pharmacology 药理学 殷 明 tel. 34204737 ( o ) myin@sjtu 生物药学楼 6-408
DESCRIPTION
Pharmacology 药理学 殷 明 Tel. 34204737 ( O ) [email protected] 生物药学楼 6-408. 参加授课教师: 毛文伟,药理学副教授 李欣燕,药理学讲师 赵文娟,药理学讲师. 教学安排: 用中文教材;英语 ppt. 讲课以中文为主,少量英文。 课后阅读一篇或以上参考文章或相关参考书章节内容(复习教科书除外)。发与本次课内容有关的学习提纲( handout ,中英文均有)。下次课适当抽查学生阅读情况(形式多样)。适当复习前次课内容。 ppt 放到学校网站上。 尝试互动式、讨论式学习。 - PowerPoint PPT PresentationTRANSCRIPT
Shanghai Jiao Tong University
参加授课教师:
毛文伟,药理学副教授
李欣燕,药理学讲师
赵文娟,药理学讲师
Shanghai Jiao Tong University 教学安排: 用中文教材;英语 ppt. 讲课以中文为主,少量英文。 课后阅读一篇或以上参考文章或相关参考书
章节内容(复习教科书除外)。发与本次课内容有关的学习提纲( handout ,中英文均有)。下次课适当抽查学生阅读情况(形式多样)。适当复习前次课内容。
ppt 放到学校网站上。 尝试互动式、讨论式学习。 有 1- 2次期中考试,记分。 每次记录学生到课情况。 约安排 30 %左右的英语考题。考试内容原则上
都在讲述的 ppt 中,起码是 ppt 涉及到的内容。
Shanghai Jiao Tong University 学习方法和要求:
掌握基本概念 (特别是总论 !)、基本理论、每类药物的共性、常用药物的特点(不同于药物手册 )
药理作用、代表性临床应用、特征性药动学特点和不良反应、主要禁忌证
知识背景: anatomy, physiology, biochemistry , cellular and molecular biology…
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Basic Principles (总论) 基本概念、原理;用来规范各论内容
重点 :
special terms and definitions
drug receptors (the most important concept in pharmacology)
Shanghai Jiao Tong University
Drug: chemical substances that are used to treat, prevent, and diagnose diseases.
Are all chemical substances used to do so?
Why?
Shanghai Jiao Tong University
What is pharmacology?
Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and then activating or inhibiting normal body processes.
Shanghai Jiao Tong University医学院课程
基础课程:分子生物学、遗传学、解剖学、生理学、生物化学、微生物学、免疫学、组织胚胎学、病原生物学、病理学、病理生理学……桥梁课程:药理学临床课程:诊断学、内科学、外科学、眼耳鼻喉科学、妇产科学、儿科学、口腔科学、皮肤性病学、传染病学、神经精神病学、流行病学、预防医学、医学心理学、中医学……
Shanghai Jiao Tong University药学院课程
化学、生物学基础课程药物化学、天然药物化学、生物技术药物桥梁课程:药理学(体外、体内药效学、药动学、毒理学)药剂学、药物分析学……
Shanghai Jiao Tong UniversityDrug Discovery Process
Shanghai Jiao Tong University
Toxicology is the branch of pharmacology, which deals with the undesirable effects of chemicals on living systems.
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Pharmacodynamics: actions of the drug on the body.
Pharmacokinetics: actions of the body on the drug.
Drug interactions: actions between a drug and another drug.
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Pharmacology involves the discovery of new drugs, the investigation of how drugs work and the use of
drugs to probe mechanisms of disease. But pharmacology also involves the elucidation and manipulation of macromolecular structures, the
analysis of regulatory mechanisms in cell biology and development, and the translation of this
information into clinical research. Thus the science of pharmacology spans the most fundamental
aspects of basic research, through transgenic animal models, to clinical investigation.
