AHA on COX inhibitors
ASPIRIN prevents MI, Cancer, and Alzheimer's disease
Celebrex and COX-2 inhibitors--American Heart Association Warnings
American Heart Association warns NSAIDs cause MI
COX-2 Inhibitors, their deadly mechanism
AHA on COX inhibitors
NSAIDs & Myocardial Infraction Risk--only ASPIRIN is safe
How VIOXX kills--jk
COX-2 INHIBITORS not as good as Ibuprofen
Continued Risk after taking VIOXX
HYDROCODONE--Opiates work for pain management
Acetaminophen, causes asthma, liver failure, & male infertility,
Acetaminophen causes male infertility
Liver failure Acetaminophen
Acetaminophen leading drug cause of liver damage
Acetaminophen increase ASTHMA risk 63%
Asthma risk and acetaminophen
Warfarin Number 1 Causes of Hospital Emergencies--WP

COX-2 prolongs the inflammation damage to arteries, and thereby promotes atherogenesis (that is why even 2 years after discontinuation of Vioxx, that group has a 50% higher rate of MI). The second effect is the inhibition of PG­-2, which entails thrombi development through the promotion of the other clotting factor TXA-2.  In addition COX-2 inhibition increases sodium and water retention leading to edema and thus exacerbations of heart failure and hypertension.  COX-2 inhibition also causes greater tissue damage (cell death) during an MI.  The non-selective NSAIDs promote less thrombi because of their inhibition of also COX-1, which reduces production of TXA-2, the platelet clotting factor.  Each NSAID has a different profile as to the suppression of COX-1 and COX-2.  Thus a non-selective  NSAIDs (reducing both COX-1 & COX-2) it effect on promoting thrombi will be less than those that suppress only COX-2 does—how much less depends on which is taken.  Only aspirin of the NSAIDs does not promote inflammation damage to arteries (atherogenesis), but rather inhibits it. 


Source American Heart Association, Circulation. 2007;115:1634-1642, Published online before print February 26, 2007, doi: 10:1161/CIRCULATIONAHA.106.181424  http://circ.ahajournals.org/cgi/content/full/115/12/1634  


Figure 5. Consequences of COX inhibition for prostacyclin and TXA2 production in normal and atherosclerotic arteries. Endothelial cells are shown as a source of prostacyclin (PGI2) and platelets as a source of TXA2. COX-2 inhibition suppresses COX-2–dependent PGI2 production in endothelial cells, which has only a marginal effect on the net antithrombotic balance owing to the importance of COX-1 as a source of PGI2 in the normal state. In the setting of atherosclerosis, however, COX-2 plays a greater role as a source of PGI2, and more TXA2 is produced; thus, inhibiting COX-2 has a more profound effect on prostanoid balance, favoring TXA2 production and promoting platelet-dependent thrombosis. Modified and reproduced from Antman et al11 with permission from the American Heart Association. Copyright 2005.

Background Scientific Information on COX Inhibitors


The primary property of this class of drugs is the inhibition of COX.11–13 There are 2 major COX isoenzymes: COX-1 is expressed constitutively (constantly) in most tissues, whereas COX-2 is induced in inflammation. Both COX-1 and COX-2 use arachidonic acid to generate the same product, prostaglandin H2. A number of enzymes further modify this product to generate bioactive lipids (prostanoids) such as prostacyclin, thromboxane A2, and prostaglandins D2, E2, and F2. These prostanoids influence immune, cardiovascular, gastrointestinal (GI), renovascular, pulmonary, central nervous system, and reproductive function.12 Of note, it is now recognized that COX-2 is expressed in normal endothelial cells in response to shear stress and that inhibition of COX-2 is associated with suppression of prostacyclin synthesis.14 On the basis of experiments in animals and observations from clinical trials and registries, it has been proposed that major cardiovascular consequences of COX-2 inhibition include a shift in the prothrombotic/antithrombotic balance on endothelial surfaces toward thrombosis; an increase in sodium and water retention, leading to edema, as well as exacerbations of heart failure and hypertension; and loss of the protective effects of COX-2 upregulation in the setting of myocardial ischemia and infarction, which leads to a larger infarct size, greater thinning of the left ventricular wall in the infarct zone, and an increased tendency to myocardial rupture.12,13,15,16

A variety of NSAIDs can block the enzymatic activity of COX; they vary in their chemical structure and relative ability to block the COX-1 versus the COX-2 isoenzymes (Figure 4). The COX-2 inhibitors also vary in their selectivity for the COX-2 versus the COX-1 enzyme (for medications currently or formerly on the market in the United States, rofecoxib > valdecoxib > parecoxib > celecoxib). Other COX-2 inhibitors are under development and may be introduced into the US market in the future. The differences in the biological effects of COX inhibitors are a consequence of the degree of selectivity for COX-2 versus COX-1 and tissue-specific variations in the distribution of COX and related enzymes that convert prostaglandin H2 into specific prostanoids.

For example, several prostanoids, including prostaglandin E2 and prostacyclin, are both hyperalgesic (elicit an increased sense of pain) and gastroprotective. Thus, nonselective COX inhibition with agents such as aspirin, ibuprofen, indomethacin, and naproxen, which inhibit both COX-1 and COX-2 enzymes, provides effective pain relief for inflammatory conditions but carries with it a risk for erosive gastritis and GI bleeding. Selective COX-2 inhibitors (valdecoxib, rofecoxib, celecoxib, and others yet in development) were developed to minimize GI toxicity because of the relative paucity of COX-2 expression in the GI tract and the relative abundance of COX-2 expression in inflamed and painful tissues.

In the cardiovascular system, the products of COX regulate complex interactions between platelets and the vessel wall. Prostacyclin is the dominant prostanoid produced by endothelial cells.17,18 In addition to producing local smooth muscle cell relaxation and vasodilation, prostacyclin can interact with platelet IP receptors, thereby antagonizing aggregation. Platelets contain only COX-1, which converts arachidonic acid to the potent proaggregatory, vasoconstrictive eicosanoid thromboxane A2 (TXA2), the major COX product formed by platelets. Nonselective COX inhibition with aspirin is effective for arterial thrombosis because of its ability to reduce COX-1–dependent production of platelet TXA2; however, selective inhibition of COX-2 could produce a relative reduction in endothelial production of prostacyclin, while leaving the platelet production of TXA2 intact. It has been speculated that this imbalance of hemostatic prostanoids might increase the risk for thrombotic cardiovascular events19,20 (Figure 5). COX-2 inhibitors, like NSAIDs, also raise blood pressure and increase the incidence of heart failure significantly compared with placebo.21,22 By elevating blood pressure, NSAIDS, particularly coxibs, attenuate the benefit of previously prescribed antihypertensive therapy and may also move certain patients not previously diagnosed as hypertensive over the threshold for initiation of treatment for hypertension.23,24

FOR THE HIGHEST RISK GROUP, those with prior MI, the excess mortality risk was approximately 6 persons per 100 per year of treatment with a COX-2 inhibitor.  {The authors of one large report estimated that in patients with a prior myocardial infarction, the excess risk of mortality is 6 deaths per 100 person-years of treatment with a COX-2 inhibitor compared with no NSAID treatment.4  In these patients, prudence dictates extra caution in the use of COX-2 inhibitors}





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