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) are widely available as over-the-counter medications in drugstores and supermarkets not only in the United States but also worldwide. In 2010, an estimated US $1.1 billion were spent on nonnarcotic analgesic drugs in the United States.1 NSAIDs are very commonly used medications despite their numerous side effects and drug interactions. For instance, the acute administration of NSAIDs has been associated with serious adverse outcomes, such as allergic reactions, renal failure, coagulation problems, and worsening of asthma. Furthermore, the long-term administration of NSAIDs can cause serious gastrointestinal (GI) adverse effects (e.g., bleeding, ulcers), renal failure, and congestive heart failure.2-4 Minor side effects, such as nausea, dizziness, or gastric irritation, have also been reported.4-6 Several studies have found that the risk for complications increases in susceptible patients, for example those who present with a history of ulcers, cardiovascular disease, diabetes, or renal complications.7,8 The risk of deleterious effects with NSAID use is increased in the elderly population,4,5,9 yet Seager and Hawkey9 found in their study that over half of 24 million NSAID prescriptions written in a year in the United Kingdom were prescribed to the elderly population. Owing to the *These authors have equally contributed to the article. a Faculty Lecturer, Montreal General Hospital, Faculty of Dentistry, McGill University. b Resident, Orofacial Pain Center, College of Dentistry, University of Kentucky. c Professor and Chief, Division of Orofacial Pain, University of Kentucky. Received for publication Jul 30, 2013; returned for revision Feb 4, 2014; accepted for publication Feb 21, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.02.028
deleterious effects of NSAIDs, Seager and Hawkey9 debated whether NSAIDs should be prescribed to manage conditions that are not life-threatening. Often overlooked is the fact that long-term use of NSAIDs can cause hypertension.10 NSAIDs also have numerous drug interactions. For instance, most NSAIDs affect platelet function, leading to increased risk of bleeding, when administered with other drugs that impair hemostasis, such as warfarin and selective serotonin reuptake inhibitors. NSAIDs also displace many other drugs, including warfarin and anticonvulsants, from albumin, thus leading to increased risk of bleeding and potentially toxic levels of the displaced drugs. Other oftenoverlooked interactions of NSAIDs follow from their reduction of the renal sodium excretion and inhibition of prostaglandin (PG) synthesis. These actions attenuate the effects of several classes of antihypertensive medications.11,12 The aim of this article is to increase awareness of the blood pressure (BP)eincreasing potential of NSAIDs and their interference with antihypertensives. First we provide an overview of the prevalence of hypertension and the effect it may have on cardiovascular disease (CVD). We then discuss the mechanisms of action of NSAIDs, with emphasis on their potential to increase BP. Finally, we discuss the most common antihypertensive medications and describe how NSAIDs may interfere with their actions.