Chair of the department of pharmacology, University of Pennsylvania
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Development of Pharmacology
早期:生活、经验的积累
《神农本草经》、 《本草纲目》
《纽伦堡药典》……
18 世纪,现代化学、物理学、医学发展
实验科学兴起:离体器官、整体动物试验,定性、定量化合物作用
Shanghai Jiao Tong University
20 世纪,生物学、电子、仪器设备发展融入广义生命科学的洪流中
现代药理学的应用
一、预防、治疗、诊断疾病
二、新药的药理学研究
三、参与生命科学的基础研究
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中国新药报批资料: (一)综述资料 1、药品名称。 2、证明性文件。 3、立题目的与依据。 4、对主要研究结果的总结及评价。 5、药品说明书、起草说明及相关参考文献。 6、包装、标签设计样稿。
Shanghai Jiao Tong University (二)药学研究资料 7、药学研究资料综述。 8、原料药生产工艺的研究资料及文献资料;制剂处方及工艺的研究资料及文献资料。 9、确证化学结构或者组份的试验资料及文献资料。 10、质量研究工作的试验资料及文献资料。 11、药品标准及起草说明,并提供标准品或者对照品。 12、样品的检验报告书。 13、原料药、辅料的来源及质量标准、检验报告书。 14、药物稳定性研究的试验资料及文献资料。 15、直接接触药品的包装材料和容器的选择依据及质量标准 。
Shanghai Jiao Tong University (三)药理毒理研究资料 16、药理毒理研究资料综述。 17、主要药效学试验资料及文献资料。 18、一般药理学的试验资料及文献资料。 19、急性毒性试验资料及文献资料。 20、长期毒性试验资料及文献资料。 21、过敏性(局部、全身和光敏毒性)、溶血性和局部(血管、 皮肤、粘膜、肌肉等)刺激性等特殊安全性试验资料和文献资料。 22、复方制剂中多种成份药效、毒性、药代动力学相互影响的试验资料及文献资料。 23、致突变试验资料及文献资料。 24、生殖毒性试验资料及文献资料。 25、致癌试验资料及文献资料。 26、依赖性试验资料及文献资料。 27、非临床药代动力学试验资料及文献资料。
Shanghai Jiao Tong University (拿到进行临床试验批文号以后)
(四)临床试验资料 28、国内外相关的临床试验资料综述。 29、临床试验计划及研究方案。 30、临床研究者手册。 31、知情同意书样稿、伦理委员会批准件。 32、临床试验报告。
Ⅰ期临床试验:正常人;观察耐受性;人体药动学。
Ⅱ期临床试验:病人;过程疗效、不良反应。
Ⅲ期临床试验:扩大的临床试验。边生产,边进行(中国)。
Ⅳ期临床试验:上市后的观察。
Shanghai Jiao Tong University 参与生命科学基础研究
药物作为“工具”( tool )、“探针”( probe )进行研究。如受体、信号通路、DNA转录等
Shanghai Jiao Tong University
Shanghai Jiao Tong University
第一节 药物的基本作用( basic actions of the drug )
一、药物作用的性质和方式(自学)
nature of drug actions
manner of drug actions
Pharmacodynamics 药效学
Shanghai Jiao Tong University
二、药物作用的选择性和两重性( selectivity and duplicity of drug actions )
Selectivity
definition: p6
why selectivity?
do people need selectivity?
