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1 약물역학위해관리학회지 2018;10:49-53 REVIEW 아스피린및비스테로이드성항염증제약물과민반응의임상적접근 가천대학교길병원내과 강성윤ㆍ이상표ㆍ이상민 Approaches to the Diagnosis and Management of Hypersensitivity Reactions to Aspirin and Nonsteroidal Anti-inflammatory Drugs Sung-Yoon Kang, MD, Sang Pyo Lee, MD, PhD and Sang Min Lee, MD, PhD Division of Pulmonology and Allergy, Department of Internal Medicine, Gachon University Gil Medical Center, Incheon, Korea Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used due to their antipyretic, analgesic, and anti-inflammatory effects. However, both aspirin and NSAIDs cause adverse reaction with an array of symptoms from mild cutaneous and gastrointestinal irritation to life-threatening anaphylaxis. NSAIDs-induced hypersensitivity reactions may be related to immunologic and non-immunological mechanisms. Although the roles of blood and skin tests are limited, the diagnosis can be established by obtaining a careful history and physical examination. Further evaluation including in oral or bronchial provocation test may be necessary to perform under the control of a skilled physician and a well-equipped facility. Given severe NSAIDs-induced hypersensitivity reactions, avoidance of the causative NSAIDs and all cross-reactive NSAIDs is the cornerstone of management. However, when treatment with aspirin or NSAIDs is necessary, desensitization can be performed. (JPERM 2018;10:49-53) Key Words: Aspirin; Nonsteroidal anti-inflammatory drugs; Adverse reaction; Hypersensitivity reaction; Desensitization 서론각종통증과발열은일상생활중에쉽게나타날수있는증상이며해열진통소염제를투여함으로써증상을조절하게되는경우가있다. 아스피린을포함한비스테로이드성항염증제 (nonsteroidal anti-inflammatory drugs, NSAIDs) 는의료기관에서많이처방될뿐만아니라일반의약품으로약국이나편의점등에서어렵지않게접할수있다. 약제의구입과접근이어렵지않다보니해열진통소염제의사용도매년 늘어나면서약물사용에따른약물유해반응도증가하는추세이며, 국내외약물유해반응을일으키는가장흔한원인약제중하나로알려져있다. 1-4) 아스피린과 NSAIDs에의한약물유해반응은경미한피부및위장관계증상에서부터생명을위협하는아나필락시스까지다양한형태의임상양상을보일수있으므로환자의적절한진단과평가및그에따른치료와예방이필요하다고볼수있겠다. 아스피린과 NSAIDs에의한약물유해반응은발생기전과예측가능성에따라약물의고유한약리작용자체혹은약물간의상호작 접수 : 2018 년 5 월 18 일, 승인 : 2018 년 8 월 22 일연락처 : 이상민, 21565, 인천시남동구남동대로 774 번길 21 가천대학교길병원내과 Tel: (032) , Fax: (032) sangminlee77@naver.com Correspondence to: Sang Min Lee, MD, PhD Division of Pulmonology and Allergy, Department of Internal Medicine, Gachon University Gil Medical Center, 21 Namdongdaero 774beon-gil, Namdong-gu, Incheon 21565, Korea Tel: , Fax: sangminlee77@naver.com

