朱亮藥學導論2藥效學-zhuliang

1、藥物效應動力學Pharmacodynamics,朱亮上海交通大學醫(yī)學院藥理學及化學生物學學科,藥物的藥效學特征,選擇性兩重性劑量/濃度-效應關系藥物-藥靶作用、受體理論,選擇性,選擇性（selectivity）：藥物對不同組織器官（作用對象）效應的差異性原因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,藥物作用和藥理學效應,藥物作用: 對機體細胞的初始作用是動因對應“特異性, specificity”特異性由“藥物化學結構——藥靶”決定藥理效應：作用的結果，引起的機體反應興奮 (Excitation)：功能增強 抑制 (Inhibition)：功能降低對應“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(Therapeutic Effects and Adverse Reactions),治療作用（therapeutic effect)對因

5、治療對癥治療補充（替代）療法不良反應（adverse drug reaction, ADR）副反應毒性反應后遺效應停藥反應繼發(fā)反應變態(tài)反應特異質反應依賴性,A型，劑量相關,B型,,副反應 (Side reaction),治療劑量出現的與用藥目的無關的作用原因：藥物作用的選擇性低是藥物的固有作用多數較輕微且可預料,毒性反應 (Toxic reaction, Toxicity)用量過大或

6、過久對機體功能、形態(tài)產生損害。 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,長期用糖皮質激素?腎上腺皮質功能低下，持續(xù)數月,后遺效應（After effect）停藥后殘留藥物引起的生物效應,停藥反應

7、 (Withdrawal reaction) 突然停藥后原有疾病加重 也稱反跳 (Rebound reaction),長期服用可樂定停藥次日血壓即急劇升高,繼發(fā)反應（secondary rection）,繼發(fā)于藥物治療之后的不良反應廣譜抗菌藥致二重感染心臟復律后心栓脫落鎮(zhèn)痛后依賴性產生,變態(tài)反應（Allergic rection）,僅見于少數病人，很小量即可引起。,與藥物藥理效應無關反應程度相差很大與劑量無明顯關系,

8、特異質反應 （idiosyncrasy）,a qualitatively abnormal reaction that occurs in only a few exposed individuals a non-immunological hypersensitivity to a substance特異質病人對某種藥物反應異常增高藥物的藥理作用在特異質病人身上的延伸、與劑量相關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?、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- 獨有的 特異的sync- 同時發(fā)生 共同krasis mixture,依賴性/成癮性（dependence/addiction）,用藥后機體產生的強迫性渴望連續(xù)定期使用該藥的行為反應，目的是感受藥物的精神效應或避免由于停藥所致的身體不適生理（軀體）性依賴心理（精神）性依賴,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，必須權衡，正確應用,藥物的量效關系 Dose-effect Relationship,量效曲線（Dose response curve）,相關概念,最大效應 Emax (效能 efficacy)劑量相關最小有效量半最大效應濃度EC50/劑量ED50效價強度 (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,半數中毒量（TD50或TC50） 使50%受試者出現毒性反應時的藥物劑量,半數致死量（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(殺蟲藥) 50 Extremely t

15、oxic 13Rat 對硫磷 三氧化二砷 5 Supertoxic 3Rat 華法林 0.4Duck 黃曲霉素B1,,,,,,,,,,,,,,治療指數 (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,藥物作用機制 Mechanism of Drug Action,非特異改變理化條件 影響細胞物質代謝 影響生理物質轉運、遞質釋放、激素分泌 改變酶的活性 影響細胞膜離子通透 影響核酸代謝 影響免疫功能 改變遺傳物質 作用

17、于受體,藥物發(fā)揮作用的方式（作用機制）,非特異性藥物作用機制:與藥物的理化性質有關.滲透壓作用:如甘露醇的脫水作用.脂溶作用:如全身麻醉藥對中樞神經系統(tǒng)的麻醉作用.影響pH:如抗酸藥中和胃酸.絡合作用:如二巰基丙醇絡合汞,砷等重金屬離子而解毒.,藥物作用靶點,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分類受體酶離子通道轉運體核酸,H+-K+ATP酶抑制劑作用模式,血管緊張素轉換酶抑制劑,,作用于鈉通道的藥物,局部麻醉藥抗癲癇藥I 類抗心律失常藥,作用于鉀通道的藥物,鉀通道阻斷藥無機離子 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、III類抗心律失常藥鉀通道開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：細胞膜超極化主要用于心血管疾?。焊哐獕?、心衰、心肌缺血,,作用于離子轉運體的藥物,,作用于神經遞質轉運體的藥物,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,,,,內源性配體,受體的特性,藥物和特異性受體