Duplicity
therapeutic actions and untoward effects
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Untoward reactions (不良反应) side effects
toxic reactivity (acute and chronic toxicity)
allergy reactions(chronic):
I, anaphylaxis
II, cytolytic reaction
III, immune complex reaction
IV, delayed allergic reaction
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urticaria (荨麻疹)
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allergic purpura过敏性紫癜
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contact dermatitis 接触性皮炎
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Polytypic erythematic rash 多形红斑型药疹
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Morbilliform rash 麻疹样药疹
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Exfoliative dermatitic rash剥脱性皮炎药疹
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Boullus pemphigus 大泡性类天疱疮
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Erythema nodosum 结节性红斑
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Secondary reaction (继发性反应)Residual effect (后遗效应)Teratogenesis (致畸作用)
“ 三致”实验:
Teratogenesis( 致畸 )
Mutagenesis( 致突变 )
Carcinogenesis( 致癌 )
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Shanghai Jiao Tong University 汉堡大学儿科医院调查:
海豹肢 (phocomelia)
1949~ 1959 无 1960 63 1961 154
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回顾性调查,妊娠三个月内无一例外地用过沙利度胺。
现在用于抗 HIV、抗癌等
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thalidomide (沙利度胺)
Left:hypnotic
(镇静剂)
Right: teratogenic
(致畸的)
Now:
Anti-HIV
Anti-tumor
Shanghai Jiao Tong University FDA 致畸药物分类 :
A 类:妊娠早期应用,未见对胎儿有损害,最安全类。
B 类:动物试验未见对胎仔有损害,但缺乏临床证明资料。多种临床常用药属此类。
C 类:动物试验中发现对胎仔有损害,但临床未观察到;或对动物及人均无充分研究资料。此类药临床选用困难,但妊娠期很多常用药属于此类。
D 类:有一定临床资料表明对胎儿有损害,但孕妇治疗必须应用,而又无合适替代药物,如抗癫痫药苯妥英。X类:已证实对胎儿有损害,并且其危害性超过临床应用所能达到的有利作用,属妊娠期禁用药物。
Shanghai Jiao Tong University 妊娠期用药损伤胎儿举例
乙醇 生长迟缓、智力低下;心、肾、眼病变
烷化剂 多发畸型、生长迟缓
卡马西平 中枢神经缺陷增加
一氧化碳 脑萎缩,智力低下 , 死胎
香豆素类 中枢神经、面部及骨骼畸形
己烯雌酚 女婴生殖道异常、阴道癌 四环素 损害胎儿骨骼、牙齿;多种先天缺陷
Shanghai Jiao Tong University Receptor theory
一、受体基本概念( basic concept of receptor )
receptor: component of a cell or organism that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed effects.
previously, a concept explaining differences
present, an entity that can be isolated and characterized molecularly and genetically
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Shanghai Jiao Tong UniversityStructure of α4β2 nAChRs
Shanghai Jiao Tong University
Macromolecular nature of drug receptors
1. Regulatory proteins: receptors; enzymes; ion channels; …
2. Transport proteins: neurotransmitter transporters; Na+/K+ATPase; …
3. Structural proteins: tubulin; …
4. Others
Shanghai Jiao Tong University 二、受体的特性
( characterization of receptor )Specificity
High affinity
Saturability
Reversibility
Subcellular or Molecular characterization
Binding data vs pharmacological activity relationship
Endogenous
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Drug shape: complementary to that of receptor site ( key and lock)
Chirality (手性) ; mirror
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(R)-2-butanol
(S)-2-butanol
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Rational drug design
isolation and characterization of receptors
CADD (computer assisted drug design )
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An experimental drug, Nevirapine (red) is shown inside a pocket of reverse transcriptase, a viral enzyme that is
essential to HIV
Shanghai Jiao Tong University 三、受体类型和受体调节( category and regulation of receptor )
(一)受体类型 ( category )
Receptor nomenclature (受体命名)
References:
1 ,《 Pharmacological reviews 》
2 , 《 Trends in pharmacological sciences 》 : receptor and ion channel nomenclature supplements
3 , IUPHAR RECEPTOR DATABASE
Shanghai Jiao Tong University Nomenclature
1, according to endogenous ligands (配体) : dopamine receptor, serotonin receptor (大多如此)
