NSAIDs, antihypertensive agents and loss of blood pressure control

NSAIDs, antihypertensive agents and loss of blood pressure control – nonsteroidal anti-inflammatory drugs

Lori L. MacFarlane

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]

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][TABULAR DATA 1 OMITTED]

The authors concluded that the average increase in mean arterial pressure secondary to indomethacin or naproxen use was 3 to 6 mm Hg in hypertensive patients, while patients receiving piroxicam, sulindac, aspirin or ibuprofen had no significant change in blood pressure. The increase induced by indomethacin and naproxen may be large enough to be clinically significant in some hypertensive patients and may thus increase the risk of complications or require intensification of antihypertensive therapy to control blood pressure.[6]

A second group conducted a similar meta-analysis of the effects of NSAIDS on blood pressure.[16] Thirty-eight randomized, placebo-controlled trials pooling more than 700 patients (mean age: 47.6 [+ or -] 2.5 years), both hypertensive and normotensive, were evaluated. In general, NSAIDs were found to increase supine mean blood pressure by 5 mm Hg, but only the trials involving patients with controlled hypertension achieved statistical significance. NSAIDs antagonized the antihypertensive effects of beta blockers more than the effects of vasodilators and diuretics. Piroxicam, indomethacin and ibuprofen affected blood pressure to the greatest degree.

In basic agreement with the previous meta-analysis,[6] the authors of the latter study concluded that the effects of this interaction may be associated with a clinically important increase in hypertension-related morbidity. However, these results are difficult to extrapolate to the elderly, among whom hypertension and NSAID use are more common. In addition, the trials included were heterogeneous with respect to antihypertensive medications and NSAID dosage. Overall, these results indicate that some NSAIDs may have moderate, short-term effects in some hypertensive patients.

Until recently, information on the prevalence of this interaction in the elderly population was limited.[7,8] In a case-control study, nearly 10,000 Medicaid enrollees 65 years of age or older who had recently started taking antihypertensive medication were evaluated for recent NSAID exposure.[17] Patients taking NSAIDs within the previous 60 days were twice as likely as control subjects to have received a prescription for an antihypertensive agent. These results were adjusted for other variables affecting prescription of antihypertensive agents (e.g., age, sex, race, nursing home residency, number of prescriptions, number of physician claims and number of days hospitalized), and the odds ratio was still significant at 1.66. These findings suggest that the use of NSAIDs in this population may increase the risk for initiation of antihypertensive therapy.

NSAIDs and Antihypertensive Agents DIURETICS

Diuretics exert their antihypertensive effects by decreasing plasma volume and total peripheral resistance.[12] Thiazide diuretics inhibit sodium and chloride reabsorption in the distal tubule in the nephron. Loop diuretics block co-transport of sodium, potassium, and chloride which results in sodium chloride diuresis.[12] The degree of response to diuretics is based on their ability to cause a reactive rise in renin levels in response to a decreased blood pressure and fluid volume. Patients with low plasma renin activity who show only a weak rise after taking diuretics are deemed “diuretic responsive.” Therefore, patients with low plasma renin activity have greater falls in blood pressure with diuretic therapy than those with high or normal plasma renin activity levels.[12]

NSAIDs interact with diuretics by reducing their natriuretic efficacy. They also blunt the diuretic-induced increase in plasma renin activity, but this effect is offset by the salt and water retention associated with prostaglandin inhibition.[18]

Several investigators have evaluated the effects of NSAIDs on the diuretic and antihypertensive efficacy of hydrochorothiazide (Esidrix, Hydrodiuril, Oretic) (Table 2). Indomethacin has been shown to reduce the diuretic effect of hydrochorothiazide, but it does not clinically affect longterm antihypertensive activity.[19] Use of piroxicam, naproxen and ibuprofen has resulted in an increase in blood pressure measurements in patients receiving hydrochorothiazide, but sulindac has not been implicated in this interaction.[19-21][TABULAR DATA 2 OMITTED]


Beta blockers have been shown to increase circulating prostaglandins, which may play a role in their antihypertensive activity.[18] Suppression of prostaglandin synthesis by NSAIDs may reduce the antihypertensive effect of beta blockers.[18] In addition, since both classes of drugs decrease plasma renin activity, NSAIDs taken before beta-blocker therapy may limit the antihypertensive action related to lowering of plasma renin activity.[18]

The interaction between beta blockers and NSAIDS has been studied in patients with controlled hypertension[22,23] (Table 2). Indomethacin has been shown to cause a significant increase in systolic and diastolic blood pressures in patients receiving labetalol.[22] Similarly, naproxen has increased systolic blood pressure in patients taking atenolol.[23] The effects of sulindac on blood pressure have been minimal.[22,23]


Hydralazine (Apresoline) is a direct and preferential vasodilator that has been shown to enhance the synthesis of PGI, and [PGE.sub.2].[12] Therefore, previous NSAID use may attenuate hydralazine’s antihypertensive activity.[24,25] Studies have failed to show an effect of NSAIDs on the hypotensive effects of vasodilators; however, no definitive studies are available.[18] Lack of data regarding this interaction is, in part, the result of decreased use of hydralazine and other vasodilators in the treatment of hypertension.


ACE inhibitors block the formation of angiotensin II, causing vasodilation and decreased production of aldosterone. Blocking ACE also results in elevated bradykinin levels.[12] Bradykinin promotes the release of vasodilatory and natriuretic prostaglandins from renal and other tissues.[18] NSAIDs may attenuate the actions of ACE inhibitors by directly inhibiting renal prostaglandin production and indirectly inhibiting ACE inhibitor-induced prostaglandin production. In the low-renin patient, prostaglandins play an important role in the hypotensive effects of ACE inhibitors. In this patient population, NSAIDs may markedly blunt the antihypertensive effect of ACE inhibitors.

