Vol. 117 No. 6 June 2014

Nonsteroidal anti-inflammatory drugs and antihypertensives:how do they relate?Zovinar Der Khatchadourian, DDS,a,* Isabel Moreno-Hay, DDS, PhD,b,* and Reny de Leeuw, DDS, PhD, MPHc

McGill University, Montreal, Quebec, Canada; University of Kentucky, Lexington, KY, USA

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely available as over-the-counter medications, despite their

numerous side effects and drug interactions. The aim of this article is to increase awareness of the hypertensive potential of

NSAIDs and their interference with antihypertensives. Patients with hypertension appear to be more susceptible than

normotensive individuals to the blood pressureeincreasing effect of NSAIDs. Most studies have found that short-term use of

NSAIDs does not pose a major risk for hypertension or increase in cardiovascular disease in healthy individuals. The calcium

channel blockers and b-blockers seem to be least affected by the concomitant use of NSAIDs. A dentist must weigh the

benefits and disadvantages of using NSAIDs in patients taking antihypertensive drugs. For those who may be at greater risk,

such as patients with hypertension and the elderly, careful selection of the class of NSAID and close monitoring are

appropriate measures, especially if long-term use is anticipated. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:

697-703)

Nonsteroidal anti-inflammatory drugs (NSAIDs) arewidely available as over-the-counter medications indrugstores and supermarkets not only in the UnitedStates but also worldwide. In 2010, an estimated US$1.1 billion were spent on nonnarcotic analgesic drugsin the United States.1

NSAIDs are very commonly used medicationsdespite their numerous side effects and drug in-teractions. For instance, the acute administration ofNSAIDs has been associated with serious adverseoutcomes, such as allergic reactions, renal failure,coagulation problems, and worsening of asthma.Furthermore, the long-term administration of NSAIDscan cause serious gastrointestinal (GI) adverse effects(e.g., bleeding, ulcers), renal failure, and congestiveheart failure.2-4 Minor side effects, such as nausea,dizziness, or gastric irritation, have also been reported.4-6

Several studies have found that the risk for complica-tions increases in susceptible patients, for examplethose who present with a history of ulcers, cardiovas-cular disease, diabetes, or renal complications.7,8 Therisk of deleterious effects with NSAID use is increasedin the elderly population,4,5,9 yet Seager and Hawkey9

found in their study that over half of 24 million NSAIDprescriptions written in a year in the United Kingdomwere prescribed to the elderly population. Owing to the

*These authors have equally contributed to the article.aFaculty Lecturer, Montreal General Hospital, Faculty of Dentistry,McGill University.bResident, Orofacial Pain Center, College of Dentistry, University ofKentucky.cProfessor and Chief, Division of Orofacial Pain, University ofKentucky.Received for publication Jul 30, 2013; returned for revision Feb 4,2014; accepted for publication Feb 21, 2014.� 2014 Elsevier Inc. All rights reserved.2212-4403/$ - see front matterhttp://dx.doi.org/10.1016/j.oooo.2014.02.028

deleterious effects of NSAIDs, Seager and Hawkey9

debated whether NSAIDs should be prescribed tomanage conditions that are not life-threatening. Oftenoverlooked is the fact that long-term use of NSAIDscan cause hypertension.10

NSAIDs also have numerous drug interactions. Forinstance, most NSAIDs affect platelet function, leadingto increased risk of bleeding, when administered withother drugs that impair hemostasis, such as warfarin andselective serotonin reuptake inhibitors. NSAIDs alsodisplace many other drugs, including warfarin and an-ticonvulsants, from albumin, thus leading to increasedrisk of bleeding and potentially toxic levels of the dis-placed drugs. Other oftenoverlooked interactions ofNSAIDs follow from their reduction of the renal so-dium excretion and inhibition of prostaglandin (PG)synthesis. These actions attenuate the effects of severalclasses of antihypertensive medications.11,12

The aim of this article is to increase awareness of theblood pressure (BP)eincreasing potential of NSAIDsand their interference with antihypertensives. First weprovide an overview of the prevalence of hypertensionand the effect it may have on cardiovascular disease(CVD). We then discuss the mechanisms of action ofNSAIDs, with emphasis on their potential to increase BP.Finally, we discuss the most common antihypertensivemedications and describe how NSAIDs may interferewith their actions.

Statement of Clinical Relevance

Dentists should be aware that NSAIDS can increaseblood pressure, especially in patients with hyperten-sion. In addition, NSAIDs can interfere with the bloodpressureeloweringmechanisms of antihypertensives.