2 50 약물역학위해관리학회지제 10 권제 2 호, 2018 용으로발생되는 A형반응과약리학적작용과무관하게투여용량에관계없이환자개인적특성에의해발생되는 B 형반응으로분류될수있으며 B형반응을아스피린과 NSAIDs 과민반응으로부르기도한다. 5) 이에본논문은아스피린과 NSAIDs에의한약물과민반응과관련된기전과진단, 그리고관리에대하여간단히살펴보고자한다. 본론 1. 아스피린및 NSAIDs 유해반응분류와발생기전아스피린및 NSAIDs에의한약물유해반응중, Type B형반응은약물노출후반응이나타나는시간, 기전과영향을받는신체부위에따라다양한형태로과민반응을일으킬수있다. 약물노출후증상이발생되는시간에따라노출후대개 1-2시간이내에서길게는 24시간이내에발생되는반응과투여 24시간이후에발생하는지연형반응으로나누며과민반응을일으키는기전에따라비면역학적 / 면역학적기전으로나누기도한다. 6) 비면역학적기전에의한반응은가성알레르기 (pseudo-allergy) 혹은특이반응 (Idiosyncrasy) 으로도명명되고있으며정확한기전은알려져있지않지만 cyclooxygenase (COX) 기능억제와관련이있을것으로보인다. 즉아스피린및 NSAIDs는세포막인지질대사에중요한 cyclooxygenase (COX) 기능을억제함으로써다양한작용을나타내는데, 특히정상세포의항상성을유지하는데관여하는 COX-1이차단될경우에상대적으로 5-Lipoxyganase 활성이증가되고그결과로 Cysteinyl leukotrienes 생성이증가되어 혈관부종, 기관지수축등증상들을일으키게된다. 7,8) 이처럼비면역학적기전에의한반응은여러 NSAIDs에대하여교차반응을보일수있으며, 교차반응의정도는 COX에대한선택적억제정도에따라다른데, 대부분의 NSAIDs는 COX-1에대한억제효과가큰비선택적 COX 차단제이므로교차반응을보인다 ( 표 1). 비면역학적기전에의한반응은크게호흡기질환 (NSAID-exacerbated respiratory disease, NERD) 및피부질환 (NSAID-exacerbated cutaneous disease, NECD, 혹은 NSAIDinduced urticaria/angioedema, NIUA) 형태로나타날수있다. NERD는만성비부비동염, 비용종및천식을가지고있는환자군에서아스피린및 NSAIDs 투여시증상이악화되는경우를말하며과거에는비부비동염이나비용종, 천식, 아스피린과민반응세가지가모두있는경우샘터의세증후 (Samter s triad) 라고불리기도했다. 9) 최근메타분석결과에따르면천식환자의 7% 가아스피린과민반응을가지고있으며중증천식은 15% 의유병률을보였다. 아울러비용종이나비부비동염을가지고있는환자에서아스피린과민성의빈 도는 9% 내외로보고되었다. 10) 약제복용후약 30분에서길게는 2시간이내비충혈감, 콧물, 코막힘에이어호흡곤란까지동반되는양상을보이며, 이외에도얼굴주변홍조, 혈관부종, 구역 / 구토및설사등의증상도같이동반되어나타날수있다. 아스피린및 NSAIDs 투여용량과 COX-1에대한선택적억제효과에비례하여증상이발현될수있으므로중증천식환자이거나비용종을동반한천식환자에게서아스피린이나 NSAIDs를투여할때에는주의를요한다. 11) NECD와 NIUA는아스피린및 NSAIDs 투여에따른피부증상인두드러기및혈관부종이나타날수있으며이중에 NECD는기존에만성두드러기나혈관부종을가지고있는환자의 1/3 정도에서약제복용 30분에서길게는 6시간이내피부증상이악화되어나타나 24시간에서 48시간까지유지되기도하며경우에따라호흡기증상도동반되는특징을가지고있다. 12) NIUA는 NECD와달리만성두드러기나혈관부종이없는일반인에서약제복용후두드러기나혈관부종으로나타날수있으며약제복용 1시간에서 6시간이내증상이나타난다. 눈이나안면부에국한된혈관부종으로나타나는게특징이며, 전신두드러기가동반되거나두드러기만나타날수도있다. NIUA 환자의 60% 정도는비염이나 Table 1. Nonsteroidal anti-inflammatory drugs based on COX-selectivity Non-selective COX (cyclooxygenase) inhibitors More COX-2 inhibitors Weakly selective COX-1 inhibitors Selective COX-2 inhibitor Acetylsalicylic acid Diclofenac Aceclofenac Indomethacin Naproxen Naproxen sodium Mefanamic acid Oxaprozin Piroxicam Sulindac Tolmetin Fenoprofen Ibuprofen Loxoprofen Ketoprofen Etodolac Ketorolac Cross-reactive at high concentrations Meloxicam Nimesulide Nabumeton Cross-reactive at high concentrations Acetaminophen (doses 1,000 mg) Diflunisal Salsalate Choline magnesium trisalicylate Celecoxib Etoricoxib Lumiracoxib Parecoxib

