【医学ppt课件】 甲状腺激素和抗甲状腺药

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 lugol ssolution 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 activityT3 T4 maintainingtimeT4 T3 T1 2ofT4andT3are6 7daysand1 2days respectively Deiodinationinmitochondriaofliverandkidney eliminatedbykidneyafferconjugatedwithglucuronicacidandsulfuricacid T3 T4canalsopasstheplacentaandentermilk Figure theamountofnormaladults thyroidhormonesproducedandmetabolizeddaily Synthesis storageandregulationofthyroidhormones IodineuptakeIodineactivationandtyrosineiodationCondensationandstorageDisintegrationandreleaseRegulation Stepsofthyroidhormonessynthesis releaseandregulation Iodineuptake I inbloodcanbeuptakenintocellsbyiodinepumpintheadenocytemembrane Theaminoacidscanbeusedtosynthesizethyroidglobulinincells Iodineactivationandtyrosineiodation I uptakenintocellscanbeoxydizedtoactiveiodinebyperoxydase ActiveiodinebindstotyrosineofTGandformsmonoiodotyrosine MIT anddiiodotyrosine DTT Condensationandstorage Inthethyroidglobulinmolecule twoDTTsarecondensedtoT4 oneDTTandoneMITarecondensedtoT3 whichareallstoredinglandalveoluscolloid Disintegrationandrelease T3andT4arereleasedintobloodafterhydrolyzedbyproteases Atthesametime someofthemcanbeturnedbacktotyrosineandI bydeiodinaseincellsandreused 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 40 120 g intravenoiusly reinjection5 15 gevery6handoraladministrationwhenawake 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 Thebioavailabilityis80 andtheplasmaproteinbindingrateis75 20 30minafteradministration thedrugturnstobecomeeffectivewithT1 2of2h Imidazoleisabsorbedslowly T1 2oftapazoleis6h Distribution Organsgenerallyalloverthebodyandcanpasstheplacenta Theconcentrationinlactoisabout3timesasinblood Metabolism Mainlyinliver fast 60 aredestroyedinvivo therestareeliminatedbyurineinaconjugativeform Carbimazolefunctionsafterturningintotapazoleinvivo PharmacologicalactionsInhibitperoxydaseinadenocytes whichresultsintheinhibitedoxydationofI toI0 Then theiodationandcoupleoftyrosinescanbestopped SothebiosynthesisofT3andT4isinhibited Buttheeffectoccursslowlyastheiodineuptakeandthehormonealreadysynthesizedarenoteffected LongtimemedicationcanleadtodecreaseofT3andT4 whichfeedbackincreasesthesecretionofTSHandmakesthyroidhyperplasyandhyperemiccompensatorily PropylthiouracilcaninhibitT4turningtoT3andcontrolT3levelinblood Soitisthefirstchoiceinhyperthyroidismcrisis severehyperthyroidismandpregnanthyperthyroidism Inhibitimmuno system ashyperthyroidismisrelatedwithabnormalimmunoreactions Thiourea PathogenesisofExophthalmoshyperthyroidismandfunctionlinkofthioureahomologues ThisdiseaseiscausedbyanautoimmuneIgGantibodyLATS longactingthyroidstimulator whichcanbindtothereceptorsonthyroidadenocytesandstimulateoversecretionofthyroidhormones Thioureahomologuescannotonlyinhibitsynthesisofthyroidhormones butalsoLATSinpatients whichisakindofimmunoinhibition Thiourea ClinicalapplicationHyperthyroidismForwhohasmildsymptomsandisnotsuitabletohaveoperationsand131Iradiotherapy GiveLargerdoseatthebeginning After1 3months symtomsdecreasedandbasalmetabolicratereturnstoalmostnormal Reducetomaintainingdosewithaperoidof1 2years 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 3 and7 respectively Commonadverseeffects Skinrash headache dinus gastrointestinaluncomfortable fatigueandsoon Severeadverseeffects Bonemarrowdepression agranulocytosisandsoon Note Periodicinspectionofhemogram Themedicationshoulebestoppedifthesymptomsaspharyngalgia fever cathaeresisoccur Thyroidcancerpatientsareforbiddentotake Iodineandiodide ActionsandapplicationsLowdoseofiodine physiologicaldose couldpreventandcuresimple endemicity goiter Add1 10000 1 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 131Imainlygenerates ray 99 withaverageandmaximumpathof0 5mmand2mmrespectively Sotheirradiationfunctionislimitedinthethyroid Itcandestroytheglandularorganbutcanseldomdestroythesurroundingtissues raygeneratedby131Iaccountsfor1 andcanbedetectedinvitro Itisusuallyusedintheexaminationofthyroidiodineuptakingfunction Radioactiveiodine 131I ClinicalapplicationThyroidiodineuptakefunctionexamination iodineuptakeratehighwhenhyperthyroid timeofiodineuptakepeakantelocationiodineuptakeratelowwhenhypothyroid timeofiodineuptakepeakretropositionHyperthyroidismTraceamountcouldbeusedindiagnosisofthyroidfunctionals