Part 2Part 2

PharmacokineticsPharmacokinetics药物代谢动力学药物代谢动力学

KineticsKinetics

ModelsModels

ParametersParameters

2.2. Transport of Drug in the Body Transport of Drug in the Body

Mechanisms of drug permeation across cell membraneMechanisms of drug permeation across cell membrane

A. aqueous channels in the intercellular junctions

B.B. lipid cell lipid cell membranesmembranes

C.C. carriers carriers (transporters) (transporters) (into or out of (into or out of cells)cells)

D.D. endocytosisendocytosis

exocytosisexocytosis

2.1 Transmembrane Transport of Drugs2.1 Transmembrane Transport of Drugs

(1) Non-carrier Transport(1) Non-carrier Transport

Simple diffusionSimple diffusion （（简单扩散简单扩散 // 单纯扩散单纯扩散）） FiltrationFiltration （（滤过滤过））

(2) Carrier-mediated Transport (2) Carrier-mediated Transport

a. Active transporta. Active transport

Characteristics of active transportCharacteristics of active transport

Involving specific carrier (Involving specific carrier (transportertransporter)) Energy-dependentEnergy-dependent SaturabilitySaturability Competition at same carrierCompetition at same carrier Moving against concentration gradient (up-hill)Moving against concentration gradient (up-hill)

b. Facilitated diffusionb. Facilitated diffusion （（易化扩散易化扩散）） ((transporter-mediated diffusiontransporter-mediated diffusion))

Involving specific carriers (Involving specific carriers (transportertransporter) ) Energy-independentEnergy-independent SaturabilitySaturability Competition with other drugsCompetition with other drugs Concentration gradient (down-hill)Concentration gradient (down-hill)

(3) Endocytosis/exocytosis(3) Endocytosis/exocytosis （（入胞入胞 // 出胞出胞））

Another classificationAnother classification

Passive transportPassive transport Simple diffusionSimple diffusion （（ 简单扩散简单扩散 // 单纯扩单纯扩

散散）） FiltrationFiltration （（滤过滤过） ） Facilitated diffusionFacilitated diffusion （（易化扩散易化扩散））

Active transportActive transport Active transport (Active transport ( 主动转运主动转运 ) ) Pinocytosis/exocytosisPinocytosis/exocytosis （（ 入 胞入 胞 // 出出

胞胞））

A. Simple diffusionA. Simple diffusion Most drugs are weak acids or bases.

Their diffusion passing through cell membrane depends the lipid-soluble state (un-ionized form)

Determinants of simple diffusionDeterminants of simple diffusion

For most drugs of small molecules (usually For most drugs of small molecules (usually are weak acids or weak bases):are weak acids or weak bases):

Lipid-soluble or un-ionized formsLipid-soluble or un-ionized forms

pKa pKa of the drug andof the drug and pHpH of the body fluidof the body fluid

TheThe pKapKa is the pH at which the concentrations of is the pH at which the concentrations of the ionized and un-ionized forms are equal.the ionized and un-ionized forms are equal.

Henderson-Hasselbalch equationHenderson-Hasselbalch equation

Weak acid drugs: Weak acid drugs: ppH - H - ppKa = log ( [AKa = log ( [A--] / [HA] )] / [HA] ) ppKa - Ka - ppH = log ( [HA] / [AH = log ( [HA] / [A--] )] )

Weak base drugs:Weak base drugs: ppKa - Ka - ppH = log ( [BHH = log ( [BH++] / [B] )] / [B] ) ppH - H - ppKa = log ( [B] / [BHKa = log ( [B] / [BH++] )] )

ppHH ppKaKaun-ionized un-ionized

formformlipid-lipid-solublesoluble

Simple Simple diffusiondiffusion

Weak Weak acidsacids

Weak Weak basesbases

And / orAnd / or

And / orAnd / or

And / orAnd / or

And / orAnd / or

Three types of functional membrane proteins.Three types of functional membrane proteins.

