藥理學 Chapter 1 總論(英文)

1DepartmentofPharmacologySchoolofPharmacyPharmacology

WhatisPharmacology?

Chapter1

Introductionbasicmedicine

Pharmacologypharmacymedicine

clinicmedicine2--drugbroadlydefinedasanychemicalthataffectlivingprocesses

--usefulinprevention,diagnosis,

treatmentofdiseases

Chapter1

IntroductionWhatisadrug?3SourcesofDrugsAnimalsPlants

MineralsSyntheticsMicrobesGeneticengineeringdrugs4基因工程藥物過程示意圖①從細胞中分離出DNA①②③④⑤⑥②限制酶截取DNA片斷③分離大腸桿菌中的質粒④DNA重組⑤用重組質粒轉化大腸桿菌⑥培養(yǎng)大腸桿菌克隆大量基因

drugTaskofPharmacologymedicinepharamacodynamicspharmacokineticsbody6DevelopmentofPharmacology上古時代公元前1世紀明代（公元1596年）近代藥理學的發(fā)展迄今7Pharmacological

researchofnewdrugs

pharmacodynamics

generalpharmacology

pharmacokinetics

toxicitology1、preclinicaltestsafetypharmacology8Pharmacological

researchofnewdrugs

Ⅰperiod:20～30caseⅡperiod:200～300case

Ⅲperiod:>400case

Ⅳperiod:clinicaltrial→2000case2、

clinicalpharmacologicaltrial9

Section1

BasicactionofdrugsChapter2

Pharmacodynamicsstimulatorsorexcitantsinhibitorsordepressantsstimulationorexcitation

depressionorinhibitiondrugaction

drugeffect

10

localaction

generalaction

Chapter2

Pharmacodynamicstherapeuticeffectadversdrugreactionselectivity

dualism11Chapter2

Pharmacodynamics

Therapeuticeffect

etiologicaltreatment

symptomatictreatment

12Chapter2

PharmacodynamicsAdversdrugreactionsideaction

econdaryreactiontoxicreactionacutetoxcitychronictoxcitycarcinogenesisteratogenesismutagenesisallergicreactionresidualeffect

withdrawalreaction13

Section2

ReceptivetheoryChapter2

PharmacodynamicsLigand(L)Effect(E)Receptor(R)14Chapter2

Pharmacodynamicsreceptortypechannel-linkdreceptorsG-proteincoupledreceptorstyrosinekinase-linkedreceptorsregulategenetranscriptionreceptors15激動藥結合區(qū)域膜外膜內激動藥結合區(qū)域

Ligand-gatedionchannelreceptors16G蛋白偶聯(lián)CN激動藥結合區(qū)域膜外膜內

G-proteincoupledrecptors17激動藥結合區(qū)域膜外膜內催化結構區(qū)域

Tyrosine-proteinkinasereceptor18激動藥結合區(qū)域膜外膜內DNA結合區(qū)域轉錄激活區(qū)域載體+藥物載體-藥物復合物載體

+藥物載體

Intracellularreceptors19Chapter2

Pharmacodynamicsreceptorregulationdownregulationupregulationhomospecificregulationheterospecificregulation20Chapter2

PharmacodynamicsLRintrinsicactivityaffinityE21Chapter2

Pharmacodynamicsreceptoragonistfullagonistpartialagonistreceptorantagonist

fullantagonistpartialantagonist2223competitiveantagonist24non-competitiveantagonist25non-competitiveantagonist26drugactionandsignaitransduction27Chapter2

PharmacodynamicsgradedresponsequantalresponseDose-responserelationship28Chapter2

Pharmacodynamicsminimumeffectivedose(thresholddose)maximumeffect(Emax)maximaldose(Max-D)medianeffectivedose(ED50)minimumtoxicdose(Tmin)medianlethaldose(LD50)Dose-responserelationshipefficacypotency29Dose-responserelationshipEmaxED50efficacypotency100%50%thresholddoseMax-DTmin30DoseResponseCurveEmaxEmax31Chapter2

PharmacodynamicsLD50therapeuticindex(TI)

=─────ED50LD5safetyindex(SI)=─────ED95(LD1-ED99)safetymargin(SM)=──────×100%ED99safetyevaluationofdrugs3233Chapter3

Pharmacokinetics

absorptiondistributionmetabolism(biotransformation)excretionSection1

physiologicaldispositionofdrugs34PharmacokineticPhaseelimination35Absorptiondistributionexcretiondrugtransportthroughmembranesmetabolismbiotransformation36

Cellmembrane

1)GIepithelialcells2)vascularendothelium3)bloodbrainbarrier(BBB)

4)subcellularmembranes一、Drugtransportacrossmembranes371234GIepithelialcellsVascularendotheliumBloodbrainbarrier(BBB)Subcellularmembranes38A.

simplediffusion1.