Statement of Clinical Relevance Dentists should be aware that NSAIDS can increase blood pressure, especially in patients with hypertension. In addition, NSAIDs can interfere with the blood pressureelowering mechanisms of antihypertensives. 697
ORAL MEDICINE 698 Khatchadourian, Moreno-Hay and de Leeuw
PREVALENCE AND IMPLICATIONS OF HYPERTENSION Hypertension is one of the known factors implicated in CVD, such as stroke, coronary heart disease, and heart failure,13,14 as well as in renal and ocular disease.14 According to the recently published Joint National Committee (JNC-8) recommendations for the management of high BP in adult populations, hypertension is defined as an average BP 140/90 mm Hg in the general population younger than 60 years, whereas in patients older than 60 years, BP 150/90 mm Hg is defined as hypertension15; for those with diabetes or chronic kidney disease, the recommended BP is 130/80 mm Hg.16 Hypertension is very common in the United States, affecting over 65 million adults.17 The American Heart Association estimates that 25% of the overall population, and 55% to 60% of those aged between 65 and 74 years, have hypertension.18 A study based on the NHANES database (National Health and Nutrition Examination Survey) performed in 2003 and 2004 found that 24.3% of the hypertensive population was unaware of their condition, and of those that were aware, only 53.7% were receiving proper treatment.19 Thus, over 60% of adults with hypertension living in the United States have uncontrolled hypertension and thus are at risk for CVD complications. Both transient and sustained elevations in BP are risk factors for cardiovascular mortality and morbidity.20 For instance, an increase of 5 mm Hg in the diastolic BP (DBP) can increase the risk of stroke by 67% and the risk of events associated with coronary heart disease by 15%.21 From a meta-analysis of 61 randomized controlled trials involving over 1 million participants,22 it was concluded that for every incremental increase of 20 mm Hg in systolic BP (SBP) and 10 mm Hg in DBP, starting with a BP of 115/75 mm Hg, the risk of CVD doubled. Randomized controlled trials have also found that lowering SBP by 10 mm Hg (and 5 mm Hg for DBP) can reduce the risk of stroke by 40% and that of ischemic heart disease by 30%.23-25 Even smaller reductions in BP can have a positive effect.18,22 Pain can also increase BP.26 MECHANISM OF ACTION OF PGs PGs are produced through oxygenation of arachidonic acid by cyclooxygenase (COX).27,28 There are 2 varieties (isoenzymes) of the COX enzyme: COX-1 and COX-2. COX-1 is constitutive and present in most normal tissues, whereas COX-2 is inducible during inflammatory processes but is constitutive to the brain and kidneys. The constitutive COX-1 enzyme plays a key role in the integrity of the GI mucosal barrier, in kidney function, in maintenance of the vascular tone, and in platelet function. PGs have many physiologic actions in the brain, the GI tract, the kidneys, and the cardiovascular system. They also play a role in bone resorption, pain, and
OOOO June 2014
inflammatory responses.29 The effects of PGs on the kidneys and cardiovascular system are most important for this review and are described in more detail than the other physiologic effects. In the central nervous system, prostaglandin E2 (PGE2) is involved in fever generation and stimulates the secretion of adrenocorticotropic hormone. It has been proposed as a sleep inducer.29 In the GI tract, PGs regulate secretion of mucus and affect GI motility. In renal function, PGs are responsible for the modulation of blood circulation and of salt and water excretion. Solute homeostasis is maintained in part by PGs, such as PGE2, which decreases the sodium resorption. In the cardiovascular system, PGs regulate BP by modulating the renin-angiotensin system (RAS). Renin is an enzyme secreted by juxtaglomerular cells; it is responsible for converting angiotensin I into angiotensin II. PGI2 stimulates the release of renin and therefore the production of angiotensin II, which has a potent vasoconstrictor effect leading to an increase in BP. In addition, angiotensin II also promotes the production of aldosterone from the adrenal cortex. Aldosterone is a steroid hormone that acts on the nephron and elevates BP by water and sodium reabsorption and potassium secretion.30 PGs further contribute to the regulation of the cardiovascular system by eliciting the contractile (PGI2) and relaxing (thromboxane A2 [TxA2]) vascular smooth muscles and by inhibiting (PGI2) or inducing (TxA2) platelet activation and aggregation. It has been proposed that the balance of the PGI2 and TxA2 systems is important for maintaining vascular homeostasis.29,31 PGs are involved in the inflammatory process along with other mediators, such as histamine and bradykinin, which are responsible for vascular permeability and edema. Furthermore, PGs are also believed to sensitize the free endings of sensory neurons, inducing hyperalgesic responses in the periphery.29 Different side effects will be produced by the selective or nonselective inhibition of the COX enzymes and thus production of PGs.32
MECHANISM OF ACTION OF NSAIDs The main mechanism of action by which NSAIDs exert their effect is by means of inhibiting the COX enzyme, thus inhibiting the production of PGs. The analgesic and anti-inflammatory effects of NSAIDs are based on the inhibition of PGs. NSAIDs may thus affect all of the aforementioned systems. There are several proposed mechanisms by which NSAIDs, by virtue of their actions on some of these systems, could raise BP. Sodium and fluid retention PGs are released to promote vasodilation and enhance renal blood flow. By blocking the tubular PGE2,
OOOO Volume 117, Number 6
NSAIDs promote sodium and fluid retention, increasing the tubular reabsorption of sodium, which may lead to an increase in BP.30,33,34 It appears that sodium retention is mostly mediated by COX-2.31,34 Renin-angiotensin system In some cases, NSAIDs may reduce BP by inhibiting the production of renin released by PG. This hypotensive effect is due to the combination of 2 processes. First of all, the aldosterone released by PGs causes increased sodium and water reabsorption and excretion of potassium, thereby increasing BP. In addition, the RAS also regulates the secretion of antidiuretic hormone. Experimental studies, under well-controlled conditions, have found selective inhibition of COX-2 to inhibit the RAS and reduce hypertension.34 Moreover, the hyporeninemia and hypoaldosteronism induced by NSAIDs may manifest as hypercalcemia due to a decrease in potassium excretion. This hypercalcemia can cause cardiac arrhythmias.30 Armstrong and Malone35 proposed that this hypercalcemic condition, although infrequent, may contribute to hypertension independently of hemodynamic and electrolyte balance. Inhibition of PG vasodilation NSAIDs may increase the BP by a direct effect on vascular smooth muscle.36 PGI2 is synthesized by prostacyclin synthase and has vasodilatory effects. The administration of NSAIDs inhibits COX-2 production of PGI2, resulting in an increase in peripheral resistance34 responsible for BP increase. Animal model studies found that the infusion of PGE2 evoked hypotension in mice. Interestingly, PGE2 was produced and increased in urinary secretion when animals were fed a high-salt diet, possibly to downregulate the BP.29 Cytochrome P-450-dependent monooxygenase system By inhibition of COX enzymes, the metabolism of the arachidonic acid is forced through alternative pathways. Examples are the lipoxygenase and P-450 cytochrome nicotinamide adenine dinucleotide phosphateedependent monooxygenase pathways. In recent years, it has been found that the metabolism of arachidonic acid by cytochrome P-450 results in the production of metabolites with potential effects on raising BP.33,34 Animal studies have found that the metabolites epoxyeicosatrienoic acid, hydroxyeicosatetraenoic acid, and 20carboxyl arachidonic acid, produced through this “third” pathway, are involved in the pathogenesis of hypertension by modification of renal function. However, data for humans in this regard are limited.37
REVIEW ARTICLE Khatchadourian, Moreno-Hay and de Leeuw 699
Given the aforementioned factors, it should be clear that the use of NSAIDs may raise the BP in some individuals, mostly through their action on PGs. Gaziano36 found that the acute effect of NSAIDs appears to cause a slight short-term increase in BP and that this is likely to be reversible. However, the effect on chronic hypertension due to the deleterious effects on the kidneys induced by the long-term use of NSAIDs is not clear and requires further research.36 A meta-analysis38 published in 2009 compared the effects of different types of NSAIDs on BP, and the authors found that a few selective COX-2 inhibitors were associated with an elevation in BP compared with placebo or nonselective NSAIDs.38 However, these selective COX-2 inhibitors are no longer on the market. The meta-analysis,38 along with other recent studies,39,40 found no differences in the incidence of hypertension between celecoxib and nonselective NSAIDs. However, a long-term study found that patients treated with celecoxib, 200 mg or 400 mg, for the prevention of colorectal adenomas had an