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1 Korean J Gastroenterol Vol. 70 No. 1, pissn eissn REVIEW ARTICLE H 2 수용체길항제의위산분비억제효과및임상적응용 심영광 1, 김나영 1,2 분당서울대학교병원내과 1, 서울대학교의과대학내과학교실및간연구소 2 The Effect of H 2 Receptor Antagonist in Acid Inhibition and Its Clinical Efficacy Young Kwang Shim 1 and Nayoung Kim 1,2 Department of Internal Medicine, Seoul National University Bundang Hospital 1, Seoungnam, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine 2, Seoul, Korea The first histamine H 2 receptor antagonists (H 2RAs) were developed in the early 1970s. They played a dominant role in treating peptic ulcer disease and gastroesophageal reflux disease (GERD). H 2RAs block the production of acid by H +, K + -ATPase at the parietal cells and produce gastric luminal anacidity for varying periods. H 2RAs are highly selective, and they do not affect H 1 receptors. Moreover, they are not anticholinergic agents. Sequential development of H 2RAs, proton pump inhibitors (PPIs), and discovery of Helicobacter pylori infection changed the paradigm of peptic ulcer disease with marked decrease of morbidity and mortality. PPIs are known to be the most effective drugs that are currently available for suppressing gastric acid secretion. Many studies have shown its superiority over H 2RAs as a treatment for acid-related disorders, such as peptic ulcer disease, GERD, and Zollinger-Ellison syndrome. However, other studies have reported that PPIs may not be able to render stomach achlorhydric and have identified a phenomenon of increasing gastric acidity at night in individuals receiving a PPI twice daily. These nocturnal acid breakthrough episodes can be eliminated with an addition of H 2RAs at night. The effectiveness of nighttime dose of H 2RA suggests a major role of histamine in nocturnal acid secretion. H 2RAs reduce secretion of gastric acid, and each H 2RA also has specific effects. For instance, nizitidine alleviates not only symptoms of GERD, but also provokes gastric emptying, resulting in clinical symptom improvement of functional dyspepsia. The aim of this paper was to review the characteristics and role of H 2RAs and assess the future strategy and treatment of upper gastrointestinal disease, including acid related disorders. (Korean J Gastroenterol 2017;70:4-12) Key Words: Peptic ulcer; Histamine H 2 antagonists; Gastric acid 서론 역사적으로치유가힘들고치유된후에도재발되면서출혈, 천공과같은합병증으로소화기질환에서큰비중을차지해온소화성궤양에대한치료는소화관생리학을근거로꾸준히발전해왔다. 위는위산을분비하여야세균제거및소화등생리적인역할을한다. 하지만방어인자에대한공격인자의 균형이깨지면서발생하는소화성궤양은의사들에게는매우큰문제였다. 1970년대초반 H 2 수용체길항제가개발되면서소화성궤양치료에큰발전이있었고, 이후 H 2 수용체길항제는소화성궤양의주요치료약제가된바있다. 1 이후 1980 년대에 H 2 수용체길항제보다훨씬강력한양성자펌프억제제 (proton pump inhibitor, PPI) 가치료약제로사용되기시작하였는데, 1983년에배양된헬리코박터파일로리가소화성 Received May 31, Revised June 17, Accepted June 19, CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 김나영, 13620, 성남시분당구구미로 173번길 82, 분당서울대학교병원내과 Correspondence to: Nayoung Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea. Tel: , Fax: , nayoungkim49@empas.com Financial support: This work was supported by the National Research Foundation of Korea (NRF) grant for the Global Core Research Center (GCRC) funded by the Korea government (MSIP) (No ). Conflict of interest: None. Korean J Gastroenterol, Vol. 70 No. 1, July

