甲狀腺激素和抗甲狀腺藥Thyroid

甲狀腺激素和抗甲狀腺藥Thyroidhormonesandantithyroiddrugs北京協(xié)和醫(yī)學(xué)院基礎(chǔ)醫(yī)學(xué)院藥理學(xué)系葉菜英甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第1頁!SummaryThyroidhormones

Necessarytomaintainnormalmetabolism,growthanddevelopment.Hypothyroidism

CauseCretinismifithappensinembryoorneonatalperiod.Causemyxedemaifithappensinadultswhenthethyroidhormonecouldbeusedinreplacementtherapy.Hyperthyroidism

Asyndromcharacterizedbythyroidoversecretionandmetabolicdisordercausedbymultiplereasons.Itcanbetreatedwithradioactiveiodine(131I)irradation,antithyroiddrugsandoperation.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第2頁!ThyroidhormonesThyroxine,T4Triiodothyreninumnatricum,T3Synthesizedandsecretedbythyroid甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第3頁!抗甲狀腺藥分為4類：硫脲類Thiourea碘和碘化物（復(fù)方碘溶液，lugol’ssolution）

）放射性碘（131I）β受體阻斷藥（心得安等從略）甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第4頁!ThyroidhormonesareiodicaminoacidsActiveponentsThyroxine,T4Triiodothyreninumnatricum,T3ChemicalconstitutionThyroidhormones甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第5頁!PhysiologicaldispositionofthyroidhormonesAbsorbedrapidlywhentakeorally,activityT3>T4，maintainingtimeT4>T3.T1/2ofT4andT3are6－7daysand1－2days,respectively.Deiodinationinmitochondriaofliverandkidney,eliminatedbykidneyafferconjugatedwithglucuronic

acidandsulfuricacid.T3,T4canalsopasstheplacentaandentermilk.Figure:theamountofnormaladults’thyroidhormonesproducedandmetabolizeddaily.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第6頁!Stepsofthyroidhormonessynthesis,releaseandregulation(Ⅰ)Iodineuptake:I－inbloodcanbeuptakenintocellsbyiodinepumpintheadenocytemembrane.Theaminoacidscanbeusedtosynthesizethyroidglobulinincells.Iodineactivationandtyrosineiodation:I－uptakenintocellscanbeoxydizedtoactiveiodinebyperoxydase.ActiveiodinebindstotyrosineofTGandformsmonoiodotyrosine(MIT)and

diiodotyrosine(DTT).甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第7頁!Synthesis,storageandreleaseofthyroidhormone

GastrointestinalI-Blood

I-I-PeroxidaseIoTGTyrIodationMITDITCon-den-sationMIT+DITDIT+DITT3T4TGAcinarluminaStorageSynthesisReleaseActivationProteaseT3T4MIT一碘酪氨酸DIT二碘酪氨酸TG甲狀腺球蛋白blood甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第8頁!Mechanismofaction（figure)ItisbelievednowthatthethermogenicactionofT3andT4isduetotheincreaseofsodiumpumpsactivityonthecellmembrane.Na+,K+—ATPaseactivityATPutilizationADPconcentrationmitochondriarespirationoxideconsumptionandheatproductionThyroidhormones甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第9頁!ThyroidclinicalapplicationReplacementtherapymainlyTherapyanddiagnosisApplication

Cretinism

Treatingtheinfantsandchildrenassoonaspossiblecouldcurethemtonormal.Iftreatingtoolate,theyneedtobetreatedalifetime.

MucousedemaIncreasethedosageofthyroidpalletgradually.Toolargedosagemayaggravateheartdiseases.Patientsinashouldbegivenafistaid,whichisinfusionofT3（40-120μg）intravenoiusly,reinjection5－15μgevery6handoraladministrationwhenawake.Hypopituitarismpatientsshouldbegivencorticalhormonefirstandfollowedbythyroidhormone.Simplegoiter ReplacementtherapycaninhibitTSHoversecretionandcontracttheglandularorgan,3-6months.T3inhibitiontestDifferentialdiagnosisforPatientswithiodinehighuptake.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第10頁!AntithyroidDrugsTherapiesofhyperthyrosisinclude131Iradiotherapy,exairesisormedication.Thioureahomologuesaremainlyusedclinically.Iodineandiodideareusedjustinpreparationforoperationsandthyroidcrisistherapy.βreceptorblockerscanbeusedasadjunctivetherapyforthyroidcrisis.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第11頁!ThioureaPhysiologicalprocessAbsorption:

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

Organsgenerallyalloverthebodyandcanpasstheplacenta.Theconcentrationinlactoisabout3timesasinblood.Metabolism:

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

甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第12頁!PathogenesisofExophthalmoshyperthyroidism

andfunctionlinkofthioureahomologuesThisdiseaseiscausedbyanautoimmuneIgGantibodyLATS(longactingthyroidstimulator),whichcanbindtothereceptorsonthyroidadenocytesandstimulateoversecretionofthyroidhormones.Thioureahomologuescannotonlyinhibitsynthesisofthyroidhormones,butalsoLATSinpatients,whichisakindofimmunoinhibition.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第13頁!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甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第14頁!IodineandiodideActionsandapplicationsLowdoseofiodine(physiologicaldose)couldpreventandcuresimple(endemicity)goiter.Add1/10000~1/100000potassiumiodideorsodiumiodidetosaltcouldpreventthedesease.LargedoseofiodinecouldinhibitthereleaseofT3andT4(duetotheinhibitionofTGhydratase).Usedasadjunctivetherapyforhyperthyroidism:①preparationbeforeoperation:administrationofaqueousiodinesolutiontwoweeksbeforeoperationdegeneratestheglandulartissue,decreasesvesselsandbleeding;②adjunctivetherapyforthyroidcrisis:couldbeusedbinedwiththioureahomologues.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第15頁!Radioactiveiodine（131I）

T1/2is8.04daysActions

131Icouldbeuptakenbythroid,participateinthesynthesisofT3,T4andisstoredinfollecularcolloid.131Imainlygeneratesβray（99％）withaverageandmaximumpathof0.5mmand2mmrespectively.Sotheirradiationfunctionislimitedinthethyroid.Itcandestroytheglandularorganbutcanseldomdestroythesurroundingtissues.Γraygeneratedby131Iaccountsfor1％andcanbedetectedinvitro.Itisusuallyusedintheexaminationofthyroidiodineuptakingfunction.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第16頁!Radioactiveiodine

AdverseeffectsandapplicationnotesHypothyroidismisthepredominantplication.Theadverseeffectscanbereducedbystrictdosecontrolandresistedbythyrine.PatientswithTotalwhitebloodcellslessthan3000/mm3arenotsuitabletotakeit.Soarepragnantandlactantwomen,patientsyoungerthan20yearsoldorwithsevereliverorkidneydeseases.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第17頁!receptorblockersClinicalapplicationAdjunctivetherapyforhyperthyroidismandhyperthyroidismcrisis.MechanismofpharmacologicalactionsExcitedsympathetic-adrenergicsystemβ1receptorblockage—heartratedropCentralβreceptorblockage—toreduceanxietyβ2receptoronNAenerginicperipheralnerveendingspresynapticmembraneblockagereducesthereleaseofNA.AppropriatelyreduceT3,T4secretion.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第18頁!硫脲類硫氧嘧啶類（thiouracil）：甲基硫氧嘧啶（methykthiouracil）丙基硫氧嘧啶（propylthiouracil）咪唑類（imidazoles）他巴唑（Tapazole，甲巰咪唑methimazole）甲亢平（卡比馬唑Carbimazole）甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第19頁!甲狀腺激素的化學(xué)結(jié)構(gòu)甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第20頁!Synthesis,storageandregulationofthyroidhormonesIodineuptakeIodineactivationandtyrosineiodationCondensationandstorageDisintegrationandreleaseRegulation甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第21頁!Condensationandstorage:Inthethyroidglobulinmolecule,twoDTTsarecondensedtoT4,oneDTTandoneMITarecondensedtoT3，whichareallstoredinglandalveoluscolloid.Disintegrationandrelease:T3andT4arereleasedintobloodafterhydrolyzedbyproteases.Atthesametime,someofthemcanbeturnedbacktotyrosineandI－bydeiodinaseincellsandreused.Regulation:Bythepositiveandnegativefeedbackregulationofhypothalamus-anteriorlobe-thyroidaxis.HypothalamussecretsTRH,anteriorlobesecretsTSHandthyroidsynthesizeT3,T4.Stepsofthyroidhormonessynthesis,releaseandregulation(Ⅱ)甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第22頁!ThyroidhormonesMechanismofactionThebindingofT3andRincreasestheuptakeofaaandglucose,resultingintheentrancetocytoplasmofT3.AfterreactingwithCBP,T3iseduced.ThefreeT3canbindRinthemitochondriaandmakeADPtoATP.Besides,itcanenterthenuclearandbindRthere,whichcanincreasethetranscriptionofDNAandthecontentofmRNA.Thenthenewproteinscanbesynthesizedandplayroles.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第23頁!Physiologicalandpharmacologicalactions