B. Carrier (transporter)-mediated B. Carrier (transporter)-mediated transporttransport

Models of transmembrane transport across the lipid bilayerModels of transmembrane transport across the lipid bilayer

2.2 Free and Bound Forms2.2 Free and Bound Forms

Plasma protein bindingPlasma protein binding

Tissue / organ affinityTissue / organ affinity

3.3. Fate of the drug in the body Fate of the drug in the body

AbsorptionAbsorption DistributionDistribution MetabolismMetabolism (Biotransformation)(Biotransformation)

ExcretionExcretion － － ADMEADME

ADME

3.1 Absorption3.1 Absorption Absorption is the transfer of a drug from its site of Absorption is the transfer of a drug from its site of

administration to the blood stream.administration to the blood stream.

Gastrointestinal tractGastrointestinal tract Parenteral injection - Parenteral injection - i.m., s.c.i.m., s.c. InhalationInhalation Transdermal Transdermal

(1) Gastrointestinal tract(1) Gastrointestinal tract

Route:Route: OralOral SublingualSublingual RectalRectal

Absorption sites:Absorption sites: Oral Oral GastricGastric IntestinalIntestinal RectalRectal

Factors influencing absorption:Factors influencing absorption:

blood flow to the absorption siteblood flow to the absorption site total surface area available for absorptiontotal surface area available for absorption contact time at the absorption surfacecontact time at the absorption surface physic-chemical properties of the drugphysic-chemical properties of the drug first-pass eliminationfirst-pass elimination

(2) Parenteral injection(2) Parenteral injection

intramuscular injection ( i.m. ) intramuscular injection ( i.m. ) subcutaneous injection ( s.c. )subcutaneous injection ( s.c. )

DeterminantsDeterminants Local blood flow; Solubility of the drugLocal blood flow; Solubility of the drug

(3) Others(3) Others

Inhalation; Intranasal; Inhalation; Intranasal; Transdermal; TopicalTransdermal; Topical

3.2 Distribution3.2 Distribution

Drug distribution is the process by which a drug Drug distribution is the process by which a drug reversibly leaves the blood stream and enters the reversibly leaves the blood stream and enters the interstitium (extracellular fluid) and / or the interstitium (extracellular fluid) and / or the cells of the tissues.cells of the tissues.

Blood flow-dependent phase of distributionBlood flow-dependent phase of distribution Selective distributionSelective distribution Tissue-plasma balance:Tissue-plasma balance: importance of measuring importance of measuring

plasma concentrationplasma concentration

(1) Binding of drug to plasma proteins(1) Binding of drug to plasma proteins

Bound drug: Bound drug:

can not distribute / inactive temporallycan not distribute / inactive temporally reversible (storage form) / percentage of bindingreversible (storage form) / percentage of binding plasma protein capacityplasma protein capacity competitive displacementcompetitive displacement

(2) Physic-chemical properties of the drug(2) Physic-chemical properties of the drug

(3) Blood flow and re-distribution(3) Blood flow and re-distribution

(4) Affinity to organs or tissues(4) Affinity to organs or tissues

(5) Barriers(5) Barriers

Blood-brain barrier (BBB)Blood-brain barrier (BBB)

Placental barrierPlacental barrier

Blood-eye barrier Blood-eye barrier

Blood-brain barrier (BBB)Blood-brain barrier (BBB)

Able to pass throughAble to pass through Unable to pass throughUnable to pass through

Small moleculesSmall molecules Large moleculesLarge molecules

Lipid-solubleLipid-soluble Water-solubleWater-soluble

Transporter-mediation Transporter-mediation

Amount of drug passing through BBBAmount of drug passing through BBB

Increases when Increases when inflammation inflammation oror larger doses used larger doses used

Placental barrier:Placental barrier:

More permeableMore permeable

Drugs for pregnant Drugs for pregnant women:women:

A, BA, B – relatively safe – relatively safe

CC - caution - caution

D,D, XX - toxic - toxic

3.3 Metabolism (biotransformation)3.3 Metabolism (biotransformation) Drug metabolism is the process transforming lipophilic drug Drug metabolism is the process transforming lipophilic drug

into more hydrophilic metabolites, which is essential for the into more hydrophilic metabolites, which is essential for the elimination of these compounds from the body and elimination of these compounds from the body and

termination of their biological activitytermination of their biological activity..

(1) Metabolism sites(1) Metabolism sites Liver:Liver: for most of the drugsfor most of the drugs Other organs/tissuesOther organs/tissues:: intestine, kidney, lung, intestine, kidney, lung,

plasma, plasma, etcetc..

(2) Phases of metabolism(2) Phases of metabolism

Phase I: Phase I: Oxidation, reduction, hydrolysisOxidation, reduction, hydrolysis most drugs are inactivatedmost drugs are inactivated few (few (prodrugsprodrugs) is activated) is activated

Phase II: Phase II: ConjugationConjugation inactivatedinactivated

Metabolites: Metabolites: more water-soluble easier to excretemore water-soluble easier to excrete

(3) Enzymes in drug metabolism(3) Enzymes in drug metabolism

Enzymes in Phase I: Enzymes in Phase I: cytochrome-Pcytochrome-P450, 450, such as such as CYP2A6, CYP3A4CYP2A6, CYP3A4

many other enzymesmany other enzymes

Enzymes in Phase II: Enzymes in Phase II: acetylase acetylase glucuronosyltransferaseglucuronosyltransferase etc.etc.

Induction of hepatic enzymes by drugsInduction of hepatic enzymes by drugs example: example: phenytoinphenytoin －－ steroids, nifedipinesteroids, nifedipine

Inhibition of hepatic enzymes by drugsInhibition of hepatic enzymes by drugs example: example: verapamilverapamil －－ diazepamdiazepam

3.4 Excretion3.4 Excretion

Removal of a drug from the body via a Removal of a drug from the body via a number of routes.number of routes.

Elimination of drugs from the bodyElimination of drugs from the bodyAction on excretory organsAction on excretory organs

3.4 Excretion3.4 Excretion

(1) Excretion routes(1) Excretion routes Kidney -Kidney -renal excretionrenal excretion

Bile Bile (hepato-enteral circulation)(hepato-enteral circulation)

LungLung GI tractGI tract MilkMilk Secretion glandsSecretion glands

3.5 Elimination and Accumulation3.5 Elimination and Accumulation

EliminationElimination （（消除消除）） MetabolismMetabolism ExcretionExcretion Distribution (stored in fat, hair, etc)Distribution (stored in fat, hair, etc)

AccumulationAccumulation （（蓄积蓄积）） Dosing rate > elimination rate Dosing rate > elimination rate

1.1. Drug concentration-time curve Drug concentration-time curve (C-T curve)(C-T curve)

2. 2. Kinetic rate processesKinetic rate processes 3. Pharmacokinetic models3. Pharmacokinetic models 4. 4. Pharmacokinetic parameters and their implicationsPharmacokinetic parameters and their implications

Kinetic ProcessesKinetic Processes

KineticsKinetics

ModelsModels

ParametersParameters

1.1. Drug concentration-time curve Drug concentration-time curve (C-T curve)(C-T curve)

Maximal (peak) concentration:Maximal (peak) concentration: CmaxCmax oror CpCp

Time to maximal concentration (Peak time ) :Time to maximal concentration (Peak time ) : TmaxTmax or or TpTp

Area under the curve:Area under the curve: AUCAUC

Multiple dosing (steady state): Multiple dosing (steady state): Css max, Css min, CssCss max, Css min, Css

Kinetic ProcessesKinetic Processes

t

C

i.m.i.m.

s.c.s.c.

OralOral

i.v.i.v.←

←

←

←

CmaxCmax

CpCp

↑ ↑ ↑Tmax, TpTmax, Tp

Tmax, Cmax and AUCTmax, Cmax and AUC

↑Tmax

←Cmax

AUC

C

t

C-T curve after multiple dosingC-T curve after multiple dosing (same dose and interval)(same dose and interval)

在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持在临床治疗中多数药物通过重复给药以期达到有效治疗血药浓度，并维持在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓在一定水平，此时给药速率与消除速率达到平衡，其血药浓度称为稳态浓度，用度，用 CssCss 表示 表示

2. 2. Kinetic rate processesKinetic rate processes

dC / dt dC / dt ＝ －＝ － KCKCnn

2.1 Zero order kinetics2.1 Zero order kinetics

n n ＝ ＝ 00 dC / dt dC / dt ＝ －＝ － KK CCtt ＝ ＝ CC00 －－ K tK t

CC00 －－ CCtt ＝ ＝ K tK t

when Cwhen Ctt ＝＝ 1/2 C1/2 C00,, t = t = tt1/21/2

thenthen, 0.5 C, 0.5 C00 ＝＝ K K tt1/21/2

tt1/21/2 ＝＝ 0.5 C0.5 C00 / K / K

Zero order kineticsZero order kinetics

A.A. same amounts of drug are same amounts of drug are eliminated per unit timeeliminated per unit time

B. B. tt1/21/2 is not a constant is not a constant

C. C. C-T curve is linear C-T curve is linear

D. D. no Css theoretically no Css theoretically

Kinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus injection of druginjection of drug

2.2 First order kinetics2.2 First order kinetics n n ＝ ＝ 11 dC / dt dC / dt ＝ －＝ － KCKC CCt t ＝ ＝ CC00ee －－ KtKt lnClnCt t ＝ ＝ lnClnC00 －－ Kt Kt KtKt ＝＝ lnClnC00 －－ lnClnCtt ＝＝ ln(Cln(C00 / C / Ctt)) when Cwhen Ctt ＝＝ 1/2C1/2C00 ，， tt ＝＝ tt1/21/2 ，，

thenthen tt1/21/2 ＝＝ ln2/Kln2/K ＝＝ 0.693/K0.693/K

First order kineticsFirst order kinetics

A.A. eliminated at same rate per unit time eliminated at same rate per unit time

B.B. tt1/21/2 is a constant is a constant

C.C. logC-T curve is linear logC-T curve is linear

D.D. steady state (Css) after 4-5 steady state (Css) after 4-5 tt1/21/2

Kinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus injection of druginjection of drug

2.3 Non-linear kinetics2.3 Non-linear kinetics

Higher concentration (Higher concentration (or larger doseor larger dose):): zero order kineticszero order kinetics Lower concentration (Lower concentration (or smaller doseor smaller dose):): first order kineticsfirst order kinetics

Because of limits in elimination capacity Because of limits in elimination capacity Examples:Examples: aspirin, phenytoin, ethanolaspirin, phenytoin, ethanol Confirmation:Confirmation: different different tt1/21/2 when given different doses when given different doses

Michaelis-Menten kineticsMichaelis-Menten kinetics

dC / dt = Vmax dC / dt = Vmax C / (Km + C) C / (Km + C) if if Km >> CKm >> C dC / dt = Vmax dC / dt = Vmax C / Km C / Km

Vmax / Km = Ke Vmax / Km = Ke － － First orderFirst order

ifif C >> KmC >> Km dC / dt = Vmax dC / dt = Vmax C / C C / C

dC / dt = -VmaxdC / dt = -Vmax － － Zero orderZero order

Kinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus injection of druginjection of drug

Kinetic properties of C-T curves after Kinetic properties of C-T curves after single dose of aspirinsingle dose of aspirin

3. Pharmacokinetic models3. Pharmacokinetic models

One-compartment modelOne-compartment model

logC

t

iv

3.2 Two-compartment model3.2 Two-compartment model

First, enter the central First, enter the central compartmentcompartment

Then, distributed to peripheral Then, distributed to peripheral compartment, and eliminatedcompartment, and eliminated

1122 2, 32, 3

logC

t

iviv

logC-T curvelogC-T curve

DistributionDistribution EliminationElimination

tt1/21/2

tt1/2 1/2

4. 4. Pharmacokinetic parameters and Pharmacokinetic parameters and their implicationstheir implications

4.1 Bioavailability 4.1 Bioavailability ( F )( F )

BioavailabilityBioavailability is the fraction of administered is the fraction of administered drug (oral) that reaches the systemic circulationdrug (oral) that reaches the systemic circulation

Absolute bioavailabilityAbsolute bioavailability （（绝对生物利用度绝对生物利用度））

F = AUCF = AUC(po, (po, sc, imsc, im)) / AUC / AUC (iv)(iv)

Relative bioavailability Relative bioavailability （（相对生物利用度相对生物利用度））

F = AUCF = AUC(tested)(tested) / AUC / AUC(standard)(standard)