2, according to drugs when unknown ligands: cannabinoid (大麻素) receptor… (不多)
3, according to receptor structure (rare)
Shanghai Jiao Tong University
Examples of the receptors:
acetylcholine receptor: M(M1-5); N(NN, M… )
adenosine receptors
adrenoceptors
angiotensin receptors
bradykinin receptors
calcium channels
chemokine receptors
dopamine receptors
histamine receptors
opioid receptors
…
Shanghai Jiao Tong University Receptor category:
according to the existing sites:
1, membrane receptors: most
2, cytosolic (胞质 ) receptors: steroidal receptors
3, nuclear receptors: peroxisome proliferator-activated (PPAR ) receptors
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According to structure, effects, signal transduction …
ionotropic receptor (促离子型受体)
G-protein coupled receptors
tyrosine kinase-linked receptors (酪氨酸激酶偶联受体)
nuclear receptors
metabotropic receptors (促代谢型受体)
…
Shanghai Jiao Tong University receptor activation causes effect(s)
Ligand-receptor binding
↓
second messenger
↓
information enlargement, differentiation or integration
↓
responses
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Duration of drug action
1. terminating when dissociation from receptor
2. persistent longer after dissociation because of coupling molecules
3. Lasting until new receptors synthesized because of covalent binding
4. Desensitization because of down-regulation
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一个细胞上的同一种受体数目通常在几百到几千之间
一个细胞上可以存在多种受体及受体亚型
某些特异性受体仅存在于特定类型的细胞
大多数药物在体内通过与特异性受体结合发挥作用
最大效应不需所有受体的激动
药物与受体的结合不仅影响受体的功能,也影响受体的数目( regulation of receptors )
Shanghai Jiao Tong University Receptor regulation
up regulation 上调
down regulation 下调
homospecific regulation 同种调节
heterospecific regulation 异种调节: βreceptor by thyroxine, glucocorticoid …
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Receptor theory 受体学说
(不作要求)
Shanghai Jiao Tong University第三节 药效学概述( pharmacodynamics )
Drugs acting at the receptors 作用于受体的药物
Mechanisms of drug action 药物作用机制
Structure-activity and dose-response relationships 构效和量效关系
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一、作用于受体的药物( drugs acting at the receptors )
agonist (激动剂 ) and partial agonist
agonist: drugs that bind to and activate the receptors in some fashion, which directly or indirectly brings about the effect.
high affinity and intrinsic activity
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Partial agonist (部分激动剂 ): produces a lower response at full receptor occupancy
high affinity and low intrinsic activity
单独作用时,显示较弱的激动作用;与完全激动剂共同作用时,显示拮抗作用
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Curve A is for a full agonist, with an EC50of about 3×10 - 8M . Curve B is for a partial agonist acting on the same receptor.
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Competitive antagonist and non-competitive antagonist (竞争性拮抗剂和非竞争性拮抗剂)
Competitive antagonist binds to a receptor with no intrinsic activity, but preventing binding by other molecules.
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不同全激动剂在相应浓度恒定时,不断增加部分激动剂浓度所得到的量效曲线。
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Non-competitive antagonist: 不与激动剂竞争受体结合,但抑制激动剂与特异性受体的结合,降低最大效应
modulating the receptor activity
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Shanghai Jiao Tong University Mechanism of drug action
Non-specific mechanisms: physical and chemical properties: 渗透压、解离度等
Specific mechanisms 特异性机制:
Targets (靶点、靶标)
Receptor: agonist 激动剂
blocker 阻断剂、拮抗剂
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Ion channel: blocker 阻断剂
modifier 调节剂
Enzyme: inhibitor抑制剂
pseudo substrate 伪底物
Transporter : inhibitor 抑制剂 pseudo substrate 伪底
物
Structure protein, DNA, etc.
Nature of the targets overlapped sometimes
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Drug action and signal transduction 药物作用和信号转导
?
agonist + receptor → → → responses (muscle contraction, gland secretion, etc.)