2 Shim YK and Kim N. The Effects of H 2 Receptor Antagonists and its Clinical Efficacy 5 궤양의원인으로밝혀지면서 PPI를이용한헬리코박터제균요법이도입되었고, 소화성궤양은내과적으로치유가능한질환이되었다. 이후노령인구증가와함께많이사용되기시작한비스테로이드소염제 (non-steroid anti-inflammatory drug, NSAID) 에의한소화성궤양발생이증가하면서소화성궤양은 NSAID와헬리코박터, 두가지원인에따라헬리코박터연관소화성궤양, 비스테로이드소염제연관소화성궤양, 헬리코박터-음성, 비스테로이드소염제-음성소화성궤양으로분류되게되었다. 2 이러한소화성궤양치료에대한여러연구에서 PPI와 H 2 수용체길항제중 PPI가소화성궤양의치료제로써우월한효과를보여준바있는데, 3,4 NSAID 연관소화성궤양치료의경우라니티딘과오메프라졸을 8주간투여할시십이지장궤양의치유율은 79% 와 93%, 위궤양의치유율은 64% 와 83% 로 PPI의치료효율이우수함이보고되었다. 5 한편비만증가와서구화된식단으로꾸준히그발생 빈도가증가하고있는위식도역류질환은초기치료후 1년이내에 80-90% 가재발하는만성질환이다. 6,7 생활습관변화와위산분비억제를통해서증상을없애고식도염의호전, 합병증을예방하는것이치료의목표이다. 위식도역류질환의치료에서도 H 2 수용체길항제에비해 PPI의효과가우수한것으로알려져있다. 8,9 또한소화성궤양이나역류성식도염뿐아니라 Zollinger-Ellison syndrome 등위산분비연관질환의치료로써 PPI가 H 2 수용체길항제에비해우월하다고발표되어있다. 3,4,10-13 그러나골다공증과같은 PPI 장기간투여에의한여러부작용이보고되고있는데, 최근에는간경화증환자에서간성혼수및자발성복막염의증가등부작용에대해증거들이보고되고있어관심이집중되고있다. 14,15 한편 PPI보다더강력한 potassium channel binding inhibitor가등장하고있고, 이에의한부작용도예측되고있어 16,17 비교적부작용이적은 H 2 수용체길항제및방어인자의적극적활용 Fig. 1. A model structure of gastric H +, K + -ATPase. The gastric H +, K + -ATPase α subunit has 3 lobes, N (ATP binding), P (phosphorylation), and A (activation) domains in the cytoplasmic domain, and 3 transmembrane segments in the membrane domain. The gastric β-subunit has a short cytoplasmic region, 1 transmembrane segment, and a heavily glycosylated extracellular region. The number of Asn sites having carbohydrates is based on pig H +, K + -ATPase, as previously described by Shin and Kim. 24 Vol. 70 No. 1, July 2017

3 6 심영광, 김나영. H 2 수용체길항제의위산분비억제효과및임상적응용 이필요하다하겠다. 이에본종설에서는 H 2 수용체길항제의역사그리고상부위장관질환의치료에서 H 2 수용체길항제의특징과효과를정리하고, 최근보고되고있는 PPI 치료의한계점과부작용을보완할수있는방법에대해검토해보고자한다. 본론 1. H +, K + -ATPase 발견과 H 2 수용체길항제의개발역사과거 H 2 수용체길항제가사용되기이전의소화성궤양치료는매우어려웠고, 합병증없는소화성궤양은수술적치료없이치료하기도했지만, 지속적인궤양재발그리고천공, 출혈등의합병증발생률이높아수술하는환자들이많았다. 또한이러한수술의경우응급수술로진행하는경우도많아 6-13% 의경우는수술후결과가좋지않았다 증상완화를위해제산제를하루 7번복용해야하는어려움과집에서절대안정을취하는등직접적비용의증가와생산량감소등간접적사회적손실이많았다. 22 이후 1976년도에 H +, K + -ATPase에대한개념이발표되었고 (Fig. 1), 23, 년 H 2 수용체길항제가개발되었다. 25,26 H 2 수용체길항제는소화성궤양의치유를혁신적으로향상시킴으로써소화성궤양질환치료의판도를변경하게되었고, H 2 수용체길항제를개발한 Sir James Black은 1988년도에노벨생리학상을수상할정도로가히의학계의혁명적인발견이되었다. H 2 수용체길 항제로소화성궤양치료를시작하면서이후소화성궤양의발생및합병증의감소를보여이와관련된여러연구들이발표되었다. 즉, Macdougall 등이 1977년에발표한간성혼수환자 50명을대상으로한연구에서 26명의대조군중 5명의환자에서위장관출혈이있었는데반해, H 2 수용체길항제로치료한 24명중한명에서만위장관출혈이있었다. 27 Jones 등이 1978년에발표한신장이식을시행한환자를대상으로한연구에서는대조군이 33명중 6명에서상부위장관출혈이있었던반면, H 2 수용체길항제로치료한환자군에서는 30명중상부위장관출혈이발생한환자가없었다. 28 이처럼간경화나만성신부전증등기존질환이심하여위점막의저항기전이떨어진환자에서의합병증치유가잘된다는논문을시작으로중증의소화성궤양치료에대한 H 2 수용체길항제효과에대한많은논문이발표되어왔다. 2. H 2 수용체길항제의약리와특성위벽세포에서의위산분비는미주신경말단에서분비되는아세틸콜린, 전정부 G 세포에서분비된가스트린, 장크롬친화세포에서분비된히스타민에의해조절되고, 위산분비의기능적주요부위는 H 2 수용체와 H +, K + -ATPase이다(Fig. 1). 24 히스타민은벽세포의 H 2 수용체에결합하여세포내의 cyclic adenosine monophosphate 농도를높이고 protein kinase A 효소를활성화시킨다. 활성화된 protein kinase A는 H +, K + -ATPase를세포질에서원형질막으로이동시키는데관여 Fig. 2. Structures of H 2 receptor antagonists. Red box indicates pyridine ring or modified structures The Korean Journal of Gastroenterology

