甲狀腺激素和抗甲狀腺藥MODELS 8 CHAPTER 3

Chapter3Module8:EndocrineDrugsEndocrineDrugsThyroidphysiologyThenormalthyroidglandsecretessufficientamountsofthethyroidhormones—triiodothyronine(T3)andtetraiodothyronine(T4,thyroxine)—tonormalizegrowthanddevelopment,bodytemperature,andenergylevels.IodidemetabolismTherecommendeddailyadultiodide(I–)*intakeis150mcg(200mcgduringpregnancy).Iodide,ingestedfromfood,water,ormedication,israpidlyabsorbedandentersanextracellularfluidpool.BiosynthesisofthyroidhormonesOncetakenupbythethyroidgland,iodideundergoesaseriesofenzymaticreactionsthatincorporateitintoactivethyroidhormoneEndocrineDrugsFIGURE:Biosynthesisofthyroidhormones.Thesitesofactionofvariousdrugsthatinterferewiththyroidhormonebiosynthesisareshown.EndocrineDrugsTransportofthyroidhormonesT4andT3inplasmaarereversiblyboundtoprotein,primarilythyroxine-bindingglobulin(TBG).Onlyabout0.04%oftotalT4and0.4%ofT3existinthefreeform.ManyphysiologicandpathologicstatesanddrugsaffectT4,T3,andthyroidtransport.However,theactuallevelsoffreehormonegenerallyremainnormal,reflectingfeedbackcontrol.PeripheralmetabolismofthyroidhormonesTheprimarypathwayfortheperipheralmetabolismofthyroxineisdeiodination.EvaluationofthyroidfunctionThyroid-pituitaryrelationshipsControlofthyroidfunctionviathyroid-pituitaryfeedback.Briefly,hypothalamiccellssecretethyrotropin-releasinghormone(TRH)EndocrineDrugsAutoregulationofthethyroidglandThethyroidglandalsoregulatesitsuptakeofiodideandthyroidhormonesynthesisbyintrathyroidalmechanismsthatareindependentofTSH.Thesemechanismsareprimarilyrelatedtothelevelofiodineintheblood.AbnormalthyroidstimulatorsInGraves’disease(seebelow),lymphocytessecreteaTSHreceptor-stimulatingantibody(TSH-RAb[stim]),alsoknownasthyroid-stimulatingimmunoglobulin(TSI).BasicpharmacologyofthyroidandantithyroiddrugsThyroidhormonesChemistryEndocrineDrugsFIGURE:Peripheralmetabolismofthyroxine.(Adapted,withpermission,fromGardnerDG,ShobackD[editors]:Greenspan’sBasic&ClinicalEndocrinology,8thed.McGraw-Hill,2007.Copyright?TheMcGraw-HillCompanies,Inc.EndocrineDrugsPharmacokineticsThyroxineisabsorbedbestintheduodenumandileum;absorptionismodifiedbyintraluminalfactorssuchasfood,drugs,gastricacidity,andintestinalflora.MechanismsofactionAmodelofthyroidhormoneactionisdepicted,whichshowsthefreeformsofthyroidhormones,T4andT3,dissociatedfromthyroid-bindingproteins,enteringthecellbyactivetransport.Withinthecell,T4isconvertedtoT3by5'-deiodinase,andtheT3entersthenucleus,whereT3bindstoaspecificT3receptorprotein,amemberofthec-erboncogenefamilyEffectsofthyroidhormonesdevelopment,function,andmaintenanceofallbodytissues.Excessorinadequateamountsresultinthesignsandsymptomsofhyperthyroidismorhypothyroidism,respectively.EndocrineDrugsThyroidpropertiesThyroidhormonesarenoteffectiveandcanbedetrimentalinthemanagementofobesity,abnormalvaginalbleeding,ordepressionifthyroidhormonelevelsarenormal.AntithyroidagentsReductionofthyroidactivityandhormoneeffectscanbeaccomplishedbyagentsthatinterferewiththeproductionofthyroidhormones,byagentsthatmodifythetissueresponsetothyroidhormones,orbyglandulardestructionwithradiationorsurgeryThioamidesThethioamidesmethimazoleandpropylthiouracilaremajordrugsfortreatmentofthyrotoxicosis.EndocrineDrugsPharmacokineticsThethioamidesactbymultiplemechanisms.Themajoractionistopreventhormonesynthesisbyinhibitingthethyroidperoxidase-catalyzedreactionsandblockingiodineorganification.Inaddition,theyblockcouplingoftheiodotyrosines.ToxicityAdversereactionstothethioamidesoccurin3–12%oftreatedpatients.Mostreactionsoccurearly,especiallynauseaandgastrointestinaldistress.Analteredsenseoftasteorsmellmayoccurwithmethimazole.AnioninhibitorsMonovalentanionssuchasperchlorate(ClO4?),pertechnetate(TcO4

