Section XIIISection XIII

Introduction ofIntroduction of

PharmacologyPharmacology- - 药理学概论药理学概论 --

Chapter 1Chapter 1

General ConceptsGeneral Concepts

Human disease: prevention and treatmentHuman disease: prevention and treatment Drug therapy Drug therapy Surgery Surgery RadiotherapyRadiotherapy Physical therapyPhysical therapy Psychological therapyPsychological therapy

药理学是药物治疗学的基础理论药理学是药物治疗学的基础理论

PharmacologyPharmacology can be defined as the study of substances that can be defined as the study of substances that interact with living systems through chemical processes, interact with living systems through chemical processes, especially by binding to regulatory molecules and activating or especially by binding to regulatory molecules and activating or inhibiting normal body processes.inhibiting normal body processes.

Medical PharmacologyMedical Pharmacology is often defined as the science of is often defined as the science of substances used to prevent, diagnose, and treat disease. substances used to prevent, diagnose, and treat disease.

－ － Katzung BG (Ed). Basic & Clinical PharmacologyBasic & Clinical Pharmacology (11th Edition). New York:McGraw-Hill, 2010.

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。础学科。

What is Pharmacology studied?What is Pharmacology studied?

Pharmacodynamics:Pharmacodynamics: the actions of the drug on the the actions of the drug on the body and the mechanismsbody and the mechanisms

Pharmacokinetics:Pharmacokinetics: the actions of the body on the the actions of the body on the drugsdrugs

Influencing factors Influencing factors on the processes of on the processes of pharmacodynamics and pharmacokineticspharmacodynamics and pharmacokinetics

DrugsDrugsHuman Human BodyBodyPharmacodynamicsPharmacodynamics

Action and mechanismAction and mechanism

PharmacokineticsPharmacokinetics

Absorption, distribution, Absorption, distribution, metabolism, excretion (metabolism, excretion (ADMEADME), ),

and drug concentration in the bodyand drug concentration in the body

Interaction between drug and human bodyInteraction between drug and human body

HumanHumanPathogensPathogens

DrugDrug

Interactions between drug , human Interactions between drug , human body, and pathogensbody, and pathogens

药剂学过程药剂学过程

药动学过程药动学过程

药效学过程药效学过程

ADME

崩解，溶出，与其他药物相互作用

Targets ；疗效，不良反应

Pharmacy Pharmacology

TherapeuticsTherapeutics

Basic Basic ResearchResearch

New New DrugDrug

Clinical Clinical PharmacologyPharmacology

Life ScienceLife Science

Screening Screening and and

EvaluationEvaluation

The Goals of PharmacologyThe Goals of Pharmacology

DrugsDrugs

药物：药物：影响机体生理、生化功能，能够用于诊断、预防影响机体生理、生化功能，能够用于诊断、预防和治疗疾病的物质。和治疗疾病的物质。

药品：药品：指用于预防、治疗、诊断人的疾病，有目的地调指用于预防、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、用法和用量的物质节人的生理机能并规定有适应证、用法和用量的物质，包包括中药材、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、放射性药品、血清疫苗、血液制品和诊断药品等。

药物和药品的概念药物和药品的概念

Drug resources and preparationDrug resources and preparation

Nature Nature sourcessources

SynthesisSynthesis

BioengineeringBioengineering

Dose Dose FormsForms

HumanHuman

PharmacyPharmacy PharmacologyPharmacology

新药定义：新药定义：未曾在中国境内上市销售的药品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。应证或制成新的复方制剂，亦按新药管理。

旧定义：旧定义：我国尚未生产过的药品我国尚未生产过的药品。。

Research and Development (R&D) Research and Development (R&D) of New Drugsof New Drugs

1.1. Preclinical testingPreclinical testing （临床前研究）（临床前研究）

2.2. Approval for clinical testing Approval for clinical testing （申请临床研究）（申请临床研究）

3.3. Clinical testing (clinical pharmacology) Clinical testing (clinical pharmacology) （临床研究）（临床研究）

4.4. Approval for production and marketing Approval for production and marketing （申请生产）（申请生产）

4 Steps of New Drug R&D4 Steps of New Drug R&D

1.1. Preclinical testing Preclinical testing

EfficacyEfficacy ((screening and evaluation by pharmacological screening and evaluation by pharmacological methodsmethods))

SafetySafety ((evaluation by toxicological methodsevaluation by toxicological methods))

