甲状腺激素和抗甲状腺药Thyroid

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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

1SummaryThyroidhormonesNecessarytomaintainnormalmetabolism,growthanddevelopment.HypothyroidismCauseCretinismifithappensinembryoorneonatalperiod.Causemyxedemaifithappensinadultswhenthethyroidhormonecouldbeusedinreplacementtherapy.HyperthyroidismAsyndromcharacterizedbythyroidoversecretionandmetabolicdisordercausedbymultiplereasons.Itcanbetreatedwithradioactiveiodine(131I)irradation,antithyroiddrugsandoperation.

2ThyroidhormonesThyroxine,T4Triiodothyreninumnatricum,T3Synthesizedandsecretedbythyroid

3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）

4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）

5ThyroidhormonesareiodicaminoacidsActivecomponentsThyroxine,T4Triiodothyreninumnatricum,T3ChemicalconstitutionThyroidhormones

6甲状腺激素的化学结构

7PhysiologicaldispositionofthyroidhormonesAbsorbedrapidlywhentakeorally,activityT3>T4，maintainingtimeT4>T3.T1/2ofT4andT3are6－7daysand1－2days,respectively.Deiodinationinmitochondriaofliverandkidney,eliminatedbykidneyafferconjugatedwithglucuronicacidandsulfuricacid.T3,T4canalsopasstheplacentaandentermilk.Figure:theamountofnormaladults’thyroidhormonesproducedandmetabolizeddaily.

8Synthesis,storageandregulationofthyroidhormonesIodineuptakeIodineactivationandtyrosineiodationCondensationandstorageDisintegrationandreleaseRegulation

9Stepsofthyroidhormonessynthesis,releaseandregulation(Ⅰ)Iodineuptake:I－inbloodcanbeuptakenintocellsbyiodinepumpintheadenocytemembrane.Theaminoacidscanbeusedtosynthesizethyroidglobulinincells.Iodineactivationandtyrosineiodation:I－uptakenintocellscanbeoxydizedtoactiveiodinebyperoxydase.ActiveiodinebindstotyrosineofTGandformsmonoiodotyrosine(MIT)anddiiodotyrosine(DTT).

10Condensationandstorage:Inthethyroidglobulinmolecule,twoDTTsarecondensedtoT4,oneDTTandoneMITarecondensedtoT3，whichareallstoredinglandalveoluscolloid.Disintegrationandrelease:T3andT4arereleasedintobloodafterhydrolyzedbyproteases.Atthesametime,someofthemcanbeturnedbacktotyrosineandI－bydeiodinaseincellsandreused.Regulation:Bythepositiveandnegativefeedbackregulationofhypothalamus-anteriorlobe-thyroidaxis.HypothalamussecretsTRH,anteriorlobesecretsTSHandthyroidsynthesizeT3,T4.Stepsofthyroidhormonessynthesis,releaseandregulation(Ⅱ)

11Synthesis,storageandreleaseofthyroidhormoneGastrointestinalI-BloodI-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

12ThyroidhormonesMechanismofactionThebindingofT3andRincreasestheuptakeofaaandglucose,resultingintheentrancetocytoplasmofT3.AfterreactingwithCBP,T3iseduced.ThefreeT3canbindRinthemitochondriaandmakeADPtoATP.Besides,itcanenterthenuclearandbindRthere,whichcanincreasethetranscriptionofDNAandthecontentofmRNA.Thenthenewproteinscanbesynthesizedandplayroles.

13Mechanismofaction（figure)ItisbelievednowthatthethermogenicactionofT3andT4isduetotheincreaseofsodiumpumpsactivityonthecellmembrane.Na+,K+—ATPaseactivityATPutilizationADPconcentrationmitochondriarespirationoxideconsumptionandheatproductionThyroidhormones

14PhysiologicalandpharmacologicalactionsKeepnormalgrowthanddevelopmentPromotesynthesisofproteinsaswellasgrowthanddevelopmentofskeletonandCNS.T3,T4deficientsecretion:causescretinismininfantsandyoungchildrenandmucousedemainadults.PromotemetabolismandincreaseheatproductionPromoteoxidation,increaseoxygenconsumption,basalmetabolicrateandheatproduction.Elevatesensitivityofsympathetic-adrenalsystemNervousness,trembling,heartbeatspeedup,bloodpressureincrease

