항혈소판제제를 포함한 약물상호작용에 미치는 프로톤펌프억제제의 영향: Safe 측면
Drug Interaction between Proton Pump Inhibitors and Clopidogrel: Safe Perspective
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클로피도그렐은 혈소판의 응집을 억제하는 약제로, 활성화되는데는 CYP 효소 중 특히, CYP2C19가 중요하다. 문제는 프로톤펌프억제제가 CYP2C19을 경쟁적 억제하여 클로피도그렐의 혈소판 응집효과를 저하시킬 수 있다. 약물역동학적 연구에 의하면, 클로피도그렐과 프로톤펌프억제제를 동시에 사용하면, 항혈소판 작용이 감소하고 이는 오메프라졸에서 가장 뚜렷하였다. 그러나 이러한 PRI 등의 역물역동학적 표지자가 임상적인 의미가 있는지는 아직 정립되지 않았다. 두 약제의 사용이 실제 심혈관계 합병증을 증가시킬 것인가에 대한 임상 연구들의 결과에 의하면, 두 약제의 동시 사용이 심혈관계 합병증을 증가시키는지는 아직 일관된 결과를 보이지 않지만 상대적 위험도도 높지 않다. 그러나 동시 투여군에서는 위장관 출혈은 의미 있게 감소한다고 생각된다. 그리고 상대적으로 아시아 인구에 많은 CYP 유전자의 대사 저하군(poor metabolizer)에서의 임상적 영향이 어떨지 앞으로의 연구가 필요한 부분이다. 클로피도그렐을 사용하는 환자에서 프로톤펌프억제제를 동시에 사용하는 경우에 대한 권고사항은 오메프라졸은 더 이상 사용하지 않고, 다른 프로톤펌프억제제를 고려하거나, H2수용체 억제제를 사용한다. 혹은 두 약제의 투여 시간을 분리하는 것도 하나의 방법이다. 그리고 클로피도그렐과 아스피린 동시 사용군에서 아스피린 단독사용군보다 중요 심혈관계 부작용이 감소하지만, 출혈 위험성 때문에 이전에 허혈성 뇌경색이 있었던 환자에게는 두 약제를 동시에 사용하는 것을 권유하지 않는다. 그리고 이전의 궤양력이 있거나, 항혈소판제제가 필요한 환자에서 위장 출혈의 위험성이 높은 경우(고령, 항응고제, 스테로이드 혹은 비스테로이드성 항염증제, 아스피린을 같이 사용하거나 Helicobacter pylori 감염군)에는 프로톤펌프억제제를 외장관 출혈을 예방하기 위해 같이 사용한다. 이 두 약제를 같이 사용할 때는 임상적인 심혈관계, 위장관계 부작용을 고려하여 득실을 평가하여 사용하여야 할 것이다.
Abstract
Clopidogrel prevent atherothrombotic complications following acute coronary syndromes by inhibiting platelet aggregation. However, in case of concomitant use of clopidogrel and proton pump inhibitor (PPI) for prophylaxis of gastrointestinal (GI) bleeding, the anti-clotting of clopidogrel will be decreased because PPI inhibit competitively cytochrome P450 enzymes, especially CYP2C19. Through several pharmacodynomic studies, omeprazole, but not other PPIs, worsens surrogate markers (e.g., platelet reactivity index) of clopidogrel efficacy. And many observational studies show concomitant use of clopidogrel and PPI have increased the risks of cardiovascular (CV) events (hazard/odds ratios = 1.25-1.5). However, only one prospective randomized trial (COGENT trial) of omeprazole vs. placebo in clopidogrel users show no difference in CV events (hazard ratio = 1.02) and decrease the risk of GI bleeding (hazard ratio = 0.13). Further well designed research will need to determine whether a pharmacodynamic effect of clopidogrel affected by PPI will be changed clinical CV events. Clinical decisions about concomitant use of PPI and clopidogrel must be balance overall risks and benefits, considering both CV and GI complications. (Korean J Med 2011;81:26-33)
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