药物不良反应之皮肤表现

1、演讲大纲药物不良反应之作用机转过敏与非过敏如何诊断药物过敏？药物反应之作用之重要皮肤表现2022/10/9Mechanism of Adverse Drug ReactionsType A: 药理作用相关者(Pharmacological)依照药理作用可预测者 为已知之作用效果之扩大表现者 常与剂量有关 必须降低剂量者. Type B: 特质性或过敏性(idiosyncratic or allergic)依照药物之药理作用无法来预测者奇异的或特直性的不良反应常非单纯之剂量相关反应(dose-response relationship)发生不良反应时，诱因药物常必须中止续用非用不可时，常须经过减

2、敏步骤 (Desensitization)2022/10/9药物过敏皮肤反应之诊断是否为药物过敏之皮肤反应？Allergic or pseudoallergic ?过敏或不良反应之类型为何？何种免疫反应？何种皮肤反应？诱发药物为何？有无交互作用或交叉反应之药物或情况？可能之预后严重性如何？2022/10/9药物反应之免疫作用机转Type I: IgE dependent (Anaphylaxis)荨麻疹、血管性水肿、休克Type II: Cytotoxic (Biological)天疱疮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史帝芬琼森征候群、毒性表皮坏死症 (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判断A

4、DR之原因药物及严重度一、临床特征原发皮疹之类型斑疹、丘疹、结节、膨疹、紫斑、水疱、脓疱皮疹之分布、数目及痒、痛等局部症状有无波及粘膜并发症状：全身性症状发烧、关节痛内脏变化、多重器官淋巴腺肿 痛2022/10/9判断ADR之原因药物二、病程、时序应纪录所有用药史：种类及起讫过去，类似药物、剂量变化其他可能交互作用之药物，隐藏药物药物代谢相关之肝、肾功能变化开始发疹日期计算出服药及发疹之间隔停药后之反应再度使用之反应2022/10/9皮肤药物反应的简单分类立即性或延迟性，自限性或持续性荨麻疹及血管性水肿、休克发疹(exanthema):麻疹样药疹局限性或泛发型(+粘膜?)发疹型多型性红斑，水疱

5、、黏膜 (SJS/TEN)局部反应固定药疹、光敏感性、水疱症、坏死等2022/10/9Severe Cutaneous ADR2022/10/9药物反应的重要皮肤病变发疹 样药疹：可能为下列之早期病变急性发疹样脓疱症(AGEP)血管炎(血清病、免疫复合体病)红皮症(剥脱性皮肤炎)伴随系统症状、嗜伊红球症之药疹(DRESS)SJS-TEN(毒性表皮坏死症)多型性红斑 SJS TEN2022/10/9立即性反应：Anaphylaxis荨麻疹Urticaria 血管性水肿Angioedema Anaphylaxis休克ADR之比例: Anaphylaxis 30%Urticaria 10% 为药物引

6、起服药至发疹间隔：分钟至小时Mortality：5%常见原因药物：-lactam: Penicillins, Cephalosporins, NSAID, contrast media, monoclonal Aby2022/10/9发疹样药疹Exanthematous Drug Eruption常见之药物不良反应皮疹From trunk to extremities Maculopapules or urticariamay confluent Purpura at ankle, feet, waistMucosa is spared可能有少数毛囊性脓疱ADR之比例: Child 10-20

7、%, Adult 50-70%服药至发疹间隔：4(7)-14days2022/10/9发疹样药疹Exanthematous Drug EruptionType IV, or 非免疫性direct binding to MHC-2 in KC(sulfa)AminoPC in Infectious mononucleosis可能为严重之药疹的前驱危险征候毛囊一致性脓疱，紫斑，Nikolskys sign, 粘膜溃疡系统性功能异常D Dx: Viral exanthema, Toxic shock syndrome, GVHD, Kawasakis, Stills2022/10/9发疹样药疹Exa

8、nthematous Drug Eruption2022/10/9Perifollicular papules with central pustulesExanthematous Rash with Purpura: Vasculitis发疹样药疹Exanthematous Drug EruptionMortality：单纯发疹样药疹为:0%其他进展？可能为严重之药疹的前驱可能为严重之药疹的前驱Hypereosinophilia: DRESSPalpable purpura, arthritis: VasculitisFacial edema: DRESS, ErythrodermaMuco

9、sa involvement: TEN, SJS Painful skin: TEN2022/10/9血管炎 VasculitisPalpable purpura可能伴随荨麻疹，发疹变化血清病、免疫复合体病 (Type III reaction)Dermato-arthritis syndrome r/o bacteremia/sepsis first可能波及多重器官ADR之比例: 10%服药至发疹间隔：7-21days, challenge 3days2022/10/9Leukocytoclastic Vasculitis有硬结的紫斑Palpable purpura表面有无坏死现象？有无血尿

10、？CheckCBC, WBC/DCLFTRFTC3, C42022/10/9血管炎 VasculitisMortality：？常见原因药物：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伴随系统症状、嗜伊红球症之药疹伴随系统症状、嗜伊红球症之药疹 Drug Rash (Reaction) with Eosinophilia and Systemic Symptoms 常与药物之代谢有关，或病毒HHV-6,7Immune +, IL-5Th2eosinophilsADR之比例: 70-90%服药至发疹间隔：15-40days停药后持续数周至数月Mortality：5-10%2022/10/9DRESS Hypersensitivity SyndromeFebrile (85%) mobilliform rash(75%)麻疹样、 浮肿、fo

12、llicular accentuation，水疱、脓疱、紫斑、红皮症好发于脸、上躯干及四肢；脸浮肿特征Systemic involvementHepatitis, myocarditis, interstitial pneumonitis, nephritis, thyroiditis etc.LymphadenopathyRx of Corticosteroids : first choiceMay relapse during tapering2022/10/9DRESS Hypersensitivity Syndrome伴随系统症状、嗜伊红球症之药疹常与药物之代谢有关：phenytoin

13、 (arene oxide) 1:1000sulfonamide (hydoxylamine?) 1:10,000常见原因药物： Aromatic Anticonvulsant( phenytoin, carbamazepine, phenobarbital)Allopurinol (in renal dysfunction)Lamotrigine (esp. with Valproate)Sulfonamide, dapsoneMinocycline, gold salt2022/10/9急性发疹样脓疱症Acute Generalized Exanthematous Pustulosis (

14、AGEP) 脸部或腋下鼠蹊开始水肿性红斑有非毛囊性小脓疱急性发疹样脓疱症(AGEP) Acute Generalized Exanthematous Pustulosis急性发烧，与皮疹同时或更早脸部或腋下鼠蹊等部位浮肿开始数小时内快速扩散躯干及上肢会波及粘膜皮疹为多样性，痒或热感水肿性红斑上有非毛囊性小脓疱水肿、紫斑，水疱，靶型疹皮疹持续1-2周Mortality：1-2%2022/10/9AGEP / EMto Pseudoephedrine2022/10/9急性发疹样脓疱症(AGEP)可能是敏感之recall reactionPatch test: 阳性率达80%Neutrophilia

15、, IL-3, 8, G-CSF from T cellsADR之比例: 70-90%服药至发疹间隔：90%)脸部水肿Scaling：lamellar, crustybrannyHyper-/hypo-thermia, Tachycardia, CHFlymphadenopathyy, hepatomegalyEosinophilia and lymphopeniaADR之比例: 19% (5.5-42%)为药物引起服药至发疹间隔：wks to mons (epoprostenol)停药后2-6wks缓解 Mortality：?2022/10/9红皮症(剥脱性皮肤炎)常见原因药物：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?多型性红斑Erythema Multiforme史帝芬琼森征候群(SJS) Stevens-Johnson Syndrome 毒性表皮坏死症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%服药至发疹间隔：14-56天一般药物为weeks, TEN 7-21days, Re-exposure 40 yearsYes = 1, No