The cardiovascular pharmacology of COX-2 inhibition.
Selective inhibitors of cyclooxygenase (COX)-2, the coxibs, were developed to inhibit inflammatory prostaglandins derived from COX-2, while sparing gastroprotective prostaglandins primarily formed by COX-1. However, COX-2-derived prostaglandins mediate not only pain and inflammation but also affect vascular function, the regulation of hemostasis/ thrombosis, and blood pressure control. All coxibs depress COX-2-dependent prostacyclin (PGI(2)) biosynthesis without effective suppression of platelet COX-1-derived thromboxane (Tx) A(2), unlike aspirin or traditional nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2. The actions of PGI(2) oppose mediators, which stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA(2). Indeed, structurally distinct inhibitors of COX-2 have increased the likelihood of hypertension, myocardial infarction and stroke in controlled clinical trials. The detection of these events in patients is related to the duration of exposure and to their baseline risk of cardiovascular disease. Thus, coxibs should be withheld from patients with preexisting cardiovascular risk factors, and exposed patients at low cardiovascular baseline risk should be monitored for changes in their risk factor profile, such as increases in arterial blood pressure.
Fries
Susanne
S
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, 809 Biomedical Research Building, 421 Curie Blvd., Philadelphia, PA 19104-6084, USA.
Grosser
Tilo
T
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D050197:Atherosclerosis / Q000517:prevention & control; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000139:chemically induced; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D004195:Disease Models, Animal; D006801:Humans; D006973:Hypertension / Q000517:prevention & control; D051379:Mice
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D001241:Aspirin