3 강성윤외. 아스피린및비스테로이드성항염증제약물과민반응의임상적접근 51 천식을가지고있는것으로보고되고있으며, 전체환자의 1/3에서만성두드러기로진행된다는보고도있다. 12,13) 면역학적기전은 COX의기능억제작용이아니라특정약물이항원으로작용하여아스피린및 NSAIDs에대한특이 immunoglobulin E (IgE) 나 CD4+ 혹은 CD8+ T세포반응이나타날수있으며, 이는여러 NSAIDs에교차반응을보이지않고특정약물또는구조적으로유사한 NSAIDs에만반응을보이는특징을가지고있다. IgE에의한반응 (Single NSAIDs-induced urticarial/angioedema or anaphylaxis, SNIU- AA) 은급성으로피부반응이나아나필락시스반응을일으킬수있으며여러 NSAIDs 약제중에 ibuprofen, diclofenac, paracetamol 및 pyrazolone계 NSAIDs가자주발생하는것으로보고되고있다 ) T세포활성에따른지연성반응 (SNIDR, single-nsaids-induced delayed reaction) 으로반점구진상발진, 고정약진, Drug reaction with eosinophilia and systemic symptoms (DRESS) 증후군, 스티븐스-존슨증후군 (Stevens-Johnson syndrome, SJS), 독성표피괴사융해 (toxic epidermal necrolysis, TEN) 의중증피부유해반응이나타날수있다. 17) 이외에도아스피린및 NSAIDs 투여후피부증상과호흡기증상이혼재되어나타나는경우나여러특정 NSAIDs에만반응을보이거나특정 NSAIDs 투여시호흡기증상만나타나는경우도있다 ( 표 2). 6) 2. 아스피린및 NSAIDs 과민반응의진단적접근아스피린및 NSAIDs에의한과민반응을진단하기위해서 과거천식, 비부비동염, 만성두드러기등기저질환확인과함께약제투여와의시간적인과관계를바탕으로하여약물복용시간, 약물투여후증상및징후의형태, 이전에아스피린을포함한동일한혹은다른 NSAIDs 약제투여이후에증상여부등의자세한병력청취가매우중요하다. 5,18) 약제투여시간에따라투여직후 24시간이후에발생되는반응인경우에는지연형과민반응의가능성이높으나투여후 6시간이내증상이나타나는경우, 증상이발생되는시간만으로어느형태의과민반응인지확인하기어렵다. 또한환자가불편감을호소하는신체부위이외에도코, 안구, 후두, 기도나소화기, 순환기증상의여부도확인하는것이필요하다. 아울러이전에아스피린을포함한동일한약제나다른 NSAIDs 복용이후에증상이동반되었다면비면역학적기전에의한과민반응의가능성이높으며반대로특정약제에국한되어나타나거나다른 NSAIDs 복용에도증상이없다면면역학적기전에의한과민반응의가능성이높다고추측해볼수있다. 6) 이와같이자세한병력청취상에서아스피린및 NSAIDs 유해반응을진단할수있지만병력청취만으로원인약물이불명확한경우에는피부반응시험 ( 피부단자, 피내시험및피부첩포검사 ) 이나 specific IgE test, basophil activation test 및 lymphocyte transformation test를시행해볼수있으나표준화된방법이정립되어있지않으며연구자보고에따라서로다른결과로인하여아직까지는진단적인가치에대한제한점을가지고있다. 따라서원인약물을확인하거나투여하고자하는 NSAIDs의안전성을 Table 2. Classification of hypersensitivity reaction to aspirin and NSAIDs 반응종류 NERD (NSAID-exacerbated respiratory disease) NECD (NSAID-exacerbated cutaneous disease) NIUA (NSAID-induced urticaria/angioedema) SNIUAA (Single NSAIDs-induced urticarial/angioedema or anaphylaxis) SNIDR (Single-NSAIDs-induced delayed reaction) 임상양상 비염, 천식증상 혈관부종 혈관부종 혈관부종, 아나필락시스 피부증상, 발열, 전신장기침범 NSAIDs, nonsteroidal anti-inflammatory drugs. 반응시간 ( 약물노출이후 ) (24시간이내, 대개 1-2시간내 ) 동반알레르기질환 천식비부비동염비폴립만성두드러기 교차반응성 예 발생기전 비면역학적 COX-1 inhibition 아니오 면역학적 IgE mediated 지연형 (24 시간이후 ) T cell mediated

4 52 약물역학위해관리학회지제 10 권제 2 호, 2018 확인하기위해서는약물유발시험을고려해야한다. 약물유발시험은일반적으로아스피린을사용하여표준검사를시행하지만특정약물에의한면역학적반응인경우에는원인약제만으로검사를진행하기도한다. NERD 진단을위한비강유발검사, 기관지유발검사그리고호흡기증상과호흡기외증상을모두보기위한경구유발검사로나누어진행할수있으며약물유발검사는기관지수축및아나필락시스등과같은심한전신반응의위험성이있을수있으므로, 많은경험과적절한시설과장비를갖춘상태에서진행해야하며, 중증지연형반응인경우경구유발시험은가급적시행하지않는것이좋다. 3. 아스피린및 NSAIDs 과민반응의치료와예방아스피린및 NSAIDs 과민반응으로진단되는경우원인약제를포함하여교차반응성이높은약제투여는피해야한다. 