4 Shim YK and Kim N. The Effects of H 2 Receptor Antagonists and its Clinical Efficacy 7 Table 1. Pharmacokinetics of H 2 Receptor Antagonists 32,33 Drug Bioavailability (%) Half-life (hr) Duration of action (hr) Metabolites Excretion Cimetidine Oral: 2.0 Parenteral: Ranitidine 50 Oral: 2.5 Parenteral: Nocturnal: 6-8 Basal: 4-5 Nocturnal: 13 Basal: 4 Famotidine Oral/Parenteral: Nocturnal and basal: (oral and IV) Nizatidine 70 Oral: 1-2 Nocturnal: Up to 12 Basal: Up to 8 Sulfoxide Mainly urine N-oxide (<4%) Mainly urine S-oxide (1%) Desmethyl (1%) S-oxide Urine: 65-70% Feces: 30-35% N2-monodesmethyl (<7%) N2-oxide (<5%) S-oxide (<6%) Urine: >90% Feces: <6% 하는세포골격단백질을인산화시킨다. 즉, 소포막에서비활성화상태로있던 H +, K + -ATPase가활성화된후소관으로이동하게된다. 소관으로이동한 H +, K + -ATPase는세포밖의 KCl와접촉하여세포내양성자와세포외 K이온을교환하면서위산이분비되는것이다. H 2 수용체는벽세포가위산분비를하는형태로만드는데중요한역할을하고, H +, K + -ATPase는위산분비의마지막기능적역할을수행한다. H 2 수용체길항제는이러한히스타민과경쟁적으로 H 2 수용체에결합하여위산분비를억제한다. H 2 수용체길항제는경구투여한후 1-3시간에혈중농도최고치에이르고, 뇌혈류장벽을통과하며전신에분포된다. 역사적으로개발된각 H 2 수용체길항제들의구조및특징을간단히비교하면다음과같다 (Fig , Table 1 32,33 ). 시메티딘 (cimetidine) 과파모티딘 (famotidine), 라니티딘 (ranitidine) 의생체이용률은간에서 1차대사를거치면서 35-60% 까지감소되지만, 니자티딘 (nizatidine) 은간대사를거치지않아생체이용률이 100% 에이른다. 약물의제거는간대사와신배설에의해이루어진다. 니자티딘은 90% 가소변으로배출되어청소율이신부전에영향을받지만간부전에영향을받지는않는다 (Fig , Table 1 32,33 ). 간 cytochrome P450에의해다른약물과의상호작용이발생할수있는데, 시메티딘과라니티딘을투여한후다른약물의대사가저하되어혈중농도의상승이가능하다. 파모티딘과니자티딘은 cytochrome P450과친화도가낮아다른약물과의상호작용이거의없으며, 라퓨티딘 (Lafutidine) 은 pyridine환을모핵으로한 H 2 수용체길항제와달리새로운화학구조를가진 H 2 수용체길항제이다 (Fig. 2) 즉, H 2 수용체길항제에의한공격인자약화와함께방어인자증강작용을발현하는라퓨티딘을추가하여혈액순환을촉진한다는개념이포함되어있다. 니자티딘과라니티딘은시메티딘에비해효력 (potency) 이 4배높고, 니자티딘은그효과가위에국한되며심혈관계나중추신경계에거의영향을미치지않는다. 파모티딘은시메티딘보다는 20배, 라니티딘보다는 7.5배위산억제의효력이높다고발표된바있다. 34 파모티딘을경구섭취한경우 1-3.5시간뒤혈중최고농도인 μg/l에도달하며, 위산분비를 50% 이상억제하기위해서는혈중농도 13 μg/l 이상을유지해야한다. 34 한편이러한 H 2 수용체길항제의부작용들에대해서도많이알려진바있는데, 이들은 H 2 수용체길항제에서공통적으로나타나는부작용들도있고, 각 H 2 수용체길항제대사과정등에따라각각다른부작용들도있다. 즉, 시메티딘을한달이상장기복용한경우여성유방증 (gynecomastia) 의부작용이 0.3-4% 에서발생가능하며, 그외다른 H 2 수용체길항제에서는아직보고된바가없다. H 2 수용체길항제를복용하면서발생할수있는다른부작용들에는설사, 두통, 어지럼증, 졸림, 변비등이있다. 또한 H 2 수용체길항제를 14일이상장기복용할시에고가스트린혈증등으로인하여위산억제효과가감소하는내성이발생하게된다. 35 약물을중단할경우에는 H 2 수용체길항제로유발된고가스트린혈증으로인한위산분비가약 9일간유지된다. 36 또한 H 2 수용체길항제는야간에위산분비의강력한억제효과가있고주간에위산분비효과는제한적이다. 37,38 이로인해주간에주로증상이발생하는경도 (Los-Angeles 분류상 A or B) 역류성식도염의치료에는 H 2 수용체길항제의효과가적다. 39 반대로 PPI는주간에강력한위산분비효과가있어경도역류성식도염의치료효과가좋다. 40,41 H 2 수용체길항제나 PPI로인한위산분비억제는철분의흡수를저하시킨다. 위산은비헴철 (non-heme iron) 을흡수할수있게촉진하고, 제1철 (ferrous form) 을더흡수가잘되는제2철 (ferric form) 로전환시키기때문이다. 42,43 따라서위산억제치료는잠재적으로철결핍을유발할수있고, 철분제제치료를방해할수있다. 증상이심해지속적으로약을복용해야하는위식도역류질환환자의경우이러한 PPI와 H 2 수용체길항제부작용과특성을고려하여주간에는 PPI를, 야간에는 H 2 수용체길항제를복용하는방법이선호되기도한다. Vol. 70 No. 1, July 2017

5 8 심영광, 김나영. H 2 수용체길항제의위산분비억제효과및임상적응용 3. H 2 수용체길항제의위산분비억제효과및임상응용 H 2 수용체길항제는벽세포의 H 2 수용체에경쟁적으로결합하여위산분비를억제하며 H 2 수용체에만매우선택적으로결합하기때문에다른히스타민수용체에거의작용을하지않는다. 44 이러한위산분비억제효과는 H 2 수용체길항제가제산제, 수크랄페이트보다훨씬우월하다. 45 PPI와의위산분비억제효과비교에있어서는아직명확하지않지만위산과관련된질환즉, Zollinger-Ellison syndrome, 역류성식도염, 소화성궤양등의치료에서 PPI가 H 2 수용체길항제에비해우월한결과를보여줬다. 3,4,10-13 그러나적절한 PPI 치료에도불구하고위산분비를완전히억제하는것은쉽지않은것으로보여진다. 정상인이나역류성식도염환자에서오메프라졸 40 mg을매일복용한경우에도위산분비가완전히억제되지않으며, 역류성식도염환자인경우 PPI의용량을높이면위산조절이향상되어호전을보인다. 46,47 또한 PPI를하루두번복용하는경우에도야간에발생하는위산분비로인하여 1 시간이상 ph가 4 미만으로유지되는야간위산분비억제실패가발생한것 48,49 은이러한현상을반증한다. 정상인과역류성식도염환자에서야간위산분비억제실패율은 69-79% 이며, 특히 PPI를저녁에복용한후 6시간이내, 수면중에특징적으로많이발생한다. 48,50 이시간대에는특히식도운동기능이저하되고, 침샘에서침의분비가줄어들어역류성식도염의치료나예방에악영향을줄수있다. 이러한야간위산분비억제실패의감소및소실을위해 H 2 수용체길항제를사용할수있다. 오메프라졸 20 mg을하루 2회복용한정상인에서라니티딘 150 mg 또는 300 mg을취침전에복용하였을때야간위산분비억제실패가소실되었으며 51 란소프라졸과파모티딘으로한연구에서도 H 2 수용체길항제가야간위산분비억제실패에효과가있었다. 41 그러나 H 2 수용체길항제는 2주이상장기간투여할경우약물내성이발생한다. 