Implication:Implication: Evaluation for absorption and drug Evaluation for absorption and drug quality controlquality control

Influence:Influence: Absorption rateAbsorption rate; ; First-pass eliminationFirst-pass elimination

C

t

AUC AUC (po)(po)

AUC AUC (iv)(iv)

Absolute bioavailability: Absolute bioavailability: F = AUC(po) / AUC (iv)F = AUC(po) / AUC (iv)

4.2 Apparent volume of distribution (4.2 Apparent volume of distribution (VVdd))

The The volume of distribution (Vvolume of distribution (Vdd)) relates the amount of relates the amount of drug in the body (D) to the concentration of drug (C) in drug in the body (D) to the concentration of drug (C) in

the blood or plasmathe blood or plasma.. i.v. i.v. V Vdd = D / C = D / C p.o.p.o. V Vdd = FD / C = FD / C

4.3 Half-life (4.3 Half-life (tt1/21/2) /) / elimination constant (elimination constant (KeKe))

The The half-life (half-life (tt1/21/2)) is the time takes for the plasma is the time takes for the plasma concentration or the amount of drug in the body concentration or the amount of drug in the body reduced by 50%.reduced by 50%.

tt1/21/2 = 0.693 / Ke = 0.693 / Ke ＝ ＝ Vd / ClVd / Cl

(First-order kinetics, for most cases)(First-order kinetics, for most cases)

KeKe:: A A constant fractionconstant fraction of drug in the body is eliminated per unit of drug in the body is eliminated per unit of time (of time (first-order kineticsfirst-order kinetics).).

Implications of Implications of tt1/21/2

Elimination rateElimination rate

Estimating the times of fully elimination and Estimating the times of fully elimination and reaching steady statereaching steady state

Classifying short- and long-acting drugsClassifying short- and long-acting drugs

Adjusting dosage regimens for patients with Adjusting dosage regimens for patients with hepatic or renal failureshepatic or renal failures

4.4 Clearance (4.4 Clearance (CLCL))

The drug in a constant volume of body fluid The drug in a constant volume of body fluid [usually plasma] is eliminated per unit of time.[usually plasma] is eliminated per unit of time. (First-order kinetics)(First-order kinetics)

CLCLss = K = Kee V Vdd = FD/AUC= FD/AUC

There are also hepatic [There are also hepatic [CLCLHH] and renal ] and renal clearances [clearances [CLCLRR]. ].

tt (min)(min)

lnClnCtt

lnClnCtt = lnC = lnC00 － － KKe e

tt

slope = - Kslope = - Kee

tt1/21/2 = 0.693 / K= 0.693 / Kee

VVdd = D / C = D / C00

CL = VCL = Vdd × K × Kee

lnClnC00

slope = - Kslope = - Kee

First order kinetics

One compartment model

Intravenous administration

Part 3Part 3

Factors Influencing Drug Factors Influencing Drug EffectsEffects

影响药物作用的因素影响药物作用的因素

DrugDrug PatientPatient

DoctorDoctor

efficacy/adverse effectsefficacy/adverse effects

drug concentrationsdrug concentrationsAdjustmentAdjustment

Dosage regimenDosage regimen

drugs, doses, drugs, doses, intervals, durationintervals, duration

A.A. Drug FactorsDrug Factors

1.1. Physic-chemical properties of drugs Physic-chemical properties of drugs

2.2. Dose forms Dose forms

3.3. Administration Administration

4.4. Multiple-drug therapy Multiple-drug therapy

5.5. Long-term drug therapy Long-term drug therapy

1.1. Physic-chemical properties of drugs Physic-chemical properties of drugs

StabilityStability Molecular sizeMolecular size Lipid- and water-solubleLipid- and water-soluble …… ……

2.2. Dose forms Dose forms

slow release formulationslow release formulation controlled release formulationcontrolled release formulation transdermal patchtransdermal patch inhalationinhalation

3.3. Administration Administration

DosesDoses Routes Routes oraloral intramuscular injectionintramuscular injection subcutaneous injectionsubcutaneous injection intravenous injection or infusionintravenous injection or infusion

Administration timeAdministration time Dosing intervalsDosing intervals Dosing durationDosing duration

