药物不良反应的皮肤表现

null藥物不良反應之皮膚表現藥物不良反應之皮膚表現臺北市立聯合醫院皮膚科(和平) 林瑞宜*演講大綱*演講大綱藥物不良反應之作用機轉 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 危險徵候Mechanism of Adverse Drug Reactions*Mechanism of Adverse Drug ReactionsType A: 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者 常與劑量有關 必須降低劑量者. Type B: 特質性或過敏性(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反應(dose-response relationship) 發生不良反應時，誘因藥物常必須中止續用 非用不可時，常須經過減敏步驟 (Desensitization)藥物過敏皮膚反應之診斷*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？藥物反應之免疫作用機轉*藥物反應之免疫作用機轉Type I: IgE dependent (Anaphylaxis) 蕁麻疹、血管性水腫、休克 Type II: Cytotoxic (Biological) 天疱瘡Pemphigus, Thromobocytopenic petechia, Type III: Immune-complex (Chemical, Connective ) 血管炎Vasculitis, 血清病serum sickness, Type IV: Cell mediated , Delayed type Granulomatous, Eczematous 史帝芬─強生徵候群、毒性表皮壞死症 (SIS-TEN) Th1-INFγ-Mono, Th2-IL-5-Eosin, IL-8 PMN, CD4/8Mechanism of Frug Hypersensitivity*Mechanism of Frug HypersensitivityAnnals of Internal Medicine 2003, 139(8): 684 判斷ADR之原因藥物及嚴重度 一、臨床特徵*判斷ADR之原因藥物及嚴重度 一、臨床特徵原發皮疹之類型 斑疹、丘疹、結節、膨疹、 紫斑、水疱、膿疱 皮疹之分布、數目及癢、痛等局部症狀 有無波及粘膜 併發症狀：全身性症狀 發燒、關節痛 內臟變化、多重器官 淋巴腺腫 痛判斷ADR之原因藥物 二、病程、時序*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 開始發疹日期 計算出服藥及發疹之間隔 停藥後之反應 再度使用之反應皮膚藥物反應的簡單分類*皮膚藥物反應的簡單分類立即性或延遲性，自限性或持續性 蕁麻疹及血管性水腫、休克 發疹(exanthema):麻疹樣藥疹 侷限性或汎發型(+粘膜?) 發疹型 多型性紅斑，水疱、黏膜 (SJS/TEN) 局部反應 固定藥疹、光敏感性、水疱症、壞死等Severe Cutaneous ADR*Severe Cutaneous ADR藥物反應的重要皮膚病變*藥物反應的重要皮膚病變發疹 樣藥疹：可能為下列之早期病變 急性發疹樣膿疱症(AGEP) 血管炎(血清病、免疫複合體病) 紅皮症(剝脫性皮膚炎) 伴隨系統症狀、嗜伊紅球症之藥疹(DRESS) SJS-TEN(毒性表皮壞死症) 多型性紅斑 SJS TEN立即性反應：Anaphylaxis*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% 為藥物引起 服藥至發疹間隔：分鐘至小時 Mortality：5% 常見原因藥物：β-lactam: Penicillins, Cephalosporins, NSAID, contrast media, monoclonal Aby發疹樣藥疹 Exanthematous Drug Eruption*發疹樣藥疹 Exanthematous Drug Eruption常見之藥物不良反應皮疹 From trunk to extremities Maculopapules or urticaria may confluent Purpura at ankle, feet, waist Mucosa is spared 可能有少數毛囊性膿疱 ADR之比例: Child 10-20%, Adult 50-70% 服藥至發疹間隔：4(7)-14days發疹樣藥疹 Exanthematous Drug Eruption*發疹樣藥疹 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 危險徵候 毛囊一致性膿疱，紫斑，Nikolsky’s sign, 粘膜潰瘍 系統性功能異常 D Dx: Viral exanthema, Toxic shock syndrome, GVHD, Kawasaki’s, Still’s發疹樣藥疹 Exanthematous Drug Eruption*發疹樣藥疹 Exanthematous Drug EruptionPerifollicular papules with central pustulesPerifollicular papules with central pustulesExanthematous Rash with Purpura: Vasculitis發疹樣藥疹 Exanthematous Drug Eruption*發疹樣藥疹 Exanthematous Drug EruptionMortality：單純發疹樣藥疹為:0% 其他進展？？？