Section XIII Introduction of Pharmacology - 药理学概论 -

Chapter 1 General Concepts

Human disease: prevention and treatment Drug therapy Drug therapy Surgery Surgery Radiotherapy Radiotherapy Physical therapy Physical therapy Psychological therapy Psychological therapy 药理学是药物治疗学的基础理论

Pharmacology can be defined as the study of substances that interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or inhibiting normal body processes. Medical Pharmacology is often defined as the science of substances used to prevent, diagnose, and treat disease. － Basic & Clinical Pharmacology － Katzung BG (Ed). Basic & Clinical Pharmacology (11th Edition). New York:McGraw-Hill, 药理学是研究药物与机体（包括病原体）相互作用的规律及其 原理，是一门为临床合理用药防治疾病提供基本理论的医学基 础学科。

What is Pharmacology studied? Pharmacodynamics: the actions of the drug on the body and the mechanisms Pharmacokinetics: the actions of the body on the drugs Influencing factors on the processes of pharmacodynamics and pharmacokinetics

Drugs Human Body Pharmacodynamics Action and mechanism Pharmacokinetics Absorption, distribution, metabolism, excretion (ADME), and drug concentration in the body Interaction between drug and human body

HumanPathogens Drug Interactions between drug, human body, and pathogens

药剂学过程 药动学过程 药效学过程 ADME 崩解，溶出，与 其他药物相互作 用 Targets ； 疗效，不良反应

Pharmacy Pharmacology Therapeutics Basic Research New Drug Clinical Pharmacology Life Science Screening and Evaluation The Goals of Pharmacology Drugs

药物： 影响机体生理、生化功能，能够用于诊断、预防 和治疗疾病的物质。 药品： 指用于预防、治疗、诊断人的疾病，有目的地调 节人的生理机能并规定有适应证、用法和用量的物质 包 括中药材、中药饮片、中成药、化学原料药及其制剂、抗生素、生化 药品、放射性药品、血清疫苗、血液制品和诊断药品等。 药品： 指用于预防、治疗、诊断人的疾病，有目的地调 节人的生理机能并规定有适应证、用法和用量的物质 ，包 括中药材、中药饮片、中成药、化学原料药及其制剂、抗生素、生化 药品、放射性药品、血清疫苗、血液制品和诊断药品等。 药物和药品的概念

Drug resources and preparation Nature sources Synthesis Bioengineering Dose Forms Human PharmacyPharmacology

 新药定义： 未曾在中国境内上市销售的药品 。 已生产的药品改变剂型、改变给药途径、增加新的适 应证或制成新的复方制剂，亦按新药管理。  旧定义： 我国尚未生产过的药品。 Research and Development (R&D) of New Drugs

1. Preclinical testing （临床前研究） 2. Approval for clinical testing （申请临床研究） 3. Clinical testing (clinical pharmacology) （临床研究） 4. Approval for production and marketing （申请生产） 4 Steps of New Drug R&D

1. Preclinical testing Efficacy (screening and evaluation by pharmacological methods) Safety (evaluation by toxicological methods) Safety (evaluation by toxicological methods) Quantity (pharmacy) Quantity (pharmacy) good laboratory practice （ GLP ） good laboratory practice （ GLP ） 2. Clinical testing Efficacy (therapeutic effects) Efficacy (therapeutic effects) Safety (adverse effects) Safety (adverse effects) Pharmacokinetics (PK parameter or bioavaibility) good clinical practice (GCP) good clinical practice (GCP)

The phases of drug development

Chapter 2 General Considerations of Pharmacology

Part 1 Pharmacodynamics 药物效应动力学

Pharmacological Action - Overview §1.1 Action and effect of drug §Action §Specifically primary action between drug and cells or molecules §Effect §Apparent functional and morphological changes induced by drug directly and/or indirectly

§1.2 Direct and indirect effects of drugs §Direct effects: §Effects resulted from the action of drug on the target organ(s) or tissue(s) §Indirect effects: §Effects resulted from functional integration of target system(s) and modulation system(s)

Action on vascular  1 receptors BP BP ↑ HR HR ↓ direct indirect Action Effect Neuroendocrine modulation

§1.3 Selectivity of drug effect §Selectivity: Organs / Tissues §Specificity: Biomolecules §Reasons of selectivity Drug distribution § Drug distribution § Biological properties of tissues or organs

bronchodilation bronchodilation BP ↑ heart rate ↑ Epinephrine Salbutamol Selective effects of βreceptor agonists on the treatment of bronchial asthma

§1.4 Basic effects of drugs §Excitation or Inhibition of the functions of the body §Kill or suppress the pathogens

1.5 Therapeutic effect and adverse reaction (desirable and undesirable effects) (desirable and undesirable effects)

Balance the ratio of benefits / risk !!