increase in the SBP of 2 mm Hg and 2.9 mm Hg, respectively, after 1 year and 2.6 mm Hg and 5.2 mm Hg, respectively, after 3 years. These results indicate a dose-dependent and possibly increasing rise of BP with the long-term use of such medications.41 Patients with hypertension appear to be more susceptible than normotensive participants to the BPincreasing effect of NSAIDs. A systematic review found an increase of þ1.1 mm Hg BP in normotensive participants taking NSAIDs. In patients with controlled hypertension, the increases were variable, ranging up to þ14.3 mm Hg for SBP and þ2.3 mm Hg for DBP.33 Among the various nonselective NSAIDs, indomethacin, naproxen, and piroxicam were associated with the greatest increase in BP in the hypertensive population.33 A review article by Morgan and Anderson concluded that salt-sensitive patients with hypertension were more likely to be affected by the use of NSAIDs.42 Frishman34 concluded that the incidence for increased BP related to NSAIDs intake was low and that increases were usually less than 5 mm Hg. However, he stated that certain patients are at a higher risk for BP increase with concomitant use of NSAIDs, such as patients with hypertension, those treated with antihypertensives, those with a history of cardiovascular disease, or those with renal or liver disease.34
MECHANISM OF ACTION OF ANTIHYPERTENSIVE MEDICATIONS BP is regulated through 3 separate mechanisms: by baroreflexes that are mediated by the sympathetic nervous system (SNS), by inflammatory mediators, and by the RAS.43 These mechanisms can affect BP on their own as well as in synchrony with each other, depending
ORAL MEDICINE 700 Khatchadourian, Moreno-Hay and de Leeuw
on the level of BP fluctuations. The baroreflexes are activated when the BP is decreased beyond a certain level, which results in the SNS increasing cardiac output and peripheral vascular resistance to counteract the reduced BP. Inflammatory cytokines will cause vasodilatation, leading to edema of tissues and decreased BP. The RAS regulates BP through water and sodium reabsorption and secretion of antidiuretic hormone. The effect of NSAIDs on the RAS is responsible for an increase in total peripheral resistance, and this negates the BP-reducing effect of all antihypertensive medications in a general fashion.
INTERACTION OF ANTIHYPERTENSIVES WITH NSAIDs In addition to raising the BP by themselves, NSAIDs can also negate the BP-lowering effects of many medications used to treat hypertension, again mostly by counteracting the PG effect of such medications. There are different modalities for the treatment of hypertension. Nonpharmacologic therapy includes lifestyle changes to promote weight loss (through diet and exercise) and to promote healthy dietary changes, including reduction in caffeine, sodium, fat, and alcohol intake and increase in fruit, fish, lean protein, and fiber intake.27,28 Another therapy for hypertension is pharmacotherapy.44 Antihypertensives are widely prescribed in the United States and elsewhere, with an estimated cost of more than US $8 million in the United States, based on a 2001 study performed by Hodgson and Cai.45 There are 5 major different classes of antihypertensives: (1) diuretics; (2) those affecting the RAS, such as the angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors; (3) vasodilators; (4) sympatholytic agents; and (5) other cardiovascular affecting medications, such as b-blockers and calciumchannel blockers.46 Often, hypertension is controlled using multiple antihypertensive agents at the same time. Each agent will decrease BP through one or more mechanisms. The JNC-8 recommends as first-line treatment the following classes of medications: thiazide-type diuretics, ACEIs, ARBs, and calcium channel blockers. It recommends further that medication classes such as the a-blockers and b-blockers, the aldosterone antagonists, and the loop diuretics should only be considered as later-in-line alternatives.15 Diuretics This class of antihypertensive medication is subdivided into several classes; the loop and thiazide-type diuretics are 2 major classes commonly prescribed to treat hypertension.18 The loop diuretics inhibit sodium reabsorption at the level of the loop of Henle by competing with chloride for the sodium/potassium cotransporter,
OOOO June 2014