4.4. Multiple-drug therapy (drug combination) Multiple-drug therapy (drug combination)

Drug-drug interactionsDrug-drug interactions pharmacypharmacy pharmacokineticspharmacokinetics pharmacodynamicspharmacodynamics

Drug effects in combination Drug effects in combination synergism:synergism: potentiation / additionpotentiation / addition antagonismantagonism

Efficacy: Efficacy: ↓↓,,↑↑

Toxicity: Toxicity: ↓↓,,↑↑

B.B. Patient FactorsPatient Factors

1.1. Physiological FactorsPhysiological Factors

1.1 Age1.1 Age

ChildrenChildren Sensitivity to drugsSensitivity to drugs Pharmacokinetic propertiesPharmacokinetic properties

ElderlyElderly Sensitivity to drugsSensitivity to drugs Pharmacokinetic propertiesPharmacokinetic properties

Age-related factors Age-related factors influencing influencing pharmacokinetic pharmacokinetic processesprocesses

1.2 Sex1.2 Sex

WomenWomen PregnancyPregnancy - malformation and dysfunction of the - malformation and dysfunction of the

fetuses fetuses LactationLactation - milk: effects on infants- milk: effects on infants

2.2. Psychological FactorsPsychological Factors

Placebo effectsPlacebo effects Placebo effects commonly are manifested as Placebo effects commonly are manifested as

alteration of mood, other subjective effects, alteration of mood, other subjective effects, and objective effects that are under autonomic and objective effects that are under autonomic or voluntary control.or voluntary control.

安慰剂（安慰剂（ placeboplacebo ））是指没有药理活性的物质（如是指没有药理活性的物质（如乳糖、淀粉等），被制成与试验药外观、气味相同乳糖、淀粉等），被制成与试验药外观、气味相同的制剂，作为临床对照试验中的阴性对照物。的制剂，作为临床对照试验中的阴性对照物。

Overall Overall responsesresponses

Pharmacological Pharmacological effectseffects

Non-specificNon-specific drug drug effectseffects

Non-specificNon-specific

medication effectsmedication effects

Natural recoveryNatural recovery No treatmentNo treatment

Absolute placebo Absolute placebo effectseffects Placebo Placebo

effectseffects

Components underlying drug effectsComponents underlying drug effects

3.3. Pathological FactorsPathological Factors

Heart diseasesHeart diseases Hepatic diseasesHepatic diseases Renal diseasesRenal diseases Gastrointestinal diseasesGastrointestinal diseases MalnutritionMalnutrition Imbalances of acid-base or electrolytesImbalances of acid-base or electrolytes

4.4. Genetic FactorsGenetic Factors

PharmacogeneticsPharmacogenetics

abnormality of drug responsesabnormality of drug responses example:example: tolerance of warfarintolerance of warfarin

abnormality of pharmacokinetic propertiesabnormality of pharmacokinetic properties example:example: fast or slow acetylationfast or slow acetylation

5.5. Individual variationIndividual variation ( ( 个体差异个体差异 ))

(1) Sensitivity to drugs(1) Sensitivity to drugs HypersensitivityHypersensitivity Hyposensitivity (tolerance)Hyposensitivity (tolerance)

(2) Abnormal responses to drugs(2) Abnormal responses to drugs Idiosyncracy (genetic abnormality)Idiosyncracy (genetic abnormality) Allergy (immunological abnormality)Allergy (immunological abnormality)

One goal in the post-genomic medicine:One goal in the post-genomic medicine:

Individualized MedicineIndividualized Medicine

6.6. ChangedChanged responses after long-term responses after long-term drug usedrug use (( 长期用药后机体对药物反应的变化长期用药后机体对药物反应的变化 ))

(1) Tolerance and tachyphylaxis (1) Tolerance and tachyphylaxis (human body)(human body)

(2) Resistance to chemotherapy (2) Resistance to chemotherapy (pathogens)(pathogens)

(3) Drug dependence (3) Drug dependence - an adaptive state that develops - an adaptive state that develops in response to repeated drug administrationin response to repeated drug administration..

