臨床藥理學(xué) 緒論(英文)

ClinicalPharmacologyIntroduction12Whatisclinicalpharmacology?Whydoweneedtostudyclinicalpharmacology?ContentsofclinicalpharmacologyPharmacogenomics

PrinciplesofrationaldruguseToday’stopics1930’s，theconcept

ofClinicalPharmacologywasfirstproposed1954,

thefirstdivision

ofClinicalPharmacology

wasestablishedatJohnHopkinsUniversity,USA1960s,thalidomidedisastershockedtheworld;inducedmuchattentiontoClinicalPharmacology1980,thefirstinternationalcongressofClinicalPharmacologywasheldinLondonevery4years,

IUPHARhostsWorldCongressofBasicandClinicalPharmacologyHistoryofClinicalPharmacology31980,

thefirstInstituteofClinicalPharmacologyinChinawasestablishedinBeijingMedicalCollege1982,ClinicalPharmacologyBranchofChinesePharmacologySocietywasfounded1983,ClinicalPharmacologyBases

wereapprovedbyMinistryofHealthofChina,fornewdrugevaluation

InChina4

I.Whatisclinicalpharmacology?Pharmacology:

Thestudyofthe

interactionofchemicalswithlivingsystems

ClinicalPharmacology:

Thestudyofthe

interactionofdrugswithhumanbody.Object:humanbodyBasis:

pharmacology,clinicalmedicine5Whatisclinicalpharmacokinetics?Pharmacokinetics(PK,藥物代謝動力學(xué)):

theactionsof

thebodyonthedrug

Clinicalpharmacokinetics

(臨床藥代學(xué)）:theactionsof

humanbody

onthedrug

Including:absorptiondistribution

metabolismexcretion6Whatisclinicalpharmacodynamics?

Pharmacodynamics（PD,藥物效應(yīng)動力學(xué)）:

theactionsofadrug

onthebody.Clinicalpharmacodynamics

(臨床藥效學(xué)):theactionsofadrug

onhumanbody.

Including:receptorinteractions,dose-responsephenomena,mechanismsoftherapeuticandtoxicaction78DrugHumanBody?absorption,distributionmetabolism,excretion?DrugeffectsanditsmechanismIncludingreceptorinteractionsdose-responsephenomenamechanismsoftherapeuticandtoxicactionII.Whydoweneedtostudyclinicalpharmacology?

91.GuaranteethesafeuseofclinicaldrugsDrug-inducedsevereharmevent:

1960s,Germany:Thalidomide:(沙立度胺,“反應(yīng)?！?stoppregnancysick

but………

1011

Thalidomidedisaster12,000seal(海豹)children,

>6000died11Now:thalidomide

(沙立度胺)Indication:(適應(yīng)證)

erythemanodosumleprosy

(麻風(fēng)結(jié)節(jié)性紅斑）1998,FDAofUSA

multiplemyeloma

(多發(fā)性骨髓瘤)

2006,FDAofUSACaution:

（警告）1.GuaranteethesafeuseofclinicaldrugsThisdrughasstrongteratogenic

(致畸)

action,

andisabsolutelyforbiddeninpregnantwomen.12Thekeyistounderstandthecharacteristicsofdrugs

inhumanbodyespeciallywhentreat

complicatedpatients

critical(危重)patients,inICUmultipleorganfailure(多臟器衰竭)patientsII.Whydoweneedclinicalpharmacology?2.Elevatetheleveloftherapy13Manydiseaseslackeffectivetreatment(cancer,Alzheimer’sdisease,……)Newdrugresearchanddevelopment(R&D)Clinicalevaluationofnewdrugsismostimportant

II.Whydoweneedclinicalpharmacology?3.Developnewdrugs14III.Maincontentsofclinical

Pharmacology15Fourbasicprocessesofdrugtherapy1.Selectionofdosageform:

drugentershumanbodydosageform(劑型)oral

injectgastro-intestinallivermetabolismextracellularwater

proteinbinding

non-binding

actionsite2.Pharmacokineticprocess:

drugarrivesactionsiteelimination(kidney,liver)

first-passeffect16pharmacologicalactiontherapeuticeffect(治療作用)3.Paharmacodynamicprocess:

drugproducespharmacologicalactiononhumanbody4.Therapeuticprocess:

pharmacologicalactionturnsintotherapeuticeffect

actionsitedesiredundesiredadversedrugreaction(ADR)（藥物不良反應(yīng)）（Aspirininhibitsplateletaggregation)

阿司匹林抑制血小板聚集(preventsthrombosis)

防止血栓形成(inducescerebralhemorrhage)

引起腦出血(Aspirintreatsischemiccerebrovasculardisease)治療缺血性腦血管病171.Clinicalpharmacokinetics

（臨床藥代學(xué)）(1)Contentofstudy:

Thetransport(轉(zhuǎn)運)

andtransform(轉(zhuǎn)化)

processesofdrugsinhumanbody,

including:

absorption,distribution,metabolism,excretion

(2)MainmethodMonitorthebloodconcentration

ofdrug

（血藥濃度監(jiān)測）

III.Maincontentsofclinicalpharmacology18Bloodconcentration--timecurveaftersingledrugdoseHalf-life(T1/2)半衰期(MEC:minimumeffectiveconcentration)峰濃度達峰時間最低有效濃度20(3)Themostimportantparametersbioavailability（生物利用度）:

thefractionofdrugabsorbedintothesystemiccirculation.volumeofdistribution（分布容積）:

theapparentspace（表觀空間）inthebodyavailabletocontainthedrugeliminationhalf-life（消除半衰期）:therateofremovalofdrugfromthebodyclearance（清除率）:

thebody’sefficiencyineliminatingdrug2021(4)SignificanceofstudyProvideevidenceformakingtheplan

ofdrugadministration

(制定給藥方案)(dose,interval)Dosingrate=CL?Css（清除率?穩(wěn)態(tài)血濃度）

(CL:clearancefromthesystemiccirculation,Css:

thesteady-stateconcentrationofdruginblood）

CL=Vm/(Km+C)

