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1 대한내과학회지 : 제 78 권제 2 호 2010 특집 (Special Review) - 상부소화관운동질환의최신지견 위식도역류질환의약물치료 : 국내에좋은치료법및최근의개발약물 원광대학교의과대학내과학교실, 소화기질환연구소 류한승 최석채 Drug therapy of gastroesophageal reflux disease: Good treatment strategies in Korea and recently developed drugs Han Seung Ryu, M.D., and Suck Chei Choi, M.D. Department of Internal Medicine and Digestive Disease Research Institute, Wonkwang University College of Medicine, Iksan, Korea The prevalence of gastroesophageal reflux disease (GERD) in Western countries ranges between 10% and 20%. Although GERD is increasing in Korea, it is difficult to actively conduct studies due to restrictions in insurance regulations and there are practical limitations to prescribe drugs conforming the evidence-based guidelines. As novel drug therapy for GERD, drugs with new mechanisms that would overcome pharmacokinetic limits of proton pump inhibitors are being investigated. In this review, with regards to drug therapy of GERD, we discuss management strategies suitable for domestic circumstances and drugs that are being newly developed. (Korean J Med 78: , 2010) Key Words: Gastroesophageal reflux disease; Drug therapy 서론최근위식도역류질환 (gastroesophageal reflux disease, GERD) 에대한많은연구결과가축적되면서다양한서구의치료가이드라인이발표되었다 1-4). 국내에서도 GERD는증가하고있으나 5-7), 서구의근거중심 (evidence-based) 의가이드라인에따라약제의처방을적용하는경우에는약제비의삭감등을포함한현실적인제한이있다. GERD의약물치료에서양성자펌프억제제 (proton pump inhibitor, PPI) 의효과는입증되어주치료약제로사용되고있다 8). 하지만일부의환자에서좋은치료효과를보이지않는경우가발견되기도한다. 본고에서는 GERD의약물치료에있어국내외연구와가 이드라인을토대로제한된보험현실에서국내에좋은치료법을생각해보고, 최근개발되고있는약물에대해살펴보고자한다. 국내에좋은위식도역류질환의약물치료법 1. PPI 의시험적투여 (proton pump inhibitor test, PPI test) 를통한진단및경험적치료 (empirical treatment) 흉부작열감과위산역류는 GERD를진단하는주요증상이지만국내에서는내시경검사를통한진단및약물치료를보험에서인정하고있다. 그러나비미란성위식도역류질환 (non-erosive reflux disease, NERD) 의빈도가높아 GERD 진

2 - The Korean Journal of Medicine: Vol. 78, No. 2, 단에있어내시경검사의민감도가낮고, 침습적이며비용이많이드는문제점이있다. 이에대한대안으로서구의가이드라인에서는사용하기쉽고비침습적인 PPI의시험적투여를통한진단및치료를제시하고있다 2,3). 1~4주간의 PPI 검사에대한메타분석에서 0.78 (95% CI, 0.66~0.86), 0.54 (CI, 0.44~0.65) 의민감도와특이도를보였으며 9), 국내에서도 esomeprazole 40 mg을 1주간투여한다기관연구에서 GERD군에서 84.3% 의양성률을보여민감도가좋음을보고하였다 10). 최근의아시아- 태평양합의에서는일차진료기관에서경고증상 (alarm symptoms) 이없는전형적증상을호소하는환자에서 4주간의경험적치료를제시하고있다 11). 그러나국내의환자들은위장관증상이심하고반복적으로발생하는경우, 위암에대한두려움으로검사를받아보기원하는경우가흔하다. 서구에비해위암유병률이매우높고내시경의접근성이좋으며경험적치료에대한보험급여제한으로인한환자부담가중등의국내현실을고려할때 PPI 검사를통한진단및경험적치료를그대로적용하기어렵다. 임상적으로는전형적인위식도역류질환의증상이있으나내시경검사금기증또는환자의거부등의사유로내시경검사로질환을확인할수없는환자나 12) NERD에서보행성 24시간식도 ph 검사를적용하기어려운일차진료기관에서사용할수있지만 10) 이에대한보다많은잘계획된연구와제도개선이필요하다. 