藥物不良反應之皮膚表現(xiàn)臺北市立聯(lián)合醫(yī)院皮膚科(和平)林瑞宜2023/8/20藥物不良反應之皮膚表現(xiàn)臺北市立聯(lián)合醫(yī)院皮膚科(和平)2023*演講大綱藥物不良反應之作用機轉(zhuǎn)過敏與非過敏如何診斷藥物過敏？藥物反應之作用之重要皮膚表現(xiàn)危險徵候*演講大綱藥物不良反應之作用機轉(zhuǎn)*MechanismofAdverseDrugReactionsTypeA:藥理作用相關者(Pharmacological)依照藥理作用可預測者為已知之作用效果之擴大表現(xiàn)者常與劑量有關必須降低劑量者.TypeB:特質(zhì)性或過敏性(idiosyncraticorallergic)依照藥物之藥理作用無法來預測者奇異的或特直性的不良反應常非單純之劑量相關反應(dose-responserelationship)發(fā)生不良反應時，誘因藥物常必須中止續(xù)用非用不可時，常須經(jīng)過減敏步驟(Desensitization)*MechanismofAdverseDrugRea*藥物過敏皮膚反應之診斷是否為藥物過敏之皮膚反應？Allergicorpseudoallergic?過敏或不良反應之類型為何？何種免疫反應？何種皮膚反應？誘發(fā)藥物為何？有無交互作用或交叉反應之藥物或情況？可能之預後嚴重性如何？*藥物過敏皮膚反應之診斷是否為藥物過敏之皮膚反應？*藥物反應之免疫作用機轉(zhuǎn)TypeI:IgEdependent(Anaphylaxis)蕁麻疹、血管性水腫、休克TypeII:Cytotoxic(Biological)天皰瘡Pemphigus,Thromobocytopenicpetechia,TypeIII:Immune-complex(Chemical,Connective)血管炎Vasculitis,血清病serumsickness,TypeIV:Cellmediated,DelayedtypeGranulomatous,Eczematous史帝芬─強生徵候群、毒性表皮壞死癥(SIS-TEN)Th1-INFγ-Mono,Th2-IL-5-Eosin,IL-8PMN,CD4/8*藥物反應之免疫作用機轉(zhuǎn)TypeI:IgEdepend*MechanismofFrugHypersensitivityAnnalsofInternalMedicine2003,139(8):

684*MechanismofFrugHypersensit*判斷ADR之原因藥物及嚴重度

一、臨床特徵原發(fā)皮疹之類型斑疹、丘疹、結(jié)節(jié)、膨疹、紫斑、水皰、膿皰皮疹之分布、數(shù)目及癢、痛等局部癥狀有無波及粘膜併發(fā)癥狀：全身性癥狀發(fā)燒、關節(jié)痛內(nèi)臟變化、多重器官淋巴腺腫痛*判斷ADR之原因藥物及嚴重度

一、臨床特徵原發(fā)皮疹之類型*判斷ADR之原因藥物

二、病程、時序應紀錄所有用藥史：種類及起訖過去，類似藥物、劑量變化其他可能交互作用之藥物，隱藏藥物藥物代謝相關之肝、腎功能變化開始發(fā)疹日期計算出服藥及發(fā)疹之間隔停藥後之反應再度使用之反應*判斷ADR之原因藥物

二、病程、時序應紀錄所有用藥史：種類*皮膚藥物反應的簡單分類立即性或延遲性，自限性或持續(xù)性蕁麻疹及血管性水腫、休克發(fā)疹(exanthema):麻疹樣藥疹侷限性或汎發(fā)型(+粘膜?)發(fā)疹型 多型性紅斑，水皰、黏膜

(SJS/TEN)局部反應固定藥疹、光敏感性、水皰癥、壞死等*皮膚藥物反應的簡單分類立即性或延遲性，自限性或持續(xù)性*SevereCutaneousADR*SevereCutaneousADR*藥物反應的重要皮膚病變發(fā)疹樣藥疹：可能為下列之早期病變急性發(fā)疹樣膿皰癥(AGEP)血管炎(血清病、免疫複合體病)紅皮癥(剝脫性皮膚炎)伴隨系統(tǒng)癥狀、嗜伊紅球癥之藥疹(DRESS)SJS-TEN(毒性表皮壞死癥)多型性紅斑

SJS

TEN*藥物反應的重要皮膚病變發(fā)疹樣藥疹：可能為下列之早期病變*立即性反應：Anaphylaxis蕁麻疹Urticaria

血管性水腫Angioedema

Anaphylaxis休克ADR之比例:Anaphylaxis30%Urticaria10%為藥物引起服藥至發(fā)疹間隔：分鐘至小時Mortality：5%常見原因藥物：β-lactam:Penicillins,Cephalosporins,NSAID,contrastmedia,monoclonalAby*立即性反應：Anaphylaxis蕁麻疹Urticaria*發(fā)疹樣藥疹

ExanthematousDrugEruption常見之藥物不良反應皮疹FromtrunktoextremitiesMaculopapulesorurticariamayconfluentPurpuraatankle,feet,waistMucosaisspared可能有少數(shù)毛囊性膿皰ADR之比例:Child10-20%,Adult50-70%服藥至發(fā)疹間隔：4(7)-14days*發(fā)疹樣藥疹

ExanthematousDrugErup*發(fā)疹樣藥疹

ExanthematousDrugEruptionTypeIV,or非免疫性directbindingtoMHC-2inKC(sulfa)AminoPCinInfectiousmononucleosis可能為嚴重之藥疹的前驅(qū)危險徵候毛囊一致性膿皰，紫斑，Nikolsky’ssign,粘膜潰瘍系統(tǒng)性功能異常DDx:Viralexanthema,Toxicshocksyndrome,GVHD,Kawasaki’s,Still’s*發(fā)疹樣藥疹

ExanthematousDrugErup*發(fā)疹樣藥疹

ExanthematousDrugEruption*發(fā)疹樣藥疹

ExanthematousDrugErupPerifollicularpapuleswithcentralpustulesExanthematousRashwithPurpura:VasculitisPerifollicularpapuleswithce*發(fā)疹樣藥疹

ExanthematousDrugEruptionMortality：單純發(fā)疹樣藥疹為:0%其他進展？？？可能為嚴重之藥疹的前驅(qū)可能為嚴重之藥疹的前驅(qū)Hypereosinophilia:DRESSPalpablepurpura,arthritis:VasculitisFacialedema:DRESS,ErythrodermaMucosainvolvement:TEN,SJSPainfulskin:TEN*發(fā)疹樣藥疹

ExanthematousDrugErup*血管炎VasculitisPalpablepurpura可能伴隨蕁麻疹，發(fā)疹變化血清病、免疫複合體病(TypeIIIreaction)Dermato-arthritissyndromer/obacteremia/sepsisfirst可能波及多重器官ADR之比例:<10%服藥至發(fā)疹間隔：7-21days,challenge<3days*血管炎VasculitisPalpablepurpur*LeukocytoclasticVasculitis有硬結(jié)的紫斑Palpablepurpura表面有無壞死現(xiàn)象？有無血尿？CheckCBC,WBC/DCLFTRFTC3,C4*LeukocytoclasticVasculitis有硬*血管炎VasculitisMortality：？？？常見原因藥物：Penicillins,NSAID(oral,topical)Sulfonamide,Cephalosporins,Anticonvulsant,Allopurinol,Thiazide,Bioproducts(G,M-CSF,biologics,etc.)*血管炎VasculitisMortality：？？？*DRESS:

DrugRasheswithEosinophiliaandSystemicSymptoms*DRESS:

DrugRasheswithEos*DRESSHypersensitivitySyndrome伴隨系統(tǒng)癥狀、嗜伊紅球癥之藥疹伴隨系統(tǒng)癥狀、嗜伊紅球癥之藥疹

DrugRash(Reaction)withEosinophiliaandSystemicSymptoms

常與藥物之代謝有關，或病毒HHV-6,7Immune+,IL-5—Th2—eosinophilsADR之比例:70-90%服藥至發(fā)疹間隔：15-40days停藥後持續(xù)數(shù)週至數(shù)月Mortality：5-10%*DRESSHypersensitivitySyndro*DRESSHypersensitivitySyndromeFebrile(85%)mobilliformrash(75%)麻疹樣、浮腫、follicularaccentuation，水皰、膿皰、紫斑、紅皮癥好發(fā)於臉、上軀幹及四肢；臉浮腫特徵SystemicinvolvementHepatitis,myocarditis,interstitialpneumonitis,nephritis,thyroiditisetc.LymphadenopathyRxofCorticosteroids:firstchoiceMayrelapseduringtapering*DRESSHypersensitivitySyndro*DRESSHypersensitivitySyndrome伴隨系統(tǒng)癥狀、嗜伊紅球癥之藥疹常與藥物之代謝有關：phenytoin(areneoxide)1:1000sulfonamide(hydoxylamine?)1:10,000常見原因藥物：AromaticAnticonvulsant(phenytoin,carbamazepine,phenobarbital)Allopurinol(inrenaldysfunction)Lamotrigine(esp.withValproate)Sulfonamide,dapsoneMinocycline,goldsalt*DRESSHypersensitivitySyndro急性發(fā)疹樣膿皰癥

AcuteGeneralizedExanthematousPustulosis(AGEP)臉部或腋下鼠蹊開始水腫性紅斑有非毛囊性小膿皰急性發(fā)疹樣膿皰癥

AcuteGeneralizedExa*急性發(fā)疹樣膿皰癥(AGEP)AcuteGeneralizedExanthematousPustulosis急性發(fā)燒，與皮疹同時或更早臉部或腋下鼠蹊等部位浮腫開始數(shù)小時內(nèi)快速擴散軀幹及上肢會波及粘膜皮疹為多樣性，癢或熱感水腫性紅斑上有非毛囊性小膿皰水腫、紫斑，水皰，靶型疹皮疹持續(xù)1-2週Mortality：1-2%*急性發(fā)疹樣膿皰癥(AGEP)AcuteGenerali*AGEP/EM

to

Pseudoephedrine*AGEP/EM

to

Pseudoephedrin*急性發(fā)疹樣膿皰癥(AGEP)可能是敏感之recallreactionPatchtest:陽性率達80%Neutrophilia,IL-3,8,G-CSFfromTcellsADR之比例:70-90%服藥至發(fā)疹間隔：<四天，一般為兩天內(nèi)常見原因藥物：?-lactame(PC,aminoPC,Cephalosporins)Macrolides,Calciumchannelblockers(esp.diltiazem)Sulfasalazine-COX2Inh*急性發(fā)疹樣膿皰癥(AGEP)可能是敏感之recallre*Erythroderma

inAnticonvulsantHypersensitivitySyndrome*Erythroderma

inAnticonvulsa*紅皮癥(剝脫性皮膚炎)Exfoliativedermatitis,Erythroderma先局部皮疹，常由flexural開始，麻疹樣2-6天內(nèi)擴展至全身(>90%)臉部水腫Scaling：lamellar,crustybrannyHyper-/hypo-thermia,Tachycardia,CHFlymphadenopathyy,hepatomegalyEosinophiliaandlymphopeniaADR之比例:19%(5.5-42%)為藥物引起服藥至發(fā)疹間隔：wkstomons(epoprostenol)停藥後2-6wks緩解Mortality：?*紅皮癥(剝脫性皮膚炎)Exfoliativederma*紅皮癥(剝脫性皮膚炎)常見原因藥物：Allopurinol,Ampicillin/Amoxicillin/Penicillins,(14%floxacillin)carbamazepine(ox-),phenobabital,phenytoindapsone,sulfasalazine,sulfonamide,clofazimine,omeprazole,phenothiazines,vancomycine,captopril,nefedipine,isoniazide,ethambutol(HIV+)*紅皮癥(剝脫性皮膚炎)常見原因藥物：*ErythemaMultiforme,SJS/TENContinuousspectrumorDifferententity?多型性紅斑ErythemaMultiforme史帝芬─強生徵候群(SJS)Stevens-JohnsonSyndrome毒性表皮壞死癥TENToxicEpidermalNecrolysisTargeterythema,Blisters,Tenderskin,Epidermaldetachment,Exfoliation,MultipleMucosalinvolvement*ErythemaMultiforme,SJS/TENC*EM→SJS(10%)→SJS/TEN→TEN(30%)*EM→SJS(10%)→SJS/TEN→TEN(30%)*Stevens-JohnsonSyndrome&

ToxicEpidermalNecrolysisCategoryIncidencepermil-yrDrugrelatedratioMortalityPrimaryeruptions(majorfeature)IsolatevsConfluenceDetachment(%BSA)InterfacevsNecrosisSystemicsymptomsTEN0.4-1.280-95%25-50%Rededema&denudedConfluence>30I<NecrosisAlwaysSJS1.2-650%5%Target&duskyredIsolated多<10Interface>Nusually*Stevens-JohnsonSyndrome&

T*ToxicEpidermalNecrolysis*ToxicEpidermalNecrolysis*Stevens-JohnsonSyndrome&ToxicEpidermalNecrolysisProdromal:URI-like1-14daysbeforeinSJS,1-3daysinTENSystemic:hepatitisADR之比例：70-90%服藥至發(fā)疹間隔：14-56天一般藥物為weeks,TEN7-21days,Re-exposure<2days)Valproate,Aromaticanticonvulsantsfirst2MsTreatment：withdrawculpitdrug,SkincareSteroid,IVIG(antisFasL)About3weeksforheal