Antagonism of Antihypertensive Drug Therapy byNonsteroidal Anti-Inflammatory Drugs

JOHN A. OATES

SUMMARY Certain nonsteroidal anti-inflammatory drugs antagonize the action of antihyperten-sive therapy. Indomethacin has been shown to abrogate the antihypertensive effect of /3-adrenergicreceptor blockers, diuretics, converting enzyme inhibitors, and several antihypertensive drug combi-nations, and the accumulated evidence on piroxicam indicates that it also raises arterial pressure intreated patients. In contrast, sulindac and aspirin do not reverse the effects of antihypertensive drugs,and currently available data indicate that they are the safest cylooxygenase inhibitors for use inhypertensive patients. In the absence of definitive information on the array of other nonsteroidal anti-inflammatory drugs, they should be considered to pose a risk similar to indomethacin until provedotherwise. The magnitude of the elevation in blood pressure varies between patients, ranging from noeffect to dangerous hypertensive responses. Generalized inhibition of the cyclooxygenase enzyme hasopposing effects on arterial pressure, lowering renin on one hand and causing sodium retention on theother. Some evidence suggests that cyclooxygenase inhibition causes the greater increments in pres-sure in patients who initially have low plasma renin activity (often the elderly). The potential forcerebral vascular catastrophes attends these drug interactions in which platelet function also issuppressed by cyclooxygenase inhibition. (Hypertension 11 [Suppl U]: II-4-II-6, 1988)

KEY WORDS • antihypertensive drugsanti-inflammatory drugs

drug interactions • nonsteroidal

THE potential for concurrent administration ofdrugs that are used in treating arthritis togeth-er with antihypertensive agents is consider-

able. Approximately 30% of the patients with arthritishave hypertension. The potential for catastrophic in-teraction is illustrated by the consequences of concur-rent administration of these drugs in a patient.

A 77-year-old retired minister had a long history ofhypertension that had been characterized as low reninessential hypertension based on a plasma renin activityof 1.05 ng/rru7hr measured after administration of furo-semide 80 mg and 3 hours of upright posture. Hisblood pressure had been frequently documented to beunder reasonable control with a combination of pro-pranolol 160 mg daily and furosemide 80 mg daily.

His second problem was osteoarthritis involving thehip as well as other joints. This was treated with sulin-dac 200 mg daily and resulted in fair control except forsporadic flare-ups. Upon reading in the newspaperabout a new arthritis drug, piroxicam, he persuaded hislocal physician to start him on this drug at a dosage of

From the Vanderbilt University School of Medicine, Nashville,Tennessee.

Address for reprints: John A. Oates, M.D., Department of Medi-cine, Vanderbilt University School of Medicine, Nashville, TN37232.

Supported by National Heart, Lung, and Blood Institute GrantHL 14192.

20 mg daily. Three weeks later, a headache developedthat became progressively worse. Fortunately, his wifehad been trained to take his blood pressure, which shefound to be 230/130 mm Hg. He was immediatelyhospitalized, during which the severe level of hyper-tension was confirmed. After the discontinuation ofpiroxicam, the blood pressure gradually returned to thelevels previously observed.

This remarkable hypertensive response to piroxicampushed the patient to the brink of disaster. It illustratesthat some nonsteroidal anti-inflammatory drugs vitiatethe action of antihypertensive drugs and that in somepatients the hypertensive response may be severe.

Indomethacin is the nonsteroidal drug most exten-sively evaluated for its potential to antagonize antihy-pertensive therapy. Indomethacin has been shown toantagonize the antihypertensive effects of /3-adrener-gic receptor blockers,1"6 diuretics,23'7 and convertingenzyme inhibitors.8"11 Indomethacin also elevates arte-rial pressure in patients receiving diuretics in combina-tion with a number of other antihypertensiveagents.12"14

In contrast to indomethacin, sulindac 400 mg dailydoes not interfere with the antihypertensive effect of y3-adrenergic receptor blockers when given either alone"or in conjunction with a diuretic16; this dosage of sulin-dac also did not elevate arterial pressure in a group ofpatients receiving a variety of antihypertensive drugs

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ANTAGONISM BY NONSTEROIDAL ANTI-INFLAMMATORY DRUGS/Oates II-5

given in combinations.14 The lack of a hypertensiveresponse to sulindac in patients on antihypertensivetherapy is convincing because in each of these studiesthere were positive controls in which other nonsteroi-dal anti-inflammatory drugs caused an elevation inpressure in the same patients. Similar to sulindac, aspi-rin in dosages of 1.95 g daily13 and 3.9 g daily14 did notraise arterial pressure in patients receiving mainte-nance therapy with combinations of antihypertensivedrugs. Although aspirin 5 g daily or in single doses of1.0-1.5 g antagonized the hypotensive effects of anacute dose of intravenously administered proprano-lol,17 the well-known differences between the hemody-namic effects of acute and chronically administered/3-adrenergic receptor blockers are such that this obser-vation cannot be extrapolated to any conclusion re-garding maintenance therapy.

Information on the vast array of other nonsteroidalanti-inflammatory drugs is only beginning to emerge.The combined evidence on piroxicam14'16 indicatesthat it, like indomethacin, raises arterial pressure intreated hypertensive patients. More information isneeded on naproxen, but that currently available sug-gests that its effect on blood pressure is more likeindomethacin than aspirin.13'l6 It would be prudent toassume that the other nonsteroidal anti-inflammatorydrugs will antagonize antihypertensive therapy untilappropriate studies prove otherwise. Currently, onlysulindac and aspirin may be considered to not abrogatethe effects of chronic antihypertensive treatment.

Thus, even though aspirin and sulindac inhibit thecyclooxygenase enzyme in some tissues when admin-istered in vivo, their effects on blood pressure in treat-ed hypertensive patients are completely different fromthose of the cyclooxygenase inhibitor indomethacin.The reasons for these qualitative differences are notknown with certainty, but several possibilities deserveconsideration. The disparate effects on blood pressurecould reflect differences in the tissue-specific biotrans-formation of the cyclooxygenase inhibitors. For exam-ple, sulindac sulfide, the active metabolite of sulindac,is oxidized back to the inactive prodrug by the kidney,an inactivation mechanism that could protect portionsof the nephron from cyclooxygenase inhibition by su-lindac sulfide.18 Metabolism also is important in thepharmacology of aspirin, which is an irreversible in-hibitor of the cyclooxygenase enzyme, whereas its me-tabolite, salicylic acid, is a weak competitive inhibitor.A further possibility is that tissue-selective distributionof drugs could occur. Finally, it is possible thatindomethacin and piroxicam antagonize antihyperten-sive drugs by an action other than cyclooxygenaseinhibition."

The mechanism whereby certain nonsteroidal anti-inflammatory drugs antagonize antihypertensive drugaction is not known. That such an elevation in bloodpressure occurs despite the reduction in renin releaseknown to result from indomethacin20 emphasizes thecomplexity of the pathophysiology that results in thiseffect. Possible explanations include, but are not limit-ed to, retention of sodium, removal of tonic vasodilata-

tion produced by prostaglandin, and alteration ofadrenergic neurotransmission.

The magnitude of hypertension evoked by indo-methacin varies considerably between patients receiv-ing the same antihypertensive drug. For example, theelevation in supine systolic pressure produced by indo-methacin in patients receiving thiazide diuretics rangesfrom no increase to an increase of 44 mm Hg.5 It islikely that in clinical practice greater elevations inblood pressure would be seen than in carefully moni-tored trials in which ethical considerations would limitthe magnitude to which blood pressure could rise be-fore intervention; the patient presented at the begin-ning of the report illustrates the potential for an eleva-tion in arterial pressure that is of major clinicalimportance.

The factors determining which patients are mostsusceptible to the hypertensive effects of indomethacinand related drugs have not been elucidated, but thepossible role of the baseline renin state deserves con-sideration and further investigation. Indeed, in a high-ly renin-dependent model of hypertension in the rat,indomethacin actually lowers blood pressure.21 Fur-thermore, in rare instances in which hypertension inhumans is unusually dependent upon renin secretion,indomethacin has produced a significant reduction inblood pressure.22'n In contrast to the effects in theseexceptionally renin-dependent hypertensive patients,inhibition of prostaglandin synthesis with indometha-cin or ibuprofen elevated arterial pressure in normalhumans with a low renin state that was produced by theadministration of fludrocortisone.24 These opposite ef-fects of indomethacin are observed at the polar ex-tremes of the renin spectrum, and more data are re-quired to ascertain whether patients with low reninessential hypertension might be at greater risk fromindomethacin and other cyclooxygenase inhibitors thatraise blood pressure in treated patients.

The potential for cerebrovascular catastrophe at-tends these drug interactions in which platelet functionalso is suppressed by cyclooxygenase inhibition. Withthe possibility of multiple physicians participating inthe care of patients who have hypertension and arthritisand because of the over-the-counter availability ofnonsteroidal anti-inflammatory drugs, the education ofpatients regarding these interactions will minimizetheir risk.

Considerable further research is required to charac-terize the pharmacological agents that evoke this inter-action, to elucidate its mechanism, and to provide abasis upon which the individuals most susceptible tothe hypertensive effects of the nonsteroidal anti-in-flammatory drugs can be identified. It is probable thatnew fundamental insights regarding cardiovascularcontrol should emerge from an understanding of themechanism of this drug interaction.

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J A OatesAntagonism of antihypertensive drug therapy by nonsteroidal anti-inflammatory drugs.

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1988 American Heart Association, Inc. All rights reserved.

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