药物不良反应之皮肤表现.ppt

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,2020年7月24日星期五,17:09:05,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,17:09:05,Mechanism of Adverse Drug Reactions,Type 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),17:09:05,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？,17:09:05,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-INF-Mono, Th2-IL-5-Eosin, IL-8 PMN, CD4/8,17:09:05,Mechanism of Frug Hypersensitivity,Annals of Internal Medicine 2003, 139(8): 684,17:09:05,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,17:09:05,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,17:09:05,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,17:09:05,Severe Cutaneous ADR,17:09:05,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,17:09:05,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：-lactam: Penicillins, Cephalosporins, NSAID, contrast media, monoclonal Aby,17:09:05,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,17:09:05,發疹樣藥疹Exanthematous Drug Eruption,Type 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，Nikolskys sign, 粘膜潰瘍 系統性功能異常 D Dx: Viral exanthema, Toxic shock syndrome, GVHD, Kawasakis, Stills,17:09:05,發疹樣藥疹Exanthematous Drug Eruption,Perifollicular papules with central pustules,Exanthematous Rash with Purpura: Vasculitis,17:09:05,發疹樣藥疹Exanthematous Drug Eruption,Mortality：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,17:09:05,血管炎 Vasculitis,Palpable 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 3days,17:09:05,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, C4,17:09:05,血管炎 Vasculitis,Mortality：？ 常見原因藥物： Penicillins, NSAID(oral, topical) Sulfonamide, Cephalosporins, Anticonvulsant, Allopurinol, Thiazide, Bio products (G,M-CSF, biologics, etc.),17:09:05,DRESS : Drug Rashes with Eosinophilia and Systemic Symptoms,17:09:05,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-5Th2eosinophils 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%,17:09:05,DRESS Hypersensitivity Syndrome,Febrile (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 tapering,17:09:05,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),臉部或腋下鼠蹊開始 水腫性紅斑 有非毛囊性小膿疱,17:09:05,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%,17:09:05,AGEP / EMto Pseudoephedrine,17:09:05,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： -lactame (PC, aminoPC, Cephalosporins) Macrolides, Calcium channel blockers (esp. diltiazem) Sulfasalazine-COX 2 Inh,17:09:05,Erythroderma in Anticonvulsant Hypersensitivity Syndrome,17:09:05,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, crustybranny 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：?,17:09:05,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+),17:09:05,Erythema Multiforme, SJS/TEN,Continuous 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 involvement,17:09:05,EMSJS(10%)SJS/TENTEN(30%),17:09:05,Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis,Category Incidence per mil-yr Drug related ratio Mortality Primary eruptions (major feature) Isolate vs Confluence Detachment (% BSA) Interface vs Necrosis Systemic symptoms,TEN 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 N usually,17:09:05,Toxic Epidermal Necrolysis,17:09:05,Stevens-Johnson Syndrome & Toxic Epidermal Necrolysis,Prodromal : 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 heal,17:09:05,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, Baktar,17:09:05,SCORTEN SEVERITY OF ILLNESS SCORE,17:09:05,Thank You for Your Attension,