Quantity Quantity (pharmacy)(pharmacy)

good laboratory practicegood laboratory practice （（ GLPGLP ））2.2. Clinical testing Clinical testing

Efficacy Efficacy (therapeutic effects)(therapeutic effects)

Safety Safety (adverse effects)(adverse effects)

PharmacokineticsPharmacokinetics (PK parameter or bioavaibility)(PK parameter or bioavaibility)

good clinical practicegood clinical practice (GCP) (GCP)

The phases of drug developmentThe phases of drug development

Chapter 2Chapter 2

General Considerations General Considerations of Pharmacologyof Pharmacology

Part 1Part 1

PharmacodynamicsPharmacodynamics药物效应动力学药物效应动力学

Pharmacological Action - Pharmacological Action - OverviewOverview

1.1 Action and effect of drug1.1 Action and effect of drug

ActionActionSpecifically primary action between drug

and cells or molecules

EffectEffectApparent functional and morphological

changes induced by drug directly and/or indirectly

1.2 Direct and indirect effects of drugs1.2 Direct and indirect effects of drugs

Direct effects: Direct effects: Effects resulted from the action of drug on

the target organ(s) or tissue(s)

Indirect effects:Indirect effects:Effects resulted from functional integration

of target system(s) and modulation system(s)

Action on Action on vascular vascular 11

receptorsreceptors

BP BP ↑

HR HR ↓

directdirect

indirectindirect

ActionAction EffectEffect

Neuroendocrine Neuroendocrine modulationmodulation

1.3 Selectivity of drug effect1.3 Selectivity of drug effect

Selectivity: Selectivity: Organs / TissuesOrgans / TissuesSpecificity: Specificity: BiomoleculesBiomolecules

Reasons of selectivityReasons of selectivity Drug distributionDrug distribution Biological properties of tissues or organsBiological properties of tissues or organs

bronchodilationbronchodilation

bronchodilationbronchodilation

BP BP ↑↑

heart rateheart rate↑↑

EpinephrineEpinephrine

SalbutamolSalbutamol

Selective effects of βreceptor agonists on the Selective effects of βreceptor agonists on the treatment of bronchial asthmatreatment of bronchial asthma

1.4 Basic effects of drugs1.4 Basic effects of drugsExcitationExcitation oror InhibitionInhibition of the functions of the bodyof the functions of the bodyKill or suppress the pathogensKill or suppress the pathogens

1.5 Therapeutic effect and adverse reaction1.5 Therapeutic effect and adverse reaction

((desirable and undesirable effectsdesirable and undesirable effects))

Balance the ratio of benefits / risk !!Balance the ratio of benefits / risk !!

1) Therapeutic effects (1) Therapeutic effects (efficacyefficacy)) 治疗作用（疗效）治疗作用（疗效）

(1) Etiological treatment (1) Etiological treatment

(2) Symptomatic treatment (2) Symptomatic treatment

(3) Supplement therapy (3) Supplement therapy

2) Adverse drug reactions (2) Adverse drug reactions (adverse effectsadverse effects) ) 不良反应不良反应

不符合用药目的，并对病人带来不适或痛苦的反应不符合用药目的，并对病人带来不适或痛苦的反应 （广（广义）义）

Box 1Box 1 现在，我国将不良反应定义为现在，我国将不良反应定义为上市药品在正常用法用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。量情况下出现的与用药目的无关的有害反应。以区别于以区别于药物药物过量（过量（ overdoseoverdose ）），在本课程中将两者合称为，在本课程中将两者合称为““不良反应不良反应”。”。

(1) Side effect(1) Side effect （副作用）（副作用） undesirable effects of undesirable effects of that drug for that therapeutic indication at usual that drug for that therapeutic indication at usual doses, usually are doses, usually are non-deleteriousnon-deleterious. . （治疗剂量时出现的（治疗剂量时出现的与治疗目的无关的药物作用）与治疗目的无关的药物作用）

(2) Toxic effect(2) Toxic effect （ 毒 性 反 应 ）（ 毒 性 反 应 ） Functional or Functional or morphological damages produced by larger doses morphological damages produced by larger doses of longer terms of drug uses. of longer terms of drug uses. （剂量过大或用药时间过长（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）体内蓄积过多时发生的危害性反应）

(3) After effect(3) After effect （ 后 遗 效 应 ）（ 后 遗 效 应 ） Effects after Effects after drug concentration in the body is lower than drug concentration in the body is lower than threshold levelthreshold level. (. ( 停药后血药浓度已降至阈浓度之下时残存的停药后血药浓度已降至阈浓度之下时残存的药理效应药理效应 ))

(4) Allergic reaction (Hypersensitivity)(4) Allergic reaction (Hypersensitivity)（变态反应，药物过敏）（变态反应，药物过敏） Abnormal Abnormal immunological reactions induced by drugsimmunological reactions induced by drugs. . ( ( 接触药物后发生的异常免疫反应 接触药物后发生的异常免疫反应 ))

(5) Idiosyncratic reactions(5) Idiosyncratic reactions （ 特 异 质 反 应 ）（ 特 异 质 反 应 ） A A genetically determined abnormal reactivity to a genetically determined abnormal reactivity to a chemical.chemical. (( 少数特异质病人对某些药物特别敏感，反应性质也可能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 与常人不同 ))

Withdrawal symptomsWithdrawal symptoms （ 停 药 反 应 ）（ 停 药 反 应 ） Clinical Clinical syndrome appeared or worsened when the drug is syndrome appeared or worsened when the drug is terminatedterminated. . ( ( 突然停药后原有疾病复发或加剧 突然停药后原有疾病复发或加剧 ))

(6) Others(6) Others Secondary reactionSecondary reaction （继发效应）（继发效应） Adverse Adverse

reactions resulting from primary therapeutic effects of reactions resulting from primary therapeutic effects of drugsdrugs.. (( 继发于药物治疗作用之后的不良反应 继发于药物治疗作用之后的不良反应 ))

Dependence Dependence （依赖性）（依赖性）

An adaptive state that develops in response to An adaptive state that develops in response to repeated drug administration.repeated drug administration.

Psychologic dependencePsychologic dependence is manifested by compulsive drug-is manifested by compulsive drug-seeking behavior.seeking behavior.

Physiologic dependencePhysiologic dependence is present when withdrawal of drug is present when withdrawal of drug produces symptoms and signs.produces symptoms and signs.

Drug addictionDrug addiction is defined as the compulsive, out-of-control is defined as the compulsive, out-of-control drug use, despite negative consequences.drug use, despite negative consequences.

Drug abuseDrug abuse: : any use of a drug for non-medical purposes.any use of a drug for non-medical purposes. ((a maladaptive pattern of drug use leading to clinically a maladaptive pattern of drug use leading to clinically

significant impairment or distress)significant impairment or distress)

The observed effect of a drug as a function of The observed effect of a drug as a function of its dose in the living system, usually drug its dose in the living system, usually drug results in a greater magnitude of effect as the results in a greater magnitude of effect as the dose increased.dose increased.

药理效应与剂量在一定范围内成比例，称为剂量药理效应与剂量在一定范围内成比例，称为剂量 --效应关系效应关系（量效关系）（量效关系）

Dose-Effect RelationshipDose-Effect Relationship

Generally consideredGenerally considered

Currently recognized Currently recognized

2.1 Dose2.1 Dose (concentration)(concentration)

Clinical or Experimental dosesClinical or Experimental doses

2.2 Responses (effects)2.2 Responses (effects)

（（ 11 ）） Graded responses Graded responses （量反应）（量反应） Response changes quantitativelyResponse changes quantitatively Measurable responses in an individualMeasurable responses in an individual

（（ 22 ）） Quantal responsesQuantal responses （质反应）（质反应） All-or-noneAll-or-none Percentage of the populationPercentage of the population

2.3 Dose-effect curve 2.3 Dose-effect curve or dose-responseor dose-response curve curve ( ( 量效曲线 量效曲线 ))

（（ 11 ）） logD-E (logC-E): logD-E (logC-E): SS-shaped curve-shaped curve

GradedGraded in vitroin vitro ：： pDpD2 2 , EC, EC50 50 , IC, IC50 50 , MIC ……, MIC ……

in vivoin vivo ：： PDPD100100, ID, ID30 30 , ……, ……

QuantalQuantal median doses: median doses: EDED50 50 , LD, LD50 50 , ID, ID5050 …… ……

（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)Concentration-effect curve (graded response)

Dose-effect curve (quantal response)Dose-effect curve (quantal response)

（（ 22 ）） Maximal effect and potencyMaximal effect and potency

Maximal effect Maximal effect (( 最大效应最大效应 )) or efficacyor efficacy (( 效能效能 )):: different different maximal magnitudes of effectsmaximal magnitudes of effects

Potency Potency (( 效 价 强 度效 价 强 度 ):): difference in doses that produce difference in doses that produce an effect at same levelan effect at same level （（等效剂量等效剂量））

药物药物作用强弱作用强弱及及敏感程度敏感程度的比较的比较

Potency:Potency: B > A > C > DB > A > C > D

Efficacy:Efficacy: A = C = D > BA = C = D > B

Slope:Slope: D > A, B, CD > A, B, C

Efficacy:Efficacy: loop diuretics > thiazide diuretics;loop diuretics > thiazide diuretics; morphine > aspirinmorphine > aspirin

Potency:Potency: difference in the effective doses of same type drugsdifference in the effective doses of same type drugs

1.4 Rask and its assessment 1.4 Rask and its assessment (( 安全性评价安全性评价 ))

（（ 11 ）） Therapeutic indexTherapeutic index （（治疗指数治疗指数 , TI, TI ）） TITI ＝＝ LDLD5050/ED/ED5050 ，，

（（ 22 ）） Safety margin: Safety margin: LDLD55 ～～ EDED9595

oror LD LD11 ～～ EDED9999

Therapeutic indexTherapeutic indexSafety marginSafety marginTherapeutic indexTherapeutic index

Mechanisms of Drug ActionsMechanisms of Drug Actions

3.1 Structure-Activity Relationship3.1 Structure-Activity Relationship (( 构效关系构效关系 ))

Both the affinity of a drug and its functional Both the affinity of a drug and its functional activity are determined by its chemical activity are determined by its chemical

structurestructure..

Relatively minor modifications in the drug Relatively minor modifications in the drug molecule may result in major changes in molecule may result in major changes in pharmacological properties.pharmacological properties.

OH

CH

NCH3

CH

CH3

CH3

CH O CH C6H5

CH2CH2

CH2

C

O

OH

CH

NCH3

CH

CH3

CH3

CH O CH C6H5

CH2CH

CH

C

O

O

OH

CH

NCH3

CH

CH3

CH3

CH O CH C6H5

CH2

CH

C

O

CH2

HO

AtropineAtropine

Peripheral Peripheral & Central& Central

ScopolamineScopolamine

CentralCentral

AnisodamineAnisodamine

PeripheralPeripheral

HO

HO CH

OH

CH2 NH2

HO

HO CH

OH

CH2 NH

CH3

NorepinephrineNorepinephrine

receptorreceptor

EpinephrineEpinephrine

, , receptors receptors

NCH2

OH

CHHO

HO

CH3

CH

CH3

IsoprenalineIsoprenaline

receptorreceptor

3.2 Non-specific mechanisms 3.2 Non-specific mechanisms (( 非特异性机制非特异性机制 ))

（（ 11 ）） Physioc-chemical reactionsPhysioc-chemical reactions Antacids, mannitol, dextran, ……Antacids, mannitol, dextran, ……

（（ 22 ）） Membrane-stablizingMembrane-stablizing Anesthetics, ethanol, ……Anesthetics, ethanol, ……

（（ 33 ）） DisinfectantsDisinfectants

3.3 Specific mechanisms3.3 Specific mechanisms (( 特异性机制特异性机制 ))

(1)(1) ReceptorReceptor (( 受体受体 ))

(2) Enzyme(2) Enzyme (( 酶酶 ))

(3) Ion channel(3) Ion channel (( 离子通道离子通道 ))

(4) Transporter(4) Transporter (( 转运体转运体 ))

(5) Immune system(5) Immune system (( 免疫系统免疫系统 ))

(6)(6) Gene therapy Gene therapy (( 基因治疗基因治疗 )) & genetic & genetic engineering drugs (engineering drugs ( 基因工程药物基因工程药物 ))

(7) Others (7) Others (( 其他其他 ))

Specific mechanismsSpecific mechanisms ： Actions on cell functionsActions on cell functions

Enzyme-targeting drugsEnzyme-targeting drugs

Acetylcholinesterase inhibitorAcetylcholinesterase inhibitor

Cyclo-oxygenase inhibitorCyclo-oxygenase inhibitor

Angiotensin converting Angiotensin converting enzyme inhibitorenzyme inhibitor

NaNa++-K-K++-ATPase inhinitor-ATPase inhinitor

HH++-K-K++-ATPase inhinitor-ATPase inhinitor

HMG-CoA reductase HMG-CoA reductase inhibitorsinhibitors

Most of antibiotics and anti-Most of antibiotics and anti-tumor drugstumor drugs

Drugs acting on ion channelsDrugs acting on ion channels

Furosemide inhibits Furosemide inhibits NaNa++-K-K++-2Cl-2Cl---transporter-transporter

Neurotransmitter transporter Neurotransmitter transporter inhibitorsinhibitors

Drugs acting on transportersDrugs acting on transporters

Targets of drugTargets of drug

4- Drug receptors4- Drug receptors

Key events in the discovery and establishment of the Key events in the discovery and establishment of the concept of receptorsconcept of receptors

4.1 Concept of receptors4.1 Concept of receptors

Receptor:Receptor: the component of a cell or organism the component of a cell or organism that interacts with a drug and initiates the chain of that interacts with a drug and initiates the chain of biochemical events leading to the drug’s observed biochemical events leading to the drug’s observed effects.effects. （受体：受体：细胞膜或细胞质的特异性细胞膜或细胞质的特异性蛋白质蛋白质，，具有具有识别、结识别、结合配体合配体，，并并发生信号转导发生信号转导的作用的作用））

Function:Function: recognizing and bindingrecognizing and binding with a specific ligand;with a specific ligand; signal transductionsignal transduction

Structure:Structure: a protein witha protein with ligand-bindingligand-binding domain anddomain and effector (transducer)effector (transducer) domain domain

Ligand:Ligand: Chemicals that can bind to Chemicals that can bind to receptors, including endogenous or receptors, including endogenous or exogenous agonists and antagonists 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 classification4.2 Receptor classification

(1) G protein-coupled receptors(1) G protein-coupled receptors ((GG 蛋白偶联受体蛋白偶联受体 , GPCR, , GPCR,

7TM7TM 受体受体 ))

(2) Ligand-gated ion channel receptors(2) Ligand-gated ion channel receptors (( 含离子通道的含离子通道的受体，配体门控离子通道受体受体，配体门控离子通道受体 ))

(3) Receptors as enzymes or coupled by enzymes(3) Receptors as enzymes or coupled by enzymes (( 具有酪氨酸激酶活性具有酪氨酸激酶活性 [[ 或偶联］或偶联］受体受体 , 1TM, 1TM 受体受体 ))

(4) Cytosolic [or nuclear] receptors(4) Cytosolic [or nuclear] receptors (( 细细胞内受体胞内受体 , ,

核内受体核内受体 ))

Another classificationAnother classification (1) (1) Cytosolic [or nuclear] receptorsCytosolic [or nuclear] receptors

(2) (2) Receptors as enzymesReceptors as enzymes (3) (3) Receptors coupled by enzymesReceptors coupled by enzymes

(4) (4) Ligand-gated ion channel receptorsLigand-gated ion channel receptors

(5) (5) G protein-coupled receptorsG protein-coupled receptors

酪氨酸激酶活性酪氨酸激酶活性 [[ 或偶联或偶联 ]] 受受体体

Black boxBlack box and and mechanistic approaches mechanistic approaches to pharmacologyto pharmacology

Examples:Examples:M cholinoceptor M cholinoceptor AdrenoceptorsAdrenoceptors5-HT receptors5-HT receptorsDA receptorsDA receptorsOpioid receptorsOpioid receptorsect.ect.

G protein-coupled receptors (GPCR)G protein-coupled receptors (GPCR)

GPCR signal GPCR signal transductiontransduction

cAMP-PKAcAMP-PKAIPIP33-Ca-Ca2+ 2+ / PKC/ PKC

PKAPKA

Ligand-gated ion channel receptorsLigand-gated ion channel receptors

Examples:Examples:

N cholinoceptorN cholinoceptor

GABAGABAAA receptor receptor

5-HT5-HT33 receptor receptor

NMDA receptorNMDA receptor

Receptors as Receptors as enzymesenzymes

Growth factor Growth factor receptorsreceptors

Receptors Receptors coupled by coupled by enzymesenzymes

Cytokine Cytokine receptorsreceptors

Cytosolic Cytosolic receptorsreceptors

Steroid receptors as Steroid receptors as transcript factorstranscript factors

Nuclear receptors:Nuclear receptors: thyroid receptor as a transcript factor thyroid receptor as a transcript factor

4.3 Interactions of drug and receptor4.3 Interactions of drug and receptor

D D ＋ ＋ R DR ER DR E

Occupation theory:Occupation theory: Drug binds to its Drug binds to its receptor, then produce physiological effectsreceptor, then produce physiological effects

Binding propertiesBinding properties

Binding assayBinding assay （（ radioactive testsradioactive tests ））KKDD ＝＝ [D][R] / [DR][D][R] / [DR]

BioassayBioassay （（ biological effect testsbiological effect tests ））E/EE/Emaxmax ＝＝ [DR] / [R[DR] / [RTT]] ＝＝ [D] / {K[D] / {KDD+[D]}+[D]}

（（ 11 ） ） AffinityAffinity （（亲和力亲和力）） ability of drug to bind to the receptorability of drug to bind to the receptor

Ligand binding testsLigand binding tests ：： KKDD ；； KKBB

In vitroIn vitro effect test effect test ：： ppDD22 （（ negative log negative log

molar concentration of the agonist which molar concentration of the agonist which produces 50produces 50 ％ ％ of the maximal effectof the maximal effect ））

（（ 22 ） ） Intrinsic activityIntrinsic activity （（内在活性内在活性）） Ability of drug to produce effects after Ability of drug to produce effects after

binding to the receptorbinding to the receptor

E/EE/Emaxmax ＝＝ αα·[DR] / [R·[DR] / [RTT]]

Concentration-effect curveConcentration-effect curve ：： different affinitydifferent affinity

same intrinsic activitysame intrinsic activity

AffinityAffinity

IntrinsicIntrinsic

activityactivity

Concentration-effect curveConcentration-effect curve ：： same affinitysame affinity

different intrinsic activitydifferent intrinsic activity

Intrinsic activityIntrinsic activity

AffinityAffinity

4.4 Agonists and antagonists4.4 Agonists and antagonists

Drugs that act on receptors can be classified Drugs that act on receptors can be classified into three types based on their affinity, into three types based on their affinity, intrinsic activity and produced physiological intrinsic activity and produced physiological

effecteffect ：：

Full agonistFull agonist ( ( 激动药激动药 )) Partial agonist Partial agonist (( 部分激动药部分激动药 )) Antagonist Antagonist (( 拮抗药拮抗药 ) )

Classification of drugs that acting on receptorsClassification of drugs that acting on receptors

Affinity Affinity Intrinsic activityIntrinsic activity EffectsEffects

AgonistAgonist YesYes YesYes （（ 100100 ％）％） YesYes AntagonistAntagonist Yes Yes NoneNone （ （ 00 ％）％） NoneNone ，， blocking agonistblocking agonist Partial Partial YesYes Weak Weak （（ 00 ～～ 100100 ％）％） Weak , Weak , agonistagonist blocking agonistblocking agonist

BoxBoxRecentlyRecently ，， there are new classes of there are new classes of drugs that act on the receptorsdrugs that act on the receptors ：：

inverse agonist inverse agonist (( 反向激动剂反向激动剂 ) or ) or negative negative antagonistantagonist （（负拮抗剂负拮抗剂）） 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 co-agonist (( 协同激动剂协同激动剂 ))

与其它激动剂共同发挥效应与其它激动剂共同发挥效应。。

AA ：： Effect of a Effect of a competitive antagonistcompetitive antagonist on agonist concentration- response on agonist concentration- response curve curve (affinity – (affinity – ppAA22))

BB ：： Effect of a Effect of a non-competitive antagonistnon-competitive antagonist on agonist concentration- on agonist concentration-response curveresponse curve

agonistagonist agonistagonist

AntagonistAntagonist

none lower highernone

lower

higher

AntagonistAntagonist

4.5 Competitive and non-competitive antagonism4.5 Competitive and non-competitive antagonism（（竞争性和非竞争性拮抗竞争性和非竞争性拮抗））

Possible mechanisms of Possible mechanisms of antagonismsantagonisms

Co-agonistCo-agonist

4.6 Regulation of receptors4.6 Regulation of receptors

(1) Desensitization (1) Desensitization （（脱敏脱敏））

Receptor phosphorylationReceptor phosphorylation Internalization or EndocytosisInternalization or Endocytosis

ReversibleReversible

同种脱敏同种脱敏 异种脱敏异种脱敏

Receptor phosphorylation and internalizationReceptor phosphorylation and internalization

(2) Changes of receptor numbers(2) Changes of receptor numbers

Down-regulationDown-regulation （向下调节，下调）

UUp-regulationp-regulation （向上调节，上调）