consequently inhibiting sodium and chloride reabsorption. Loop diuretics can also stimulate renal PG synthesis, particularly of PGE2, which is a vasodilator. Thus, the NSAIDs, by virtue of blocking renal PGE2 synthesis, will increase sodium reabsorption and reduce the effect of loop diuretics. The thiazide-type diuretics exert their effect in the distal convoluted tubule, where the reabsorption of sodium and chloride is inhibited. These agents also reduce calcium and uric acid excretion. Hyperreninemia and hypoaldosteronism induced by NSAIDs can negate the effect of diuretics,18,35 possibly owing to resulting hyperkalemia. Another category of diuretics prescribed for hypertension is the potassium-sparing family. In this group of antihypertensives, one subclass acts as competitive antagonist of aldosterone, whereas another one is independent of aldosterone function. The first subclass can be affected by NSAIDs’ effect at the RAS level. The second subclass, usually used in combination with thiazide diuretics, can increase renal vascular resistance; thus combination of this potassium-sparing diuretic with NSAIDs can result in acute renal failure lasting for several days associated with secretion of PGE2.47 Angiotensin systemeaffecting agents Angiotensin II increases BP in several ways: through the aldosterone system, by increasing the response to catecholamines, and by causing vasoconstriction mediated by release of PGE2.48 Angiotensin-converting enzyme (ACE) is involved in the production of angiotensin II; thus, its inhibition will lower the levels of this hormone.11 Consequently, there is a decrease in aldosterone and an activation of bradykinin (a potent vasodilator), which further reduces BP. The ARBs will antagonize the effects of angiotensin II by blocking its action at the receptor level. Renin blockers will inhibit the production of angiotensin I, a precursor to angiotensin II, once again affecting the RAS system. ACEIs, ARBs, and renin inhibitors increase levels of bradykinin in the system. Bradykinin will contribute to the vasodilatory effects of these antihypertensive medications, and this effect is mediated through stimulation of PGE2 synthesis, as seen in animal studies.48 NSAIDs, by virtue of inhibiting the PG synthesis, can interfere with the vasodilatory effects of bradykinin and angiotensin II. This effect is more pronounced in individuals with hypertension who have low renin levels.18 Vasodilators Vasodilators are rarely used as primary medications to control hypertension. The exact mechanism of vasodilators is unknown, but it is believed, based on animal experiments, to be mediated by the PG pathways49 through relaxation of smooth muscles in arterioles. The relaxation of the smooth muscles decreases resistance in
OOOO Volume 117, Number 6
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 with NSAIDs.18 Their vasodilatory effect may be inhibited through the inhibition of the RAS by NSAIDs. Sympatholytic agents Agents in this group modulate BP centrally by exerting their agonistic action at the a2-adrenoreceptor, or peripherally by blocking the a-adrenoreceptor or badrenoreceptor. These are G-protein coupled receptors that block calcium influx. The centrally acting agents reduce the release of catecholamines; consequently, there is a failure to activate the sympathetic reflex arc pathway at the brain stem vasomotor center, which is associated with aortic baroreceptors involved in BP homeostasis. There is reduced sympathetic flow to the peripheral cardiovascular system, which decreases cardiac output. The sympatholytic agents are rarely used in hypertension therapy because of their systemic widespread undesirable effects. Nevertheless, clonidine is still prescribed for patients having drug-resistant hypertension. These medications are not directly affected by concomitant use of NSAIDs.18 The peripherally acting a1-adrenoreceptor antagonists exert a vasodilatory effect on arterioles and venules, which consequently reduces the peripheral vascular resistance. The peripherally acting a1-adrenoreceptor antagonist also reduces sodium reabsorption in the kidneys, thus promoting excretion of fluids. Consequently, the NSAIDs will affect this class of medication by inhibiting PGE2 in the renal tubules, which promotes sodium reabsorption and fluid retention.21,50 The b-blockers block the action of epinephrine and norepinephrine at the b-adrenergic receptors. The antihypertensive effects are primarily through stimulation of b1 receptors found in the myocardium and the kidney. At the cardiovascular level, these agents lower cardiac output and inhibit release of renin, which consequently affects the RAS by lowering production of angiotensin and aldosterone. NSAIDs inhibit renin release as well. With less renin in the system, the effect of b1 selective blockers is blunted.18 Propranolol is a nonselective b-blocker, acting on b1 and b2 receptors. Propranolol has been found to stimulate PGI2 synthesis, which in turn promotes vasodilation.51 NSAIDs block PGI2 synthesis, thus negating the effectiveness of propranolol at the PGI2 level.34 Calcium channel blockers Calcium channel blockers inhibit calcium influx in smooth muscle cells, resulting in vasodilation of arteries and reduced cardiac output. Morgan and Anderson (2003) performed a double-blind crossover study