35 무작위위약-대조군연구에서파모티딘 40 mg을저녁식후 1회복용시에첫날 24시간위내평균 ph 3.2에서 28일째 1.9까지감소하였고, 라니티딘 300 mg 하루네번복용하였을때첫날 24시간위내평균 ph 5.0에서 7일째 3.0, 라니티딘 300 mg을하루세번복용하였을때 24시간위내평균 ph 4.3에서 14일째 2.4까지감소하였다. 35 이처럼 H 2 수용체길항제약물내성이발생하는기전에대해서는가스트린과의연관성을들어설명하고있다. 즉 H 2 수용체길항제는위 ph 를상승시킴과동시에혈중가스트린농도를상승시키는데, 가스트린은간접적으로장크롬친화세포로부터의히스타민분비를통해위산을분비하고, 또한직접적으로가스트린수용체에결합하여벽세포에서위산분비를촉진시킴으로써약제내성을유발시킨다 소화성궤양에서의 H 2 수용체길항제의유용성소화성궤양은그원인에따라크게헬리코박터연관궤양, 비스테로이드소염제연관궤양, 헬리코박터-음성, 비스테로이드소염제-음성궤양으로분류되는데, 2 H 2 수용체길항제로비스테로이드소염제연관궤양을치료할시비스테로이드소염제를중단하지않으면중단할경우보다궤양의치유속도가느리다 표준용량의 H 2 수용체길항제는비스테로이드소염제연관궤양의예방에는효과적이지않다. 시메티딘 400 mg을 10개월간취침전에복용하였으나궤양의예방에효과적이지않았으며, 56 라니티딘은십이지장궤양의발생률은감소시켰으나위궤양의발생률은감소시키지못했다. 57,58 비스테로이드소염제연관궤양의치유는더강력한위산억제효과가있는 PPI가 H 2 수용체길항제보다우월하다. 59 즉, 비스테로이드소염제연관위궤양발생억제및위궤양치유에있어서는 PPI가 H 2 수용체길항제보다우월하다고정리할수있겠다. 그러나파모티딘의경우고용량을준경우가표준용량의 H 2 수용체길항제나위약 (placebo) 보다비스테로이드소염제연관위궤양에서더나은치료효과를보이며, 60 또한방어인자촉진제의병용투여에의한비스테로이드소염제연관소화성궤양예방이나치료방법도적극모색하고있기에반드시 PPI로만치료가가능하다고하기는어려울수있겠다. 한편, 아직도이견이많기는하나헬리코박터감염이비스테로이드소염제연관궤양의발생을증가시키지않는다는주장도많다. 61,62 헬리코박터는비스테로이드소염제로인한프로스타글란딘합성억제를방해하여 63 오히려헬리코박터양성환자에서헬리코박터음성환자에비해더높은비스테로이드소염제연관궤양의치유율을보인다 위식도역류질환에서의 H 2 수용체길항제의유용성위식도역류질환은임상에서접하게되는흔한위장관질환중에하나이다. 위식도역류질환은다인성 (multifactorial) 질환으로, 역류된위액의산성도증가, 식도나식도상부점막의역류물에대한증가된민감도, 위식도역류현상의과도한발생, 역류물에대한식도의청소능저하등에영향을받는다. 따라서이와관련된하부식도조임근 (lower esophageal sphincter, LES) 의기능장애에의한낮은 LES압과일시적 LES 이완, 해부학적기전중대표적인열공허니아 (hiatal hernia), 식도배출장애, 복압증가, 내장과민성, 점막방어인자손상, 중추감작 (central sensitization), 정신적요소등은잘알려진위식도역류질환의병태생리학적기전이다. 점막손상 (mucosal break) 이나합병증의유무는위식도역류질환의진단에반드시필요한사항은아니지만, 내시경으로관찰되는점막손상의유무에따라미란성식도염 (erosive esophagitis) 과비미란성역류질환 (non-erosive reflux disease) 으로나누어진다. 역 The Korean Journal of Gastroenterology

6 Shim YK and Kim N. The Effects of H 2 Receptor Antagonists and its Clinical Efficacy 9 류성식도염의경우남성이여성보다높고비미란성역류질환은여성에서높아성차의학의예를잘보여준다. 65 위식도역류질환의치료목적은증상개선, 식도염의치료, 합병증예방과재발의방지이다. 역류성식도염의중증도는식도가산에노출되는정도와기간과관계가있다. 약제에의한위산역류효과도산역류증상과식도염증의개선과직접관련이있다. 가장기본적인치료약제로 PPI가대표적인약물이다. H 2 수용체길항제도 PPI와마찬가지로증상의호전과식도염의치유에있어위약보다유의한효과가있다. 66 H 2 수용체길항제는작용시작시간이빠르고증상이심하지않은환자에서효과가있다. PPI와 H 2 수용체길항제의증상개선효과를비교했을때 PPI는 H 2 수용체길항제에비해우월한효과를보였다. 전형적인산역류증상을가진환자의증상소실에대한위약대비상대위험도에서 PPI가 0.37로, H 2 수용체길항제 0.77에비해우월한결과를보였다 그러나이러한주치료제인 PPI에반응이없는불응성환자에대해서는여러병태생리기전에근거한약물들이연구되고있으나아직은이에대한연구결과가제한적이다. PPI를하루두번복용함에도위산분비가지속되는경우가있는데, 특히밤에일어나는야간분비억제실패가발생하는경우가많다. 69 이러한경우에취침전 H 2 수용체길항제를병용투여하는경우에효과적이다. 70,71 이처럼 PPI 단독치료로증상조절이잘되지않는경우에 H 2 수용체길항제가도움이될수있다. 6. H 2 수용체길항제의위장관운동개선효과역류성식도염은부적절한식도운동과위산분비로생긴만성적인병리학적상태이다. 72,73 위산억제를위한치료약제로써 PPI가 H 2 수용체길항제보다우월한효과를보이지만, 74,75 H 2 수용체길항제중하나인니자티딘은시메티딘, 파모티딘, 라니티딘과달리아세틸콜린분해효소를억제하고콜린신경의시냅스에아세틸콜린의농도를높여위장관의운동을활성화시키는유일한효과를지닌다. 76,77 아세틸콜린은직접적으로위장관운동을자극하고그렐린 (ghrelin) 의분비를촉진하여시상하부자극을통해더욱위장관운동을향상시킨다. 78 위장관의운동이향상되어있는상태에서위장관운동조절약물을투여하게되면식도의연동운동향상과하부식도괄약근압력의증가, 위배출 (gastric emptying) 의향상으로인해역류성식도염의치유에도움이되고호전상태가유지된다. 79,80 니자티딘은강력한위장운동촉진효과가있고콜린신경활성화로인해침의분비를증가시킨다. 81,82 침분비의증가는식도로역류된위산을없애고, 역류성식도염의치료에도움이된다. 83,84 결 론 소화성궤양이나역류성식도염, Zollinger-Ellision syndrome 등의위산관련위장관질환의치료제로 H 2 수용체길항제나 PPI가많이사용되고있고, 그중에서도 PPI의치료효과가더우수하다고알려져있다. 그러나 PPI도위산의분비를완전히억제하지는못하며, PPI를하루두번복용할경우에도야간위산분비억제실패등의한계점이있다. H 2 수용체길항제를같이복용할경우이를보완할수있을것으로보인다. 또한 H 2 수용체길항제중니자티딘은위장관운동을향상시키고침분비를증가시키는효과가있어역류성식도염의치료에도움이된다. 