甲状腺激素和抗甲状腺药Thyroid

甲状腺激素和抗甲状腺药Thyroidhormonesandantithyroiddrugs北京协和医学院基础医学院药理学系叶菜英甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第1页!SummaryThyroidhormones

Necessarytomaintainnormalmetabolism,growthanddevelopment.Hypothyroidism

CauseCretinismifithappensinembryoorneonatalperiod.Causemyxedemaifithappensinadultswhenthethyroidhormonecouldbeusedinreplacementtherapy.Hyperthyroidism

Asyndromcharacterizedbythyroidoversecretionandmetabolicdisordercausedbymultiplereasons.Itcanbetreatedwithradioactiveiodine(131I)irradation,antithyroiddrugsandoperation.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第2页!ThyroidhormonesThyroxine,T4Triiodothyreninumnatricum,T3Synthesizedandsecretedbythyroid甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第3页!抗甲状腺药分为4类：硫脲类Thiourea碘和碘化物（复方碘溶液，lugol’ssolution）

）放射性碘（131I）β受体阻断药（心得安等从略）甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第4页!ThyroidhormonesareiodicaminoacidsActiveponentsThyroxine,T4Triiodothyreninumnatricum,T3ChemicalconstitutionThyroidhormones甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第5页!PhysiologicaldispositionofthyroidhormonesAbsorbedrapidlywhentakeorally,activityT3>T4，maintainingtimeT4>T3.T1/2ofT4andT3are6－7daysand1－2days,respectively.Deiodinationinmitochondriaofliverandkidney,eliminatedbykidneyafferconjugatedwithglucuronic

acidandsulfuricacid.T3,T4canalsopasstheplacentaandentermilk.Figure:theamountofnormaladults’thyroidhormonesproducedandmetabolizeddaily.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第6页!Stepsofthyroidhormonessynthesis,releaseandregulation(Ⅰ)Iodineuptake:I－inbloodcanbeuptakenintocellsbyiodinepumpintheadenocytemembrane.Theaminoacidscanbeusedtosynthesizethyroidglobulinincells.Iodineactivationandtyrosineiodation:I－uptakenintocellscanbeoxydizedtoactiveiodinebyperoxydase.ActiveiodinebindstotyrosineofTGandformsmonoiodotyrosine(MIT)and

diiodotyrosine(DTT).甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第7页!Synthesis,storageandreleaseofthyroidhormone

GastrointestinalI-Blood

I-I-PeroxidaseIoTGTyrIodationMITDITCon-den-sationMIT+DITDIT+DITT3T4TGAcinarluminaStorageSynthesisReleaseActivationProteaseT3T4MIT一碘酪氨酸DIT二碘酪氨酸TG甲状腺球蛋白blood甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第8页!Mechanismofaction（figure)ItisbelievednowthatthethermogenicactionofT3andT4isduetotheincreaseofsodiumpumpsactivityonthecellmembrane.Na+,K+—ATPaseactivityATPutilizationADPconcentrationmitochondriarespirationoxideconsumptionandheatproductionThyroidhormones甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第9页!ThyroidclinicalapplicationReplacementtherapymainlyTherapyanddiagnosisApplication

Cretinism

Treatingtheinfantsandchildrenassoonaspossiblecouldcurethemtonormal.Iftreatingtoolate,theyneedtobetreatedalifetime.

MucousedemaIncreasethedosageofthyroidpalletgradually.Toolargedosagemayaggravateheartdiseases.Patientsinashouldbegivenafistaid,whichisinfusionofT3（40-120μg）intravenoiusly,reinjection5－15μgevery6handoraladministrationwhenawake.Hypopituitarismpatientsshouldbegivencorticalhormonefirstandfollowedbythyroidhormone.Simplegoiter ReplacementtherapycaninhibitTSHoversecretionandcontracttheglandularorgan,3-6months.T3inhibitiontestDifferentialdiagnosisforPatientswithiodinehighuptake.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第10页!AntithyroidDrugsTherapiesofhyperthyrosisinclude131Iradiotherapy,exairesisormedication.Thioureahomologuesaremainlyusedclinically.Iodineandiodideareusedjustinpreparationforoperationsandthyroidcrisistherapy.βreceptorblockerscanbeusedasadjunctivetherapyforthyroidcrisis.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第11页!ThioureaPhysiologicalprocessAbsorption:

Easytobeabsorbedwhentakenorally.Thiouracilisthemostfasttobeabsorbed.Thebioavailabilityis80％andtheplasmaproteinbindingrateis75%.20－30minafteradministration,thedrugturnstobeeeffectivewithT1/2of2h.Imidazoleisabsorbedslowly.T1/2oftapazoleis6h.Distribution:

Organsgenerallyalloverthebodyandcanpasstheplacenta.Theconcentrationinlactoisabout3timesasinblood.Metabolism:

Mainlyinliver,fast.60％aredestroyedinvivo,therestareeliminatedbyurineinaconjugativeform.Carbimazolefunctionsafterturningintotapazoleinvivo.

甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第12页!PathogenesisofExophthalmoshyperthyroidism

andfunctionlinkofthioureahomologuesThisdiseaseiscausedbyanautoimmuneIgGantibodyLATS(longactingthyroidstimulator),whichcanbindtothereceptorsonthyroidadenocytesandstimulateoversecretionofthyroidhormones.Thioureahomologuescannotonlyinhibitsynthesisofthyroidhormones,butalsoLATSinpatients,whichisakindofimmunoinhibition.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第13页!Comparisonamongmonthioureahomologuesdrugs

drugpotency

therapeuticdosemaintenanceadverseeffects

agranulemia (mg/d) doseincidence(%)incidence(%)

mildmoderatesevere

(mg/d)

Methyl 1 200-300 400-600 13.8 0.5 thiouracil 300-400 50-100Propyl 0.75 3.3 0.4thiouracilTapazole10 20-30 40-60 7.1 0.1Carbimazole10 30-40 5-10 1.9 0.8甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第14页!IodineandiodideActionsandapplicationsLowdoseofiodine(physiologicaldose)couldpreventandcuresimple(endemicity)goiter.Add1/10000~1/100000potassiumiodideorsodiumiodidetosaltcouldpreventthedesease.LargedoseofiodinecouldinhibitthereleaseofT3andT4(duetotheinhibitionofTGhydratase).Usedasadjunctivetherapyforhyperthyroidism:①preparationbeforeoperation:administrationofaqueousiodinesolutiontwoweeksbeforeoperationdegeneratestheglandulartissue,decreasesvesselsandbleeding;②adjunctivetherapyforthyroidcrisis:couldbeusedbinedwiththioureahomologues.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第15页!Radioactiveiodine（131I）

T1/2is8.04daysActions

131Icouldbeuptakenbythroid,participateinthesynthesisofT3,T4andisstoredinfollecularcolloid.131Imainlygeneratesβray（99％）withaverageandmaximumpathof0.5mmand2mmrespectively.Sotheirradiationfunctionislimitedinthethyroid.Itcandestroytheglandularorganbutcanseldomdestroythesurroundingtissues.Γraygeneratedby131Iaccountsfor1％andcanbedetectedinvitro.Itisusuallyusedintheexaminationofthyroidiodineuptakingfunction.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第16页!Radioactiveiodine

AdverseeffectsandapplicationnotesHypothyroidismisthepredominantplication.Theadverseeffectscanbereducedbystrictdosecontrolandresistedbythyrine.PatientswithTotalwhitebloodcellslessthan3000/mm3arenotsuitabletotakeit.Soarepragnantandlactantwomen,patientsyoungerthan20yearsoldorwithsevereliverorkidneydeseases.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第17页!receptorblockersClinicalapplicationAdjunctivetherapyforhyperthyroidismandhyperthyroidismcrisis.MechanismofpharmacologicalactionsExcitedsympathetic-adrenergicsystemβ1receptorblockage—heartratedropCentralβreceptorblockage—toreduceanxietyβ2receptoronNAenerginicperipheralnerveendingspresynapticmembraneblockagereducesthereleaseofNA.AppropriatelyreduceT3,T4secretion.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第18页!硫脲类硫氧嘧啶类（thiouracil）：甲基硫氧嘧啶（methykthiouracil）丙基硫氧嘧啶（propylthiouracil）咪唑类（imidazoles）他巴唑（Tapazole，甲巯咪唑methimazole）甲亢平（卡比马唑Carbimazole）甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第19页!甲状腺激素的化学结构甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第20页!Synthesis,storageandregulationofthyroidhormonesIodineuptakeIodineactivationandtyrosineiodationCondensationandstorageDisintegrationandreleaseRegulation甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第21页!Condensationandstorage:Inthethyroidglobulinmolecule,twoDTTsarecondensedtoT4,oneDTTandoneMITarecondensedtoT3，whichareallstoredinglandalveoluscolloid.Disintegrationandrelease:T3andT4arereleasedintobloodafterhydrolyzedbyproteases.Atthesametime,someofthemcanbeturnedbacktotyrosineandI－bydeiodinaseincellsandreused.Regulation:Bythepositiveandnegativefeedbackregulationofhypothalamus-anteriorlobe-thyroidaxis.HypothalamussecretsTRH,anteriorlobesecretsTSHandthyroidsynthesizeT3,T4.Stepsofthyroidhormonessynthesis,releaseandregulation(Ⅱ)甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第22页!ThyroidhormonesMechanismofactionThebindingofT3andRincreasestheuptakeofaaandglucose,resultingintheentrancetocytoplasmofT3.AfterreactingwithCBP,T3iseduced.ThefreeT3canbindRinthemitochondriaandmakeADPtoATP.Besides,itcanenterthenuclearandbindRthere,whichcanincreasethetranscriptionofDNAandthecontentofmRNA.Thenthenewproteinscanbesynthesizedandplayroles.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第23页!Physiologicalandpharmacologicalactions

Keepnormalgrowthanddevelopment

PromotesynthesisofproteinsaswellasgrowthanddevelopmentofskeletonandCNS.T3,T4deficientsecretion:causescretinismininfantsandyoungchildrenandmucousedemainadults.

Promotemetabolismandincreaseheatproduction

Promoteoxidation,increaseoxygenconsumption,basalmetabolicrateandheatproduction.

Elevatesensitivityofsympathetic-adrenalsystem

Nervousness,trembling,heartbeatspeedup,bloodpressureincrease甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第24页!AdverseeffectsAdverseeffectOverdoseCombinationContraindicationhyperthyreosisoldpeopleheartdiseasebishydroxycoumarindantinaoraspirindiabeteshypertensionCoronaryheartdiseasepyknocardiathyroidcrisis:anxiety,fear,restlessness,highbodytemperature,increaseandirregularheartrate,increasepulsepressure,congestiveheartfailurewithvomit,diarrheaanddehydrationwhichleadtoaanddeathAnginaorheartinfarctionIncreasetoxicityofthyroidhormone甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第25页!硫脲类硫氧嘧啶类：甲基硫氧嘧啶丙基硫氧嘧啶咪唑类他巴唑（又称甲巯咪唑）甲亢平（又称卡比马唑）甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第26页!PharmacologicalactionsInhibitperoxydaseinadenocytes,whichresultsintheinhibitedoxydationofI－toI0.Then,theiodationandcoupleoftyrosinescanbestopped.SothebiosynthesisofT3andT4isinhibited.Buttheeffectoccursslowlyastheiodineuptakeandthehormonealreadysynthesizedarenoteffected.LongtimemedicationcanleadtodecreaseofT3andT4,whichfeedbackincreasesthesecretionofTSHandmakesthyroidhyperplasyandhyperemicpensatorily.PropylthiouracilcaninhibitT4turningtoT3andcontrolT3levelinblood.Soitisthefirstchoiceinhyperthyroidismcrisis,severehyperthyroidismandpregnanthyperthyroidism.Inhibitimmuno-system(ashyperthyroidismisrelatedwithabnormalimmunoreactions).Thiourea甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第27页!ThioureaClinicalapplicationHyperthyroidism

Forwhohasmildsymptomsandisnotsuitabletohaveoperationsand131Iradiotherapy.GiveLargerdoseatthebeginning.After1~3months,symtomsdecreasedandbasalmetabolicratereturnstoalmostnormal.Reducetomaintainingdosewithaperoidof1~2years.Alsocanbeusedasadjunctivetherapyof131Iradiotherapy.

Preparationbeforeoperation

Medicationbeforeoperationisgoodtodecreasebleedinginoperationandpreventthyroidcrisisafteroperation.Adjunctivemedicationofthyroidcrisis

Besidesintegratemeasures,largedoseofThioureahomologuescanbeusedasadjunctivetherapy,SoisPropranolol.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是第28页!ThioureaAdverseeffects

Althoughtherearelotsofadverseeffectsofthioureahomologues,incidencesofpropylthiouracilandtapazolearelower,3％and7％respectively.Commonadverseeffects：

Skinrash,headache,dinus,gastrointestinalunfortable,fatigueandsoon.

Severeadverseeffects：

Bonemarrowdepression,agranulocytosisandsoon.Note:Periodicinspectionofhemogram.Themedicationshoulebestoppedifthesymptomsaspharyngalgia,fever,cathaeresisoccur.Thyroidcancerpatientsareforbiddentotake.甲状腺激素和抗甲状腺药Thyroid共33页，您现在浏览的是