可能為嚴重之藥疹的前驅 可能為嚴重之藥疹的前驅 Hypereosinophilia: DRESS Palpable purpura, arthritis: Vasculitis Facial edema: DRESS, Erythroderma Mucosa involvement: TEN, SJS Painful skin: TEN血管炎 Vasculitis*血管炎 VasculitisPalpable purpura 可能伴隨蕁麻疹，發疹變化 血清病、免疫複合體病 (Type III reaction) Dermato-arthritis syndrome r/o bacteremia/sepsis first 可能波及多重器官 ADR之比例: < 10% 服藥至發疹間隔：7-21days, challenge < 3daysLeukocytoclastic Vasculitis*Leukocytoclastic Vasculitis有硬結的紫斑 Palpable purpura 表面有無壞死現象？ 有無血尿？ Check CBC, WBC/DC LFT RFT C3, C4血管炎 Vasculitis*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.)DRESS : Drug Rashes with Eosinophilia and Systemic Symptoms*DRESS : Drug Rashes with Eosinophilia and Systemic SymptomsDRESS Hypersensitivity Syndrome伴隨系統症狀、嗜伊紅球症之藥疹*DRESS Hypersensitivity Syndrome伴隨系統症狀、嗜伊紅球症之藥疹伴隨系統症狀、嗜伊紅球症之藥疹 Drug Rash (Reaction) with Eosinophilia and Systemic Symptoms 常與藥物之代謝有關，或病毒HHV-6,7 Immune +, IL-5—Th2—eosinophils ADR之比例: 70-90% 服藥至發疹間隔：15-40days 停藥後持續數週至數月 Mortality：5-10%DRESS Hypersensitivity Syndrome*DRESS Hypersensitivity SyndromeFebrile (85%) mobilliform rash(75%) 麻疹樣、 浮腫、follicular accentuation，水疱、膿疱、紫斑、紅皮症 好發於臉、上軀幹及四肢；臉浮腫特徵 Systemic involvement Hepatitis, myocarditis, interstitial pneumonitis, nephritis, thyroiditis etc. Lymphadenopathy Rx of Corticosteroids : first choice May relapse during taperingDRESS Hypersensitivity Syndrome伴隨系統症狀、嗜伊紅球症之藥疹*DRESS Hypersensitivity Syndrome伴隨系統症狀、嗜伊紅球症之藥疹常與藥物之代謝有關： phenytoin (arene oxide) 1:1000 sulfonamide (hydoxylamine?) 1:10,000 常見原因藥物： Aromatic Anticonvulsant( phenytoin, carbamazepine, phenobarbital) Allopurinol (in renal dysfunction) Lamotrigine (esp. with Valproate) Sulfonamide, dapsone Minocycline, gold salt急性發疹樣膿疱症 Acute Generalized Exanthematous Pustulosis (AGEP) 急性發疹樣膿疱症 Acute Generalized Exanthematous Pustulosis (AGEP) 臉部或腋下鼠蹊開始 水腫性紅斑 有非毛囊性小膿疱急性發疹樣膿疱症(AGEP) Acute Generalized Exanthematous Pustulosis*急性發疹樣膿疱症(AGEP) Acute Generalized Exanthematous Pustulosis急性發燒，與皮疹同時或更早 臉部或腋下鼠蹊等部位浮腫開始 數小時內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疱 水腫、紫斑，水疱，靶型疹 皮疹持續1-2週 Mortality：1-2%AGEP / EM to Pseudoephedrine*AGEP / EM to Pseudoephedrine急性發疹樣膿疱症(AGEP)*急性發疹樣膿疱症(AGEP)可能是敏感之recall reaction Patch test: 陽性率達80% Neutrophilia, IL-3, 8, G-CSF from T cells ADR之比例: 70-90%服藥至發疹間隔： <四天，一般為兩天內 常見原因藥物： ß-lactame (PC, aminoPC, Cephalosporins) Macrolides, Calcium channel blockers (esp. diltiazem) Sulfasalazine-COX 2 InhErythroderma in Anticonvulsant Hypersensitivity Syndrome*Erythroderma in Anticonvulsant Hypersensitivity Syndrome紅皮症(剝脫性皮膚炎) Exfoliative dermatitis, Erythroderma*紅皮症(剝脫性皮膚炎) Exfoliative dermatitis, Erythroderma先局部皮疹，常由flexural開始，麻疹樣 2-6天內擴展至全身(>90%) 臉部水腫 Scaling：lamellar, crustybranny Hyper-/hypo-thermia, Tachycardia, CHF lymphadenopathyy, hepatomegaly Eosinophilia and lymphopenia ADR之比例: 19% (5.5-42%)為藥物引起 服藥至發疹間隔：wks to mons (epoprostenol) 停藥後2-6wks緩解 Mortality：?紅皮症(剝脫性皮膚炎)*紅皮症(剝脫性皮膚炎)常見原因藥物： Allopurinol, Ampicillin/Amoxicillin/Penicillins, (14% floxacillin) carbamazepine (ox-), phenobabital, phenytoin dapsone, sulfasalazine, sulfonamide, clofazimine, omeprazole, phenothiazines, vancomycine, captopril, nefedipine, isoniazide, ethambutol (HIV+)Erythema Multiforme, SJS/TEN*Erythema Multiforme, SJS/TENContinuous spectrum or Different entity? 多型性紅斑Erythema Multiforme 史帝芬─強生徵候群(SJS) Stevens-Johnson Syndrome 毒性表皮壞死症TEN Toxic Epidermal Necrolysis Target erythema, Blisters, Tender skin, Epidermal detachment, Exfoliation, Multiple Mucosal involvementnull*EM→SJS(10%)→SJS/TEN→TEN(30%)Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis*Stevens-Johnson Syndrome & Toxic Epidermal NecrolysisCategory Incidence per mil-yr Drug related ratio Mortality Primary eruptions (major feature) Isolate vs Confluence Detachment (% BSA) Interface vs Necrosis Systemic symptomsTEN 0.4-1.2 80-95% 25-50% Red edema & denuded Confluence > 30 I < Necrosis Always SJS 1.2-6 50% 5% Target & dusky red Isolated 多 < 10 Interface > N usually Toxic Epidermal Necrolysis*Toxic Epidermal NecrolysisStevens-Johnson Syndrome & Toxic Epidermal Necrolysis*Stevens-Johnson Syndrome & Toxic Epidermal NecrolysisProdromal : URI-like 1-14 days before in SJS, 1-3 days in TEN Systemic: hepatitis ADR 之比例：70-90% 服藥至發疹間隔：14-56天一般藥物為weeks, TEN 7-21days, Re-exposure <2 days) Valproate, Aromatic anticonvulsants first 2 Ms Treatment：withdraw culpit drug, Skin care Steroid, IVIG (anti sFasL) About 3 weeks for healStevens-Johnson Syndrome & Toxic Epidermal Necrolysis*Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis常見原因藥物： Allopurinol, Ampicillin/Amoxicillin/Penicillins, Aromatic anticonvulsants Barbiturates, carbamazepine (ox-), phenytoin Lamotrigine, Valproic acid Phenylbutazone, Piroxicam Sulfa, sulfasalazine, BaktarSCORTEN SEVERITY OF ILLNESS SCORE*SCORTEN SEVERITY OF ILLNESS SCOREnull*