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PREVALENCE AND IMPLICATIONS OFHYPERTENSIONHypertension is one of the known factors implicated inCVD, such as stroke, coronary heart disease, and heartfailure,13,14 as well as in renal and ocular disease.14 Ac-cording to the recently published Joint National Com-mittee (JNC-8) recommendations for the management ofhigh BP in adult populations, hypertension is defined asan average BP� 140/90mmHg in the general populationyounger than 60 years, whereas in patients older than 60years, BP� 150/90 mm Hg is defined as hypertension15;for those with diabetes or chronic kidney disease, therecommended BP is � 130/80 mm Hg.16 Hypertensionis very common in the United States, affecting over 65million adults.17 The American Heart Association esti-mates that 25% of the overall population, and 55% to60% of those aged between 65 and 74 years, have hy-pertension.18 A study based on the NHANES database(National Health and Nutrition Examination Survey)performed in 2003 and 2004 found that 24.3% of thehypertensive population was unaware of their condition,and of those that were aware, only 53.7% were receivingproper treatment.19 Thus, over 60% of adults with hy-pertension living in the United States have uncontrolledhypertension and thus are at risk for CVD complications.

Both transient and sustained elevations in BP are riskfactors for cardiovascular mortality and morbidity.20 Forinstance, an increase of 5 mm Hg in the diastolic BP(DBP) can increase the risk of stroke by 67% and the riskof events associated with coronary heart disease by15%.21 From ameta-analysis of 61 randomized controlledtrials involving over 1 million participants,22 it wasconcluded that for every incremental increase of 20 mmHg in systolic BP (SBP) and 10 mm Hg in DBP, startingwith a BP of 115/75 mm Hg, the risk of CVD doubled.Randomized controlled trials have also found thatlowering SBP by 10 mmHg (and 5 mmHg for DBP) canreduce the risk of stroke by 40% and that of ischemic heartdisease by 30%.23-25 Even smaller reductions in BP canhave a positive effect.18,22 Pain can also increase BP.26

MECHANISM OF ACTION OF PGsPGs are produced through oxygenation of arachidonicacid by cyclooxygenase (COX).27,28 There are 2 vari-eties (isoenzymes) of the COX enzyme: COX-1 andCOX-2. COX-1 is constitutive and present in mostnormal tissues, whereas COX-2 is inducible duringinflammatory processes but is constitutive to the brainand kidneys. The constitutive COX-1 enzyme plays akey role in the integrity of the GI mucosal barrier, inkidney function, in maintenance of the vascular tone,and in platelet function.

PGs have many physiologic actions in the brain, theGI tract, the kidneys, and the cardiovascular system.They also play a role in bone resorption, pain, and

inflammatory responses.29 The effects of PGs on thekidneys and cardiovascular system are most importantfor this review and are described in more detail than theother physiologic effects.

In the central nervous system, prostaglandin E2

(PGE2) is involved in fever generation and stimulatesthe secretion of adrenocorticotropic hormone. It hasbeen proposed as a sleep inducer.29 In the GI tract, PGsregulate secretion of mucus and affect GI motility. Inrenal function, PGs are responsible for the modulationof blood circulation and of salt and water excretion.Solute homeostasis is maintained in part by PGs, suchas PGE2, which decreases the sodium resorption. In thecardiovascular system, PGs regulate BP by modulatingthe renin-angiotensin system (RAS). Renin is anenzyme secreted by juxtaglomerular cells; it isresponsible for converting angiotensin I into angio-tensin II. PGI2 stimulates the release of renin andtherefore the production of angiotensin II, which has apotent vasoconstrictor effect leading to an increase inBP. In addition, angiotensin II also promotes the pro-duction of aldosterone from the adrenal cortex. Aldo-sterone is a steroid hormone that acts on the nephronand elevates BP by water and sodium reabsorption andpotassium secretion.30 PGs further contribute to theregulation of the cardiovascular system by eliciting thecontractile (PGI2) and relaxing (thromboxane A2

[TxA2]) vascular smooth muscles and by inhibiting(PGI2) or inducing (TxA2) platelet activation and ag-gregation. It has been proposed that the balance of thePGI2 and TxA2 systems is important for maintainingvascular homeostasis.29,31 PGs are involved in the in-flammatory process along with other mediators, such ashistamine and bradykinin, which are responsible forvascular permeability and edema. Furthermore, PGs arealso believed to sensitize the free endings of sensoryneurons, inducing hyperalgesic responses in the pe-riphery.29 Different side effects will be produced by theselective or nonselective inhibition of the COX en-zymes and thus production of PGs.32

MECHANISM OF ACTION OF NSAIDsThe main mechanism of action by which NSAIDs exerttheir effect is by means of inhibiting the COX enzyme,thus inhibiting the production of PGs. The analgesicand anti-inflammatory effects of NSAIDs are based onthe inhibition of PGs. NSAIDs may thus affect all of theaforementioned systems. There are several proposedmechanisms by which NSAIDs, by virtue of their ac-tions on some of these systems, could raise BP.