§1) Therapeutic effects (efficacy)  治疗作用（疗效） § (1) Etiological treatment § (2) Symptomatic treatment § (3) Supplement therapy

 2) Adverse drug reactions (adverse effects) 不良反应  不符合用药目的，并对病人带来不适或痛苦的反应（广义） Box 1 现在，我国将不良反应定义为上市药品在正常用法用量情 况下出现的与用药目的无关的有害反应。以区别于药物过量 （ overdose ），在本课程中将两者合称为 “ 不良反应 ” 。 现在，我国将不良反应定义为上市药品在正常用法用量情 况下出现的与用药目的无关的有害反应。以区别于药物过量 （ overdose ），在本课程中将两者合称为 “ 不良反应 ” 。

 (1) Side effect （副作用） undesirable effects of that drug for that therapeutic indication at usual doses, usually are non-deleterious. （治疗剂量时出现的与 治疗目的无关的药物作用）  (2) Toxic effect （毒性反应） Functional or morphological damages produced by larger doses of longer terms of drug uses. （剂量过大或用药时间过长体 内蓄积过多时发生的危害性反应）  (3) After effect （后遗效应） Effects after drug concentration in the body is lower than threshold level. ( 停药后血药浓度已降至阈浓度之下时残存的药理效应 )

 (4) Allergic reaction (Hypersensitivity) （变态反应，药物过敏） Abnormal immunological reactions induced by drugs. ( 接 触药物后发生的异常免疫反应 )  (5) Idiosyncratic reactions （特异质反应） A genetically determined abnormal reactivity to a chemical. ( 少数特异质病人对某些药物特别敏感，反应性质也可能 与常人不同 )

 Withdrawal symptoms （停药反应） Clinical syndrome appeared or worsened when the drug is terminated. ( 突然停药后原有疾病复发或加剧 ) §(6) Others  Secondary reaction （继发效应） Adverse reactions resulting from primary therapeutic effects of drugs. ( 继 发于药物治疗作用之后的不良反应 )

 Dependence （依赖性） §An adaptive state that develops in response to repeated drug administration. §Psychologic dependence is manifested by compulsive drug- seeking behavior. §Physiologic dependence is present when withdrawal of drug produces symptoms and signs. §Drug addiction is defined as the compulsive, out-of-control drug use, despite negative consequences. §Drug abuse: any use of a drug for non-medical purposes. § (a maladaptive pattern of drug use leading to clinically significant impairment or distress)

§The observed effect of a drug as a function of its dose in the living system, usually drug results in a greater magnitude of effect as the dose increased.  药理效应与剂量在一定范围内成比例，称为剂量 - 效 应关系（量效关系） Dose-Effect Relationship

Generally considered Currently recognized

2.1 Dose (concentration) Clinical or Experimental doses Clinical or Experimental doses 2.2 Responses (effects) （ 1 ） Graded responses （量反应） Response changes quantitatively Response changes quantitatively Measurable responses in an individual Measurable responses in an individual （ 2 ） Quantal responses （质反应） All-or-none All-or-none Percentage of the population Percentage of the population

§2.3 Dose-effect curve or dose-response curve  ( 量效曲线 ) § （ 1 ） logD-E (logC-E): S-shaped curve §Gradedin vitro ： pD 2, EC 50, IC 50, MIC …… §Graded in vitro ： pD 2, EC 50, IC 50, MIC …… § in vivo ： PD 100, ID 30, …… §Quantalmedian doses: ED 50, LD 50, ID 50 …… §Quantal median doses: ED 50, LD 50, ID 50 …… 用药个体的一半出现某种效应所需剂量，半数效量 ）  （ 用药个体的一半出现某种效应所需剂量，半数效量 ）