PassivetransportB.

facilitated

diffusionC.

aqueousdiffusion39acrossmembraneoflipidacrossaqueouschannelcarriertransportoutsideinside1.

Passivetransport40

simplediffusion

R=D’A(C1-C2)/XR:

diffusionrate

D’:

diffusion

constantA:

areaofmembrane(C1-C2):

concentrationgradientofdrugsX:

thicknessofmembrane41

Foraweakacid

kaHAH++A-[H+][A-]ka=─────[HA]

ka:dissociationconstantpH=-logconcentration[H+]

-logKaispKa42

Foraweakacid

[A-]pKa=pH-log────

[HA]

[A-]pH-pKa

=

log────

[HA]10pH-pKa=

[A-]/[HA]43Foraweakbase

ka[H+][B]BH+H++BKa=─────

[BH+]

[BH+]pKa–pH=log────[B]10pka–pH=

[BH+]

/

[B]44

Foraweakacid

[unionized]pKa=pH+log───────[ionized]

10PH-pka=[ionized]/[unionized]Foraweakbase

[ionized]pKa=pH+log───────[unionized]

10pka-pH=[ionized]/[unionized]45

If[A-]=[HA]or[B]=[BH+]---pKa=pH

---asubstanceishalfionizedandhalfnonionized

MustbecarefulyoumustknowpKa

[A-]pH-pKa=log───[HA]

[BH+]orpKa–pH=log────[B]46

2.activetransportExamle:Na+-K+ATPase47

3.cytosispinocytosisexocytosis4849

1.Absorption

themovementofadrugfromitssiteofadministrationintothebloodstream二、drugprocessinbodyBloodstreamdrugdrug501)

First-passeffectinfluencingfactorthefirstpasseffectcanbeavoidedby…

sublingualrectuminhalationimsc51GIhepaticportalvein

livervenacava

52

2)Bioavailability

fractionofanadministereddrugthatreachesthesystemiccirculationforIV,Bioavailability=1.0

5354Minimumeffectiveconcentration55

2.DistributionBloodstreamdrugdrugenterstheextracellularfluidsandtissuesofthebodydrugcell56

1)

bindingofdrugbyplasmaproteinsinfluencingfactor2)

bloodstreamoforgan3)

affinityoftissue4)

bloodbrainbarrier5)

placentalbarrier5758ApparentVolumeofDistribution(Vd)Vdishypotheticalvolume

Vd=A/C59

3.Metabolism

twophasesoxidationsreductionshydrolyses

thefirstphase

conjugationsthesecondphase60Hepaticmicrosomalenzymesenzymeinhibitorenzymeinducermixedfunctionoxidases61624.Excretion

excretionofkidneysexcretionofbileexcretionofmammarygland63

Hepatoenteralcirculationliver--bilegallbladder

duodenumexcrete4.Excretion

64消除transportandtransformationofdrugs65

Section2

Basicconcept

ofpharmacokineticsA.

Time-concentrationcurvethresholddoseCmaxTpeakTCmin66

B.HalfLife(t1/2)

firstorderkinetics

t1/2=0.693/Kzeroorderkinetics

t1/2=0.5C/K67C.Drugeliminationrate

dc/dt=-KCn

C:concentrationofthedrugK:eliminationrateconstantn=1firstorderkinetics

-dc/dt=KC1n=0zeroorderkinetics

-dc/dt=KC0=Vmax68

D.

Clearance(CL)CL=Vd.Kor0.693.Vd/t1/2690210123456SteadystateconCss.maxCss.min7

E.Steadystateconcentration(Css)

70血藥濃度100200300802460002468100200300時間（半衰期）10020030002460ABC8MTCMEC三種不同給藥方案對穩(wěn)態(tài)濃度的影響A.縮短給藥時間B.增加給藥劑量C.負荷量給藥71RoutesofDrugAdministrationcommonabbreviations…po

=peros=oraliv

=intravenous=intotheveinim

=intramuscular=intothemusclesc

=subcutaneous=betweentheskinandmuscleip

=intraperitoneal=withintheperitonealcavityicv

=intracerebroventricular= directlyintotheventricleofthebrain72Chapter4

Factorsaffectingeffectofdrugs

ageandsexmentalandpathologicfactorsindividualvariationandgeneticsspeciesvariationSection1

Factorsaboutorganismaspect73ageandsexage

infants

agedpeople74ageandsexsexmalefemale75mentalfactor

spiritandbodydiseasebodyandspiritdiseaseplaceboactions

mentalandpathologicfactors76

mentalandpathologicfactorspathologicfactordystrophyrenalinadequacyhepaticinadequacy77individualvariationandgeneticfactorsindividualvariationhypersensitivereactiont