REVIEW ARTICLE Khatchadourian, Moreno-Hay and de Leeuw 701
comparing use of indomethacin in patients taking either calcium channel blockers or ACEIs. They concluded that indomethacin had less effect on calcium channel blocking agents than on ACEIs.52 Similarly, in another randomized controlled trial, Houston et al.53 found no significant differences in BP when naproxen or ibuprofen were added to the regimens of patients with well-controlled hypertension taking verapamil. Most major antihypertensives exert their effect, completely or partially, through the PG-mediated mechanisms, except for calcium channel blockers52 and possibly b-blockers and a2-adrenoreceptor agonists.18 It is likely that NSAIDs’ interference with intrarenal blood flow through PG inhibition is the main reason for the BP-raising effect,34 thus antagonizing the effects of antihypertensive drugs and consequently increasing hypertension-related morbidity.14,18 A prospective clinical trial of 88 treated patients with hypertension54 found that all antihypertensive medications except calcium channel blockers are affected by NSAIDs’ vasoconstrictive effect, confirming findings in several review articles.18,44,55 The trial found stronger effects in hypertensive vs normotensive participants and found that they were dose-dependent, similar to results found in a review article35 and 2 meta-analyses of clinical data.50,56 On the other hand, a recent cohort study compared the effect of NSAIDs on different antihypertensive drugs, including ACEIs, calcium channel blockers, b-blockers, a-blockers, and diuretics. This study found that diuretics, ACEIs, and calcium channel blockers were affected by NSAIDs, whereas b-blockers were not.57 A review article published in 2006 ranked the effect of NSAIDs on antihypertensive drugs in the following order of severity of interaction: ACEIs/ARBs, diuretics, b-blockers, and calcium antagonists or a-blockers.55 Sheridan et al.58 stated that nonpharmacologic confounding factors, such as sodium intake and exercise, affect the BP readings and are hard to account for. They concluded that the effect of NSAIDs on increasing BP significantly is debatable. Moreover, other potential confounding factors should be controlled in patients with inadequately controlled hypertension.
CONCLUSION Most studies have found that short-term use of NSAIDs does not pose a major risk for hypertension or increase in CVD. It is likely that NSAIDs’ interference with RAS is the main reason for the BP-raising effect, and the extent is variable. Patients with hypertension appear to be more susceptible than normotensive participants to the BP-increasing effect of NSAIDs. Given that the elderly are more likely to use NSAIDs and that they have a higher prevalence of hypertension than the younger population, this group should be considered
ORAL MEDICINE 702 Khatchadourian, Moreno-Hay and de Leeuw
more susceptible to this effect as well. Of all the BP medications, the calcium channel blockers and bblockers seem to be least affected by the concomitant use of NSAIDs. Sympatholytic agents are also among the least affected drugs; however, they are not often used for BP control. Of all the NSAIDs, piroxicam, naproxen, and indomethacin seem to have the highest hypertensive effect, especially in patients with hypertension. Celecoxib has a similar hypertensive effect as nonselective NSAIDs in short-term studies but may have an increased effect on hypertension when used over longer periods. A dentist must weigh the benefits and disadvantages of using NSAIDs in patients taking antihypertensive drugs. Conservative, short-term therapy should not be an issue for most of these patients. Caution is also recommended when prescribing NSAIDs in patients with a history of GI disease, CVD, diabetes, or renal or hepatic impairment. For those who may be at a greater risk, careful selection of the class of NSAID and close monitoring are appropriate measures, especially if long-term use is anticipated. Other classes of analgesics may also be considered, such as opioids and acetaminophen. As dentists, we belong to the health care team responsible for the overall management of health issues in our patients. We thank Ms Aline Shogher Markarian, BPharm, DESS, for her comments and critical review of this publication.