(C:

concentrationofdruginblood)

1.Clinicalpharmacokinetics2.Clinicalpharmacodynamics

（臨床藥效學(xué)）(1)ContentsofstudyFunctionchanges

ofhumanbodyinducedbydrugactionActionandmechanismofdrug

(receptorinteractions,etc.)RelationshipbetweendoseandeffectofdrugIII.Maincontentofclinicalpharmacology22(MEC:minimumeffectiveconcentration)最低有效濃度23Therapeuticgoal:

obtainandmaintainconcentrationswithinthetherapeuticwindowforthedesiredresponsewithaminimumoftoxicity.

Drugresponse

belowMECforthedesiredeffect:

subtherapeutic（未達治療劑量的）,

aboveMECforanadverseeffect:toxicity

Therapeuticwindow(治療窗）243.Adversedrugreaction(ADR)藥物不良反應(yīng)(1)Contentsofstudysideeffect 副作用toxiceffect 毒性反應(yīng)anaphylacticreaction 過敏反應(yīng)dependence 依賴性withdrawsyndrome撤藥綜合征carcinogeniceffect致癌作用teratogeniceffect致畸形作用

III.Maincontentofclinicalpharmacology25Forexample:

Antibioticsabuse（抗生素濫用）

floraimbalance菌群失調(diào)

secondaryinfection繼發(fā)性感染

drugresistance耐藥性(2)Physician-induceddiseasesHormoneabuse(steroid類固醇)hepatonecrosis肝壞死

osteonecrosis骨壞死26

liver

(drugsthat

maydamageliver,patientswithliverdisease)

kidney（drugsthatmay

damagekidney,

patientswithkidneydisease)

pregnantwomen:

teratogenicaction(致畸作用)

oldpeople:theclearanceofmanydrugsisdecreased

Whatshouldwedo?

(3)PaymuchattentionOrgans

Specialpopulation(特殊人群)2701/27/2014,

ADRInformationNotification(59th):

“Bevigilantto(警惕)severeADRofCefazolin

(頭孢唑林)

injection”

2013,theCenterreceivedADRreportsof349cases,mainly:systemicdamage(shock89cases),respiratorydamage,skindamage

NationalCenterforADRMonitering,China

國家藥品不良反應(yīng)監(jiān)測中心2829Doctor’sresponsibilityAdoctorwhodoesonlyasimplething

mayrescuemanypeople’slifeandhealth.

Todiscoverandreportadversedrugreaction(ADR).

--Chiefeditor,JournalofADR

294.Interactionofdrugs

藥物相互作用

Contentsofstudy:Changesineffectsoftwoandmoredrugswhentheyareusedsimultaneously

(同時)oroneafteranother.

III.Maincontentofclinicalpharmacology30Hepaticdrug-metabolizingenzyme（肝藥酶）About

50CYParefunctionallyactiveinhumanTheyarecategorizedinto

17families8to10isoformsinthe

CYP1,CYP2,CYP3

areinvolvedinthemajorityofalldrugmetabolismreactions

inhumanbeings.CytochromeP-450(CYP)細(xì)胞色素P-4503132CYP3A4andCYP3A5areinvolvedinthemetabolismofabout50%ofdrugs.IsoformsintheCYP2CfamilyandCYP2D6subfamilyalsoareinvolvedtoalargeextentinthemetabolismofdrugs.

Awomantakescarbamazepine

(卡馬西平)

totreatepilepsy(癲癇).Complain:unplannedpregnancy.Why?

Co-administrationofantiseizure

(抗癲癇藥)

andoralcontraceptives

(口服避孕藥)CarbamazepineinducesCYP3A4.OralcontraceptivesaremetabolizedbyCYP3A4.Whathappens?Treatmentwithcarbamazepinecanenhancethedegradationoforalcontraceptives.335.Clinicalresearchandevaluation

ofnewdrugs

III.MaincontentsofclinicalpharmacologyEverynewdrugmustcompleteclinicaltrials

before

itsmanufactureisapprovedClinicalpharmacologyresearchplaysthemostimportantroleinnewdrugdevelopment

34IV.Pharmacogenomics

藥物基因組學(xué)

3536Newwords:

gene（基因）

genome

（基因組）

genomics（基因組學(xué)）

pharmacogenomics（藥物基因組學(xué)）Whatispharmacogenomics?studyofthegeneticvariations(遺傳變異)

thatcauseindividualdifferencesindrugresponse3637

*

Enzymesthathavefunctional

allelicvariants(等位基因變異）3738CPY2D6hasgeneticpolymorphisms

(基因多態(tài)性)inCYP2D6gene：about

70singlenucleotidepolymorphisms(SNP,單核苷多態(tài)性)Asaresult,4phenotypicsubpopulations(顯型亞群)ofmetabolizers

(代謝者)exist:poor(PM),intermediate(IM),

extensive(EM),ultra-rapid(UM)3839CPY2D6Morethan65

commonlyuseddrugsaremetabolizedbyCYP2D6,tricyclicantidepressants(三環(huán)類抗抑郁藥)opiates(阿片制劑)TheclinicalimportanceoftheCYP2D6polymorphism:PMs:ADRorinefficacy?Ums:ADRorinefficacy?3940SignificancePrecisionmedicine(精準(zhǔn)醫(yī)學(xué))2015,USAPresident

Obamaproposed“Precisionmedicineplan”:basedongenomic(基因組學(xué))andproteomic

(蛋白組學(xué))

detection,

treatpatientsaimingatind