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1、Part 2Pharmacokinetics药物代谢动力学药物代谢动力学药物代谢动力学药物代谢动力学KineticsKineticsModelsModelsParametersParameters2. Transport of Drug in the BodyMechanisms of drug permeation across cell membraneMechanisms of drug permeation across cell membraneA. aqueous channels in the intercellular junctionsB.B. lipid cell lipi
2、d cell membranesmembranes C.C. carriers carriers (transporters) (transporters) (into or out of (into or out of cells)cells)D.D. endocytosisendocytosis exocytosis exocytosis 2.1 Transmembrane Transport of Drugs(1) Non-carrier Transport(1) Non-carrier Transport Simple diffusionSimple diffusion（简单扩散简单扩
3、散简单扩散简单扩散/ / / /单纯扩散单纯扩散单纯扩散单纯扩散） FiltrationFiltration（滤过滤过滤过滤过）(2) Carrier-mediated Transport (2) Carrier-mediated Transport a. Active transport Characteristics of active transportCharacteristics of active transport Involving specific carrier ( Involving specific carrier (transportertransporter) )
4、Energy-dependent Energy-dependent Saturability Saturability Competition at same carrier Competition at same carrier Moving against concentration gradient (up-hill) Moving against concentration gradient (up-hill)b. Facilitated diffusion（易化扩散易化扩散易化扩散易化扩散） ( (transporter-mediated diffusiontransporter-m
5、ediated diffusion) ) Involving specific carriers ( Involving specific carriers (transportertransporter) ) Energy-independent Energy-independent Saturability Saturability Competition with other drugs Competition with other drugs Concentration gradient (down-hill) Concentration gradient (down-hill)(3)
6、 Endocytosis/exocytosis（入胞入胞入胞入胞/ / / /出胞出胞出胞出胞）Another classificationPassive transportSimple diffusionSimple diffusion（简单扩散简单扩散简单扩散简单扩散/ / / /单纯扩散单纯扩散单纯扩散单纯扩散）FiltrationFiltration（滤过滤过滤过滤过） Facilitated diffusionFacilitated diffusion（易化扩散易化扩散易化扩散易化扩散）Active transportActive transport (Active transpor
7、t (主动转运主动转运主动转运主动转运) ) Pinocytosis/exocytosisPinocytosis/exocytosis（入胞入胞入胞入胞/ / / /出胞出胞出胞出胞）A. Simple diffusionMost drugs are weak acids or bases. Their diffusion passing through cell membrane depends the lipid-soluble state (un-ionized form)Determinants of simple diffusion For most drugs of small m
8、olecules (usually are weak acids or weak bases): Lipid-soluble or un-ionized forms pKa of the drug and pH of 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
9、equal.Henderson-Hasselbalch equationWeak acid drugs: pH - pKa = log ( A- / HA ) pKa - pH = log ( HA / A- )Weak base drugs: pKa - pH = log ( BH+ / B ) pH - pKa = log ( B / BH+ ) pHpKaun-ionized un-ionized formformlipid-lipid-solublesolubleSimple Simple diffusiondiffusionWeak acidsWeak basesAnd / orAn
10、d / orAnd / orAnd / orAnd / orAnd / orAnd / orAnd / orThree types of functional membrane proteins. B. Carrier (transporter)-mediated transportModels of transmembrane transport across the lipid bilayerModels of transmembrane transport across the lipid bilayer2.2 Free and Bound Forms Plasma protein bi
11、nding Tissue / organ affinity3. Fate of the drug in the body Absorption Distribution Metabolism (Biotransformation)(Biotransformation) Excretion ADMEADME3.1 AbsorptionAbsorption Absorption is is the the transfer transfer of of a a drug drug from from its its site site of of administration to the blo
12、od stream.administration to the blood stream. Gastrointestinal tract Parenteral injection - i.m., s.c. Inhalation Transdermal (1) Gastrointestinal tractRoute: OralOral Sublingual Sublingual Rectal RectalAbsorption sites: Oral Oral GastricGastric Intestinal Intestinal Rectal RectalFactors influencing
13、 absorption: blood flow to the absorption siteblood flow to the absorption site total surface area available for absorption total surface area available for absorption contact time at the absorption surface contact time at the absorption surface physic-chemical properties of the drug physic-chemical
14、 properties of the drug first-pass eliminationfirst-pass elimination(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 drug Local blood
