대한내과학회지 : 제 76 권제 3 호 2009 특집 (Special Review) - 주요알레르기질환의진단과치료 기관지천식의최신약물치료지침 한양대학교의과대학내과학교실 윤호주 Updated drug therapy guideline of asthma Ho Joo Yoon, M.D. Department of Internal Medicine, Division of Pulmonary Medicine, Hanyang University College of Medicine, Seoul, Korea Asthma is a serious health problem throughout the world with high prevalence and increased socioeconomic burden. So in order to have a better understanding and medication for this illness, many scientific advances have been made. To specify, Global Initiative for Asthma (GINA) and National Asthma Education and Prevention Program (NAEPP) have played a leading role in disseminating information about the care for patients based on a process of continuous review of published scientific investigations. For these outstanding accomplishments, GINA and NAEPP guidelines are now being widely adopted, translated and reproduced, forming the basis for many national guidelines throughout the world. These guidelines recommend a change in approach to asthma management with asthma control, rather than asthma severity, being the focus of treatment decisions. Most importantly, these provide stepwise drug therapy of asthma based on the level of control. This session will mainly focus on updated stepwise drug therapy. (Korean J Med 76:260-267, 2009) Key Words: Asthma; Drug therapy; Guideline 서론천식은기도의만성염증질환으로전세계적으로유병률이증가하고사회경제적부담이증가하여각나라마다심각한건강문제로대두되고있다. 우리나라에서도 2007년도국민건강영양조사통계자료에의하면천식의유병률이 20~ 60세에서 2.3~8.9%, 70세이상노인에서 15.6% 에달한다 1). 분자생물학의발전에따라천식의발병기전이새롭게밝혀지고, 천식의치료와관리에있어큰발전이있었지만천식으로인한사망률, 이환율이여전히감소하지않고있다. 따라서이러한문제를해결하기위해천식의진단과치료를위한임상지침이 1980년대중반부터발표되었으나, 전세계적으로보급되지는못하고각나라별로사용되는제한적지침이었다. 이후미국국립보건원의 NHLBI (National Heart, Lung, and Blood Institute) 가 NAEPP (National Asthma Education and Prevention Program) 을구성하여 1991년전문가패 널보고 (Expert Panel Report 1) 를발표하였고, 곧이어세계보건기구와함께 GINA (Global Initiative for Asthma) 지침을발표하면서전세계적으로가장많이이용하고있는지침이되었다. GINA와 NAEPP 지침도수정보완되면서전문가의견에서근거중심으로, 천식의중증도에따른단계적치료에서천식조절정도에근거한단계적치료로지침이변경되었다. 이러한치료지침을통해천식이사회문제가되고있는국가의천식치료의사에게치료가이드라인을제시하였으며우리나라에서도이를바탕으로우리실정에맞는한국의기관지천식치료지침서를발간하였다. 본강좌에서는세계적으로가장많이이용되고있는 2006 GINA 지침과 2007 NAEPP 의전문가패널보고 (Expert Panel Report 3) 를중심으로천식의최신약물치료지침을알아보고자한다 2, 3). - 260 -
- Ho Joo Yoon. Updated drug therapy guideline of asthma - Table 1. Levels of asthma control (GINA) Characteristic Daytime symptoms Limitations of activities Controlled (all of the following) None (twice or less per week) None (twice or less per week) Partly controlled (any measure ) More than twice a week Uncontrolled Nocturnal symptoms/ awakening Need for reliever/rescue treatment Lung function (PEF or FEV1)# Exacerbations None None (twice or less per week) Normal None Any More than twice a week <80% pred or personal best (if known) One or more per year" One in any week+ PEF, peak expiratory flow; FEV1, forced expiratory volume in one second; % pred, % predicted; #, lung function is not a reliable test for children aged 5 yrs; ", any exacerbation should prompt review of maintenance treatment to ensure that it is adequate; +, by definition, an exacerbation in any week makes that an uncontrolled asthma week. Any Table 2. Assessing asthma control in adults (NAEPP) Classification of Asthma Control ( 12 years of age) Components of Control Not Very Poorly Well Controlled Well Controlled Controlled Symptoms 2 days/week >2 days/week Throughout the day Nighttime awakenings 2 x/month 1-3 x/week 4 x/week Interference with normal activity None Some limitation Extremely limited Short-acting β 2-agonist use for symptom control (not 2 days/week >2 days/week Several times per day prevention of EIB) Impairment >80% predicted/ 60-80% predicted/ <60% predicted/ FEV1 or peak flow personal best personal best personal best Validated questionnaires ATAQ ACQ ACT 0 0.75 20 1~2 1.5 16-19 3~4 N/A 15 Exacerbations requiring oral 0-1/year 2/year systemic corticosteroids Consider severity and interval since last exacerbation Risk Progressive loss of lung function Evaluation requires long-term follow-up care. Treatment-related adverse Medication side effects can vary in intensity from none to very troublesome effects and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk. ATAQ, Asthma Therapy Assessment Questionnaire; ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test - 261 -
- 대한내과학회지 : 제 76 권제 3 호통권제 583 호 2009 - Figure 1. Management approach based on control for adults (GINA) 단계적약물치료 2006년이전의 GINA 지침은천식의심한정도에따른단계적치료를권장하였다. 즉, 간헐성천식, 경증지속성천식, 중등증지속성천식, 중증지속성천식으로분류하고각단계별로치료지침을제시하였다. 천식이잘조절되지않고증상이지속되면단계를올리고증상이잘조절되면서 3개월이상유지되면치료단계를낮추었다. 그러나 2006 GINA 지침과 2007 NAEPP 지침에서는천식의조절정도를먼저평가하고 ( 표 1, 2) 2, 3), 조절정도에따라약물치료단계를각각 5단계와 6단계로나누어제시하고있다 ( 그림 1, 2) 2, 3). 이는천식치료를하는의사가더효율적으로지침을환자에게적용할수있고, 천식의조절정도를평가하여치료에이용함으로써천식치료의목표를달성하는데도도움이된다. 천식환자는현재치료내용과치료의순응도및천식조절상태를평가해야한다. 천식조절정도를평가하는방법은천식조절검사 (Asthma Control Test) 4). 천식조절설문 (Asthma Control Questionnaire) 5), 천식치료평가설문 (Asthma Therapy Assessment Questionnaire) 6), 천식조절점수체계 (Asthma Control Scoring System) 7) 등여러가지가개발되었으며의료진이환자의천식조절상태를평가하거나환자가천식행동지침의 - 262 -
- 윤호주. 기관지천식의최신약물치료지침 - Figure 2. Stepwise approach for managing asthma in adults (NAEPP) 일환으로자신의상태를평가하는등다양한용도에유용하게사용하고있다. 천식치료약물의선택은환자의현재의천식조절정도와치료내용에의해결정된다. 예를들면, 천식이현재치료로조절되지않으면천식조절이달성될때까지치료단계를올려야한다. 만일, 천식이조절된상태로최소한 3개월동안유지되면치료단계를내려볼수있는데천식조절상태를유지하면서가장낮은치료단계및용량을정하기위함이다. 천식이부분조절된경우는치료단계를올려야할지반드시고려해야한다. GINA와 NAEPP 지침에서천식조절달성을위한치료를각각도식적으로제시하였다 ( 그림 1, 2) 2, 3). GINA와 NAEPP 지침에서천식조절달성을위한치료단계는각각 5단계와 6단계로제시하고있으나매우유사하므로 GINA 지침을기준으로서술하고자한다. 각치료단계마다다른치료약제를선택할수있는옵션을두고있는데약제들의효능은동일하지않지만천식조절을위한대체약물로사용할수있다. 1단계에서 5단계로올라갈수록 치료효능이더큰약제를선택하게된다. 지속적으로천식증상이있는환자에게처음천식치료약제를사용하는경우대부분 2단계치료로시작하고, 매우천식이잘조절되고있지않을경우에는 3단계치료로시작해볼수있다. 모든치료단계에서증상완화제인속효성기관지확장제는환자의증상을신속히개선하기위해서항상준비되어있어야한다. 그러나현재의치료에서증상완화제를규칙적으로사용한다는것은천식이조절되고있지않음을의미하므로치료단계를올려조절제를증가시켜야한다. 증상완화제를사용할필요성을줄이거나없애는것이천식치료의목표이고이를통해서치료성공을예측할수있다. 1단계치료 : 필요할때증상완화제사용치료 1단계는증상완화제를필요할때사용하는것으로, 환자의주간증상이별로없고, 즉기침, 천명및호흡곤란이일주일에 2회이하이거나야간증상은더드물게있을때적용한다. 환자는증상이없을때폐기능이정상이고야 - 263 -
- The Korean Journal of Medicine: Vol. 76, No. 3, 2009 - Table 3. Estimated equipotent daily doses of inhaled glucocorticosteroids for adults Drug Low daily dose µg Medium daily dose µg High daily dose µg Beclomethasone dipropionate Budesonide Ciclesonide Flunisolide Fluticasone propionate Mometasone furoate Triamcinolone acetonide 200~500 200~400 80~160 500~1000 100~250 200~400 400~1000 >500~1000 >400~800 >160~320 >1000~2000 >250~500 >400~800 >1000~2000 >1000~2000 >800~1600 >320~1280 >2000 >500~1000 >800~1200 >2000 간수면장애도없다. 만일증상이더자주나타나거나, 주기적으로악화된다면증상완화제외에규칙적인조절제를사용하는 2단계이상의치료가필요하다 8, 9). 1단계치료에해당하는환자에서증상완화제로속효성베타2항진제를추천한다. 흡입항콜린제, 속효성경구베타2 항진제및속효성테오필린등이대체제이지만약효시작시간이더늦거나부작용이더흔한경우가많다. 2단계치료 : 증상완화제와한가지조절제사용치료 2단계부터 5단계까지는조절제를규칙적으로사용하고필요할때마다증상완화제를사용한다. 2단계에서는저용량흡입스테로이드를조절제로사용하는것을권장한다 9, 10). 흡입스테로이드대신사용할수있는조절제로는류코트리엔조절제가있다 11-13). 류코트리엔조절제는흡입스테로이드를사용할수없거나사용하려하지않는환자, 흡입스테로이드로인하여목이쉬는등부작용이심한경우, 또는알레르기비염이동반된천식환자에게사용할수있다 14). 그외대체제로서방형테오필린이나흡입크로몰린 15) 등이있으나 1차조절제로추천되지는않는다. 3단계치료 : 증상완화제와하나혹은두가지조절제사용 3단계치료의조절제로저용량흡입스테로이드와흡입지속성베타2 항진제를함께사용하는것을추천한다 16-18). 이렇게두조절제를혼합하여사용하면부가적인효과가있으므로저용량흡입스테로이드로도일반적으로충분하며, 3~ 4개월사용하여천식조절이되지않을경우에만용량을올린다. 3단계치료의조절제로다른방법은중등용량혹은고용량흡입스테로이드를단독사용하는것이다 19, 20). 그외저용량흡입스테로이드와류코트리엔조절제 21) 를함께사용하 는방법과저용량흡입스테로이드와서방형테오필린을함께사용하는방법등이있다. 4단계치료 : 증상완화제와두가지이상의조절제사용 4단계치료에사용하는조절제는 2단계와 3단계치료에서사용하였던약제를기반으로사용하게된다. 3단계치료로천식이조절되지않는다면반드시천식전문가에게의뢰하여야한다. 권장하는조절제는중등용량혹은고용량흡입스테로이드와흡입지속성베타2 항진제를함께사용하는것이다. 흡입스테로이드는중등용량에서고용량으로증가시켜도추가로얻는효과가상대적으로적으므로 19, 22) 고용량의흡입스테로이드제는흡입스테로이드를중등용량으로사용하면서함께흡입지속성베타2 항진제및다른조절제 ( 류코트리엔조절제나서방형테오필린 ) 를사용하여도천식조절이되지않을때만, 3~6 개월만일시적으로사용하여효과여부를판단하기를권한다. 흡입스테로이드의용량구분의기준은표 3과같다 23). 류코트리엔조절제를중등혹은고용량흡입스테로이드에추가하여사용하는것은효과가잘입증되었지만, 지속성베타2 항진제를흡입스테로이드에추가하는것보다는효과가작다 24). 중간용량또는고용량흡입스테로이드와지속성베타2 항진제를함께사용하면서추가로서방형테오필린을저용량으로사용하는것도효과가있다. 5단계치료 : 증상완화제와조절제의추가투여사용 4단계치료에서사용하는조절제에추가하여경구스테로이드를사용하면효과를볼수도있지만부작용을고려하여사용을결정하여야한다 25, 26). 항 IgE를다른조절제에추가하여사용하면알레르기천식을호전시킬수있는데, 고용량의흡입스테로이드혹은경구스테로이드를포함한다른 - 264 -
- Ho Joo Yoon. Updated drug therapy guideline of asthma - 조절제조합치료로천식조절이되지않을경우사용할수있다 27-29). 조절상태유지치료천식이잘조절되면천식조절상태를유지하면서비용을최소로하고안전성을최대로하는가장낮은치료단계및용량을정하기위해서지속적인모니터링이필수적이다. 또한천식은변동성이큰질환이므로주기적으로치료내용을조정할필요가있다. 일반적으로환자는첫방문후 1개월후추적하고천식이조절되면 3개월마다방문을권장한다. 급성악화가있을경우에는 2주이내적어도 1개월이내에반드시다시병원을방문하여야한다. 약제사용기간및약제조정조절제로사용하는약제대부분은치료시작수일내에천식이호전되기시작하지만최고로호전되는데까지는 3~ 4개월걸리는경우도있다 23, 30). 천식이일단조절되고나면약제용량을줄일수있는데그기전은장기간기도염증에의한어떤변화가가역적으로개선되기때문일것으로추정하고있다. 천식이다시잘조절되지않거나그런징후가있을때와급성악화가발생하였을때는치료약제를증가시킨다. 천식치료단계낮추기의실제천식이조절된후약제를줄이는시기와방법및줄이는양에대해서연구된바가거의없지만치료단계를낮추는방법은천식조절을달성하는데사용한약제의종류와용량에따라환자에따라차이가있다. 천식치료단계를낮추는방법에대한구체적인내용을살펴보면, 첫째, 흡입스테로이드제단독으로중등용량또는고용량으로사용하는경우 3개월간격으로스테로이드용량을반으로줄여천식조절상태를유지할수있는지시도해야한다 31). 둘째, 저용량흡입스테로이드제단독으로천식이조절되면환자대부분이하루 1회사용으로변환하여천식을조절된상태로유지할수있다 32). 셋째, 흡입스테로이드와지속성베타2 항진제를함께사용하여천식이조절된상태라면흡입스테로이드용량을먼저서서히줄이고지속성베타2 항진제는동일용량으로유지한다 33). 만일천식조절상태가유지되면흡입스테로이드용량을더줄여서저용량까지낮추고그다음에는지속성베타2 항진제를중단할수있다. 다른방법으로지속성베타2 항진제를일찍중단하 고흡입스테로이드용량을동일하게단독으로사용할수도있지만, 이경우일부환자는천식이다시조절되지않기도한다. 넷째, 흡입스테로이드에추가하여지속성베타2 항진제외에다른조절제를함께사용하여천식을조절한경우, 흡입스테로이드용량을서서히줄여서저용량까지낮춘다음함께사용하는조절제를중단한다. 다섯째, 조절제를줄여서최소량으로천식이조절되고최소량의조절제로환자증상재발이 1년동안없으면조절제를중단해볼수있다. 천식치료단계높이기의실제증상이재발하거나나빠지면천식조절이잘되지않는것으로판단하여주기적으로치료단계를조정해야한다 34). 치료단계를높이는방법을구체적으로살펴보면, 첫째, 속효성단기작용성약제또는속효성지속성약제와같은기관지확장제는증상이나빠지게한원인이없어질때까지반복적으로사용하여악화된천식증상을일시적으로개선시킨다. 1~2 일이상반복적으로기관지확장제사용이계속필요하면치료단계를높이는것을고려하여야한다. 둘째, 흡입스테로이드제는성인에서천식의급성악화때용량을 4배이상증가시켜서사용하면경구스테로이드를단기간사용하는정도의효과가있다 34). 이러한고용량치료는 7~14 일동안계속유지해야하며, 이방법을표준화하는데는더연구가필요하다. 셋째, 흡입스테로이드제와포모테롤과같은속효성지속성기관지확장제의병합치료는증상완화제및유지치료조절제로사용이가능하다 35). 흡입스테로이드와속효성지속형베타2 항진제를한용기에병합하여유지치료조절제로사용하면서증상완화제로도사용하여천식조절을잘할수있다. 다른조절제와다른증상완화제를함께사용할때에도비슷한효과가있는지에대한연구는아직없다. 넷째, 급성악화때에는보통고용량베타2 항진제와경구또는정맥으로스테로이드를사용한다. 2006 GINA 지침은이전지침의내용을대폭간소화하면서천식조절의개념을통한치료를제시하고있다. 2008년수정된 GINA 지침도큰변화는없고, 실제일차의료기관의천식치료의사에게적용이용이한지침으로평가받고있다. 최근의 GINA와 NAEPP 두지침모두근거중심지침이며천식조절에근거한단계적치료를제시하고있다. 천식약물치료에서주치료제는여전히흡입스테로이드이며, 특히, NAEPP 에서는 3단계에서저용량스테로이드와지속성베타2항진제흡입과중등용량스테로이드흡입제가동등한효과를보이는것으로제시하고있다. 두지침모두에 - 265 -
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