2. 초기치료 (initial treatment) PPI는최근의메타분석에서식도염의치유율이히스타민 2 -수용체길항제 (histamine 2-receptor antagonists, H 2RA) 나위약에비해월등함을보였다 8). 현재 PPI는 GERD의주치료약제로사용되고있으며다양한약제간에유사한효능을보이나국내식약청허가기준에따른보험급여범위에다소차이가있는점을고려해야한다. GERD의초기치료목표는환자의증상과점막결손의치유이고, 이를달성하기위하여적절한기간및용량을고려하여치료약제를선택하여야한다. Genval workshop에서는 NERD, LA-A나 B에해당하는미란성식도염 (erosive esophagitis, ERD) 경우는 2~4주간, LA-C 나 D의 ERD는 8주간의초기치료를권고하고있다 1). ERD 환자를대상으로한 PPI 치료에대한 43개연구의메타분석에서 4, 8, 12주에각각 65%, 80%, 84% 의치유율을보여 ERD에서 8주간의치료가합리적이었다 13). 국내에서도 esomeprazole 40 mg을 8주간투여한다기관공동연구에서 ERD 환자군의 92% 에서증상호전을 91% 에서식도염의호전을보였으며 14), 표준용량 (standard dose) 의 rabeprazole 연구에서도 8주투여에서 86% 의식도염의호전을보고하였다 15). 그러나내시경상경도의식도염에서는단기간의치료로도효과를보이며 16-18), esomeprazole 40 mg을투여한국내연구에서도식도염의치유율이 4주 81%, 8주 91% 였으나두군간에통계적으로유의한차이가없었다 14). 국내다수의연구들에서식도염이경한경우가대부분이고 19-21), 제한된보험현실을고려할때, LA-C, D의심한 ERD에서는 8주치료를 LA-A, B의 ERD에서는 4주치료후증세가지속될경우 4주의추가적인치료를고려할수있다. NERD에서는 PPI의치료효과가 ERD보다낮은것으로알려져있다 22). 최근의국내연구에서도 NERD에서 ERD보다표준용량의 PPI 8주치료에불응성인경우가많았다 23). 따라서 NERD 환자의적절한초기치료기간은환자의증상에대한세밀한문진을토대로충분한약제투여가필요하고이에대한추가연구가필요하다. 내시경검사에서심한식도염환자에서고용량 PPI 투여는논란이있다. 대부분의서구가이드라인에서는초기치료로서고용량 PPI 투여를권고하지않는다 1,3,4). 최근의코크란분석에서는두배용량의 PPI 치료가표준용량보다식도염의치유율이높은것으로나타났지만하위그룹분석에서는 12개무작위연구중 7개에서두치료간의치유율의차이가없는것으로나타났다 8). 고용량 PPI 치료의일반적기준은표준용량의초기치료에도증상이지속되거나또는통증의돌파 (breakthrough) 가있는경우이다 1-3). 미국의전향적다기관연구에서도표준용량의 PPI 치료에실패한경우두배용량으로 6주간치료하였을때흉부작열감및산역류증상이 20% 정도호전되었다 24). 국내에서는내시경에서식도염이심한정도에관계없이먼저표준용량의 PPI 치료후반응이없는경우에제한적으로고용량으로치료하는전략이좋을듯하다. 3. 유지치료 (maintenance treatment) GERD는성공적인초기치료가되어도약제중단시약 40~70% 의경우에재발하므로 23,25-27), 장기적인치료전략이필요하다. 약제의지속적인사용에따르는비용부담과부작용을고려하여적절한유지치료전략을수립해야한다. 미국소화기학회에서는 ERD의경우단계적하향접근 (stepdown) 을통해증상조절을위한최소용량을매일투여하는지속요법 (continuous therapy) 을 NERD는요구요법 (on-de

3 - Han Seung Ryu, et al. Drug therapy of gastroesophageal reflux disease - mand therapy) 을권고하고있다 4). 식도염은내시경소견이심할수록재발을잘하며 28), 표준용량이상을지속적으로투여함에도재발하는경우가있을수있다 29). 한단일기관연구에서도 esomeprazole 20 mg으로 6개월간장기치료한결과지속요법군과요구요법군에서각각 81%, 58% 에서관해상태를유지하여 ERD에서요구요법은적절치않았다 30). 최근의 17개의연구를종합한체계적종설에서도 ERD에서요구요법이효과적이지못함을제시한바있다 31). 이러한결과는 ERD에서는요구요법보다는지속요법치료전략을세우는것이적절하다는것을보여준다. NERD의경우요구요법은효과적이며 31), 지속요법에서발생할수있는부작용이적어치료가잘유지되고 32), 비용- 효과적이다 33). 국내에서지속요법또는요구요법의장단점과국내의여건에맞는치료전략을만드는데필요한체계적인연구가필요하다. 지속요법에서 PPI의용량에관한코크란분석에서표준용량을사용하는것이 GERD의재발방지에가장효과적이었다 34). 그러나한미국의다기관무작위이중맹검연구에서 6주간의 esomeprazole 40 mg 투여에서 93.6%, 20 mg에서 93.2% 로유사한식도염의치료유지효과를보였으며 35), 국내연구에서도유지용량 (maintenance dose) 의 rabeprazole에서무증상을유지하는경우가 90.6% 였다 36). 현보험에서도대개유지용량의 PPI 투여를인정하는경향을고려할때 ERD 환자에서유지용량의 PPI를사용하는것이현실적이나환자마다식도염의심한정도또는치료의반응정도가다르기때문에개별화치료전략이필요한경우가있다. 