三、受體與藥物的相互作用 受體結(jié)合量與效應(yīng)的關(guān)系： D+R DR E,,,,受體相對(duì)結(jié)合量（[DR] / RT）決定效應(yīng)的相對(duì)強(qiáng)弱（E/Emax）,[DR],[RT],[D],K

24、D＋[D],E DR D Emax RT KD+D,,,,=,=,E DR D Emax RT KD+D,=,=,,,,,KD值為EC50時(shí)的藥物濃度值,,D = 0,,,,效應(yīng)為,0,,D,>,,>,K,D,,,,DR / R,T,= 100%,,達(dá)最大效應(yīng),,

25、DR / R,T,= 50%,,即,EC,50,時(shí)，,K,D,= D,,,,,親和力 (Affinity),,100% ? ? ? 0,,,內(nèi)在活性 (Intrinsic activity, ?),作用于受體的藥物分類(lèi),An inverse agonist is an agent that binds to the same receptor as an endogenous agonist but induces a pharmaco

26、logical response opposite to that agonist.Nelson (2007). ""Phenotypic" pharmacology: the influence of cellular environment on G protein-coupled receptor antagonist and inverse agonist pharmacology."

27、 Biochem Pharmacol,患者，男，20歲，xx年xx月xx日xx時(shí)在YY會(huì)所昏迷，送急診搶救。入院時(shí)意識(shí)喪失，口唇發(fā)紺，體格檢查顯示四肢外周靜脈遍布注射針眼，呼吸每分鐘6-7次，脈搏52次/min，血壓55/25mmHg，瞳孔呈針尖樣大小，心肺聽(tīng)診未發(fā)現(xiàn)異常，生理反射存在，病理反射未引出，血常規(guī)、血糖、電解質(zhì)檢查及心電圖未發(fā)現(xiàn)異常，初步診斷為急性阿片類(lèi)藥物中毒，經(jīng)某特異性拮抗劑并對(duì)癥和支持治療，患者蘇醒并逐漸恢復(fù)。,問(wèn)題：

28、藥物有哪些不良反應(yīng)類(lèi)型，各有何特點(diǎn)？本例屬于何種不良反應(yīng)？作用于受體的藥物如何分類(lèi)，各有何特點(diǎn)？本例中“特異性”搶救藥物最有可能是什么？其作用機(jī)制為何？,翻轉(zhuǎn)式miniPBL試題,Regulation of the activity of a receptor with conformation-selective drugs,Bylund et al. Quantitative versus qualitative data

29、: 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. However, som

30、e 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 base

31、line response measured in the absence of drug. Inverse agonists, unlike full agonists, stabilize the inactive R form. All of the constitutively active receptors are forced into the inactive state by the inverse agonist.

32、 This decreases the number of activated receptors to below that observed in the absence of drug. Thus, inverse agonists reverse the constitutive activity of receptors and exert the opposite pharmacological effect of rece

33、ptor 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 i

34、f an agonist is not present.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 becau

35、se they possess strong affinity.,競(jìng)爭(zhēng)性和非競(jìng)爭(zhēng)性拮抗,降低其親和力，而不改變內(nèi)在活性 增加激動(dòng)藥劑量后量效曲線平行右移,,,競(jìng)爭(zhēng)性拮抗藥 (Competitive antagonist),與激動(dòng)藥競(jìng)爭(zhēng)同一受體，可逆性結(jié)合,劑量比 (Dose ratio),增加后的激動(dòng)藥劑量（D’） 原激動(dòng)藥劑量（D）,,劑量比為2時(shí)（ D’/D = 2 ）競(jìng)爭(zhēng)性拮抗藥濃度的負(fù)對(duì)數(shù) 反映拮抗藥的拮抗

36、強(qiáng)度，pA2越大，所需拮抗藥濃度越小，拮抗作用越強(qiáng),拮抗參數(shù)(antagonist parameter, pA2, ) p for logarithm, like pH; A for antagonist,,,,,激動(dòng)藥 ＋遞增劑量的競(jìng)爭(zhēng)性拮抗藥,激動(dòng)藥,,,,,,,劑量比,對(duì)數(shù)濃度（激動(dòng)藥 ）,最大效應(yīng)（%）,非競(jìng)爭(zhēng)性拮抗藥 (Noncompetitive antagonist, Irreversible antagonist