또한강력한위산분비억제로인한 PPI의부작용이많이밝혀지고있는바, H 2 수용체길항제의특징과장점을잘파악하여상부위장관질환의치료가이루어지기를기대한다. REFERENCES 1. Pounder R. Histamine H2-receptor antagonists. Baillieres Clin Gastroenterol 1988;2: Shim YK, Kim N. Nonsteroidal anti-inflammatory drug and aspirin-induced peptic ulcer disease. Korean J Gastroenterol 2016; 67: Brunner G, Creutzfeldt W, Harke U, Lamberts R. Therapy with omeprazole in patients with peptic ulcerations resistant to extended high-dose ranitidine treatment. Digestion 1988;39: Double blind comparative study of omeprazole and ranitidine in patients with duodenal or gastric ulcer: a multicentre trial. Cooperative study group. Gut 1990;31: Yeomans ND. New data on healing of nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Omeprazole NSAID Steering Committee. Am J Med 1998;104(3A):56S-61S; discussion 79S-80S. 6. Lagergren J, Bergström R, Lindgren A, Nyrén O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340: Katz PO. Pathogenesis and management of gastroesophageal reflux disease. J Clin Gastroenterol 1991;13 Suppl 2:S6-S Fass R, Ofman JJ, Gralnek IM, et al. Clinical and economic assessment of the omeprazole test in patients with symptoms suggestive of gastroesophageal reflux disease. Arch Intern Med 1999; 159: Habu Y, Oyasu K, Wakamatsu T, et al. Cost-effectiveness of the treatment of reflux esophagitis: proton pump inhibitor versus histamine-2-receptor antagonist. Nihon Rinsho 2000;58: Delchier JC, Soule JC, Mignon M, et al. Effectiveness of omeprazole in seven patients with zollinger-ellison syndrome resistant to histamine H2-receptor antagonists. Dig Dis Sci 1986;31: Lamers CB, Lind T, Moberg S, Jansen JB, Olbe L. Omeprazole in zollinger-ellison syndrome. Effects of a single dose and of long- Vol. 70 No. 1, July 2017

7 10 심영광, 김나영. H 2 수용체길항제의위산분비억제효과및임상적응용 term treatment in patients resistant to histamine H2-receptor antagonists. N Engl J Med 1984;310: Ducrotté P, Guillemot F, Elouaer-Blanc L, et al. Comparison of omeprazole and famotidine on esophageal ph in patients with moderate to severe esophagitis: a cross-over study. Am J Gastroenterol 1994;89: Bate CM, Keeling PW, O'Morain C, et al. Comparison of omeprazole and cimetidine in reflux oesophagitis: symptomatic, endoscopic, and histological evaluations. Gut 1990;31: Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology 2016;64: Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology 2017;152: Li H, Meng L, Liu F, Wei JF, Wang YQ. H+/K+-ATPase inhibitors: a patent review. Expert Opin Ther Pat 2013;23: Andersson K, Carlsson E. Potassium-competitive acid blockade: a new therapeutic strategy in acid-related diseases. Pharmacol Ther 2005;108: Hallenbeck GA. What is the best elective operation for duodenal ulcer? Can Med Assoc J 1970;103: Luff AP. Collective investigation into the after-history of gastro-enterostomy. Br Med J 1930;1: Kemp D. An evaluation and comparison of the early and late results of standardized polya gastrectomy. Gut 1967;8: Whittaker LD Jr, Judd ES, Stauffer MH. Analysis of use of vagotomy with drainage procedure in surgical management of duodenal ulcer. Surg Gynecol Obstet 1967;125: Kang JM, Seo PJ, Kim N, et al. Analysis of direct medical care costs of peptic ulcer disease in a Korean tertiary medical center. Scand J Gastroenterol 2012;47: Sachs G, Chang HH, Rabon E, Schackman R, Lewin M, Saccomani G. A nonelectrogenic H+ pump in plasma membranes of hog stomach. J Biol