15ThyroidclinicalapplicationReplacementtherapymainlyTherapyanddiagnosisApplicationCretinismTreatingtheinfantsandchildrenassoonaspossiblecouldcurethemtonormal.Iftreatingtoolate,theyneedtobetreatedalifetime.MucousedemaIncreasethedosageofthyroidpalletgradually.Toolargedosagemayaggravateheartdiseases.Patientsincomashouldbegivenafistaid,whichisinfusionofT3（40-120μg）intravenoiusly,reinjection5－15μgevery6handoraladministrationwhenawake.Hypopituitarismpatientsshouldbegivencorticalhormonefirstandfollowedbythyroidhormone.SimplegoiterReplacementtherapycaninhibitTSHoversecretionandcontracttheglandularorgan,3-6months.T3inhibitiontestDifferentialdiagnosisforPatientswithiodinehighuptake.

16AdverseeffectsAdverseeffectOverdoseCombinationContraindicationhyperthyreosisoldpeopleheartdiseasebishydroxycoumarindantinaoraspirindiabeteshypertensionCoronaryheartdiseasepyknocardiathyroidcrisis:anxiety,fear,restlessness,highbodytemperature,increaseandirregularheartrate,increasepulsepressure,congestiveheartfailurewithvomit,diarrheaanddehydrationwhichleadtocomaanddeathAnginaorheartinfarctionIncreasetoxicityofthyroidhormone

17AntithyroidDrugsTherapiesofhyperthyrosisinclude131Iradiotherapy,exairesisormedication.Thioureahomologuesaremainlyusedclinically.Iodineandiodideareusedjustinpreparationforoperationsandthyroidcrisistherapy.βreceptorblockerscanbeusedasadjunctivetherapyforthyroidcrisis.

18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）

19ThioureaPhysiologicalprocessAbsorption:Easytobeabsorbedwhentakenorally.Thiouracilisthemostfasttobeabsorbed.Thebioavailabilityis80％andtheplasmaproteinbindingrateis75%.20－30minafteradministration,thedrugturnstobecomeeffectivewithT1/2of2h.Imidazoleisabsorbedslowly.T1/2oftapazoleis6h.Distribution:Organsgenerallyalloverthebodyandcanpasstheplacenta.Theconcentrationinlactoisabout3timesasinblood.Metabolism:Mainlyinliver,fast.60％aredestroyedinvivo,therestareeliminatedbyurineinaconjugativeform.Carbimazolefunctionsafterturningintotapazoleinvivo.

20PharmacologicalactionsInhibitperoxydaseinadenocytes,whichresultsintheinhibitedoxydationofI－toI0.Then,theiodationandcoupleoftyrosinescanbestopped.SothebiosynthesisofT3andT4isinhibited.Buttheeffectoccursslowlyastheiodineuptakeandthehormonealreadysynthesizedarenoteffected.LongtimemedicationcanleadtodecreaseofT3andT4,whichfeedbackincreasesthesecretionofTSHandmakesthyroidhyperplasyandhyperemiccompensatorily.PropylthiouracilcaninhibitT4turningtoT3andcontrolT3levelinblood.Soitisthefirstchoiceinhyperthyroidismcrisis,severehyperthyroidismandpregnanthyperthyroidism.Inhibitimmuno-system(ashyperthyroidismisrelatedwithabnormalimmunoreactions).Thiourea

21PathogenesisofExophthalmoshyperthyroidismandfunctionlinkofthioureahomologuesThisdiseaseiscausedbyanautoimmuneIgGantibodyLATS(longactingthyroidstimulator),whichcanbindtothereceptorsonthyroidadenocytesandstimulateoversecretionofthyroidhormones.Thioureahomologuescannotonlyinhibitsynthesisofthyroidhormones,butalsoLATSinpatients,whichisakindofimmunoinhibition.

22ThioureaClinicalapplicationHyperthyroidismForwhohasmildsymptomsandisnotsuitabletohaveoperationsand131Iradiotherapy.GiveLargerdoseatthebeginning.After1~3months,symtomsdecreasedandbasalmetabolicratereturnstoalmostnormal.Reducetomaintainingdosewithaperoidof1~2years.Alsocanbeusedasadjunctivetherapyof131Iradiotherapy.PreparationbeforeoperationMedicationbeforeoperationisgoodtodecreasebleedinginoperationandpreventthyroidcrisisafteroperation.AdjunctivemedicationofthyroidcrisisBesidesintegratemeasures,largedoseofThioureahomologuescanbeusedasadjunctivetherapy,SoisPropranolol.

