Consideration for long-term safety issues of PPI 성균관대학교의과대학삼성서울병원소화기내과이준행 1. 서론 PPI (proton pump inhibitor) 는위식도역류질환치료의중심이되는약물이다. 과거 H 2 RA (histamine 2 receptor antagonist) 에반응하지않던환자들이 PPI 도입후현저한증상개선과삶의질향상을보였던예는많다. H 2 RA에서는유즙분비, 여성형유방증, 발기부전, 몇몇약물과의상호작용등이잘알려진반면, PPI는눈에띄는부작용 (side effect) 이적기때문에상대적으로안전한약제로인식되고있다. 그러나다른약물들과마찬가지로 PPI에도어느정도의부작용이동반된다 (Table 1) 1. 최근본학회지에 PPI 사용시경험할수있는부작용과그대책 이라는제목의종설이발표된바있으며, 2 해외에도오늘의주제에대한적지않은논문들이있다. 3-7 따라서본고에서는임상적으로관심이높은몇몇이슈들에대하여짧게검토하고자한다. 2. 약물부작용의분류안전성정보관리규정 ( 식품의약품안전청고시제 2004-30호 ) 에서약품안전성평가와관련된용어는다음과같이정의되고있다. 8 부작용은의약품을정상적인용량에따라투여할경우발생하는모든의도되지않은효과를말하며, 유해사례 (adverse event/adverse experience), 실마리정보 (signal), 약물유해반응 (adverse drug reaction, ADR) 등을포함한다. 유해사례는의약품의투여 사용중발생한바람직하지않고의도되지않은징후, 증상또는질병을말하며, 당해의약품과반드시인과관계가있어야하는것은아니다. 실마리정보는인과관계가알려지지아니하거나입증자료가불충분하지만그인과관계를배제할수없어계속적인관찰이요구되는정보를말한다. 약물유해반응은의약품을정상적으로투여 사용한때에발생한해롭고의도하지아니한반응으로서해당의약품과의인과관계를배제할수없는경우를말한다. 8 3. PPI와다른약제와의상호작용 PPI는시토크롬 P-450계효소작용에의해간에서대사되므로시토크롬 P-450에의해대사되는여러약제와상호작용을일으킨다. 또한 PPI에의하여위의산도가변화되므로케토코나졸의흡수가감소되는등다양한영향이있다. 9 PPI와다른약제와의상호작용은공통적인부분과개별약제에서특이한부분등다양하게나타난다. 오메프라졸은비스무스, 카페인, 카바마제핀, 다이아제팜, 디곡신, 메페니토인, 페니토인, 니페디핀, 와파린등다양한약제의흡수와대사, 배설에영향을미친다. 10 오메프라졸은
CYP2C19에의한스스로의대사를억제할뿐만아니라 CYP2C19에의한다른약제의대사도억제시킨다. 에시탈로프람, 플루오세틴, 올란자핀, 펜다미딘, 서트랄린, 보리코나졸이이에해당하나임상적의의는밝혀져있지않다. 9 케토코나졸은오메프라졸의대사를억제하는데이는 CYP3A4를억제하는것과관련이깊다. 11 플루복사민은 CYP2C19를억제하여오메프라졸의배설을억제한다. 12 란소프라졸은 CYP1A2의작용을유도하여투여초기의테오필린의혈중농도를낮출수있다. 13 클래리스로마이신과같이복용하였을때는 CYP3A4에의한란소프라졸의대사가억제되어혈중농도가높아진다. 14 라베프라졸은 CYP2C19에의한영향이상대적으로적다. 9 4. PPI와대장암 PPI에의한장기적인위산억제는위산저하증을유발하고, 혈청가스트린치를상승시킨다. 15 가스트린은대장점막을포함한소화기계상피세포의성장촉진인자로작용하기때문에, 16 가스트린치의상승은위장관암발생을상승시킬우려가있다. 또한위산저하증은세균과증식을일으켜이차담즙산형성을촉진한다는점도고려되어야한다. 최근영국에서시행된대규모환자대조군연구에서 5년이상장기간 PPI 사용과대장암발생에는상관관계가없다고보고되었다. 17 덴마크에서시행된비슷한디자인의연구에서도 PPI의사용과대장암발생위험사이에상관관계가없었다. 18 네덜란드의환자대조군연구에서는 PPI 사용과대장암의관계를위치에따라분석하였는데, 좌측대장암뿐만아니라우측대장암발생위험과도상관관계가없었다. 19 앞으로 PPI 사용환자에서대장암발생률이높아지는지에대한보다장기간의추적관찰이필요하겠지만현재로서는세개의대규모연구에서그위험성이입증되지않았기때문에지나치게우려하기보다는차분하게추이를지켜볼때라고생각된다. 5. PPI와소장세균과증식 (SIBO) 이론적으로장기간 PPI를복용하면저염산증이초래되어장관감염에노출될위험이높다. 20 특히 H. pylori 감염이있는환자에서위내 ph는 H. pylori 감염이없는그룹보다높으며, 장내세균수가더많았다. 20 Spiegel 등 21 에의하면과민성장증후군환자에서소장세균과증식 (small bowel bacterial overgrowth, SIBO) 이흔하고, 이들에서 PPI 복용자가많다고보고하였다. PPI 사용으로소장세균과증식이발생하면, 섭취한 nitrate가 nitrites 와 N- nitrosoamines으로보다쉽게전환될것으로추정할수있다. 그러나정상군과비교하여 PPI 사용군에서 nitrites 및 N-nitrosoamines이증가하지않는다는결과도있다. 20 아직까지 PPI 사용과위산분비억제에의한 N-nitroamine생성이위선암발생에미치는영향은불명확하다고할것이다. PPI 사용자에서 C. difficile 원내감염이흔하다는보고도있다. 22 특히고령의환자에서
는 C. difficile 이외의살모넬라, 캄필로박터감염증이호발한다. 23 6. PPI와 clopidogrel 아스피린과 clopidogrel과같은항혈소판제투여가증가하면서 PPI와의상호작용에대한관심이높다. 2006년 Gilard 등 24 은 clopidogrel과 PPI의상호작용에관한결과를발표하였다. 당시 clopidogrel의활성화에시토크롬 P-450계가필요하므로 25, 같은시스템에의하여대사되는 PPI와서로영향을주고받을수있을것으로추정되었다. 24 아스피린과 clopidogrel 을동시에투여받고있는환자에게 omeprazole 혹은위약을투여한후혈소판활성을조사한연구에서 omeprazole을복용한그룹의혈소판활성의감소가대조군에비하여유의하게낮았다 (-32.6% 대 -43.3%, p<0.001). 26 즉 omeprazole이 clopidogrel의약리작용을약화시켰다. 최근 Ho 등 27 은급성관상동맥증후군으로치료후 clopidogrel을복용하면서추적관찰한 8,205명을대상으로한후향적연구에서 PPI 복용군의사망률과재입원율이유의하게높다고보고하였다. PPI의약제간차이에대한연구는아직미진한실정이다. 28 최근 CYP2C19 기능이낮은환자에서는 clopidogrel의활성형농도가낮고, 이로인하여혈소판이억제되지않아심혈관계합병증이많다는흥미로운연구가 NEJM에발표된바있다. 29 CYP2C19 기능이낮으면 clopidogrel이활성화되지않을뿐만아니라, PPI의혈중농도가높아지므로이들의상호작용이더욱나쁜방향으로전개될이론적인가능성이있다. 향후이에대한연구결과가기다려진다. 아직까지 clopidogrel과 PPI의병용투여에따른위험성에대한논쟁이계속되고있으며, 30 현시점에서는 clopidogrel을복용하는환자에서 PPI를보다명확한적응증을기반으로투여하는것이좋다는입장이다. 7. 결론 PPI는기존의위산억제제에비하여안전성이높은약제로소개되면서도입되었다. 그러나, 위식도역류질환의유병률증가와함께 PPI 사용자도많아지면서최근에는 PPI 장기사용시발생할수있는합병증에대한관심이높다. 다른모든약물과마찬가지로적절한적응증을가진환자에서적절한용량의 PPI를적절한기간동안사용하는것 31,32 이최선일것으로생각된다.
Table 1. Adverse effects of proton pump inhibitors (selected)and their level of evidence 1 Categories Adverse effects Level of evidences Cancerㄴ Colorectal cancer Two large negative case-control studies Gastric carcinoid tumors No macrocarcinoids in humans described Gastric cancer Plausible in the presence of Helicobacter pylori No human case reported Infections Clostridum difficile Systemic review; OR 1.94 Other bacterial enteric infections Systemic review; OR 3.33 Acute gastroenteritis in children Prospective study; OR 3.58 Community-acquired pneumonia GERD may be a confounding factor. Recent negative case-control study Nutritional Osteoporosis and hip fracture Case-control study; AOR 2.65 for age >65 years and high-dose PPI for > 1 year Vitamin B 12 deficiency Conflicting data Possible low risk in elderly patients Others AIN Idiosyncratic; rare Panic attacks/anxiety Case report only Hepatitis Case reports only Reduced gallbladder motility Small study in healthy volunteers
Table 2. Risk of colorectal cancer from a case-control study in UK 17 Adjusted OR (95% CI) Cumulative duration of PPI use < 1.5 DDD/day 1.5 DDD/day Nonuser Reference Reference 1-2 years 1.2 (0.9-1.5) 1.6 (0.5-4.8) 2-3 years 0.9 (0.6-1.3) 1.3 (0.4-4.3) 3-4 years 1.0 (0.6-1.9) 1.6 (0.4-5.8) 4-5 years 1.1 (0.6 1.9) 1.8 (0.4-8.5) > 5 years 1.0 (0.6-1.8) 2.2 (0.5-10.3)
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