藥物不良反應之皮膚表現(xiàn)

1、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)2022/10/9Mechanism of Adverse Drug ReactionsType A: 藥理作用相關(guān)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(guān) 必須降低劑量者. Type B: 特質(zhì)性或過敏性(idiosyncratic or allergic)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(guān)反應(dose-response relationship)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

2、敏步驟 (Desensitization)2022/10/9藥物過敏皮膚反應之診斷是否為藥物過敏之皮膚反應？Allergic or pseudoallergic ?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？可能之預后嚴重性如何？2022/10/9藥物反應之免疫作用機轉(zhuǎn)Type I: IgE dependent (Anaphylaxis)蕁麻疹、血管性水腫、休克Type II: Cytotoxic (Biological)天皰瘡Pemphigus, Thromobocytopenic petechia,Type III: Immune

3、-complex (Chemical, Connective )血管炎Vasculitis, 血清病serum sickness, Type IV: Cell mediated , Delayed typeGranulomatous, Eczematous史帝芬瓊森征候群、毒性表皮壞死癥 (SIS-TEN)Th1-INF-Mono, Th2-IL-5-Eosin, IL-8 PMN, CD4/82022/10/9Mechanism of Frug HypersensitivityAnnals of Internal Medicine 2003, 139(8): 684 2022/10/9判斷A

4、DR之原因藥物及嚴重度一、臨床特征原發(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并發(fā)癥狀：全身性癥狀發(fā)燒、關(guān)節(jié)痛內(nèi)臟變化、多重器官淋巴腺腫 痛2022/10/9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(guān)之肝、腎功能變化開始發(fā)疹日期計算出服藥及發(fā)疹之間隔停藥后之反應再度使用之反應2022/10/9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):麻疹樣藥疹局限性或泛發(fā)型(+粘膜?)發(fā)疹型多型性紅斑，水皰

5、、黏膜 (SJS/TEN)局部反應固定藥疹、光敏感性、水皰癥、壞死等2022/10/9Severe Cutaneous ADR2022/10/9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、免疫復合體病)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 TEN2022/10/9立即性反應：Anaphylaxis蕁麻疹Urticaria 血管性水腫Angioedema Anaphylaxis休克ADR之比例: Anaphylaxis 30%Urticaria 10% 為藥物引

6、起服藥至發(fā)疹間隔：分鐘至小時Mortality：5%常見原因藥物：-lactam: Penicillins, Cephalosporins, NSAID, contrast media, monoclonal Aby2022/10/9發(fā)疹樣藥疹Exanthematous Drug Eruption常見之藥物不良反應皮疹From trunk to extremities Maculopapules or urticariamay confluent Purpura at ankle, feet, waistMucosa is spared可能有少數(shù)毛囊性膿皰ADR之比例: Child 10-20

7、%, Adult 50-70%服藥至發(fā)疹間隔：4(7)-14days2022/10/9發(fā)疹樣藥疹Exanthematous Drug EruptionType IV, or 非免疫性direct binding to MHC-2 in KC(sulfa)AminoPC in Infectious mononucleosis可能為嚴重之藥疹的前驅(qū)危險征候毛囊一致性膿皰，紫斑，Nikolskys sign, 粘膜潰瘍系統(tǒng)性功能異常D Dx: Viral exanthema, Toxic shock syndrome, GVHD, Kawasakis, Stills2022/10/9發(fā)疹樣藥疹Exa

8、nthematous Drug Eruption2022/10/9Perifollicular papules with central pustulesExanthematous Rash with Purpura: Vasculitis發(fā)疹樣藥疹Exanthematous Drug EruptionMortality：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: DRESSPalpable purpura, arthritis: VasculitisFacial edema: DRESS, ErythrodermaMuco

9、sa involvement: TEN, SJS Painful skin: TEN2022/10/9血管炎 VasculitisPalpable purpura可能伴隨蕁麻疹，發(fā)疹變化血清病、免疫復合體病 (Type III reaction)Dermato-arthritis syndrome r/o bacteremia/sepsis first可能波及多重器官ADR之比例: 10%服藥至發(fā)疹間隔：7-21days, challenge 3days2022/10/9Leukocytoclastic Vasculitis有硬結(jié)的紫斑Palpable purpura表面有無壞死現(xiàn)象？有無血尿

10、？CheckCBC, WBC/DCLFTRFTC3, C42022/10/9血管炎 VasculitisMortality：？常見原因藥物：Penicillins, NSAID(oral, topical) Sulfonamide, Cephalosporins, Anticonvulsant, Allopurinol, Thiazide, Bio products (G,M-CSF, biologics, etc.)2022/10/9DRESS : Drug Rashes with Eosinophilia and Systemic Symptoms2022/10/9DRESS Hypers

11、ensitivity Syndrome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 Drug Rash (Reaction) with Eosinophilia and Systemic Symptoms 常與藥物之代謝有關(guān)，或病毒HHV-6,7Immune +, IL-5Th2eosinophilsADR之比例: 70-90%服藥至發(fā)疹間隔：15-40days停藥后持續(xù)數(shù)周至數(shù)月Mortality：5-10%2022/10/9DRESS Hypersensitivity SyndromeFebrile (85%) mobilliform rash(75%)麻疹樣、 浮腫、fo

12、llicular accentuation，水皰、膿皰、紫斑、紅皮癥好發(fā)于臉、上軀干及四肢；臉浮腫特征Systemic involvementHepatitis, myocarditis, interstitial pneumonitis, nephritis, thyroiditis etc.LymphadenopathyRx of Corticosteroids : first choiceMay relapse during tapering2022/10/9DRESS Hypersensitivity Syndrome伴隨系統(tǒng)癥狀、嗜伊紅球癥之藥疹常與藥物之代謝有關(guān)：phenytoin

13、 (arene oxide) 1:1000sulfonamide (hydoxylamine?) 1:10,000常見原因藥物： Aromatic Anticonvulsant( phenytoin, carbamazepine, phenobarbital)Allopurinol (in renal dysfunction)Lamotrigine (esp. with Valproate)Sulfonamide, dapsoneMinocycline, gold salt2022/10/9急性發(fā)疹樣膿皰癥Acute Generalized Exanthematous Pustulosis (

14、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(AGEP) Acute Generalized Exanthematous Pustulosis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)快速擴散軀干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周Mortality：1-2%2022/10/9AGEP / EMto Pseudoephedrine2022/10/9急性發(fā)疹樣膿皰癥(AGEP)可能是敏感之recall reactionPatch test: 陽性率達80%Neutrophilia

15、, IL-3, 8, G-CSF from T cellsADR之比例: 70-90%服藥至發(fā)疹間隔：90%)臉部水腫Scaling：lamellar, crustybrannyHyper-/hypo-thermia, Tachycardia, CHFlymphadenopathyy, hepatomegalyEosinophilia and lymphopeniaADR之比例: 19% (5.5-42%)為藥物引起服藥至發(fā)疹間隔：wks to mons (epoprostenol)停藥后2-6wks緩解 Mortality：?2022/10/9紅皮癥(剝脫性皮膚炎)常見原因藥物：Allopu

16、rinol, Ampicillin/Amoxicillin/Penicillins, (14% floxacillin) carbamazepine (ox-), phenobabital, phenytoin dapsone, sulfasalazine, sulfonamide, clofazimine, omeprazole, phenothiazines, vancomycine, captopril, nefedipine, isoniazide, ethambutol (HIV+)2022/10/9Erythema Multiforme, SJS/TENContinuous spe

17、ctrum or Different entity?多型性紅斑Erythema Multiforme史帝芬瓊森征候群(SJS) Stevens-Johnson Syndrome 毒性表皮壞死癥TEN Toxic Epidermal NecrolysisTarget erythema, Blisters, Tender skin, Epidermal detachment, Exfoliation, Multiple Mucosal involvement2022/10/9EMSJS(10%)SJS/TENTEN(30%)2022/10/9Stevens-Johnson Syndrome & T

18、oxic Epidermal NecrolysisCategoryIncidence per mil-yrDrug related ratioMortalityPrimary eruptions (major feature)Isolate vs ConfluenceDetachment (% BSA)Interface vs NecrosisSystemic symptomsTEN80-95%25-50% Red edema & denudedConfluence 30I NecrosisAlwaysSJS1.2-6 50%5%Target & dusky redIsolated 多 Nusually2022/10/9Toxic Epidermal Necrolysis2022/10/9Stevens-Johnson Syndrome & Toxic Epidermal NecrolysisProdromal : URI-like1-14 days before in SJS, 1-3 days in TENSystemic: hepatitisADR 之比例：70-90%服藥至發(fā)疹間隔：14-56天一般藥物為weeks, TEN 7-21days, Re-exposure 40 yearsYes = 1, No