15、 flow; Solubility of the drug (3) Others Inhalation; Intranasal; Inhalation; Intranasal; Transdermal; Topical Transdermal; Topical3.2 DistributionDrug Drug distribution distribution is is the the process process by by which which a a drug drug reversibly reversibly leaves leaves the the blood blood
16、stream stream and and enters enters the the interstitium interstitium (extracellular (extracellular fluid) fluid) and and / / or or the the cells of the tissues.cells of the tissues. Blood flow-dependent phase of distribution Blood flow-dependent phase of distribution Selective distribution Selectiv
17、e distribution Tissue-plasma Tissue-plasma balance:balance: importance importance of of measuring measuring plasma concentrationplasma concentration(1) Binding of drug to plasma proteins Bound drug: can not distribute / inactive temporallycan not distribute / inactive temporallyreversible (storage f
18、orm) / percentage of bindingreversible (storage form) / percentage of bindingplasma protein capacityplasma protein capacitycompetitive displacementcompetitive displacement (2) Physic-chemical properties of the drug (2) Physic-chemical properties of the drug (3) Blood flow and re-distribution (3) Blo
19、od 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 barrier Placental barrier Blood-eye barrier Blood-eye barrier Blood-brain barrier (BBB)Blood-brain barrier (BBB) Able
20、 to pass throughAble to pass through Unable to pass throughUnable to pass through Small molecules Small molecules Large moleculesLarge molecules Lipid-solubleLipid-soluble Water-solubleWater-soluble Transporter-mediation Transporter-mediation Amount of drug passing through BBBAmount of drug passing
21、through BBB Increases when Increases when inflammation inflammation oror larger doses used larger doses usedPlacental barrier:More permeable Drugs for pregnant Drugs for pregnant women:women:A, BA, B relatively safe relatively safeC C - caution - cautionD,D, X X - toxic - toxic3.3 Metabolism (biotra
22、nsformation) Drug Drug metabolism metabolism is is the the process process transforming transforming lipophilic lipophilic drug drug into into more more hydrophilic hydrophilic metabolites, metabolites, which which is is essential essential for for the the elimination elimination of of these these c
23、ompounds compounds from from the the body body and and termination termination of their biological activityof 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, l
24、ung, 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 Phas
25、e II: Phase II: ConjugationConjugation inactivated inactivated Metabolites: Metabolites: more water-soluble easier to excretemore water-soluble easier to excrete (3) Enzymes in drug metabolism Enzymes in Phase I: cytochrome-P450, 450, such as such as CYP2A6, CYP3A4CYP2A6, CYP3A4 many other enzymes E
26、nzymes in Phase II: acetylase glucuronosyltransferase etc. Induction of hepatic enzymes by drugs example: example: phenytoinphenytoinsteroids, nifedipinesteroids, nifedipineInhibition of hepatic enzymes by drugs example: example: verapamilverapamildiazepamdiazepam3.4 ExcretionRemoval Removal of of a
27、 a drug drug from from the the body body via via a a number of routes.number of routes.Elimination of drugs from the bodyAction on excretory organs3.4 Excretion(1) Excretion routes Kidney -Kidney -renal excretionrenal excretion Bile Bile (hepato-enteral circulation)(hepato-enteral circulation) Lung
28、Lung GI tract GI tract MilkMilk Secretion glands Secretion glands3.5 Elimination and AccumulationEliminationElimination（消除消除消除消除） MetabolismMetabolism Excretion Excretion Distribution (stored in fat, hair, etc) Distribution (stored in fat, hair, etc)AccumulationAccumulation（蓄积蓄积蓄积蓄积） Dosing rate eli
29、mination 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 implicationsPharmacokin
30、etic parameters and their implicationsKinetic ProcessesKineticsKineticsModelsModelsParametersParameters1. 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
31、 (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, CssKinetic ProcessestCi.m.i.m.s.c.s.c.OralOrali.v.i.v.CmaxCmaxCpCp
32、Tmax, TpTmax, TpTmax, Cmax and AUCTmax, Cmax and AUCTmaxCmax AUCCtC-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
33、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，用度，用度，用CssCss表示表示表示表示 2. Kinetic rate processes dC / dt KCn2.1 Zero order kinetics n n 0 0 dC / dt dC / dt KK C Ct t C C0 0K tK t C C0 0C Ct t K tK t when C when
34、Ct t1/2 C1/2 C0 0, , t = t = t t1/21/2 thenthen, 0.5 C, 0.5 C0 0 K K t t1/21/2 t t1/21/20.5 C0.5 C0 0 / K / KZero order kineticsA.A. same amounts of drug are same amounts of drug are eliminated per unit time eliminated per unit timeB. B. t t1/21/2 is not a constant is not a constantC. C. C-T curve i
35、s linear C-T curve is linearD. D. no Css theoretically no Css theoreticallyKinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus injection of druginjection of drug2.2 First order kinetics n 1 dC / dt KC Ct t C0 0eKt lnCt t lnC0 0Kt KtlnC0 0lnCt tln(C
36、0 0 / Ct t) when Ct t1/2C0 0，tt1/21/2， then t1/21/2ln2/K0.693/KFirst order kinetics A.A. eliminated at same rate per unit time eliminated at same rate per unit time B.B. t1/21/2 is a constant is a constantC.C. logC-T curve is linear logC-T curve is linearD.D. steady state (Css) after 4-5 steady stat
37、e (Css) after 4-5 t1/21/2 Kinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus injection of druginjection of drug2.3 Non-linear kineticsHigher concentration (Higher concentration (or larger doseor larger dose): ): zero order kineticszero order kinet
38、icsLower concentration (Lower concentration (or smaller doseor smaller dose): ): first order kineticsfirst order kineticsBecause of limits in elimination capacity Because of limits in elimination capacity Examples:Examples: aspirin, phenytoin, ethanolaspirin, phenytoin, ethanol Confirmation:Confirma
39、tion: different different t t1/21/2 when given different doses when given different dosesMichaelis-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 order if if C KmC Km dC / dt = Vma
40、x dC / dt = Vmax C / C C / C dC / dt = -Vmax dC / dt = -Vmax Zero orderKinetic properties of C-T curves after single bolus Kinetic properties of C-T curves after single bolus injection of druginjection of drugKinetic properties of C-T curves after Kinetic properties of C-T curves after single dose o
41、f aspirinsingle dose of aspirin3. Pharmacokinetic modelsOne-compartment modellogCtiv3.2 Two-compartment modelFirst, enter the central First, enter the central compartmentcompartmentThen, distributed to peripheral Then, distributed to peripheral compartment, and eliminatedcompartment, and eliminated1
42、 12 22, 32, 3logCtiv iv logC-T curvelogC-T curveDistributionDistributionEliminationEliminationt1/21/2 t1/2 1/2 4. Pharmacokinetic parameters and their implications 4.1 Bioavailability ( F ) BioavailabilityBioavailability is the fraction of administered is the fraction of administered drug (oral) tha
43、t reaches the systemic circulationdrug (oral) that reaches the systemic circulationAbsolute bioavailability（绝对生物利用度绝对生物利用度绝对生物利用度绝对生物利用度） F = AUC(po, (po, sc, imsc, im) ) / AUC (iv)(iv)Relative bioavailability （相对生物利用度相对生物利用度相对生物利用度相对生物利用度） F = AUC(tested)(tested) / AUC(standard)(standard)Implicatio
44、n:Implication: Evaluation for absorption and drug Evaluation for absorption and drug quality controlquality controlInfluence:Influence: Absorption rateAbsorption rate; ; First-pass eliminationFirst-pass eliminationCtAUC (po)AUC (iv)Absolute bioavailability: Absolute bioavailability: F = AUC(po) / AU
45、C (iv)F = AUC(po) / AUC (iv)4.2 Apparent volume of distribution (Vd d) The The volume of distribution (Vvolume of distribution (Vd d) ) 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 bl
