Selective COX-2 inhibitors and risk of myocardial infarction.
Selective inhibitors of cyclooxygenase-2 (COX-2, 'coxibs') are highly effective anti-inflammatory and analgesic drugs that exert their action by preventing the formation of prostanoids. Recently some coxibs, which were designed to exploit the advantageous effects of non-steroidal anti-inflammatory drugs while evading their side effects, have been reported to increase the risk of myo cardial infarction and atherothrombotic events. This has led to the withdrawal of rofecoxib from global markets, and warnings have been issued by drug authorities about similar events during the use of celecoxib or valdecoxib/parecoxib, bringing about questions of an inherent atherothrombotic risk of all coxibs and consequences that should be drawn by health care professionals. These questions need to be addressed in light of the known effects of selective inhibition of COX-2 on the cardiovascular system. Although COX-2, in contrast to the cyclooxygenase-1 (COX-1) isoform, is regarded as an inducible enzyme that only has a role in pathophysiological processes like pain and inflammation, experimental and clinical studies have shown that COX-2 is constitutively expressed in tissues like the kidney or vascular endothelium, where it executes important physiological functions. COX-2-dependent formation of prostanoids not only results in the mediation of pain or inflammatory signals but also in the maintenance of vascular integrity. Especially prostacyclin (PGI(2)), which exerts vasodilatory and antiplatelet properties, is formed to a significant extent by COX-2, and its levels are reduced to less than half of normal when COX-2 is inhibited. This review outlines the rationale for the development of selective COX-2 inhibitors and the pathophysiological consequences of selective inhibition of COX-2 with special regard to vasoactive prostaglandins. It describes coxibs that are current ly available, evaluates the current knowledge on the risk of atherothrombotic events associated with their intake and critically discusses the consequences that should be drawn from these insights.
Krotz
Florian
F
Institute of Cardiology, Medical Polyclinic, Ludwig Maximilians University, Munich, Germany. fkroetz@lmu.de
Schiele
Thomas M
TM
Klauss
Volker
V
Sohn
Hae-Young
HY
D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects*; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D008565:Membrane Proteins; D009203:Myocardial Infarction / Q000139:chemically induced*; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D013927:Thrombosis / Q000139:chemically induced; D013928:Thromboxane A2 / Q000096:biosynthesis
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D013928:Thromboxane A2; D011464:Epoprostenol; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases