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NSAIDs, antihypertensive agents and loss of blood pressure control

American Family Physician, March, 1995 by Lori L. MacFarlane, Deborah J. Orak, William M. Simpson

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly taken by patients receiving antihypertensive therapy. Arthritis and other ailments requiring treatment with NSAIDs are frequent among hypertensive patients, especially in elderly persons. It has been estimated that as many as 20 million patients in the United States are concurrently receiving therapy with NSAIDs and antihypertensive agents.[1]

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NSAIDs have been reported to diminish the blood pressure-lowering effects of many antihypertensive agents.[2,3] Therefore, when a physician is considering NSAID therapy in a hypertensive patient, the magnitude and extent of this antagonistic effect should be assessed. A slight change in blood pressure may not be clinically significant, but a severe interaction could precipitate a hypertensive emergency. The Medical Research Council4 studied patients with mild hypertension and found that a decrease in mean arterial pressure of approximately 5 mm Hg reduced the relative risk of stroke by 45 percent (mean arterial pressure equals one-third systolic pressure plus two-thirds diastolic pressure). A further evaluation of this study and other randomized trials of antihypertensive regimens found a 35 to 40 percent reduction in stroke incidence when mean diastolic blood pressure was reduced by 5 to 6 mm Hg.[5] Thus, the risk of stroke may rise in patients with well-controlled hypertension who are then given NSAIDs and have an increase in blood pressure.[6] This risk is probably greater in the elderly[7,8]

The effect of this drug interaction is supported by several case reports. In elderly patients, piroxicam (Feldene) and ibuprofen (Advil, Motrin, Nuprin) have been shown to interfere with the antihypertensive efficacy of beta-adrenergic blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors.[2,9] In one case, severe headaches developed and blood pressure increased to 230/130 mm Hg in a patient receiving a combination of propranolol, furosemide and piroxicam.[2] In addition, in women with pregnancy-induced hypertension controlled with beta-adrenergic blockers, acute hypertension has been reported to develop after administration of indomethacin (Indocin) for the treatment of premature contractions.[10,11]

Prostaglandins as Mediators of Blood Pressure

Prostaglandins have several effects on blood pressure. Prostacyclin (PG[I.sub.2]) relaxes vascular smooth muscle and promotes natriuresis by reducing renal vascular resistance.[12] Prostaglandin [E.sub.2] (PG[E.sub.2]), a vasodilator, inhibits renal tubular reabsorption of sodium and chloride and tubular responsiveness to vasopressin (antidiuretic hormone).[1] Therefore, intrarenal vasodilatory prostaglandins attenuate renal response to various vasoconstrictor stimuli, including angiotensin II and norepinephrine.[1,12] Renal prostaglandins sustain renal circulation when threatened by any situation that may compromise renal perfusion and, thus, are important regulators of blood pressure homeostasis.[12]

NSAIDs and Blood Pressure

The chief mechanism through which NSAIDs contribute to hypertension and decrease antihypertensive efficacy appears to be inhibition of prostaglandin synthesis[1,13-15] Figure 1 .[15] This inhibition results in an increase in sodium reabsorption and water retention. NSAIDs have been shown to decrease renin levels, but sodium/water retention and decreased vasodilation caused by prostaglandin inhibition appear to be more important in decreasing antihypertensive efficacy.[13,14] Thus, NSAIDs affect the actions of antihypertensive agents whose mechanism of action involves a counter-regulatory increase in vasodilatory prostaglandins.[16] This group of agents includes thiazides and loop diuretics, beta-adrenergic blockers, alphaadrenergic blockers and ACE inhibitors.

In the first meta-analysis[6] studies evaluating NSAIDs and their effects on blood pressure, three questions were examined: (1) What is the degree to which NSAIDs affect blood pressure? (2) What are the differences in effects among NSAIDs? (3) What is the difference in blood pressure effects in normotensive versus hypertensive patients? Fifty-four studies were included in the analysis. Patients with mild hypertension (mean age: 46 years; mean arterial pressure: 105 mm Hg) comprised the majority of the population.

In normotensive patients, NSAID use did not result in a significant change in mean arterial pressure (Table 1). In hypertensive patients, the average increase in mean arterial pressure with indomethacin use was 4.77 mm Hg; with naproxen (Naprosyn) use, 6.10 mm Hg; with piroxicam use, 2.86 mm Hg, and with sulindac (Clinoril) use, 2.2 mm Hg. Patients receiving placebo and ibuprofen actually had a decrease in mean arterial pressure. After adjustment for dietary salt intake, naproxen and indomethacin were found to have increased mean arterial pressure by more than 3.5 mm Hg, while piroxicam, sulindac, ibuprofen, aspirin and placebo were found to have little effect on blood pressure.[6]

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NSAIDs, antihypertensive agents and loss of blood pressure control

American Family Physician, March, 1995 by Lori L. MacFarlane, Deborah J. Orak, William M. Simpson

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