23Comparisonamongcommonthioureahomologuesdrugsdrugpotencytherapeuticdosemaintenanceadverseeffectsagranulemia(mg/d)doseincidence(%)incidence(%)mildmoderatesevere(mg/d)Methyl1200-300400-60013.80.5thiouracil300-40050-100Propyl0.753.30.4thiouracilTapazole1020-3040-607.10.1Carbimazole1030-405-101.90.8

24ThioureaAdverseeffectsAlthoughtherearelotsofadverseeffectsofthioureahomologues,incidencesofpropylthiouracilandtapazolearelower,3％and7％respectively.Commonadverseeffects：Skinrash,headache,dinus,gastrointestinaluncomfortable,fatigueandsoon.Severeadverseeffects：Bonemarrowdepression,agranulocytosisandsoon.Note:Periodicinspectionofhemogram.Themedicationshoulebestoppedifthesymptomsaspharyngalgia,fever,cathaeresisoccur.Thyroidcancerpatientsareforbiddentotake.

25IodineandiodideActionsandapplicationsLowdoseofiodine(physiologicaldose)couldpreventandcuresimple(endemicity)goiter.Add1/10000~1/100000potassiumiodideorsodiumiodidetosaltcouldpreventthedesease.LargedoseofiodinecouldinhibitthereleaseofT3andT4(duetotheinhibitionofTGhydratase).Usedasadjunctivetherapyforhyperthyroidism:①preparationbeforeoperation:administrationofaqueousiodinesolutiontwoweeksbeforeoperationdegeneratestheglandulartissue,decreasesvesselsandbleeding;②adjunctivetherapyforthyroidcrisis:couldbeusedcombinedwiththioureahomologues.

26IodineandiodideAdverseeffectsandapplicationnotesAcuteeffects:acutecircumscribededema，laryngealedemaandapnoea.Chronictoxicity:mouthandthroatburningsensation,increasesecretionofsalivary,eyeirritationandsoon.Inducedysthyroidandhyperthyroidismafterlongmedication.Iodinecouldpassintothemilkandthroughplacenta,leadingtoneonatgoiter.Pregnantandlactantwomenshouletakethedrugwithcausious.Allergicandactivetuberculosispatientsareforbiddentotake.

27Radioactiveiodine（131I）T1/2is8.04daysActions131Icouldbeuptakenbythroid,participateinthesynthesisofT3,T4andisstoredinfollecularcolloid.131Imainlygeneratesβray（99％）withaverageandmaximumpathof0.5mmand2mmrespectively.Sotheirradiationfunctionislimitedinthethyroid.Itcandestroytheglandularorganbutcanseldomdestroythesurroundingtissues.Γraygeneratedby131Iaccountsfor1％andcanbedetectedinvitro.Itisusuallyusedintheexaminationofthyroidiodineuptakingfunction.

28Radioactiveiodine（131I）ClinicalapplicationThyroidiodineuptakefunctionexamination:iodineuptakeratehighwhenhyperthyroid,timeofiodineuptakepeakantelocationiodineuptakeratelowwhenhypothyroid,timeofiodineuptakepeakretropositionHyperthyroidismTraceamountcouldbeusedindiagnosisofthyroidfunctionalstatusandthyroidadenoma.

29RadioactiveiodineAdverseeffectsandapplicationnotesHypothyroidismisthepredominantcomplication.Theadverseeffectscanbereducedbystrictdosecontrolandresistedbythyrine.PatientswithTotalwhitebloodcellslessthan3000/mm3arenotsuitabletotakeit.Soarepragnantandlactantwomen,patientsyoungerthan20yearsoldorwithsevereliverorkidneydeseases.

30receptorblockersValuableadjunctivetherapydrugsforhyperthyroidismandthyroidcrisis.Theycouldimprovesymptomscausedbyaugmentedsympatheticactivitysuchasspeedupheartrateandincreaseheartcontractionforce.TheycanalsoreducethethyroidhormonesecretionandT3synthesisbyinhibiting5`-deiodinase.Controlhyperthyroidismsymptomsandcanbeusedinpreparationbeforeoperation.

31receptorblockersClinicalapplicationAdjunctivetherapyforhyperthyroidismandhyperthyroidismcrisis.MechanismofpharmacologicalactionsExcitedsympathetic-adrenergicsystemβ1receptorblockage—heartratedropCentralβreceptorblockage—toreduceanxietyβ2receptoronNAenerginicperipheralnerveendingspresynapticmembraneblockagereducesthereleaseofNA.AppropriatelyreduceT3,T4secretion.

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