?),andthiocyanate(SCN?)canblockuptakeofiodidebytheglandthroughcompetitiveinhibitionoftheiodidetransportmechanism.Sincetheseeffectscanbeovercomebylargedosesofiodides,theireffectivenessissomewhatunpredictable.

EndocrineDrugsIodidesPriortotheintroductionofthethioamidesinthe1940s,iodideswerethemajorantithyroidagents;todaytheyarerarelyusedassoletherapy.PharmacodynamicsIodideshaveseveralactionsonthethyroid.Theyinhibitorganificationandhormonereleaseanddecreasethesizeandvascularityofthehyperplasticgland.Insusceptibleindividuals,iodidescaninducehyperthyroidism(Jod-Basedowphenomenon)orprecipitatehypothyroidism.

ClinicaluseofiodideDisadvantagesofiodidetherapyincludeanincreaseinintraglandularstoresofiodine,whichmaydelayonsetofthioamidetherapyorpreventuseofradioactiveiodinetherapyforseveralweeks.Toxicity Adversereactionstoiodine(iodism)areuncommonandinmostcasesreversibleupondiscontinuance.Radioactiveiodinetheonlyisotopeusedfortreatmentofthyrotoxicosis.(Othersareusedindiagnosis.)Administeredorallyinsolutionassodium,itisrapidlyabsorbed,concentratedbythethyroid,

andincorporatedintostoragefollicles.EndocrineDrugsEndocrineDrugsAdrenoceptor-blockingagentsBetablockerswithoutintrinsicsympathomimeticactivity(eg,metoprolol,propranolol,atenolol)areeffectivetherapeuticadjunctsinthemanagementofthyrotoxicosissincemanyofthesesymptomsmimicthoseassociatedwithsympatheticstimulation.ClinicalpharmacologyofthyroidandantithyroiddrugsHypothyroidismHypothyroidismisasyndromeresultingfromdeficiencyofthyroidhormonesandismanifestedlargelybyareversibleslowingdownofallbodyfunctions.Ininfantsandchildren,thereisstrikingretardationofgrowthanddevelopmentthatresultsindwarfismandirreversiblementalretardation.ManagementofhypothyroidismExceptforhypothyroidismcausedbydrugs,whichcanbetreatedinsomecasesbysimplyremovingthedepressantagent,thegeneralstrategyofreplacementtherapyisappro-priate.Themostsatisfactorypreparationislevothyroxine,administeredaseitherabrandedorgenericpreparation.EndocrineDrugsSpecialproblemsinmanagementofhypothyroidismMyxedemaandcoronaryarterydiseaseSincemyxedemafrequentlyoccursinolderpersons,itisoftenassociatedwithunderlyingcoronaryarterydisease.Inthissituation,thelowlevelsofcirculatingthyroidhormoneactuallyprotecttheheartagainstincreasingdemandsthatcouldresultinanginapectorisormyocardialinfarction.MyxedemacomaMyxedemacomaisanendstateofuntreatedhypothyroidism.Itisassociatedwithprogressiveweakness,stupor,hypothermia,hypoventilation,hypoglycemia,hyponatremia,waterintoxication,shock,anddeath.EndocrineDrugsHypothyroidismandpregnancyHypothyroidwomenfrequentlyhaveanovulatorycyclesandarethereforerelativelyinfertileuntilrestorationoftheeuthyroidstate.Thishasledtothewidespreaduseofthyroidhormoneforinfertility,althoughthereisnoevidenceforitsusefulnessininfertileeuthyroidpatientsSubclinicalhypothyroidismSubclinicalhypothyroidism,definedasanelevatedTSHlevelandnormalthyroidhormonelevels,isfoundin4–10%ofthegeneralpopulationbutincreasesto20%inwomenolderthanage50.Drug-inducedhypothyroidismDrug-inducedhypothyroidismcanbesatisfactorilymanagedwithlevothyroxinetherapyiftheoffendingagentcannotbestopped.HyperthyroidismHyperthyroidism(thyrotoxicosis)istheclinicalsyndromethatresultswhentissuesareexposedtohighlevelsofthyroidhormone.