Chem 1976;251: Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 2013;19: Black JW, Duncan WA, Durant CJ, Ganellin CR, Parsons EM. Definition and antagonism of histamine H 2-receptors. Nature 1972;236: Okabe S, Takeuchi K, Urushidani T, Takagi K. Effects of cimetidine, a histamine H2-receptor antagonist, on various experimental gastric and duodenal ulcers. Am J Dig Dis 1977;22: Macdougall BR, Bailey RJ, Williams R. H2-receptor antagonists and antacids in the prevention of acute gastrointestinal haemorrhage in fulminant hepatic failure. Two controlled trials. Lancet 1977;1: Jones RH, Rudge CJ, Bewick M, Parsons V, Weston MJ. Cimetidine: prophylaxis against upper gastrointestinal haemorrhage after renal transplantation. Br Med J 1978;1: Bossi A, Romeo G, Pezzoli A. Side-effects, structure, and H2-receptor antagonists. Lancet 1992;339: Song WJ, Kim MH, Lee SM, et al. Two cases of h(2)-receptor antagonist hypersensitivity and cross-reactivity. Allergy Asthma Immunol Res 2011;3: Aihara T, Nakamura E, Amagase K, et al. Pharmacological control of gastric acid secretion for the treatment of acid-related peptic disease: past, present, and future. Pharmacol Ther 2003;98: Berardi RR, Tankanow RM, Nostrant TT. Comparison of famotidine with cimetidine and ranitidine. Clin Pharm 1988;7: Frank WO, Young M, Palmer RH, Karlstadt R, Rockhold F, Mounce W. Once-daily bedtime dosing regimen of cimetidine in the treatment of gastric ulcer. Clin Ther 1988;11: Weir DG. Peptic ulceration. Br Med J (Clin Res Ed) 1988;296: Wilder-Smith CH, Ernst T, Gennoni M, Zeyen B, Halter F, Merki HS. Tolerance to oral H2-receptor antagonists. Dig Dis Sci 1990; 35: Fullarton GM, McLauchlan G, Macdonald A, Crean GP, McColl KE. Rebound nocturnal hypersecretion after four weeks treatment with an H2 receptor antagonist. Gut 1989;30: Nwokolo CU, Smith JT, Gavey C, Sawyerr A, Pounder RE. Tolerance during 29 days of conventional dosing with cimetidine, nizatidine, famotidine or ranitidine. Aliment Pharmacol Ther 1989;4 Suppl 1: Komazawa Y, Adachi K, Mihara T, et al. Tolerance to famotidine and ranitidine treatment after 14 days of administration in healthy subjects without helicobacter pylori infection. J Gastroenterol Hepatol 2003;18: Adachi K, Fujishiro H, Katsube T, et al. Predominant nocturnal acid reflux in patients with Los Angeles grade C and D reflux esophagitis. J Gastroenterol Hepatol 2001;16: Festen HP, Schenk E, Tan G, Snel P, Nelis F. Omeprazole versus high-dose ranitidine in mild gastroesophageal reflux disease: short-and long-term treatment. The Dutch Reflux Study Group. Am J Gastroenterol 1999;94: Katsube T, Adachi K, Kawamura A, et al. Helicobacter pylori infection influences nocturnal gastric acid breakthrough. Aliment Pharmacol Ther 2000;14: Bezwoda W, Charlton R, Bothwell T, Torrance J, Mayet F. The importance of gastric hydrochloric acid in the absorption of nonheme food iron. J Lab Clin Med 1978;92: Golubov J, Flanagan P, Adams P. Inhibition of iron absorption by omeprazole in rat model. Dig Dis Sci 1991;36: Wallace JL, Sharkey KA. Pharmacotherapy of gastric acidity, peptic ulcers and gastroesophageal reflux disease. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman s the pharmacological basis of therapeutics. 12th ed. New York: McGraw- Hill Education, 2011: Qadeer MA, Richter JE, Brotman DJ. Hospital acquired gastrointestinal bleeding outside the critical care unit: risk factors, role of acid suppression, and endoscopy findings. J Hosp Med 2006; 1: Leite LP, Johnston BT, Just RJ, Castell DO. Persistent acid secretion during omeprazole therapy: a study of gastric acid profiles in patients demonstrating failure of omeprazole therapy. Am J Gastroenterol 1996;91: Kuo B, Castell DO. Optimal dosing of omeprazole 40 mg daily: ef- The Korean Journal of Gastroenterology

8 Shim YK and Kim N. The Effects of H 2 Receptor Antagonists and its Clinical Efficacy 11 fects on gastric and esophageal ph and serum gastrin in healthy controls. Am J Gastroenterol 1996;91: Peghini PL, Katz PO, Bracy NA, Castell DO. Nocturnal recovery of gastric acid secretion with twice-daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93: Katz PO, Anderson C, Khoury R, Castell DO. Gastro-oesophageal reflux associated with nocturnal gastric acid breakthrough on proton pump inhibitors. Aliment Pharmacol Ther 1998;12: Fackler WK, Vaezi MF, Ours TM, Richter JE. Nocturnal acid breakthrough cannot be eliminated in patients with atypical gastroesophageal reflux disease. Gastroenterology 2000;118:A Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric acid breakthrough on omeprazole: a controlled study in normal subjects. Gastroenterology 1998;115: Walsh JH, Richardson CT, Fordtran JS. ph dependence of acid secretion and gastrin release in normal and ulcer subjects. J Clin Invest 1975;55: Lancaster-Smith MJ, Jaderberg ME, Jackson DA. Ranitidine in the treatment of non-steroidal anti-inflammatory drug associated gastric and duodenal ulcers. Gut 1991;32: Walan A, Bader JP, Classen M, et al. Effect of omeprazole and ranitidine on ulcer healing and relapse rates in patients with benign gastric ulcer. N Engl J Med 1989;320: Soll AH, Achord JL, Bozymski G, et al. Medical treatment of peptic ulcer disease: practice guidelines. JAMA 1996;275: Roth SH, Bennett RE, Mitchell CS, Hartman RJ. Cimetidine therapy in nonsteroidal anti-inflammatory drug gastropathy. Doubleblind long-term evaluation. Arch Intern Med 1987;147: Ehsanullah RS, Page MC, Tildesley G, Wood JR. Prevention of gastroduodenal damage induced by non-steroidal anti-inflammatory drugs: controlled trial of ranitidine. BMJ 1988;297: Robinson MG, Griffin JW Jr, Bowers J, et al. Effect of ranitidine on gastroduodenal mucosal damage induced by nonsteroidal antiinflammatory drugs. Dig Dis Sci 1989;34: Jones DB, Howden CW, Burget DW, Kerr GD, Hunt RH. Acid suppression in duodenal ulcer: a meta-analysis to define optimal dosing with antisecretory drugs. Gut 1987;28: Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996;334: Graham DY, Lidsky MD, Cox AM, et al. Long-term nonsteroidal antiinflammatory drug use and helicobacter pylori infection. Gastroenterology 1991;100: National institutes of health consensus development conference panel statement: management of hepatitis C. Hepatology 1997;26(3 Suppl 1):2S-10S. 63. Hudson N, Balsitis M, Filipowicz F, Hawkey CJ. Effect of helicobacter pylori colonisation on gastric mucosal eicosanoid synthesis in patients taking non-steroidal anti-inflammatory drugs. Gut 1993;34: Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338: Kim YS, Kim N, Kim GH. Sex and gender differences in gastroesophageal reflux disease. J Neurogastroenterol Motil 2016;22: van Pinxteren B, Numans ME, Bonis PA, Lau J. Short term treatment with proton pump inhibitors, H2 receptor antagonists and prokinetics for gastro oesophageal reflux disease like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2006;(3):CD Khan M, Santana J, Donnellan C, Preston C, Moayyedi P. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007;(2):CD Dean BB, Gano AD Jr, Knight K, Ofman JJ, Fass R. Effectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004;2: Zacny J, Zamakhshary M, Sketris I, Veldhuyzen van Zanten S. Systematic review: the efficacy of intermittent and on demand therapy with histamine H2 receptor antagonists or proton pump inhibitors for gastro oesophageal reflux disease patients. Aliment Pharmacol Ther 2005;21: Fackler WK, Ours TM, Vaezi MF, Richter JE. Long-term effect of H2RA therapy on nocturnal gastric acid breakthrough. Gastroenterology 2002;122: Mainie I, Tutuian R, Castell DO. Addition of a H2 receptor antagonist to PPI improves acid control and decreases nocturnal acid breakthrough. J Clin Gastroenterol 2008;42: Dodds WJ, Hogan WJ, Helm JF, Dent J. Pathogenesis of reflux esophagitis. Gastroenterology 1981;81: Isolauri J, Laippala P. Prevalence of symptoms suggestive of gastro-esophageal reflux disease in an adult population. Ann Med 1995;27: Vigneri S, Termini R, Leandro G, et al. A comparison of five maintenance therapies for reflux esophagitis. N Engl J Med 1995; 333: Kawano S, Murata H, Tsuji S, et al. Randomized comparative study of omeprazole and famotidine in reflux esophagitis. J Gastroenterol Hepatol 2002;17: Neya T, Itano N, Mizutani M, Yamasato T, Takaki M, Nakayama S. The effect of cisapride on neural 5-HT receptors in guinea-pig isolated ileum. Eur J Pharmacol 1984;106: Ueki S, Matsunaga Y, Yoneta T, Tamaki H, Itoh Z. Gastroprokinetic activity of nizatidine during the digestive state in the dog and rat. Arzneimittelforschung 1999;49: Futagami S, Shimpuku M, Song JM, et al. Nizatidine improves clinical symptoms and gastric emptying in patients with functional dyspepsia accompanied by impaired gastric emptying. Digestion 2012;86: Inauen W, Emde C, Weber B, et al. Effects of ranitidine and cisapride on acid reflux and oesophageal motility in patients with reflux oesophagitis: a 24 hour ambulatory combined ph and manometry study. Gut 1993;34: Sekiguchi T, Nishioka T, Matsuzaki T, et al. Comparative efficacy of acid reflux inhibition by drug therapy in reflux esophagitis. Gastroenterol Jpn 1991;26: Adachi K, Ono M, Kawamura A, Yuki M, Fujishiro H, Kinoshita Y. Nizatidine and cisapride enhance salivary secretion in humans. Aliment Pharmacol Ther 2002;16: Vol. 70 No. 1, July 2017

9 12 심영광, 김나영. H 2 수용체길항제의위산분비억제효과및임상적응용 82. Adachi K, Furuta K, Katsube T, et al. Nizatidine and cisapride increase salivary secretion in rats. Dig Dis Sci 2004;49: Sonnenberg A, Steinkamp U, Weise A, et al. Salivary secretion in reflux esophagitis. Gastroenterology 1982;83: Helm JF, Dodds WJ, Hogan WJ, Soergel KH, Egide MS, Wood CM. Acid neutralizing capacity of human saliva. Gastroenterology 1982;83(1 Pt 1): The Korean Journal of Gastroenterology