비면역학적기전에의한과민반응인경우 COX-1 억제효과가있는비선택적 COX 차단제인대부분의 NSAIDs 사이는교차반응을보이므로사용을피해야하며, 반면 COX-1 억제효과가미미한 acetaminophen이나선택적으로 COX-2 억제효과가우세한약제 (nimesulide, meloxicam) 와선택적 COX-2 차단제 (celecoxib, etoricoxib) 는비교적안전하게사용해볼수있겠다. 18,19) 하지만이들약제도일부환자에서는교차반응이있어투여시증상을일으킬수있으므로주의를요하며, NSAIDs 치료가필요한경우투여하고자하는약제를소량에서부터치료용량에까지경구유발검사를통하여안전성을확인한후투약하는것이좋겠다. 면역학적기전에의한과민반응인경우원인약제나구조가비슷한 NSAIDs는피해야하며, 이외의약제는투여해볼수있으나경구유발시험을통하여교차반응이없는것을확인하는과정이필요하다. 지속적으로아스피린및 NASIDs 사용이필요한질환 ( 심혈관계및근골격계질환 ) 을가지고있는경우탈감작요법을시행해볼수있으며, 아스피린및 NASIDs 과민성천식, 비부비동염환자들중기존의약물치료에충분히반응하지않고증상조절을위해빈번하게전신스테로이드투여가필요한경우및반복되는비용종이있을경우에도원인약제에대한탈감작요법을시행함으로써환자의치료에도움이될수있다. 1,20) 탈감작요법은소량의원인약제투여를통해인체의면역반응을변화시켜일시적인면역관용을유도하는과정으로점점약제의용량을늘려결국치료용량의약물을사용할수있게하는방법이다. 현재까지비면역학적기전에의한과민반응중 NERD인경우탈감작에의한효과가있는반면에 NECD 또는 NIUA 환자에서의탈감작요법에대한효과는아직이견이많으며근거가충분하지않다. 20,21) 면역학적기전에의한과민반응인경우에는탈감 작요법을권장하지않는다. 22) 탈감작요법의효과를유지하기위해서는목표용량을지속적으로복용해야하며중단하게되면중단 2-5일후에과민반응이다시나타날수있다. 23) 결론아스피린및 NSAIDs는약물유해반응의원인약물중가장흔한원인으로서경증에서부터중증에이르기까지신체의여러다양한모습과다양한기전을통해서나타날수있다. 아스피린및 NSAIDs에의한과민반응이있을경우반응기전을이해하고자세하게병력을청취하였을때약물유해반응과그유형을진단할수있으며, 이러한병력청취만으로진단이애매한경우에는확진을위한약물유발시험을시행한다. 진단이후반응유형에따라서해당약제의투여중지혹은감량투여, 다른약제로의대체, 나아가탈감작요법을통해서치료혹은예방할수있다. 이외에도아스피린및 NSAIDs 과민반응에대하여다른의료인과의정보를공유하고, 환자교육및약물정보카드등의안전장치를제공함으로써약물과민반응을예방할수있다. REFERENCES 1. Laidlaw TM, Cahill KN. Current Knowledge and Management of Hypersensitivity to Aspirin and NSAIDs. J Allergy Clin Immunol Pract 2017;5: Rew SY, Koh YI, Shin HY, Park SH, Ryu SH, Kim HN, et al. Reporting and clinical features of adverse drug reactions from a single university hospital. Korean J Asthma, Allergy Clin Immunol 2011;31: Kim MH, Jung HY, Sohn MK, Kim SE, Lee YW, Park JW, et al. Clinical features of adverse drug reactions in a tertiary care hospital in Korea. Korean J Asthma, Allergy Clin Immunol 2008;28: Choi JH, Shin YS, Suh CH, Nahm DH, Park HS. The frequency of adverse drug reactions in a tertiary care hostpital in Korea. Korean Journal of Medicine 2004;67: Kowalski ML, Makowska JS. Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice? Allergy Asthma Immunol Res 2015;7: Dona I, Salas M, Perkins JR, Barrionuevo E, Gaeta F, Cornejo-Garcia JA, Campo P, Torres MJ. Hypersensitivity Reactions to Non- Steroidal Anti-Inflammatory Drugs. Curr Pharm Des 2016;22: Meade EA, Smith WL, DeWitt DL. Differential inhibition of

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<30332E20C6AFC1FD20B1E8C3B6BFEC2E687770> 대한내과학회지 : 제 87 권제 6 호 2014 http://dx.doi.org/10.3904/kjm.2014.87.6.659 특집 (Special Review) - 약물알레르기 아스피린및비스테로이드성항염증제과민반응 인하대학교의학전문대학원내과학교실 김철우 Hypersensitivity to Aspirin and Nonsteroidal Anti-inflammatory