甲状腺激素及抗甲状腺药Thyroidhormonesandantithyroid.ppt

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,SummaryThyroidhormonesNecessarytomaintainnormalmetabolism,growthanddevelopment.HypothyroidismCauseCretinismifithappensinembryoorneonatalperiod.Causemyxedemaifithappensinadultswhenthethyroidhormonecouldbeusedinreplacementtherapy.HyperthyroidismAsyndromcharacterizedbythyroidoversecretionandmetabolicdisordercausedbymultiplereasons.Itcanbetreatedwithradioactiveiodine(131I)irradation,antithyroiddrugsandoperation.,Thyroidhormones,Thyroxine,T4Triiodothyreninumnatricum,T3Synthesizedandsecretedbythyroid,抗甲状腺药,分为4类：硫脲类Thiourea碘和碘化物（复方碘溶液，lugolssolution）放射性碘（131I）受体阻断药（心得安等从略）,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）,ThyroidhormonesareiodicaminoacidsActivecomponentsThyroxine,T4Triiodothyreninumnatricum,T3Chemicalconstitution,Thyroidhormones,甲状腺激素的化学结构,Physiologicaldispositionofthyroidhormones,Absorbedrapidlywhentakeorally,activityT3T4，maintainingtimeT4T3.T1/2ofT4andT3are67daysand12days,respectively.Deiodinationinmitochondriaofliverandkidney,eliminatedbykidneyafferconjugatedwithglucuronicacidandsulfuricacid.T3,T4canalsopasstheplacentaandentermilk.Figure:theamountofnormaladultsthyroidhormonesproducedandmetabolizeddaily.,Synthesis,storageandregulationofthyroidhormones,IodineuptakeIodineactivationandtyrosineiodationCondensationandstorageDisintegrationandreleaseRegulation,Stepsofthyroidhormonessynthesis,releaseandregulation(),Iodineuptake:Iinbloodcanbeuptakenintocellsbyiodinepumpintheadenocytemembrane.Theaminoacidscanbeusedtosynthesizethyroidglobulinincells.Iodineactivationandtyrosineiodation:Iuptakenintocellscanbeoxydizedtoactiveiodinebyperoxydase.ActiveiodinebindstotyrosineofTGandformsmonoiodotyrosine(MIT)anddiiodotyrosine(DTT).,Condensationandstorage:Inthethyroidglobulinmolecule,twoDTTsarecondensedtoT4,oneDTTandoneMITarecondensedtoT3，whichareallstoredinglandalveoluscolloid.Disintegrationandrelease:T3andT4arereleasedintobloodafterhydrolyzedbyproteases.Atthesametime,someofthemcanbeturnedbacktotyrosineandIbydeiodinaseincellsandreused.Regulation:Bythepositiveandnegativefeedbackregulationofhypothalamus-anteriorlobe-thyroidaxis.HypothalamussecretsTRH,anteriorlobesecretsTSHandthyroidsynthesizeT3,T4.,Stepsofthyroidhormonessynthesis,releaseandregulation(),Synthesis,storageandreleaseofthyroidhormone,GastrointestinalI-,BloodI-,I-,Peroxidase,Io,TG,Tyr,Iodation,MIT,DIT,Con-den-sation,MIT+DIT,DIT+DIT,T3,T4,TG,Acinarlumina,Storage,Synthesis,Release,Activation,Protease,T3,T4,MIT一碘酪氨酸DIT二碘酪氨酸TG甲状腺球蛋白,blood,Thyroidhormones,MechanismofactionThebindingofT3andRincreasestheuptakeofaaandglucose,resultingintheentrancetocytoplasmofT3.AfterreactingwithCBP,T3iseduced.ThefreeT3canbindRinthemitochondriaandmakeADPtoATP.Besides,itcanenterthenuclearandbindRthere,whichcanincreasethetranscriptionofDNAandthecontentofmRNA.Thenthenewproteinscanbesynthesizedandplayroles.,Mechanismofaction（figure)ItisbelievednowthatthethermogenicactionofT3andT4isduetotheincreaseofsodiumpumpsactivityonthecellmembrane.Na+,K+ATPaseactivityATPutilizationADPconcentrationmitochondriarespirationoxideconsumptionandheatproduction,Thyroidhormones,Physiologicalandpharmacologicalactions,KeepnormalgrowthanddevelopmentPromotesynthesisofproteinsaswellasgrowthanddevelopmentofskeletonandCNS.T3,T4deficientsecretion:causescretinismininfantsandyoungchildrenandmucousedemainadults.PromotemetabolismandincreaseheatproductionPromoteoxidation,increaseoxygenconsumption,basalmetabolicrateandheatproduction.Elevatesensitivityofsympathetic-adrenalsystemNervousness,trembling,heartbeatspeedup,bloodpressureincrease,Thyroidclinicalapplication,ReplacementtherapymainlyTherapyanddiagnosisApplicationCretinismTreatingtheinfantsandchildrenassoonaspossiblecouldcurethemtonormal.Iftreatingtoolate,theyneedtobetreatedalifetime.MucousedemaIncreasethedosageofthyroidpalletgradually.Toolargedosagemayaggravateheartdiseases.Patientsincomashouldbegivenafistaid,whichisinfusionofT3（40-120g）intravenoiusly,reinjection515gevery6handoraladministrationwhenawake.Hypopituitarismpatientsshouldbegivencorticalhormonefirstandfollowedbythyroidhormone.SimplegoiterReplacementtherapycaninhibitTSHoversecretionandcontracttheglandularorgan,3-6months.T3inhibitiontestDifferentialdiagnosisforPatientswithiodinehighuptake.,Adverseeffects,Adverseeffect,Overdose,Combination,Contraindication,hyperthyreosis,oldpeopleheartdisease,bishydroxycoumarindantinaoraspirin,diabeteshypertensionCoronaryheartdiseasepyknocardia,thyroidcrisis:anxiety,fear,restlessness,highbodytemperature,increaseandirregularheartrate,increasepulsepressure,congestiveheartfailurewithvomit,diarrheaanddehydrationwhichleadtocomaanddeath,Anginaorheartinfarction,Increasetoxicityofthyroidhormone,AntithyroidDrugs,Therapiesofhyperthyrosisinclude131Iradiotherapy,exairesisormedication.Thioureahomologuesaremainlyusedclinically.Iodineandiodideareusedjustinpreparationforoperationsandthyroidcrisistherapy.receptorblockerscanbeusedasadjunctivetherapyforthyroidcrisis.,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）,Thiourea,PhysiologicalprocessAbsorption:Easytobeabsorbedwhentakenorally.Thiouracilisthemostfasttobeabsorbed.Thebioavailabilityis80andtheplasmaproteinbindingrateis75%.2030minafteradministration,thedrugturnstobecomeeffectivewithT1/2of2h.Imidazoleisabsorbedslowly.T1/2oftapazoleis6h.Distribution:Organsgenerallyalloverthebodyandcanpasstheplacenta.Theconcentrationinlactoisabout3timesasinblood.Metabolism:Mainlyinliver,fast.60aredestroyedinvivo,therestareeliminatedbyurineinaconjugativeform.Carbimazolefunctionsafterturningintotapazoleinvivo.,PharmacologicalactionsInhibitperoxydaseinadenocytes,whichresultsintheinhibitedoxydationofItoI0.Then,theiodationandcoupleoftyrosinescanbestopped.SothebiosynthesisofT3andT4isinhibited.Buttheeffectoccursslowlyastheiodineuptakeandthehormonealreadysynthesizedarenoteffected.LongtimemedicationcanleadtodecreaseofT3andT4,whichfeedbackincreasesthesecretionofTSHandmakesthyroidhyperplasyandhyperemiccompensatorily.PropylthiouracilcaninhibitT4turningtoT3andcontrolT3levelinblood.Soitisthefirstchoiceinhyperthyroidismcrisis,severehyperthyroidismandpregnanthyperthyroidism.Inhibitimmuno-system(ashyperthyroidismisrelatedwithabnormalimmunoreactions).,Thiourea,PathogenesisofExophthalmoshyperthyroidismandfunctionlinkofthioureahomologues,ThisdiseaseiscausedbyanautoimmuneIgGantibodyLATS(longactingthyroidstimulator),whichcanbindtothereceptorsonthyroidadenocytesandstimulateoversecretionofthyroidhormones.Thioureahomologuescannotonlyinhibitsynthesisofthyroidhormones,butalsoLATSinpatients,whichisakindofimmunoinhibition.,Thiourea,ClinicalapplicationHyperthyroidismForwhohasmildsymptomsandisnotsuitabletohaveoperationsand131Iradiotherapy.GiveLargerdoseatthebeginning.After13months,symtomsdecreasedandbasalmetabolicratereturnstoalmostnormal.Reducetomaintainingdosewithaperoidof12years.Alsocanbeusedasadjunctivetherapyof131Iradiotherapy.PreparationbeforeoperationMedicationbeforeoperationisgoodtodecreasebleedinginoperationandpreventthyroidcrisisafteroperation.AdjunctivemedicationofthyroidcrisisBesidesintegratemeasures,largedoseofThioureahomologuescanbeusedasadjunctivetherapy,SoisPropranolol.,Comparisonamongcommonthioureahomologuesdrugs,drugpotencytherapeuticdosemaintenanceadverseeffectsagranulemia(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,Thiourea,AdverseeffectsAlthoughtherearelotsofadverseeffectsofthioureahomologues,incidencesofpropylthiouracilandtapazolearelower,3and7respectively.Commonadverseeffects：Skinrash,headache,dinus,gastrointestinaluncomfortable,fatigueandsoon.Severeadverseeffects：Bonemarrowdepression,agranulocytosisandsoon.Note:Periodicinspectionofhemogram.Themedicationshoulebestoppedifthesymptomsaspharyngalgia,fever,cathaeresisoccur.Thyroidcancerpatientsareforbiddentotake.,Iodineandiodide,ActionsandapplicationsLowdoseofiodine(physiologicaldose)couldpreventandcuresimple(endemicity)goiter.Add1/100001/100000potassiumiodideorsodiumiodidetosaltcouldpreventthedesease.LargedoseofiodinecouldinhibitthereleaseofT3andT4(duetotheinhibitionofTGhydratase).Usedasadjunctivetherapyforhyperthyroidism:preparationbeforeoperation:administrationofaqueousiodinesolutiontwoweeksbeforeoperationdegeneratestheglandulartissue,decreasesvesselsandbleeding;adjunctivetherapyforthyroidcrisis:couldbeusedcombinedwiththioureahomologues.,Iodineandiodide,AdverseeffectsandapplicationnotesAcuteeffects:acutecircumscribededema，laryngealedemaandapnoea.Chronictoxicity:mouthandthroatburningsensation,increasesecretionofsalivary,eyeirritationandsoon.Inducedysthyroidandhyperthyroidismafterlongmedication.Iodinecouldpassintothemilkandthroughplacenta,leadingtoneonatgoiter.Pregnantandlactantwomenshouletakethedrugwithcausious.Allergicandactivetuberculosispatientsareforbiddentotake.,Radioactiveiodine（131I）T1/2is8.04days,Actions131Icouldbeuptakenbythroid,participateinthesynthesisofT3,T4andisstoredinfollecularcolloid.131Imainlygeneratesray（99）withaverageandmaximumpathof0.5mmand2mmrespectively.Sotheirradiationfunctionislimitedinthethyroid.Itcandestroytheglandularorganbutcanseldomdestroythesurroundingtissues.raygeneratedby131Iaccountsfor1andcanbedetectedinvitro.Itisusuallyusedintheexaminationofthyroidiodineuptakingfunction.,Radioactiveiodine（131I）,ClinicalapplicationThyroidiodineuptakefunctionexamination:iodineuptakeratehighwhenhyperthyroid,timeofiodineuptakepeakantelocationiodineuptakeratelowwhenhypothyroid,timeofiodineuptakepeakretropositionHyperthyroidismTraceamountcouldbeusedindiagnosisofthyroidfunctiona