The influence of indomethacin on the hypotensive action of enalapril (Vasotec) has been studied in patients with mild to moderate hypertension.[26] The combination of enalapril and indomethacin was shown to increase mean arterial pressure by approximately 5.5 mm Hg when compared with enalapril alone (Table 2). Indomethacin has also been shown to blunt the antihypertensive action of captopril (Capoten).[18]


Central [alpha.sub.2] agonists stimulate [alpha.sub.2] receptors and inhibit efferent sympathetic activity in the peripheral vasculature.[12] Studies of the interaction between NSAIDS and central [alpha.sub.2] agonists are limited and mainly involve the effects of a single dose of an antihypertensive agent in the animal model. NSAIDs may antagonize the action of central [alpha.sub.2] agonists by increasing total peripheral resistance.[18]


Peripheral alpha, blockers act at the postsynaptic [alpha.sub.1] receptor, leading to both arteriolar and venous dilation.[12] Prostaglandins can alter vascular responses to sympathetic nerve stimulation, and prazosin (Minipress) has been shown to enhance the synthesis of [PG.sub.2] and [PGE.sub.2].[24] Through prostaglandin inhibition, NSAIDs increase vascular resistance and may attenuate the vasodilatory effect of peripheral alpha, blockers. Clinical trials reporting the interaction between NSAIDs and peripheral [alpha.sub.1] blockers in hypertensive subjects are lacking.[18] However, in an eight-hour study, indomethacin was found to blunt the hypotensive action of prazosin in normotensive subjects.[27]


Calcium channel blockers produce smooth muscle relaxation by blocking the inward movement of calcium ions in vascular smooth muscle. This action decreases the force of contraction of vascular smooth muscle and produces vasodilation. Calcium channel blockers induce natriuresis and diuresis, which may contribute to their hypotensive activity.[28-30] Clinical trials have evaluated the effects of sulindac and diclofenac (Cataflam, Voltaren) in elderly hypertensive patients treated with nifedipine (Adalat, Procardia)[31] (Table 2). The addition of either of these NSAIDs did not affect blood pressure. In healthy volunteers, indomethacin did not affect the antihypertensive efficacy of felodipine (Plendil).[32] Similar studies failed to find blood pressure changes with diltiazem Cardizem).[18]

Clinical Significance and Recommendations

Extrapolation of results from reported studies to all primary care patients is difficult because of the variations in blood pressure parameters measured and the populations studied. Although the problem of interaction between NSAIDs and antihypertensive medication may not occur in everyone, it should be considered when patients are receiving both medications, and therapy should be adjusted accordingly if blood pressure control becomes difficult.

Additional trials are necessary to determine the long-term effects of NSAIDs and antihypertensive agents on blood pressure control. Until then, the following recommendations should be considered: (1) blood pressure should be monitored frequently when NSAIDs are combined with diuretics, beta blockers or ACE inhibitors; (2) it appears that NSAIDs may be used with calcium channel blockers without an effect on blood pressure control; (3) indomethacin, the most potent prostaglandin inhibitor, appears to alter blood pressure control to a greater extent than weaker agents, such as sulindac. Although this supposition may be related to the fact that indomethacin has been studied more than the other NSAIDs, caution should still be exercised when combining indomethacin and antihypertensive agents; (4) NSAID use and its necessity should be evaluated before initiating therapy with an antihypertensive agent, before increasing the dosage of an antihypertensive agent and before adding an additional antihypertensive drug, and (5) if patients have lost blood pressure control while taking an NSAID/antihypertensive combination, acetaminophen or nonacetylated salicylates (choline-magnesium salicylate [Trilisate], salsalate [Amigesic, Disalcid, Salsitab]) may be considered as alternative therapy. These agents do not alter prostaglandin synthesis and, therefore, should not attenuate antihypertensive efficacy.

It is also important to consider the nonprescription availability of the NSAID preparation ibuprofen and, more recently, naproxen sodium (Aleve). Most patients have access to these agents without the supervision of their physician or pharmacist.

Figure 1 adapted from Carmichael J, Shankel S. Effects Of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function. Am J Med 1985;78:992-1000. Used with permission.


[1.] Houston MC. Nonsteroidal anti-inflammatory drugs and antihvpertensives. Am J Med 1991;90 (Suppl 5A):42S-7SS. [2.] Oates JA. Antagonism of antihypertensive drug therapy by nonsteroidal anti-inflammatory drugs. Hypertension 1988;11(3 Pt 2):II4-6. [3.] The fifth report of the joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154-83. [4.] MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J [Clin Res] 1985;291:97-104. [5.] Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, et al. Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990;335:827-38. [6.] Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993; 153:477-84. 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LORI L. MACFARLANE, PHARM.D. is an assistant professor in the Department of Community Pharmacy Practice and Administration, College of Pharmacy, Medical University of South Carolina, Charleston. She graduated from the College of Pharmacy, Dalhousie University, Nova Scotia, and obtained a doctorate from the College of Pharmacy, Medical University of South Carolina, where she also completed a pharmacy residency in family medicine.

DEBORAH J. ORAK, PHARM.D. is a pediatric pharmacy resident in the Department of Hospital Pharmacy Practice and Administration at the Medical University of South Carolina, where she received her degree.

WILLIAM M. SIMPSON, M.D. is a professor of family medicine and associate medical director of the occupational and environmental medicine office in the Department of Family Medicine at the Medical University of South Carolina. He is a graduate of the Medical University of South Carolina School of Medicine and completed a fellowship in geriatrics at Johns Hopkins University of Medicine, Baltimore.

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