Sodium and fluid retentionPGs are released to promote vasodilation and enhancerenal blood flow. By blocking the tubular PGE2,

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NSAIDs promote sodium and fluid retention, increasingthe tubular reabsorption of sodium, which may lead toan increase in BP.30,33,34 It appears that sodium reten-tion is mostly mediated by COX-2.31,34

Renin-angiotensin systemIn some cases, NSAIDs may reduce BP by inhibitingthe production of renin released by PG. This hypoten-sive effect is due to the combination of 2 processes.First of all, the aldosterone released by PGs causesincreased sodium and water reabsorption and excretionof potassium, thereby increasing BP. In addition, theRAS also regulates the secretion of antidiuretic hor-mone. Experimental studies, under well-controlledconditions, have found selective inhibition of COX-2 toinhibit the RAS and reduce hypertension.34

Moreover, the hyporeninemia and hypoaldosteron-ism induced by NSAIDs may manifest as hypercalce-mia due to a decrease in potassium excretion. Thishypercalcemia can cause cardiac arrhythmias.30 Arm-strong and Malone35 proposed that this hypercalcemiccondition, although infrequent, may contribute to hy-pertension independently of hemodynamic and elec-trolyte balance.

Inhibition of PG vasodilationNSAIDs may increase the BP by a direct effect onvascular smooth muscle.36 PGI2 is synthesized byprostacyclin synthase and has vasodilatory effects. Theadministration of NSAIDs inhibits COX-2 productionof PGI2, resulting in an increase in peripheral resis-tance34 responsible for BP increase. Animal modelstudies found that the infusion of PGE2 evoked hypo-tension in mice. Interestingly, PGE2 was produced andincreased in urinary secretion when animals were fed ahigh-salt diet, possibly to downregulate the BP.29

Cytochrome P-450-dependent monooxygenasesystemBy inhibition of COX enzymes, the metabolism of thearachidonic acid is forced through alternative pathways.Examples are the lipoxygenase and P-450 cytochromenicotinamide adenine dinucleotide phosphateedependentmonooxygenase pathways. In recent years, it has beenfound that the metabolism of arachidonic acid bycytochrome P-450 results in the production of metab-olites with potential effects on raising BP.33,34 Animalstudies have found that the metabolites epoxyeicosa-trienoic acid, hydroxyeicosatetraenoic acid, and 20-carboxyl arachidonic acid, produced through this“third” pathway, are involved in the pathogenesis ofhypertension by modification of renal function. How-ever, data for humans in this regard are limited.37

Given the aforementioned factors, it should be clearthat the use of NSAIDs may raise the BP in some in-dividuals, mostly through their action on PGs. Gaz-iano36 found that the acute effect of NSAIDs appears tocause a slight short-term increase in BP and that this islikely to be reversible. However, the effect on chronichypertension due to the deleterious effects on the kid-neys induced by the long-term use of NSAIDs is notclear and requires further research.36

A meta-analysis38 published in 2009 compared theeffects of different types of NSAIDs on BP, and theauthors found that a few selective COX-2 inhibitorswere associated with an elevation in BP compared withplacebo or nonselective NSAIDs.38 However, theseselective COX-2 inhibitors are no longer on the market.The meta-analysis,38 along with other recentstudies,39,40 found no differences in the incidence ofhypertension between celecoxib and nonselectiveNSAIDs. However, a long-term study found that pa-tients treated with celecoxib, 200 mg or 400 mg, for theprevention of colorectal adenomas had an increase inthe SBP of 2 mm Hg and 2.9 mm Hg, respectively, after1 year and 2.6 mm Hg and 5.2 mm Hg, respectively,after 3 years. These results indicate a dose-dependentand possibly increasing rise of BP with the long-termuse of such medications.41

Patients with hypertension appear to be more sus-ceptible than normotensive participants to the BP-increasing effect of NSAIDs. A systematic reviewfound an increase of þ1.1 mm Hg BP in normotensiveparticipants taking NSAIDs. In patients with controlledhypertension, the increases were variable, ranging upto þ14.3 mm Hg for SBP and þ2.3 mm Hg for DBP.33

Among the various nonselective NSAIDs, indometh-acin, naproxen, and piroxicam were associated with thegreatest increase in BP in the hypertensive popula-tion.33 A review article by Morgan and Andersonconcluded that salt-sensitive patients with hypertensionwere more likely to be affected by the use of NSAIDs.42

Frishman34 concluded that the incidence for increasedBP related to NSAIDs intake was low and that increaseswere usually less than 5 mm Hg. However, he statedthat certain patients are at a higher risk for BP increasewith concomitant use of NSAIDs, such as patients withhypertension, those treated with antihypertensives,those with a history of cardiovascular disease, or thosewith renal or liver disease.34

MECHANISM OF ACTION OFANTIHYPERTENSIVE MEDICATIONSBP is regulated through 3 separate mechanisms: bybaroreflexes that are mediated by the sympathetic ner-vous system (SNS), by inflammatory mediators, and bythe RAS.43 These mechanisms can affect BP on theirown as well as in synchrony with each other, depending

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on the level of BP fluctuations. The baroreflexes areactivated when the BP is decreased beyond a certainlevel, which results in the SNS increasing cardiacoutput and peripheral vascular resistance to counteractthe reduced BP. Inflammatory cytokines will causevasodilatation, leading to edema of tissues anddecreased BP. The RAS regulates BP through waterand sodium reabsorption and secretion of antidiuretichormone. The effect of NSAIDs on the RAS isresponsible for an increase in total peripheral resistance,and this negates the BP-reducing effect of all antihy-pertensive medications in a general fashion.

INTERACTION OF ANTIHYPERTENSIVES WITHNSAIDsIn addition to raising the BP by themselves, NSAIDscan also negate the BP-lowering effects of many med-ications used to treat hypertension, again mostly bycounteracting the PG effect of such medications. Thereare different modalities for the treatment of hyperten-sion. Nonpharmacologic therapy includes lifestylechanges to promote weight loss (through diet and ex-ercise) and to promote healthy dietary changes,including reduction in caffeine, sodium, fat, and alcoholintake and increase in fruit, fish, lean protein, and fiberintake.27,28 Another therapy for hypertension is phar-macotherapy.44 Antihypertensives are widely pre-scribed in the United States and elsewhere, with anestimated cost of more than US $8 million in the UnitedStates, based on a 2001 study performed by Hodgsonand Cai.45 There are 5 major different classes of anti-hypertensives: (1) diuretics; (2) those affecting theRAS, such as the angiotensin-converting enzyme in-hibitors (ACEIs), angiotensin receptor blockers(ARBs), and renin inhibitors; (3) vasodilators; (4)sympatholytic agents; and (5) other cardiovascularaffecting medications, such as b-blockers and calcium-channel blockers.46 Often, hypertension is controlledusing multiple antihypertensive agents at the same time.Each agent will decrease BP through one or moremechanisms. The JNC-8 recommends as first-linetreatment the following classes of medications: thia-zide-type diuretics, ACEIs, ARBs, and calcium channelblockers. It recommends further that medication classessuch as the a-blockers and b-blockers, the aldosteroneantagonists, and the loop diuretics should only beconsidered as later-in-line alternatives.15

DiureticsThis class of antihypertensive medication is subdividedinto several classes; the loop and thiazide-type diureticsare 2 major classes commonly prescribed to treat hyper-tension.18 The loop diuretics inhibit sodium reabsorptionat the level of the loop of Henle by competing withchloride for the sodium/potassium cotransporter,

consequently inhibiting sodium and chloride reabsorp-tion. Loop diuretics can also stimulate renal PG synthesis,particularly of PGE2, which is a vasodilator. Thus, theNSAIDs, by virtue of blocking renal PGE2 synthesis, willincrease sodium reabsorption and reduce the effect ofloop diuretics. The thiazide-type diuretics exert their ef-fect in the distal convoluted tubule, where the reabsorp-tion of sodium and chloride is inhibited. These agents alsoreduce calcium and uric acid excretion. Hyperreninemiaand hypoaldosteronism induced by NSAIDs can negatethe effect of diuretics,18,35 possibly owing to resultinghyperkalemia. Another category of diuretics prescribedfor hypertension is the potassium-sparing family. In thisgroup of antihypertensives, one subclass acts ascompetitive antagonist of aldosterone, whereas anotherone is independent of aldosterone function. The firstsubclass can be affected by NSAIDs’ effect at the RASlevel. The second subclass, usually used in combinationwith thiazide diuretics, can increase renal vascular resis-tance; thus combination of this potassium-sparing diureticwith NSAIDs can result in acute renal failure lasting forseveral days associated with secretion of PGE2.

47

Angiotensin systemeaffecting agentsAngiotensin II increases BP in several ways: throughthe aldosterone system, by increasing the response tocatecholamines, and by causing vasoconstrictionmediated by release of PGE2.

48 Angiotensin-convertingenzyme (ACE) is involved in the production of angio-tensin II; thus, its inhibition will lower the levels of thishormone.11 Consequently, there is a decrease in aldo-sterone and an activation of bradykinin (a potentvasodilator), which further reduces BP.

The ARBs will antagonize the effects of angiotensin IIby blocking its action at the receptor level. Renin blockerswill inhibit the production of angiotensin I, a precursor toangiotensin II, once again affecting the RAS system.

ACEIs, ARBs, and renin inhibitors increase levels ofbradykinin in the system. Bradykinin will contribute tothe vasodilatory effects of these antihypertensive med-ications, and this effect is mediated through stimulationof PGE2 synthesis, as seen in animal studies.48 NSAIDs,by virtue of inhibiting the PG synthesis, can interferewith the vasodilatory effects of bradykinin and angio-tensin II. This effect is more pronounced in individualswith hypertension who have low renin levels.18

VasodilatorsVasodilators are rarely used as primary medications tocontrol hypertension. The exact mechanism of vasodi-lators is unknown, but it is believed, based on animalexperiments, to be mediated by the PG pathways49

through relaxation of smooth muscles in arterioles. Therelaxation of the smooth muscles decreases resistance in

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the arterioles and hence reduces BP. On the other hand,the vasodilators increase plasma renin concentration,resulting in an increase in sodium and water retention.There are very few data regarding their interaction withNSAIDs.18 Their vasodilatory effect may be inhibitedthrough the inhibition of the RAS by NSAIDs.

Sympatholytic agentsAgents in this group modulate BP centrally by exertingtheir agonistic action at the a2-adrenoreceptor, orperipherally by blocking the a-adrenoreceptor or b-adrenoreceptor. These are G-protein coupled receptorsthat block calcium influx.

The centrally acting agents reduce the release of cat-echolamines; consequently, there is a failure to activatethe sympathetic reflex arc pathway at the brain stemvasomotor center, which is associated with aortic baro-receptors involved in BP homeostasis. There is reducedsympathetic flow to the peripheral cardiovascular sys-tem, which decreases cardiac output. The sympatholyticagents are rarely used in hypertension therapy because oftheir systemic widespread undesirable effects. Never-theless, clonidine is still prescribed for patients havingdrug-resistant hypertension. These medications are notdirectly affected by concomitant use of NSAIDs.18

The peripherally acting a1-adrenoreceptor antagonistsexert a vasodilatory effect on arterioles and venules,which consequently reduces the peripheral vascularresistance. The peripherally acting a1-adrenoreceptorantagonist also reduces sodium reabsorption in thekidneys, thus promoting excretion of fluids. Conse-quently, the NSAIDs will affect this class of medicationby inhibiting PGE2 in the renal tubules, which promotessodium reabsorption and fluid retention.21,50

The b-blockers block the action of epinephrine andnorepinephrine at the b-adrenergic receptors. The antihy-pertensive effects are primarily through stimulation of b1receptors found in the myocardium and the kidney. At thecardiovascular level, these agents lower cardiac output andinhibit release of renin, which consequently affects theRAS by lowering production of angiotensin and aldoste-rone. NSAIDs inhibit renin release aswell.With less reninin the system, the effect of b1 selective blockers is blunt-ed.18 Propranolol is a nonselective b-blocker, acting on b1and b2 receptors. Propranolol has been found to stimulatePGI2 synthesis, which in turn promotes vasodilation.51

NSAIDs block PGI2 synthesis, thus negating the effec-tiveness of propranolol at the PGI2 level.

34

Calcium channel blockersCalcium channel blockers inhibit calcium influx insmooth muscle cells, resulting in vasodilation of ar-teries and reduced cardiac output. Morgan and Ander-son (2003) performed a double-blind crossover study

comparing use of indomethacin in patients taking eithercalcium channel blockers or ACEIs. They concludedthat indomethacin had less effect on calcium channelblocking agents than on ACEIs.52 Similarly, in anotherrandomized controlled trial, Houston et al.53 found nosignificant differences in BP when naproxen oribuprofen were added to the regimens of patients withwell-controlled hypertension taking verapamil.

Most major antihypertensives exert their effect,completely or partially, through the PG-mediatedmechanisms, except for calcium channel blockers52 andpossibly b-blockers and a2-adrenoreceptor agonists.18

It is likely that NSAIDs’ interference with intrarenalblood flow through PG inhibition is the main reason forthe BP-raising effect,34 thus antagonizing the effects ofantihypertensive drugs and consequently increasinghypertension-related morbidity.14,18

A prospective clinical trial of 88 treated patients withhypertension54 found that all antihypertensive medica-tions except calcium channel blockers are affected byNSAIDs’ vasoconstrictive effect, confirming findings inseveral review articles.18,44,55 The trial found strongereffects in hypertensive vs normotensive participants andfound that they were dose-dependent, similar to resultsfound in a review article35 and 2 meta-analyses ofclinical data.50,56

On the other hand, a recent cohort study compared theeffect of NSAIDs on different antihypertensive drugs,including ACEIs, calcium channel blockers, b-blockers,a-blockers, and diuretics. This study found that di-uretics, ACEIs, and calcium channel blockers wereaffected by NSAIDs, whereas b-blockers were not.57 Areview article published in 2006 ranked the effect ofNSAIDs on antihypertensive drugs in the followingorder of severity of interaction: ACEIs/ARBs, diuretics,b-blockers, and calcium antagonists or a-blockers.55

Sheridan et al.58 stated that nonpharmacologic con-founding factors, such as sodium intake and exercise,affect the BP readings and are hard to account for. Theyconcluded that the effect of NSAIDs on increasing BPsignificantly is debatable. Moreover, other potentialconfounding factors should be controlled in patientswith inadequately controlled hypertension.

CONCLUSIONMost studies have found that short-term use of NSAIDsdoes not pose a major risk for hypertension or increasein CVD. It is likely that NSAIDs’ interference withRAS is the main reason for the BP-raising effect, andthe extent is variable. Patients with hypertension appearto be more susceptible than normotensive participantsto the BP-increasing effect of NSAIDs. Given that theelderly are more likely to use NSAIDs and that theyhave a higher prevalence of hypertension than theyounger population, this group should be considered

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more susceptible to this effect as well. Of all the BPmedications, the calcium channel blockers and b-blockers seem to be least affected by the concomitantuse of NSAIDs. Sympatholytic agents are also amongthe least affected drugs; however, they are not oftenused for BP control. Of all the NSAIDs, piroxicam,naproxen, and indomethacin seem to have the highesthypertensive effect, especially in patients with hyper-tension. Celecoxib has a similar hypertensive effect asnonselective NSAIDs in short-term studies but mayhave an increased effect on hypertension when usedover longer periods.

A dentist must weigh the benefits and disadvantages ofusing NSAIDs in patients taking antihypertensive drugs.Conservative, short-term therapy should not be an issuefor most of these patients. Caution is also recommendedwhen prescribingNSAIDs in patients with a history of GIdisease, CVD, diabetes, or renal or hepatic impairment.For thosewhomay be at a greater risk, careful selection ofthe class of NSAID and close monitoring are appropriatemeasures, especially if long-term use is anticipated.Other classes of analgesics may also be considered, suchas opioids and acetaminophen. As dentists, we belong tothe health care team responsible for the overall man-agement of health issues in our patients.

We thank Ms Aline Shogher Markarian, BPharm, DESS, forher comments and critical review of this publication.

REFERENCES1. IMS Health. Top 20 Global Therapeutic Classes. 2010 ed. Dan-

bury, CT: IMS Health; 2010.2. Blower AL, Brooks A, Fenn GC, et al. Emergency admissions for

upper gastrointestinal disease and their relation to NSAID use.Aliment Pharmacol Ther. 1997;11:283-291.

3. Hawkey CJ, Cullen DJ, Greenwood DC, Wilson JV, Logan RF.Prescribing of nonsteroidal anti-inflammatory drugs in generalpractice: determinants and consequences. Aliment PharmacolTher. 1997;11:293-298.

4. Page J, Henry D. Consumption of NSAIDs and the developmentof congestive heart failure in elderly patients: an underrecognizedpublic health problem. Arch Intern Med. 2000;160:777-784.

5. Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal antiin-flammatory drugs as a trigger of clinical heart failure. Epidemi-ology. 2003;14:240-246.

6. Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP. Risk factors forNSAID-associated upper GI clinical events in a long-term pro-spective study of 34 701 arthritis patients. Aliment PharmacolTher. 2010;32:1240-1248.

7. Cangiano JL, Figueroa J, Palmer R. Renal hemodynamic effectsof nabumetone, sulindac, and placebo in patients with osteoar-thritis. Clin Ther. 1999;21:503-512.

8. Forrest JB, Camu F, Greer IA, et al. Ketorolac, diclofenac, andketoprofen are equally safe for pain relief after major surgery. Br JAnaesth. 2002;88:227-233.

9. Seager JM, Hawkey CJ. ABC of the upper gastrointestinal tract:indigestion and non-steroidal anti-inflammatory drugs. BMJ.2001;323:1236-1239.

10. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclo-oxygenase-2 inhibitors and their effects on blood pressure. ArchIntern Med. 2005;165:490-496.

11. Katzung BG, Masters SB, Trevor AJ. Basic and Clinical Phar-macology. 12th ed. New York, NY: McGraw Hill Medical; 2012.

12. White WB. Hypertension associated with therapies to treatarthritis and pain. Hypertension. 2004;44:123-124.

13. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regi-mens to lower blood pressure on major cardiovascular events inolder and younger adults: meta-analysis of randomised trials.BMJ. 2008;336:1121-1123.

14. Cushman WC. The burden of uncontrolled hypertension:morbidity and mortality associated with disease progression.J Clin Hypertens (Greenwich). 2003;5(3 suppl 2):14-22.

15. James PA, Oparil S, Carter BL, et al. 2014 Evidence-basedguideline for the management of high blood pressure in adults:report from the panel members appointed to the Eighth JointNational Committee (JNC 8). JAMA. 2014;311:507-520.

16. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of theJoint National Committee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252.

17. Fields LE, Burt VL, Cutler JA, Hughes J, Roccella EJ, Sorlie P.The burden of adult hypertension in the United States 1999 to2000: a rising tide. Hypertension. 2004;44:398-404.

18. Ruoff GE. The impact of nonsteroidal anti-inflammatory drugs onhypertension: alternative analgesics for patients at risk. Clin Ther.1998;20:376-387:discussion 75.

19. Ong KL, Cheung BMY, Man YB, Lau CP, Lam KSL. Preva-lence, awareness, treatment, and control of hypertension amongUnited States adults 1999-2004. Hypertension. 2007;49:69-75.

20. Grossman E, Messerli FH. Drug-induced hypertension: an un-appreciated cause of secondary hypertension. Am J Med.2012;125:14-22.

21. Johnson AG. NSAIDs and blood pressure: clinical importance forolder patients. Drugs Aging. 1998;12:17-27.

22. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Pro-spective Studies Collaboration. Age-specific relevance of usualblood pressure to vascular mortality: a meta-analysis of individualdata for one million adults in 61 prospective studies [Erratumappears in Lancet 2003;361:1060]. Lancet. 2002;360:1903-1913.

23. Collins R, MacMahon S. Blood pressure, antihypertensive drugtreatment and the risks of stroke and of coronary heart disease. BrMed Bull. 1994;50:272-298.

24. Neal B, MacMahon S, Chapman N. Effects of ACE inhibitors,calcium antagonists, and other blood-pressure-lowering drugs:results of prospectively designed overviews of randomised trials.Blood Pressure Lowering Treatment Trialists’ Collaboration.Lancet. 2000;356:1955-1964.

25. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, andcoronary heart disease. Part 2, Short-term reductions in bloodpressure: overview of randomised drug trials in their epidemio-logical context. Lancet. 1990;335:827-838.

26. Brand HS, Abraham-Inpijn L. Cardiovascular responses inducedby dental treatment. Eur J Oral Sci. 1996;104:245-252.

27. Livingston A. Mechanism of action of nonsteroidal anti-inflam-matory drugs. Vet Clin North Am Small Anim Pract. 2000;30:773-781, vi.

28. Bjorkman DJ. The effect of aspirin and nonsteroidal anti-inflam-matory drugs on prostaglandins. Am J Med. 1998;105:8S-12S.

29. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: struc-tures, properties, and functions. Physiol Rev. 1999;79:1193-1226.

30. Brater DC. Effects of nonsteroidal anti-inflammatory drugs onrenal function: focus on cyclooxygenase-2-selective inhibition.Am J Med. 1999;107:65S-70S:discussion 70S-71S.

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31. Hermann M, Ruschitzka F. Coxibs, non-steroidal anti-inflammatory drugs and cardiovascular risk. Intern Med J.2006;36:308-319.

32. Johnson DL, Hisel TM, Phillips BB. Effect of cyclooxygenase-2inhibitors on blood pressure. Ann Pharmacother. 2003;37:442-446.

33. Snowden S, Nelson R. The effects of nonsteroidal anti-inflam-matory drugs on blood pressure in hypertensive patients. CardiolRev. 2011;19:184-191.

34. Frishman WH. Effects of nonsteroidal anti-inflammatory drugtherapy on blood pressure and peripheral edema. Am J Cardiol.2002;89:18D-25D.

35. Armstrong EP, Malone DC. The impact of nonsteroidal anti-inflammatory drugs on blood pressure, with an emphasis onnewer agents. Clin Ther. 2003;25:1-18.

36. Gaziano JM. Nonnarcotic analgesics and hypertension. Am JCardiol. 2006;97:10-16.

37. Rahman M, Wright JT Jr, Douglas JG. The role of the cyto-chrome P450-dependent metabolites of arachidonic acid in bloodpressure regulation and renal function: a review. Am J Hypertens.1997;10:356-365.

38. Chan CC, Reid CM, Aw TJ, Liew D, Haas SJ, Krum H. Do COX-2 inhibitors raise blood pressure more than nonselective NSAIDsand placebo? An updated meta-analysis. J Hypertens. 2009;27:2332-2341.

39. Wang J, Mullins CD, Mamdani M, Rublee DA, Shaya FT. Newdiagnosis of hypertension among celecoxib and nonselectiveNSAID users: a population-based cohort study. Ann Pharmac-other. 2007;41:937-943.

40. White WB, West CR, Borer JS, et al. Risk of cardiovascularevents in patients receiving celecoxib: a meta-analysis of ran-domized clinical trials. Am J Cardiol. 2007;99:91-98.

41. Solomon SD, Pfeffer MA, McMurray JJV, et al. Effect of cele-coxib on cardiovascular events and blood pressure in two trialsfor the prevention of colorectal adenomas. Circulation. 2006;114:1028-1035.

42. Morgan T, Anderson A. The effect of nonsteroidal anti-inflam-matory drugs on blood pressure in patients treated with differentantihypertensive drugs. J Clin Hypertens (Greenwich). 2003;5:53-57.

43. Benowitz NL. Antihypertensive agents. In: Katzung B, Masters S,Trevor A, eds. Basic and Clinical Pharmacology. 12th ed. NewYork, NY: McGraw-Hill Medical; 2012.

44. Chou CM. Evaluation and treatment of hypertension. Rheum DisClin North Am. 1999;25:521-537.

45. Hodgson TA, Cai L. Medical care expenditures for hypertension,its complications, and its comorbidities. Med Care. 2001;39:599-615.

46. Stolbach A, Chanmugam A. Chapter 190: Antihypertensiveagents. In: Tintinalli J, Stapczynski J, Ma OJ, Cline D,Cydulka R, Meckler G, eds. Tintinalli’s Emergency Medicine: A

Comprehensive Study Guide. 7th ed. New York, NY: McGraw-Hill Medical; 2011.

47. Sica DA. Diuretic therapy in cardiovascular disease. In:Black HR, Elliott WJ, eds. Hypertension: A Companion toBraunwald’s Heart Disease. Philadelphia, PA: Elsevier HealthSciences; 2012.

48. Cooper CL, Shaffer JE, Malik KU. Mechanism of action ofangiotensin II and bradykinin on prostaglandin synthesis andvascular tone in the isolated rat kidney. Effect of Caþþ antago-nists and calmodulin inhibitors. Circ Res. 1985;56:97-108.

49. Dyer R, Huttner J, Tan S, Mulrow P. Prostaglandin synthesis byvascular smooth muscle cells stimulated by bradykinin, prazosin,and hydralazine. Prog Lipid Res. 1981;20:557-560.

50. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effectsof nonsteroidal anti-inflammatory drugs on blood pressure. ArchIntern Med. 1993;153:477-484.

51. Beckmann ML, Gerber JG, Byyny RL, LoVerde M, Nies AS.Propranolol increases prostacyclin synthesis in patients withessential hypertension. Hypertension. 1988;12:582-588.

52. MorganTO,AndersonA,BertramD.Effect of indomethacinonbloodpressure in elderly people with essential hypertension well controlledon amlodipine or enalapril. Am J Hypertens. 2000;13:1161-1167.

53. Houston MC, Weir M, Gray J, et al. The effects of nonsteroidalanti-inflammatory drugs on blood pressures of patients with hy-pertension controlled by verapamil. Arch Intern Med. 1995;155:1049-1054.

54. Pavlicevic I, Kuzmanic M, Rumboldt M, Rumboldt Z. Interactionbetween antihypertensives and NSAIDs in primary care: acontrolled trial. Can J Clin Pharmacol. 2008;15:e372-e382.

55. Elliott WJ. Drug interactions and drugs that affect blood pressure.J Clin Hypertens (Greenwich). 2006;8:731-737.

56. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. AnnIntern Med. 1994;121:289-300.

57. Ishiguro C, Fujita T, Omori T, Fujii Y, Mayama T, Sato T.Assessing the effects of non-steroidal anti-inflammatory drugs onantihypertensive drug therapy using post-marketing surveillancedatabase. J Epidemiol. 2008;18:119-124.

58. Sheridan R, Montgomery AA, Fahey T. NSAID use and BP intreated hypertensives: a retrospective controlled observationalstudy. J Hum Hypertens. 2005;19:445-450.

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