37、)在拮抗藥作用下，激動(dòng)藥的親和力和內(nèi)在活性均降低，增加劑量也不能恢復(fù)到無(wú)拮抗藥時(shí)的Emax,激動(dòng)藥,藥物的對(duì)數(shù)濃度,最大效應(yīng)（%）,機(jī)制：拮抗藥與受體成強(qiáng)鍵結(jié)合，如共價(jià)鍵，解離速率=0，相當(dāng)于滅活了部分受體 拮抗藥阻斷了受體結(jié)合后的某一中介反應(yīng)環(huán)節(jié)，受體的結(jié)合未受影響,脫敏(desensitization) 長(zhǎng)期用激動(dòng)藥后反應(yīng)性下降,受體的調(diào)節(jié) 維持機(jī)體內(nèi)環(huán)境穩(wěn)定,非特異性脫敏：對(duì)某類(lèi)激動(dòng)藥 脫敏后，對(duì)其它受體激動(dòng)藥

38、也反應(yīng)性下降 機(jī)制 ? 受體有共同反饋調(diào)節(jié)機(jī)制 ? 信號(hào)傳導(dǎo)通路某共同環(huán)節(jié)被調(diào)節(jié),特異性脫敏：僅對(duì)某類(lèi)激動(dòng)藥 脫敏 機(jī)制 ? 受體磷酸化；受體內(nèi)移,增敏（hypersensitization） 長(zhǎng)期用拮抗藥后反應(yīng)性增強(qiáng),Acceptor,Many drugs also interact with acceptors (e.g., serum albumin) within the bo

39、dy. 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 drug'

40、s actions.,受體類(lèi)型,Ligand gated ion channels (ionotropic)G-protein-coupled receptors (metabotropic)Receptors with tyrosine kinase activityIntracellular receptors,1. 門(mén)控離子通道型受體（離子通道型受體，Ligand-Gated Channels） 配體：N-ACh、GAB

41、A、興奮性氨基酸（甘氨酸、谷氨酸、天門(mén)冬氨酸）,5個(gè)亞單位組成反復(fù)4次穿過(guò)細(xì)胞膜,受體活化 離子通道開(kāi)放 膜去極化或超極化,,,,2. G-蛋白偶聯(lián)受體 (G protein-coupled receptor) 最多，其作用需G-蛋白參與,,Receptors make up the largest group of drug targets with 193 proteins accou

42、nting 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 for

43、 Chemistry,Robert LefkowitzProfessor of Howard Hughes Medical Institute and Duke University,Brian KobikaProfessor of Stanford University School of Medicine,肽鏈，7個(gè)?-螺旋反復(fù)穿過(guò)細(xì)胞膜 氨基酸組成不同導(dǎo)致配體特異性 細(xì)胞內(nèi)部分有GP結(jié)合區(qū),GPCR classifica

44、tion,G-蛋白 (鳥(niǎo)苷酸結(jié)合調(diào)節(jié)蛋白)： 細(xì)胞膜內(nèi)側(cè)，由?、?、? 亞單位組成 Gs：激活A(yù)C cAMP? Gi： 抑制AC cAMP?,,,3. 具酪氨酸激酶活性的受體 （Receptors with tyrosine kinase activity） 細(xì)胞外段，與配體結(jié)合區(qū) 中間段，穿透細(xì)胞膜 細(xì)胞內(nèi)段，酪氨酸激酶,配體：胰島素、胰島素樣生長(zhǎng)因子、上皮生長(zhǎng)因子、血小板生長(zhǎng)因子

45、、淋巴因子,配體與細(xì)胞外段結(jié)合 構(gòu)型改變 酪氨酸激酶活化 殘基磷酸化 激活細(xì)胞內(nèi)蛋白激酶 DNA、RNA合成加速 蛋白合成加速 產(chǎn)生生物學(xué)效應(yīng),,,,,,,,4. 細(xì)胞內(nèi)受體 （Intracellular Receptor）,配體 皮質(zhì)激素、性激素、甲狀腺激素、Vit.D,Intracellular Mechanism: Steroid,,Eff

46、ect,第二信使 (Second Messengers)細(xì)胞外信號(hào)如何進(jìn)入細(xì)胞內(nèi)？,通過(guò)膜上的信號(hào)系統(tǒng)，增加細(xì)胞內(nèi)第二信使的濃度而發(fā)揮作用,1. cAMP,3. Calcium & Phosphoinositides（磷酸肌醇),Well-Established Second Messengers,2. cGMP,促濾泡素,黃體生成素,促甲狀腺素,甲狀旁腺素,thyrotropin-releasing-