EndocrineDrugsGraves’diseaseThemostcommonformofhyperthyroidismisGraves’disease,ordiffusetoxicgoiter.ThepresentingsignsandsymptomsofGraves’diseasearesetforthPathophysiologyGraves’diseaseisconsideredtobeanautoimmunedisorderinwhichhelperTlymphocytesstimulateBlymphocytestosynthesizeantibodiestothyroidalantigens.Theantibodydescribedpreviously(TSH-RAb[stim])isdirectedagainsttheTSHreceptorsiteinthethyroidcellmembraneandhasthecapacitytostimulategrowthandbiosyntheticactivityofthethyroidcell.LaboratorydiagnosisInmostpatientswithhyperthyroidism,T3,T4,FT4,andFT3areelevatedandTSHissuppressed.Radioiodineuptakeisusuallymarkedlyelevatedaswell.Antithyroglobulin,thyroidperoxidase,andTSH-RAb[stim]antibodiesareusuallypresent.EndocrineDrugsManagementofGraves’diseaseThethreeprimarymethodsforcontrollinghyperthyroidismareantithyroiddrugtherapy,surgicalthyroidectomy,anddestructionoftheglandwithradioactiveiodine.

AntithyroidDrugTherapyThyroidectomyRadioactiveIodineD.AdjunctstoAntithyroidTherapy

ToxicuninodulargoiterandtoxicmultinodulargoiterTheseformsofhyperthyroidismoccurofteninolderwomenwithnodulargoiters.FT4ismoderatelyelevatedoroccasionallynormal,butFT3orT3isstrikinglyelevated.EndocrineDrugsSubacutethyroiditisDuringtheacutephaseofaviralinfectionofthethyroidgland,thereisdestructionofthyroidparenchymawithtransientreleaseofstoredthyroidhormones.AsimilarstatemayoccurinpatientswithHashimoto’sthyroiditis.Theseepisodesoftransientthyrotoxicosishavebeentermedspontaneouslyresolvinghyperthyroidism.SpecialproblemsThyroidstormThyroidstorm,orthyrotoxiccrisis,issuddenacuteexacerbationofallofthesymptomsofthyrotoxicosis,presentingasalife-threateningsyndrome.Vigorousmanagementismandatory.Propranolol,1–2mgslowlyintravenouslyor40–80mgorallyevery6hours,ishelpfultocontroltheseverecardiovascularmanifestations.OpthalmopathyAlthoughsevereophthalmopathyisrare,itisdifficulttotreat.Managementrequireseffectivetreatmentofthethyroiddisease,usuallybytotalsurgicalexcisionor131Iablationoftheglandplusoralprednisonetherapy.DermopathyDermopathyorpretibialmyxedemawilloftenrespondtotopicalcorticosteroidsappliedtotheinvolvedareaandcoveredwithanocclusivedressing

ThyrotoxicosisduringpregnancyIdeally,womeninthechildbearingperiodwithseverediseaseshouldhavedefinitivetherapywith131Iorsubtotalthyroidec-tomypriortopregnancyinordertoavoidanacuteexacerbationofthediseaseduringpregnancyorfollowingdelivery.EndocrineDrugsNeonatalGraves’diseaseGraves’diseasemayoccurinthenewborninfant,eitherduetopassageofmaternalTSH-RAb[stim]throughtheplacenta,stimulatingthethyroidglandofthe