요구요법에서의적합한 PPI 용량은유지용량도효과적이며 37), 표준용량과유지용량간에치료효과의큰차이가없다 38-40). 4. 식도외증상의치료국내에서비심인성흉통, 만성기침, 후두염, 천식, 쉰목소리 (hoarseness), 인두구 (globus) 등식도외증상은 20~55% 에서 GERD와동반된다 41). 증상의발생은복합적인원인이많기에증상만으로 GERD를예측하기는어렵다 42). GERD와연관된비심인성흉통에서 PPI 검사및경험적치료는최근두개의메타분석에서좋은민감도및특이도를보였다 43,44). 두배용량의 rabeprazole을사용한국내연구에서도 2주이상투여하였을때민감도와특이도가각각 81%, 62% 로좋은결과를보였고 45), 미국에서는 4주투여를권고하고있다 4). 그러나국내연구가부족하며정확한용량 과치료기간이확립되어있지않다. 만성기침환자에대한고용량 PPI 요법은최근 5개무작위대조군연구에대한메타분석에서일부효과적이나일관된결과를보이지않았다 46). 식도외증상에관련된각각의연구들중에서 22명의후두염환자를대상으로두배용량의 lansoprazole을사용한이중맹검연구에서 50% 의반응률을보여경험적 PPI 치료가효과적이었으나 47), 두배용량의 esomeprazole을 16주간투여한연구에서는위약군과차이가없었다 48). 천식환자에서는 GERD가동반된경우고용량의 PPI 요법이효과가있었다 49). 만성기침에대한국내연구에서는 31% 만이 GERD였으며이중 63% 가 PPI 치료에반응하였고 50), 인두구환자에서도 22% 만이 GERD로진단되었다 51). 서구에서는 GERD가동반된만성기침, 후두염, 천식에서 PPI 치료를제시하고있으나 4,11), 국내에서이에관련된연구는시작단계이며국내의보험상황을고려한가이드라인의제시가필요하다. 최근의개발약물 1. 위산분비억제제속효성 omeprazole (immediate-release omeprazole, Zegerid, Santarus, San Diego, USA) 은기존약제에장용피복 (enteric coating) 을제거하여빠르게흡수되며중탄산나트륨을추가하여약제의위산분해를막도록제조한복합제이다 52). 중탄산나트륨으로인해복용 30분내에위내산도가상승하여가스트린 (gastrin) 분비를자극하고위벽세포 (parietal cell) 가활성화되면서 omeprazole이빠르게작용하게한다 53). 주로 nocturnal acid breakthrough에대한효능연구에서다른 PPI 제제보다효과적임이입증되었다 54,55). 2004년 FDA에공인되었으며야간증상과요구요법에사용될수있다. Dexlansoprazole (Kapidex TM, Takeda Pharmaceuticals North America, Inc., USA) 은 lansoprazole의거울상이성질체 (enantiomer) 로복용후 1~2시간과 4~5시간두번의최고혈중농도와긴반감기를가진약물이다 56). 보다지속적인위산분비억제효과를가지며 3상시험에서 ERD, NERD 치료에효과적이고 ERD의유지요법에안전함을보고하였다 57-60). 본약제는 2009년 1월 FDA에승인되었다. Tenatoprazole은 omeprazole과유사한구조를가진새로운 PPI이다. Omeprzole 은대부분의 PPI에공통적인 benzimidazole기를가지나 tenatoprazole은 imidazopyridine 기를가지는차이로체내대사가느려작용시간이길다 61,62). 건강자원자

4 - 대한내과학회지 : 제 78 권제 2 호통권제 594 호 를대상으로한연구에서강력한야간산분비억제능과긴작용시간을보였다 63,64). 위산펌프길항제 (acid pump antagonist) 는벽세포의 H +,K + - ATPase 의 K + 결합부위에경쟁적으로작용하여 H + 교환을방해하는가역적인기전으로산분비를억제한다 65). 약물의 pka 값이높고낮은 ph에서안정하여산성환경에서고농도로농축되며보다빠르고강력한산분비억제효과를기대할수있다 66). AZD0865 는새롭게개발된위산펌프길항제이며 esomeprazole과비교연구에서우월성을입증하지못했으나 67,68), 약제투여방법을달리한추가연구가필요하다는견해가있다 65). 2. 일과성하부식도괄약근이완 (transient lower esophageal sphincter relaxation, tlesr) 억제제식도역류의주된병인으로서 tlesr에연관된신경전달과정에작용하는약제가 GERD 치료에효과적일수있다 69). Gamma-aminobutyric acid type B (GABA B) 수용체작동제 (agonist) 인 baclofen은소규모연구에서 tlesr을감소시켜산및비산역류에효과적이며 70-72), 식도열공탈장 (hiatal hernia) 환자에도움이된다는연구가있다 73). 그러나 baclofen은현훈 (dizziness) 과기면 (somnolence) 등중추성부작용이문제가되어이를개선한 AZD9343, AZD3355 등의약제가연구중이다 74,75). Glutamate는대사성 glutamate 수용체 (metabotropic glutamate receptor, mglur) 에작용하여미주신경을통한위장관감각전달과 tlesr에관여한다 76). 