Cardiovascular Aspects of Prostaglandin Inhibition
Cardiovascular Aspects of Prostaglandin Inhibition
Specific cyclooxygenase (COX)-2 inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs for the treatment of arthritis and pain, and have become extremely popular agents worldwide due to their low rate of gastrointestinal side effects. Hypertension and arthritis are common comorbidities in older patients; thus, interference with blood pressure control, or the efficacy of antihypertensive therapies in hypertensive patients, through COX inhibition, becomes an important clinical issue. This paper reviews some of these cardiovascular issues, including blood pressure and potential thrombotic effects of prostaglandin inhibition in patients with pain and arthritis. The data focus on the responses to COX-2 inhibition by both conventional nonspecific nonsteroidal anti-inflammatory drugs and the COX-2 specific inhibitors used for the management of arthritis.
Prostaglandins function as autacoids responsible for normal physiologic functions in the gastrointestinal tract, kidney, reproductive system, platelets, and vasculature. Prostaglandins (and thromboxane) are also key mediators of inflammation and pain. The biosyn-thesis of prostaglandins from arachidonic acid is dependent on cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandin-H2 (PGH2), an unstable endoperoxide intermediate, in a rate-limiting reaction. Stable prostaglandins are then produced by isomerases and synthases.
Two distinct COX isoforms have been described. The COX isoform designated as COX-1 is expressed constitutively in most tissues throughout the body, including the gastrointestinal tract, kidneys, and platelets. COX-2, however, is typically expressed at low levels in normal tissue, but is induced to high levels of expression by inflammatory mediators at sites of inflammation. COX-2 also plays a key role in mediating pain.
One of the clinically relevant products of COX-2 in response to inflammation is prostacyclin (PGI2). This prostanoid is produced in the vascular endothelium, where it is involved in increasing the blood flow to damaged tissue, reducing leukocyte adherence, and inhibiting platelet aggregation.
Basic experiments in animals have been conducted to try and define the cardiovascular effects of COX-2 inhibition. However, the results from canine models have been inconclusive. In a study by Black and coworkers, the selective COX-2 inhibiting agent, MF-tricyclic (a tricyclic methyl sulfone derivative), and indomethacin, a nonspecific COX inhibitor, had no effect on mean arterial blood pressure (BP), heart rate, or other parameters of blood flow in normal animals. However, in a study in canines by Hennan et al., high doses of celecoxib led to a significant reduction in vasodilation in response to arachidonic acid compared with the control group; based on these data the authors suggested that the inhibition of COX-2-derived PGI2 may lead to an increased risk of adverse cardiovascular events in patients receiving COX-2 inhibitors.
In contrast to the studies suggesting "harm" from COX-2 inhibitors, other studies suggest that COX-2 inhibitors may reduce plaque formation in atherosclerosis and may affect platelet function. Low-density lipoprotein receptor knockout mice, fed a Western diet, were treated for 6 weeks with the COX-2 inhibitors rofecoxib or indomethacin. Treated mice showed a reduction in the number of atherosclerotic plaques compared with untreated animals. A recent study in mice suggests that PGI2 antagonizes the action of thromboxane B2 (TxB2). Therefore, selective COX-2 inhibitors, which inhibit the production of PGI2, but not TxB2, may enhance thrombosis through this potential mechanism on platelet function.
In a recent clinical trial, Altman and coworkers from Argentina evaluated the effects of meloxicam, a selective COX-2 inhibitor, in 120 patients with acute coronary syndrome. In this study, patients with angina and ST-segment depression, but no evidence of myocardial infarction (MI), were randomized to receive either meloxicam or placebo in addition to standard care for acute coronary syndrome (aspirin and heparin). Following both short-term (average of 4.5 days) and longer-term treatment (30 days of therapy), patients randomized to receive meloxicam had a 50% reduction in recurrent angina and other related vascular events. These data suggest that plaque stabilization may have occurred following COX-2 inhibition; and, while not definitive, this study suggests that a larger trial should be performed in this high-risk population to determine the potential benefits of these agents in acute coronary syndrome.
Specific cyclooxygenase (COX)-2 inhibitors are as effective as nonspecific nonsteroidal anti-inflammatory drugs for the treatment of arthritis and pain, and have become extremely popular agents worldwide due to their low rate of gastrointestinal side effects. Hypertension and arthritis are common comorbidities in older patients; thus, interference with blood pressure control, or the efficacy of antihypertensive therapies in hypertensive patients, through COX inhibition, becomes an important clinical issue. This paper reviews some of these cardiovascular issues, including blood pressure and potential thrombotic effects of prostaglandin inhibition in patients with pain and arthritis. The data focus on the responses to COX-2 inhibition by both conventional nonspecific nonsteroidal anti-inflammatory drugs and the COX-2 specific inhibitors used for the management of arthritis.
Prostaglandins function as autacoids responsible for normal physiologic functions in the gastrointestinal tract, kidney, reproductive system, platelets, and vasculature. Prostaglandins (and thromboxane) are also key mediators of inflammation and pain. The biosyn-thesis of prostaglandins from arachidonic acid is dependent on cyclooxygenase (COX) enzymes, which convert arachidonic acid to prostaglandin-H2 (PGH2), an unstable endoperoxide intermediate, in a rate-limiting reaction. Stable prostaglandins are then produced by isomerases and synthases.
Two distinct COX isoforms have been described. The COX isoform designated as COX-1 is expressed constitutively in most tissues throughout the body, including the gastrointestinal tract, kidneys, and platelets. COX-2, however, is typically expressed at low levels in normal tissue, but is induced to high levels of expression by inflammatory mediators at sites of inflammation. COX-2 also plays a key role in mediating pain.
One of the clinically relevant products of COX-2 in response to inflammation is prostacyclin (PGI2). This prostanoid is produced in the vascular endothelium, where it is involved in increasing the blood flow to damaged tissue, reducing leukocyte adherence, and inhibiting platelet aggregation.
Basic experiments in animals have been conducted to try and define the cardiovascular effects of COX-2 inhibition. However, the results from canine models have been inconclusive. In a study by Black and coworkers, the selective COX-2 inhibiting agent, MF-tricyclic (a tricyclic methyl sulfone derivative), and indomethacin, a nonspecific COX inhibitor, had no effect on mean arterial blood pressure (BP), heart rate, or other parameters of blood flow in normal animals. However, in a study in canines by Hennan et al., high doses of celecoxib led to a significant reduction in vasodilation in response to arachidonic acid compared with the control group; based on these data the authors suggested that the inhibition of COX-2-derived PGI2 may lead to an increased risk of adverse cardiovascular events in patients receiving COX-2 inhibitors.
In contrast to the studies suggesting "harm" from COX-2 inhibitors, other studies suggest that COX-2 inhibitors may reduce plaque formation in atherosclerosis and may affect platelet function. Low-density lipoprotein receptor knockout mice, fed a Western diet, were treated for 6 weeks with the COX-2 inhibitors rofecoxib or indomethacin. Treated mice showed a reduction in the number of atherosclerotic plaques compared with untreated animals. A recent study in mice suggests that PGI2 antagonizes the action of thromboxane B2 (TxB2). Therefore, selective COX-2 inhibitors, which inhibit the production of PGI2, but not TxB2, may enhance thrombosis through this potential mechanism on platelet function.
In a recent clinical trial, Altman and coworkers from Argentina evaluated the effects of meloxicam, a selective COX-2 inhibitor, in 120 patients with acute coronary syndrome. In this study, patients with angina and ST-segment depression, but no evidence of myocardial infarction (MI), were randomized to receive either meloxicam or placebo in addition to standard care for acute coronary syndrome (aspirin and heparin). Following both short-term (average of 4.5 days) and longer-term treatment (30 days of therapy), patients randomized to receive meloxicam had a 50% reduction in recurrent angina and other related vascular events. These data suggest that plaque stabilization may have occurred following COX-2 inhibition; and, while not definitive, this study suggests that a larger trial should be performed in this high-risk population to determine the potential benefits of these agents in acute coronary syndrome.