NSAIDs and COX-2 Inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDs) have potentially adverse effects on blood pressure.[10,11] NSAIDs block both cyclooxygenase-1 (COX-1) and COX-2 enzymes, which leads to a reduction in prostaglandin formation. These drugs can have widespread beneficial and harmful effects, depending on the patient context. Drug-induced hypertension associated with NSAIDs is due to the renal effects of these drugs. Specifically, NSAIDs cause dose-related increases in sodium and water retention. This effect is also seen with COX-2 selective agents, such as celecoxib.
The COX-1 and COX-2 isoforms are both expressed within the normal adult kidney, with COX-1 in the glomerulus and afferent arteriole and COX-2 in the afferent arteriole, the podocytes, and macula densa. The specific location of each of these isoenzymes in the kidney translates into notably different effects on renal function. The prostaglandins produced by COX-1 primarily affect renal homeostasis by promoting vasodilation in the renal vascular bed, reducing renal vascular resistance, and consequently increasing renal perfusion. Prostaglandins produced by the COX- 2 isoenzyme have diuretic and natriuretic effects.[12,13] In patients who are hemodynamically compromised, the effects of the two isoenzymes are essential for the maintenance of renal perfusion because of their vasodilatory effects. Because NSAIDs block the production of the COX-1 and COX-2 prostaglandins, renal side effects are not uncommon, occurring in approximately 1% to 5% of NSAID users.
By inhibiting COX-2’s natriuretic effect, thereby increasing sodium retention, all NSAIDs carry with them the consequent risk of increased fluid retention. Additionally, the inhibition of vasodilating prostaglandins and the production of vasoconstricting factors, namely endothelin-1, can contribute to the induction of hypertension in a normotensive and/or controlled hypertensive patient.
In a comparison of celecoxib with diclofenac conducted in 287 patients with arthritis, cardiovascular and renal side effects were seen in 79 patients (27.8%), with hypertension being the most common (16.6%). There was no statistical difference in the incidence of hypertension between the traditional NSAID and COX-2 groups. This initiation of hypertension by NSAIDs is especially important in the discussion of COX-2 safety in light of the fact that hypertensive status is a key risk factor in the progression of virtually all cardiovascular diseases including stroke, myocardial infarction, and congestive heart failure.
A recent meta-analysis of COX-2 inhibitors and their effects on blood pressure was published. Data were collected in 45,451 patients from 19 clinical trials. Interestingly, there appeared to be a somewhat greater blood pressure elevation with COX- 2 inhibitors compared with placebo and nonselective NSAIDs (e.g., ibuprofen and diclofenac). Rofecoxib appeared to confer a greater risk of developing clinically important elevations in both systolic and diastolic pressures in comparison to celecoxib. However, rofecoxib was voluntarily pulled from the market in 2004 due to concerns about increased risk of heart attack and stroke.
Because of the widespread availability of NSAIDs without a prescription, many patients with hypertension may be at risk for aggravated blood pressure effects caused by these drugs. Pharmacists should take a careful medication history and specifically inquire about OTC use of NSAIDs. Patients with hypertension should be more closely monitored for blood pressure elevations when using NSAIDs. Patients should be counseled that this adverse effect tends to be dose related, but it is not always predictable. The adverse effect of all NSAIDs and COX-2 inhibitors on blood pressure may have the most clinical significance in the elderly, in whom the prevalence of arthritis, hypertension, and NSAID use is high.