최근 mglur5 조절제인 ADX10059가 GERD 환자의증상과역류감소에효과적일수있음을제시하였으며 77), 2상임상시험이진행중이다 78). 결론우리나라에서 GERD의치료는내시경시행없이증상만으로진단한후경고증상이없는경우에경험적 PPI 치료는시도해볼수있다. 하지만위암발생이많은국내의여건과환자의기질적질환에대한두려움에대한해결방안을가져야만한다. 국내 ERD의경우주로경도의식도염이기에표준용량의 PPI로 4주정도치료한후유지용량으로지속요법을시행하는것이, 심한 ERD의경우는 8주표준용량으로치료후유지용량으로지속요법을시행하는것이좋다. NERD는 ERD에비해 PPI 치료에반응정도가좋지않지만 4주정도표준용량으로치료를시도한후좋은반응을보이 면요구요법으로유지치료의전략을세워야한다. 고용량의 PPI 투여는표준용량에반응이없거나식도외증상과연관성이있는경우좋은효과를기대할수있지만국내보험급여기준에서제한하고있기에현실적으로사용하기에는어렵다. 최근 GERD 치료약제의개발은 PPI의부작용을줄이고, 약효의증대및지속시간을늘릴수있는약제를개발하고있다. 또한주요병태생리에관여하고있는일과성하부식도괄약근이완을억제할수있는약제의개발이초기임상연구단계에있다. 중심단어 : 위식도역류질환 ; 약물치료 REFERENCES 1) An evidence-based appraisal of reflux disease management: the Genval Workshop Report. Gut 44(Suppl 2):S1-S16, ) Armstrong D, Marshall JK, Chiba N, Enns R, Fallone CA, Fass R, Hollingworth R, Hunt RH, Kahrilas PJ, Mayrand S, Moayyedi P, Paterson WG, Sadowski D, van Zanten SJ. Canadian Consensus Conference on the management of gastroesophageal reflux disease in adults: update Can J Gastroenterol 19:15-35, ) DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 100: , ) Kahrilas PJ, Shaheen NJ, Vaezi MF, Hiltz SW, Black E, Modlin IM, Johnson SP, Allen J, Brill JV. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology 135: , ) Cho YS, Choi MG, Jeong JJ, Chung WC, Lee IS, Kim SW, Han SW, Choi KY, Chung IS. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Asan-si, Korea. Am J Gastroenterol 100: , ) Yang SY, Lee OY, Bak YT, Jun DW, Lee SP, Lee SH, Park GT, Yoon BC, Choi HS, Hahm JS, Lee MH, Lee DH. Prevalence of gastroesophageal reflux disease symptoms and uninvestigated dyspepsia in Korea: a population-based study. Dig Dis Sci 53: , ) Kim JI, Kim SG, Kim N, Kim JG, Shin SJ, Kim SW, Kim HS, Sung JK, Yang CH, Shim KN, Park SJ, Park JY, Baik GH, Lee SW, Park JJ, Hong SJ, Lee GH, Seo GS, Lee SI, Jung HC. Changing prevalence of upper gastrointestinal disease in Koreans from 1995 to Eur J Gastroenterol Hepatol 21: , ) Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis

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8 - 대한내과학회지 : 제 78 권제 2 호통권제 594 호 Curr Opin Pharmacol 8: , ) Keywood C, Wakefield M, Tack J. A proof-of-concept study evaluating the effect of ADX10059, a metabotropic glutamate receptor-5 negative allosteric modulator, on acid exposure and symptoms in gastro-oesophageal reflux disease. Gut 58: , ) Press-releases. Addex starts phase IIb ADX10059, proton pump inhibitor combination study in GERD patients. Available from: