Chapter 2 Pharmacodynamics 药物效应动力学 §Pharmacological action - Overview §Dose-effect relationship §Mechanisms of drug actions §Drug receptors

Chapter 2Chapter 2

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

Pharmacological action - Pharmacological action - OverviewOverview

Dose-effect relationshipDose-effect relationship

Mechanisms of drug actionsMechanisms of drug actions

Drug receptorsDrug receptors

1-1- 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 modNeuroendocrine modulationulation

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 ofβreceptor agonists on the treaSelective effects ofβreceptor agonists on the treatment of bronchial asthmatment of bronchial asthma


1.4 Therapeutic effect and adverse reaction1.4 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 (Efficacy)1) Therapeutic effects (Efficacy)

(1) Etiological treatment (1) Etiological treatment

(2) Symptomatic treatment (2) Symptomatic treatment

(3) Supplement therapy (3) Supplement therapy


2) Adverse drug reactions (Adverse effec2) Adverse drug reactions (Adverse effects)ts)

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（广义）（广义）

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

GI ↓GI ↓

MydriasisMydriasis

Gland ↓Gland ↓

Bladder↓Bladder↓

HR ↑HR ↑

ConstipationConstipation

Dry mouthDry mouth

Blurring visionBlurring vision

Urine retentionUrine retention

PalpitationPalpitation

AtropineAtropine


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

Local & system toxicityLocal & system toxicity Reversible & irreversible toxic reactions Reversible & irreversible toxic reactions Acute & delayed/chronic toxicityAcute & delayed/chronic toxicity Teratogenic / carcinogenic effectsTeratogenic / carcinogenic effects


Box 2Box 2 药源性疾病药源性疾病 (drug-induced di(drug-induced diseases)seases)

严重的不良反应可以引起疾病，这种由药物不严重的不良反应可以引起疾病，这种由药物不良反应引起的疾病称为药源性疾病，它主要是良反应引起的疾病称为药源性疾病，它主要是不合理用药造成的。药源性疾病实际上是药物不合理用药造成的。药源性疾病实际上是药物不良反应在一定条件下产生的后果，一般来说，不良反应在一定条件下产生的后果，一般来说，药源性疾病不包括因使用药物超过极量所引起药源性疾病不包括因使用药物超过极量所引起的急性中毒。的急性中毒。


(3) After effect(3) After effect

Effects after drug concentration in the body is loEffects after drug concentration in the body is lower than threshold level.wer 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停药后血药浓度已降至阈浓度之下时残存的药理效应 ))

Short-lastingShort-lasting ：： e.g.e.g. BarbituratesBarbituratesLong-lastingLong-lasting ：： e.g.e.g. GlucocorticoidsGlucocorticoids


(4) Allergic reaction ( Hypersensitivity )(4) Allergic reaction ( Hypersensitivity )

Abnormal immunological reactions induced by Abnormal immunological reactions induced by drugs.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 ))

Types I, II, III, IVTypes I, II, III, IV

Skin, fever, blood-forming organs, Skin, fever, blood-forming organs, anapanaphylactic shockhylactic shock


(5) Idiosyncratic reactions(5) Idiosyncratic reactions

A genetically determined abnormal reactivity to a cA genetically determined abnormal reactivity to a chemical.hemical.

(( 少数特异质病人对某些药物特别敏感，反应性质也可能与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常人不同 ))

Genetic abnormalityGenetic abnormality Examples:Examples: Deficiency of erythrocytic glucose-6-phosphate dDeficiency of erythrocytic glucose-6-phosphate d

ehydrogenaseehydrogenase Hypersensitivity to scolineHypersensitivity to scoline


(6) Others(6) Others

Secondary reactionSecondary reaction

Adverse reactions resulting from primary therAdverse reactions resulting from primary therapeutic effects of drugs.apeutic effects of drugs.

(( 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 ))

Example:Example: Broad-spectrum antibiotics induce overgrowth of resisBroad-spectrum antibiotics induce overgrowth of resis

tant bacteria (tant bacteria (superinfectionsuperinfection))


Withdrawal symptomsWithdrawal symptoms

Clinical syndrome appeared or worsened when Clinical syndrome appeared or worsened when the drug is terminated.the drug is terminated.

( ( 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 ))

Examples:Examples: PropranololPropranolol －－ CHDCHD ClonidineClonidine －－ hypertensionhypertension Anti-epileptic drugsAnti-epileptic drugs －－ epilepsyepilepsy


DependenceDependence

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

Psychologic dependencePsychologic dependence is manifested by compulsive drug-seis manifested by compulsive drug-seeking behavior.eking 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 dis defined as the compulsive, out-of-control drug use, despite negative consequences.rug 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 signa maladaptive pattern of drug use leading to clinically sign

ificant impairment or distress)ificant impairment or distress)


Box 3Box 3 药物不良反应的分型药物不良反应的分型剂量关系密切型剂量关系密切型 (( 甲型甲型 )) ：：是药物固有药理作用的延续和是药物固有药理作用的延续和

增强，包括的副作用、毒性反应。具有剂量依赖性和可预增强，包括的副作用、毒性反应。具有剂量依赖性和可预测性的特点。测性的特点。

剂量关系不密切型剂量关系不密切型 (( 乙型乙型 )) ：：与药物固有药理作用无关的与药物固有药理作用无关的异常反应，与变态反应或高敏体质有关。具有与剂量无关异常反应，与变态反应或高敏体质有关。具有与剂量无关和难以预测的特点。和难以预测的特点。

特殊型（丙型）：特殊型（丙型）：药物引起的癌症、畸胎、染色体畸变等。药物引起的癌症、畸胎、染色体畸变等。


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

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 -- 效应关效应关系系（量效关系）（量效关系）

In vitroIn vitro studies: studies: concentration-effect relationshipconcentration-effect relationship

2-2- Dose-Effect RelationshipDose-Effect Relationship

2.1 Dose2.1 Dose （（ concentrationconcentration ））ClinicalClinical ：： Threshold dosesThreshold doses (( 阈剂量阈剂量 )) Therapeutic (usual) dosesTherapeutic (usual) doses (( 治疗量，常用量治疗量，常用量 )) Maximal dosesMaximal doses (( 极量极量 )) Toxic dosesToxic doses (( 中毒量中毒量 )) Lethal dosesLethal doses (( 致死量致死量 )) MIC and other concentrationsMIC and other concentrations

ExperimentalExperimental ：： in vivoin vivo - - EDED5050, TD, TD5050, LD, LD5050 , …… , ……

in vitroin vitro -- ICIC5050, EC, EC5050, ……, ……


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 or dose-response curve2.3 Dose-effect curve or dose-response 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)

Individual variability ofIndividual variability of dose-effect curvedose-effect curve

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

Maximal effect (Maximal effect ( 最大效应最大效应 ) or efficacy () or efficacy ( 效能效能 ):): diffdifferent maximal magnitudes of effectserent maximal magnitudes of effects

Potency (Potency ( 效价强度效价强度 ):): difference in doses that proddifference in doses that produce an effect at same leveluce an 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 Risk and its assessment (1.4 Risk 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

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Chapter 2 Pharmacodynamics 药物效应动力学 §Pharmacological action - Overview §Dose-effect relationship §Mechanisms of drug actions §Drug receptors