Concentration-effect curve (graded response)

Dose-effect curve (quantal response)

§ （ 2 ） Maximal effect and potency §Maximal effect ( 最大效应 ) or efficacy ( 效能 ) : different maximal magnitudes of effects  Potency ( 效价强度 ): difference in doses that produce an effect at same level （等效剂量） 药物作用强弱及敏感程度的比较  药物作用强弱及敏感程度的比较

Potency: B > A > C > D Efficacy: A = C = D > B Slope: D > A, B, C Efficacy: loop diuretics > thiazide diuretics; morphine > aspirin Potency: difference in the effective doses of same type drugs

 1.4 Rask and its assessment ( 安全性评价 ) § （ 1 ） Therapeutic index （ 治疗指数, TI ） § TI ＝ LD 50 /ED 50 ， § （ 2 ） Safety margin: LD 5 ～ ED 95 § or LD 1 ～ ED 99

Therapeutic index Safety margin Therapeutic index

Mechanisms of Drug Actions §3.1 Structure-Activity Relationship  ( 构效关系 ) §Both the affinity of a drug and its functional activity are determined by its chemical structure. §Relatively minor modifications in the drug molecule may result in major changes in pharmacological properties.

Atropine Peripheral & Central ScopolamineCentral AnisodaminePeripheral

Norepinephrine  receptor Epinephrine ,  receptors Isoprenaline  receptor

 3.2 Non-specific mechanisms ( 非特异性机制 ) § （ 1 ） Physioc-chemical reactions § Antacids, mannitol, dextran, …… § （ 2 ） Membrane-stablizing § Anesthetics, ethanol, …… § （ 3 ） Disinfectants

 3.3 Specific mechanisms ( 特异性机制 ) (1) Receptor ( 受体 ) (1) Receptor ( 受体 ) (2) Enzyme ( 酶 ) (2) Enzyme ( 酶 ) (3) Ion channel ( 离子通道 ) (3) Ion channel ( 离子通道 ) (4) Transporter ( 转运体 ) (4) Transporter ( 转运体 ) (5) Immune system ( 免疫系统 ) (5) Immune system ( 免疫系统 ) (6) Gene therapy ( 基因治疗 ) & genetic (6) Gene therapy ( 基因治疗 ) & genetic engineering drugs ( 基因工程药物 ) engineering drugs ( 基因工程药物 ) (7) Others ( 其他 ) (7) Others ( 其他 )

Specific mechanisms Actions on cell functions Specific mechanisms ： Actions on cell functions

Enzyme-targeting drugs Acetylcholinesterase inhibitor Cyclo-oxygenase inhibitor Angiotensin converting enzyme inhibitor Na + -K + -ATPase inhinitor H + -K + -ATPase inhinitor HMG-CoA reductase inhibitors Most of antibiotics and anti- tumor drugs

Drugs acting on ion channels

Furosemide inhibits Na + -K + -2Cl - -transporter Neurotransmitter transporter inhibitors Drugs acting on transporters

Targets of drug

4- Drug receptors Key events in the discovery and establishment of the concept of receptors

§4.1 Concept of receptors  Receptor: the 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. 受体：细胞膜或细胞质的特异性蛋白质，具有识别、结合 配体，并发生信号转导的作用 ）  Receptor: the 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. （ 受体：细胞膜或细胞质的特异性蛋白质，具有识别、结合 配体，并发生信号转导的作用 ） §Function: recognizing and binding with a specific ligand; signal transduction §Structure: a protein with ligand-binding domain and effector (transducer) domain

§Ligand: Chemicals that can bind to receptors, including endogenous or exogenous agonists and antagonists 配体：  ( 配体：能与受体特异性结合的物质，分为激动剂和拮抗剂； 根据来源分为内源性和外源性两类 )

§4.2 Receptor classification §(1) G protein-coupled receptors (G 蛋白偶联受体, GPCR, 7TM 受体 ) §(2) Ligand-gated ion channel receptors ( 含离子通道的 受体，配体门控离子通道受体 ) §(3) Receptors as enzymes or coupled by enzymes  ( 具有酪氨酸激酶活性 [ 或偶联］受体, 1TM 受体 ) §(4) Cytosolic [or nuclear] receptors ( 细胞内受体, § 核内受体 )