46、ood or plasmathe blood or plasma. i.v. Vd d = D / C p.o. Vd d = FD / C4.3 Half-life (t1/2) / elimination constant (elimination constant (KeKe) ) The The half-life (half-life (t1/21/2) ) is the time takes for the plasma is the time takes for the plasma concentration or the amount of drug in the body
47、concentration or the amount of drug in the body reduced by 50%.reduced by 50%. t1/2 = 0.693 / Ke Vd / 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 elimi
48、nated per unit of time (of time (first-order kineticsfirst-order kinetics). ).Implications of t1/21/2 Elimination rate Elimination rate Estimating the times of fully elimination and Estimating the times of fully elimination and reaching steady statereaching steady state Classifying short- and long-a
49、cting drugs Classifying short- and long-acting drugs Adjusting dosage regimens for patients with Adjusting dosage regimens for patients with hepatic or renal failureshepatic or renal failures4.4 Clearance (CL)The drug in a constant volume of body fluid The drug in a constant volume of body fluid usu
50、ally plasma is eliminated per unit of time.usually plasma is eliminated per unit of time. (First-order kinetics)(First-order kinetics)CLs s = Ke e Vd d = FD/AUC There are also hepatic There are also hepatic CLCLHH and renal and renal clearances clearances CLCLR R. . t (min)(min)lnCt tlnCt t = lnC0 0
51、 Ke e tslope = - Ke et1/21/2 = 0.693 / Ke eVd d = D / C0 0CL = Vd d Ke elnC0 0slope = - Ke eFirst order kineticsOne compartment modelIntravenous administrationPart 3 Factors Influencing Drug Effects 影响药物作用的因素影响药物作用的因素影响药物作用的因素影响药物作用的因素DrugPatientDoctorefficacy/adverse effectsefficacy/adverse effects
52、drug concentrationsdrug concentrationsAdjustmentAdjustmentDosage regimenDosage regimendrugs, doses, drugs, doses, intervals, durationintervals, durationA. Drug Factors1. 1. Physic-chemical properties of drugs Physic-chemical properties of drugs2. 2. Dose forms Dose forms3. 3. Administration Administ
53、ration4. 4. Multiple-drug therapy Multiple-drug therapy5. 5. Long-term drug therapy Long-term drug therapy 1. Physic-chemical properties of drugs Stability Stability Molecular size Molecular size Lipid- and water-soluble Lipid- and water-soluble 2. Dose forms slow release formulationslow release for
54、mulation controlled release formulation controlled release formulation transdermal patch transdermal patch inhalation inhalation3. Administration Doses Routes oraloral intramuscular injection intramuscular injection subcutaneous injection subcutaneous injection intravenous injection or infusion intr
55、avenous injection or infusion Administration time Dosing intervals Dosing duration4. Multiple-drug therapy (drug combination) Drug-drug interactions pharmacy pharmacy pharmacokinetics pharmacokinetics pharmacodynamics pharmacodynamics Drug effects in combination synergism:synergism: potentiation / a
56、dditionpotentiation / addition antagonism antagonismEfficacy: , ,Toxicity: ,B. Patient Factors1. Physiological Factors1.1 AgeChildren Sensitivity to drugsSensitivity to drugs Pharmacokinetic properties Pharmacokinetic propertiesElderly Sensitivity to drugs Sensitivity to drugs Pharmacokinetic proper
57、ties Pharmacokinetic propertiesAge-related factors Age-related factors influencing influencing pharmacokinetic pharmacokinetic processesprocesses1.2 SexWomen Pregnancy - malformation and dysfunction of the fetuses Lactation - milk: effects on infants2. Psychological Factors Placebo effects Placebo e
58、ffects 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 con
59、trol.安慰剂（安慰剂（安慰剂（安慰剂（placeboplacebo）是指没有药理活性的物质（如乳是指没有药理活性的物质（如乳是指没有药理活性的物质（如乳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、气味相同的糖、淀粉等），被制成与试验药外观、气味相同的糖、淀粉等），被制成与试验药外观、气味相同的糖、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。制剂，作为临床对照试验中的阴性对照物。制剂，作为临床对照试验中的阴性对照物。制剂，作为临床对照试验中的阴性对照物。 Overall Overall responsesresponsesPharmacol
60、ogical Pharmacological effectseffectsNon-specificNon-specific drug drug effectseffectsNon-specificNon-specific medication effectsmedication effectsNatural recoveryNatural recoveryNo treatmentNo treatmentAbsolute placebo Absolute placebo effectseffectsPlacebo Placebo effectseffectsComponents underlyi
61、ng drug effectsComponents underlying drug effects3. Pathological Factors Heart diseases Heart diseases Hepatic diseases Hepatic diseases Renal diseases Renal diseases Gastrointestinal diseasesGastrointestinal diseases Malnutrition Malnutrition Imbalances of acid-base or electrolytes Imbalances of ac
62、id-base or electrolytes4. Genetic Factors Pharmacogenetics 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 acetylat
63、ionfast or slow acetylation5. Individual variation (个体差异个体差异个体差异个体差异)(1) Sensitivity to drugs(1) Sensitivity to drugs Hypersensitivity Hypersensitivity Hyposensitivity (tolerance) Hyposensitivity (tolerance)(2) Abnormal responses to drugs(2) Abnormal responses to drugs Idiosyncracy (genetic abnormal
64、ity)Idiosyncracy (genetic abnormality) Allergy (immunological abnormality) Allergy (immunological abnormality)One goal in the post-genomic medicine:One goal in the post-genomic medicine: Individualized Medicine6. Changed responses after long-term drug 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长期用药后机体对药物反
65、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) (3) Drug Drug dependence dependence - - an an adaptive adaptive state state that that develops deve
66、lops 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剂学过程药剂学过程药动学过程药动学过程药动学过程药动学过程药效学过程药效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；用药程序药学特点；用药程序药学特点；用药程序跨膜转运；跨膜转运；跨膜转运；跨膜转运；ADMEADME及其影响因素；及其影响因素；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血药浓度及动力学参数血药浓度及动力学参数
67、基本作用特点；基本作用特点；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；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；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影响因素影响因素药物：药物：药物：药物：理化特点，理化特点，理化特点，理化特点，剂型，给药方式，剂型，给药方式，剂型，给药方式，剂型，给药方式，联合应用联合应用联合应用联合应用机体：机体：机体：机体：生理、精生理、精生理、精生理、精神、病理、遗传神、病理、遗传神、病理、遗传神、病理、遗传因素，长期用药因素，长期
68、用药因素，长期用药因素，长期用药后的改变后的改变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药动学过程药动学过程跨膜转运：跨膜转运：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）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：及其影响因素：及其影响因素：A A：GIGI吸收吸收吸收吸收/ /首过消除；首过消除；首过消除；首过消除； D D：血浆蛋白结合，药物理化特点，血浆蛋白结合，药物理化特点，血浆蛋白结合，药物理化特点，血浆蛋白结合，药物理化特点，BBBBBBMM：肝药酶；肝
69、药酶；肝药酶；肝药酶； E E：肾排泄；胆汁排泄肾排泄；胆汁排泄肾排泄；胆汁排泄肾排泄；胆汁排泄/ /肝肠循环肝肠循环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：曲线：曲线：CmaxCmax，TmaxTmax，AUCAUC，CssCss； 房室模型：房室模型：房室模型：房室模型：一室，二室；一室，二室；一室，二室；一室，二室； 速率过程：速率过程：速率过程：速率过程：一级，零级一级，零级一级，零级一级，零级/ /非线性非线性非线性非线性; ; 药动学参数：药动学参数：药动学参数：药动学参数：生物利用度生物利用度生物利
70、用度生物利用度F F，表观分布容积表观分布容积表观分布容积表观分布容积VdVd，半衰期，半衰期，半衰期，半衰期t t1/21/2，消除速率常数，消除速率常数，消除速率常数，消除速率常数KKe e，清除率，清除率，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药效学过程药效学过程基本作用特点：基本作用特点：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：治疗作用与不良反应：治疗作用与不良反应： 治疗作用：治疗作用：治疗作用：治疗作用：对因，对症，补充对因，对症，补充对因，对症，补充
71、对因，对症，补充不良反应：不良反应：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：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特异性作用机制特异性作用机制）
72、：）：）：）：受体：受体：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：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；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：联合应用：联合应用：协同、拮抗，有利、有害协同、拮抗，有利、有害协同、拮抗，有利、有害协同、拮抗，有利、有害机体因素：机体因素：机体因素：机体因素： 生理：生理
73、：生理：生理：年龄、性别等年龄、性别等年龄、性别等年龄、性别等 精神：精神：精神：精神：安慰剂效应等安慰剂效应等安慰剂效应等安慰剂效应等 病理：病理：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：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：长期用药后的改变：长期用药后的改变：耐受耐受耐受耐受/ / / /快速耐受，耐药，依赖性快速耐受，耐药，依赖性快速耐受，耐药，依赖性快速耐受，耐药，依赖性/
74、/ / /成瘾成瘾成瘾成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，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？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？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？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（怎么理解药动学基本过程（怎么理解药动学基本过程（ADMEADME）和药动学参数的关）和药动学参数的关）和药动学参数的关）和药动学参数的关系？系？系？系？药物血浆消除半衰期（药物血浆消除半衰期（药物血浆消除半衰期（药物血浆消除半衰期（t t1/21/2）在临床应用中有何意义？）在临床应用中有何意义？）在临床应用中有何意义？）在临床应用中有何意义？