受体类型及亚型繁多,但可分为几个类型
信号转导的效应体系种类有限
受体的调节、各种水平上的相互作用,产生复杂的生理调节
Shanghai Jiao Tong University
Shanghai Jiao Tong University
Five basic mechanisms of transmembrane signaling
1. A lipid-soluble ligand that cross the membrane and acts on an intracellular receptor, eg. steroid hormones, thyroid hormone.
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Shanghai Jiao Tong University2. A transmembrane receptor protein whose intracellular enzymatic activity is allosterically regulated by a ligand that binds to a site on the protein’s extracellular domain.
3. A transmembrane receptor that binds and stimulates a protein tyrosine kinase.
Ligand-regulated transmembrane enzymes including receptor tyrosine kinases
insulin, epidermal growth factor, platelet-derived factor, transforming growth factor, atrial natriuretic factor, …
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Transforming growth factor-beta
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4. Ligand-gated transmembrane ion channels that can be induced to open or close by the binding of a ligand.
acetylcholine, GABA, excitatory amino acids
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Shanghai Jiao Tong University
Shanghai Jiao Tong University
5. Transmembrane receptor protein that stimulate GTP-binding signal transducer protein (G protein), which in turn generates an intracellular second messenger.
catecholamines, glucagon,histamine, serotonin, opioids, hormones, acetylcholine, photons,……
Shanghai Jiao Tong University
Shanghai Jiao Tong University
(DAG)
The hormones
Calcium and phosphoinositides
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Structure-activity and dose-response relationship (构效与量效关系)
Structure-activity relationship (main topic in medicinal chemistry)
Dose-response relationship
Minimum effective dose 最小有效量
Maximum effect, Emax 最大效应
Minimum toxic dose 最小中毒量
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2. Graded response and quantal response 量反应和质反应 ( 1 ) grade response
efficacy 效能: Emax
potency 效价: concentration (EC50) or dose (ED50) of a drug required to produce 50% of that drug’s maximal effect
药物的临床应用依赖于效能而非效价
Shanghai Jiao Tong University
Shanghai Jiao Tong University
0
5
10
15
20
25
0 100 200 300 400 5000
5
10
15
20
25
0 100 200 300 400 500
Erythropoietin and AnemiaErythropoietin and Anemia
Erythropoietin Dose [units/kg]Erythropoietin Dose [units/kg]
Peak HemPeak Hematocrit Incratocrit Increment [%]ement [%]
Eschbach et al. NEJM 316:73-8, 1987Eschbach et al. NEJM 316:73-8, 1987
0 100 200 300 400 500
20
15
10
5
0
Shanghai Jiao Tong University 法尼基转移酶
↓
原癌基因 ras→RAS 蛋白→法尼基化
→致癌活性
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Endpoints to Monitor Drug EffectEndpoints to Monitor Drug Effect
LLEVELEVEL EENDPOINTNDPOINT
MolecularMolecular Farnesyltransferase inhibitionFarnesyltransferase inhibition
CellularCellular Proliferation rate, apoptosisProliferation rate, apoptosis
TumorTumor Response (change in tumor size)Response (change in tumor size)
OrganismOrganism Survival, quality of lifeSurvival, quality of life
Farnesyltransferase Inhibitors for CancerFarnesyltransferase Inhibitors for Cancer
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(2)quantal response 质反应:
半数致死量( median lethal dose ,LD50 )
治疗指数( therapeutic index,TI )
TI= LD50/ED50
Shanghai Jiao Tong University
Shanghai Jiao Tong University
安全指数( safety index) = LD5/ED95
安全界限( safety margin ) =( LD1-ED95 ) /ED99
Shanghai Jiao Tong University小结
药物通常通过激动或抑制体内生命过程发挥作用药物主要通过与靶点结合,大都经由比较复杂的信号转导过程产生作用量-效关系是衡量特异性药物作用的关键参数
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Suggested reading:
郭家彬、李学军 . 现代生物学对药物发现的影响 . 生理科学进展 2007 ;38 ( 1 ): 25-31