Another classification (1) Cytosolic [or nuclear] receptors (1) Cytosolic [or nuclear] receptors (2) Receptors as enzymes (2) Receptors as enzymes (3) Receptors coupled by enzymes (3) Receptors coupled by enzymes (4) Ligand-gated ion channel receptors (4) Ligand-gated ion channel receptors (5) G protein-coupled receptors (5) G protein-coupled receptors 酪氨酸激酶活性 [ 或偶联 ] 受体

Black box and mechanistic approaches to pharmacology

Examples: M cholinoceptor Adrenoceptors 5-HT receptors DA receptors Opioid receptors ect. G protein-coupled receptors (GPCR)

GPCR signal transduction cAMP-PKA IP 3 -Ca 2+ / PKC PKA

Ligand-gated ion channel receptors Examples: N cholinoceptor GABA A receptor 5-HT 3 receptor NMDA receptor

Receptors as enzymes Growth factor receptors Receptors coupled by enzymes Cytokine receptors

Cytosolic receptors Steroid receptors as transcript factors

Nuclear receptors: thyroid receptor as a transcript factor

§4.3 Interactions of drug and receptor §D ＋ R DR E §Occupation theory: Drug binds to its receptor, then produce physiological effects

§Binding properties §Binding assay （ radioactive tests ） §K D ＝ [D][R] / [DR] §Bioassay （ biological effect tests ） §E/E max ＝ [DR] / [R T ] ＝ [D] / {K D +[D]}

§ （ 1 ） Affinity （ 亲和力 ） § ability of drug to bind to the receptor §Ligand binding tests ： K D ； K B §In vitro effect test ： pD 2 （ negative log molar concentration of the agonist which produces 50 ％ of the maximal effect ）

§ （ 2 ） Intrinsic activity （ 内在活性 ） § Ability of drug to produce effects after binding to the receptor E/E max ＝ α·[DR] / [R T ] § E/E max ＝ α·[DR] / [R T ]

Concentration-effect curve ： different affinity same intrinsic activity same intrinsic activity Affinity Intrinsicactivity

Concentration-effect curve ： same affinity different intrinsic activity different intrinsic activity Intrinsic activity Affinity

§4.4 Agonists and antagonists §Drugs that act on receptors can be classified into three types based on their affinity, intrinsic activity and produced physiological effect ：  Full agonist ( 激动药 )  Partial agonist ( 部分激动药 )  Antagonist ( 拮抗药 )

§Classification of drugs that acting on receptors § Affinity Intrinsic activity Effects §Agonist Yes Yes （ 100 ％） Yes §Antagonist Yes None （ 0 ％） None ， § blocking agonist §Partial Yes Weak （ 0 ～ 100 ％） Weak, §agonist blocking agonist

Box Recently ， there are new classes of drugs that act on the receptors ： inverse agonist ( 反向激动剂 ) or negative antagonist （ 负拮抗剂 ） 具有拮抗剂特点，本身又产生与激动剂相反的效应 。 具有拮抗剂特点，本身又产生与激动剂相反的效应 。 co-agonist ( 协同激动剂 ) 与其它激动剂共同发挥效应 。 与其它激动剂共同发挥效应 。

A ： Effect of a competitive antagonist on agonist concentration- response curve (affinity – pA 2 ) B ： Effect of a non-competitive antagonist on agonist concentration- response curve agonist agonist Antagonist none lowerhigher none lower higher Antagonist  4.5 Competitive and non-competitive antagonism （竞争性和非竞争性拮抗）

Possible mechanisms of antagonisms Co-agonist

§4.6 Regulation of receptors  (1) Desensitization （ 脱敏 ） § Receptor phosphorylation § Internalization or Endocytosis

Reversible 同种脱敏 异种脱敏

Receptor phosphorylation and internalization

§(2) Changes of receptor numbers  Down-regulation  Down-regulation （ 向下调节，下调 ）  Up-regulation  Up-regulation （ 向上调节，上调 ）