22、結合方式: (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 可飽和性 (Saturable): 與受體數量有限有關 可逆性 (Reversible)：結合后可解離；可置換多樣性 (multiple-variation) 競爭性 (competition),受體的特征,三、受體與藥物的相互作用 受體結合量與效應的關系： D+R DR E,,,,受體相對結合量（[DR] / RT）決定效應的相對強弱（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時的藥物濃度值,,D = 0,,,,效應為,0,,D,>,,>,K,D,,,,DR / R,T,= 100%,,達最大效應,,

25、DR / R,T,= 50%,,即,EC,50,時，,K,D,= D,,,,,親和力 (Affinity),,100% ? ? ? 0,,,內在活性 (Intrinsic activity, ?),作用于受體的藥物分類,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時在YY會所昏迷，送急診搶救。入院時意識喪失，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，心肺聽診未發(fā)現異常，生理反射存在，病理反射未引出，血常規(guī)、血糖、電解質檢查及心電圖未發(fā)現異常，初步診斷為急性阿片類藥物中毒，經某特異性拮抗劑并對癥和支持治療，患者蘇醒并逐漸恢復。,問題：

28、藥物有哪些不良反應類型，各有何特點？本例屬于何種不良反應？作用于受體的藥物如何分類，各有何特點？本例中“特異性”搶救藥物最有可能是什么？其作用機制為何？,翻轉式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.,競爭性和非競爭性拮抗,降低其親和力，而不改變內在活性 增加激動藥劑量后量效曲線平行右移,,,競爭性拮抗藥 (Competitive antagonist),與激動藥競爭同一受體，可逆性結合,劑量比 (Dose ratio),增加后的激動藥劑量（D’） 原激動藥劑量（D）,,劑量比為2時（ D’/D = 2 ）競爭性拮抗藥濃度的負對數 反映拮抗藥的拮抗

36、強度，pA2越大，所需拮抗藥濃度越小，拮抗作用越強,拮抗參數(antagonist parameter, pA2, ) p for logarithm, like pH; A for antagonist,,,,,激動藥 ＋遞增劑量的競爭性拮抗藥,激動藥,,,,,,,劑量比,對數濃度（激動藥 ）,最大效應（%）,非競爭性拮抗藥 (Noncompetitive antagonist, Irreversible antagonist

37、)在拮抗藥作用下，激動藥的親和力和內在活性均降低，增加劑量也不能恢復到無拮抗藥時的Emax,激動藥,藥物的對數濃度,最大效應（%）,機制：拮抗藥與受體成強鍵結合，如共價鍵，解離速率=0，相當于滅活了部分受體 拮抗藥阻斷了受體結合后的某一中介反應環(huán)節(jié)，受體的結合未受影響,脫敏(desensitization) 長期用激動藥后反應性下降,受體的調節(jié) 維持機體內環(huán)境穩(wěn)定,非特異性脫敏：對某類激動藥 脫敏后，對其它受體激動藥

38、也反應性下降 機制 ? 受體有共同反饋調節(jié)機制 ? 信號傳導通路某共同環(huán)節(jié)被調節(jié),特異性脫敏：僅對某類激動藥 脫敏 機制 ? 受體磷酸化；受體內移,增敏（hypersensitization） 長期用拮抗藥后反應性增強,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.,受體類型,Ligand gated ion channels (ionotropic)G-protein-coupled receptors (metabotropic)Receptors with tyrosine kinase activityIntracellular receptors,1. 門控離子通道型受體（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、天門冬氨酸）,5個亞單位組成反復4次穿過細胞膜,受體活化 離子通道開放 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?-螺旋反復穿過細胞膜 氨基酸組成不同導致配體特異性 細胞內部分有GP結合區(qū),GPCR classifica

44、tion,G-蛋白 (鳥苷酸結合調節(jié)蛋白)： 細胞膜內側，由?、?、? 亞單位組成 Gs：激活AC cAMP? Gi： 抑制AC cAMP?,,,3. 具酪氨酸激酶活性的受體 （Receptors with tyrosine kinase activity） 細胞外段，與配體結合區(qū) 中間段，穿透細胞膜 細胞內段，酪氨酸激酶,配體：胰島素、胰島素樣生長因子、上皮生長因子、血小板生長因子

45、、淋巴因子,配體與細胞外段結合 構型改變 酪氨酸激酶活化 殘基磷酸化 激活細胞內蛋白激酶 DNA、RNA合成加速 蛋白合成加速 產生生物學效應,,,,,,,,4. 細胞內受體 （Intracellular Receptor）,配體 皮質激素、性激素、甲狀腺激素、Vit.D,Intracellular Mechanism: Steroid,,Eff

46、ect,第二信使 (Second Messengers)細胞外信號如何進入細胞內？,通過膜上的信號系統(tǒng)，增加細胞內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-