Keepnormalgrowthanddevelopment

PromotesynthesisofproteinsaswellasgrowthanddevelopmentofskeletonandCNS.T3,T4deficientsecretion:causescretinismininfantsandyoungchildrenandmucousedemainadults.

Promotemetabolismandincreaseheatproduction

Promoteoxidation,increaseoxygenconsumption,basalmetabolicrateandheatproduction.

Elevatesensitivityofsympathetic-adrenalsystem

Nervousness,trembling,heartbeatspeedup,bloodpressureincrease甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第24頁!AdverseeffectsAdverseeffectOverdoseCombinationContraindicationhyperthyreosisoldpeopleheartdiseasebishydroxycoumarindantinaoraspirindiabeteshypertensionCoronaryheartdiseasepyknocardiathyroidcrisis:anxiety,fear,restlessness,highbodytemperature,increaseandirregularheartrate,increasepulsepressure,congestiveheartfailurewithvomit,diarrheaanddehydrationwhichleadtoaanddeathAnginaorheartinfarctionIncreasetoxicityofthyroidhormone甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第25頁!硫脲類硫氧嘧啶類：甲基硫氧嘧啶丙基硫氧嘧啶咪唑類他巴唑（又稱甲巰咪唑）甲亢平（又稱卡比馬唑）甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第26頁!PharmacologicalactionsInhibitperoxydaseinadenocytes,whichresultsintheinhibitedoxydationofI－toI0.Then,theiodationandcoupleoftyrosinescanbestopped.SothebiosynthesisofT3andT4isinhibited.Buttheeffectoccursslowlyastheiodineuptakeandthehormonealreadysynthesizedarenoteffected.LongtimemedicationcanleadtodecreaseofT3andT4,whichfeedbackincreasesthesecretionofTSHandmakesthyroidhyperplasyandhyperemicpensatorily.PropylthiouracilcaninhibitT4turningtoT3andcontrolT3levelinblood.Soitisthefirstchoiceinhyperthyroidismcrisis,severehyperthyroidismandpregnanthyperthyroidism.Inhibitimmuno-system(ashyperthyroidismisrelatedwithabnormalimmunoreactions).Thiourea甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第27頁!ThioureaClinicalapplicationHyperthyroidism

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

Preparationbeforeoperation

Medicationbeforeoperationisgoodtodecreasebleedinginoperationandpreventthyroidcrisisafteroperation.Adjunctivemedicationofthyroidcrisis

Besidesintegratemeasures,largedoseofThioureahomologuescanbeusedasadjunctivetherapy,SoisPropranolol.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是第28頁!ThioureaAdverseeffects

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

Skinrash,headache,dinus,gastrointestinalunfortable,fatigueandsoon.

Severeadverseeffects：

Bonemarrowdepression,agranulocytosisandsoon.Note:Periodicinspectionofhemogram.Themedicationshoulebestoppedifthesymptomsaspharyngalgia,fever,cathaeresisoccur.Thyroidcancerpatientsareforbiddentotake.甲狀腺激素和抗甲狀腺藥Thyroid共33頁，您現(xiàn)在瀏覽的是