药理学基本概念药理学基本概念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

药学特点；用药程序药学特点；用药程序

跨膜转运；跨膜转运；

ADMEADME 及其影响因素；及其影响因素；

血药浓度及动力学参数血药浓度及动力学参数

基本作用特点；基本作用特点；

治疗作用与不良反应；治疗作用与不良反应；

量效关系；量效关系；

与靶分子相互作用：如受体与靶分子相互作用：如受体

影响因素影响因素药物：药物：理化特点，理化特点，剂型，给药方式，剂型，给药方式，联合应用联合应用

机体：机体：生理、精生理、精神、病理、遗传神、病理、遗传因素，长期用药因素，长期用药后的改变后的改变

药理学基本概念药理学基本概念药动学过程药动学过程

跨膜转运：跨膜转运：主动转运；被动转运（含简单扩散）主动转运；被动转运（含简单扩散）

ADMEADME 及其影响因素：及其影响因素：AA ：： GIGI 吸收吸收 // 首过消除； 首过消除； DD ：：血浆蛋白结合，药物理化特血浆蛋白结合，药物理化特点，点， BBBBBB

MM ：：肝药酶；肝药酶； EE ：：肾排泄；胆汁排泄肾排泄；胆汁排泄 // 肝肠循环肝肠循环

血药浓度及动力学参数血药浓度及动力学参数：：C-TC-T 曲线：曲线： CmaxCmax ，， TmaxTmax ，， AUCAUC ，， CssCss ； ； 房室模型：房室模型：一室，二一室，二室； 室；

速率过程：速率过程：一级，零级一级，零级 // 非线性非线性 ; ; 药动学参数：药动学参数：生物利用度生物利用度 FF ，，表观分布容积表观分布容积 VdVd ，半衰期，半衰期 tt1/21/2 ，消除速率常数，消除速率常数 KKee ，清除率，清除率 ClCl

药理学基本概念药理学基本概念药效学过程药效学过程

基本作用特点：基本作用特点：作用与效应；选择性作用与效应；选择性

治疗作用与不良反应： 治疗作用与不良反应： 治疗作用：治疗作用：对因，对症，补充对因，对症，补充

不良反应：不良反应：副反应，毒性反应，变态反应，后遗效应，特异质反应等副反应，毒性反应，变态反应，后遗效应，特异质反应等

量效关系：量效关系：效能，效价强度，治疗指数 效能，效价强度，治疗指数 ( ( TI = LDTI = LD50 50 / ED/ ED50 50 ))

与靶分子相互作用与靶分子相互作用（（特异性作用机制特异性作用机制）：）：受体：受体：亲和力，内在活性，激动药，拮抗药，部分激动药亲和力，内在活性，激动药，拮抗药，部分激动药

影响因素影响因素

药理学基本概念药理学基本概念

药物因素：药物因素：理化特点，剂型，给药方式；理化特点，剂型，给药方式；

联合应用：联合应用：协同、拮抗，有利、有害协同、拮抗，有利、有害

机体因素：机体因素： 生理：生理：年龄、性别等年龄、性别等

精神：精神：安慰剂效应等安慰剂效应等

病理：病理：肝、肾、胃肠道功能，疾病状态等肝、肾、胃肠道功能，疾病状态等

遗传：遗传：药物代谢、效应的个体差异药物代谢、效应的个体差异

长期用药后的改变：长期用药后的改变：耐受耐受 // 快速耐受，耐药，依赖性快速耐受，耐药，依赖性 // 成成瘾瘾

思考题思考题一个催眠药口服后，从给药后到作用发挥和作用消除，一个催眠药口服后，从给药后到作用发挥和作用消除，在体内经历哪些过程？在体内经历哪些过程？

你认为药物作用基本规律主要有哪些方面？你认为药物作用基本规律主要有哪些方面？

为什么血浆白蛋白及体内各种酶不能称为药物受体？为什么血浆白蛋白及体内各种酶不能称为药物受体？

怎么理解药动学基本过程（怎么理解药动学基本过程（ ADMEADME ）和药动学参数的）和药动学参数的关系？关系？

药物血浆消除半衰期（药物血浆消除半衰期（ tt1/21/2 ）在临床应用中有何意义？）在临床应用中有何意义？