REFERENCES 1. IMS Health. Top 20 Global Therapeutic Classes. 2010 ed. Danbury, 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 general practice: determinants and consequences. Aliment Pharmacol Ther. 1997;11:293-298. 4. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med. 2000;160:777-784. 5. Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure. Epidemiology. 2003;14:240-246. 6. Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP. Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients. Aliment Pharmacol Ther. 2010;32:1240-1248. 7. Cangiano JL, Figueroa J, Palmer R. Renal hemodynamic effects of nabumetone, sulindac, and placebo in patients with osteoarthritis. Clin Ther. 1999;21:503-512. 8. Forrest JB, Camu F, Greer IA, et al. Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery. Br J Anaesth. 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.
OOOO June 2014 10. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165:490-496. 11. Katzung BG, Masters SB, Trevor AJ. Basic and Clinical Pharmacology. 12th ed. New York, NY: McGraw Hill Medical; 2012. 12. White WB. Hypertension associated with therapies to treat arthritis and pain. Hypertension. 2004;44:123-124. 13. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older 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-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. 16. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint 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 to 2000: a rising tide. Hypertension. 2004;44:398-404. 18. Ruoff GE. The impact of nonsteroidal anti-inflammatory drugs on hypertension: 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. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension. 2007;49:69-75. 20. Grossman E, Messerli FH. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med. 2012;125:14-22. 21. Johnson AG. NSAIDs and blood pressure: clinical importance for older patients. Drugs Aging. 1998;12:17-27. 22. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies [Erratum appears in Lancet 2003;361:1060]. Lancet. 2002;360:1903-1913. 23. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med 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, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827-838. 26. Brand HS, Abraham-Inpijn L. Cardiovascular responses induced by dental treatment. Eur J Oral Sci. 1996;104:245-252. 27. Livingston A. Mechanism of action of nonsteroidal anti-inflammatory drugs. Vet Clin North Am Small Anim Pract. 2000;30: 773-781, vi. 28. Bjorkman DJ. The effect of aspirin and nonsteroidal anti-inflammatory drugs on prostaglandins. Am J Med. 1998;105:8S-12S. 29. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79:1193-1226. 30. Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-70S:discussion 70S-71S.
OOOO Volume 117, Number 6 31. Hermann M, Ruschitzka F. Coxibs, non-steroidal antiinflammatory drugs and cardiovascular risk. Intern Med J. 2006;36:308-319. 32. Johnson DL, Hisel TM, Phillips BB. Effect of cyclooxygenase-2 inhibitors on blood pressure. Ann Pharmacother. 2003;37: 442-446. 33. Snowden S, Nelson R. The effects of nonsteroidal anti-inflammatory drugs on blood pressure in hypertensive patients. Cardiol Rev. 2011;19:184-191. 34. Frishman WH. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Cardiol. 2002;89:18D-25D. 35. Armstrong EP, Malone DC. The impact of nonsteroidal antiinflammatory drugs on blood pressure, with an emphasis on newer agents. Clin Ther. 2003;25:1-18. 36. Gaziano JM. Nonnarcotic analgesics and hypertension. Am J Cardiol. 2006;97:10-16. 37. Rahman M, Wright JT Jr, Douglas JG. The role of the cytochrome P450-dependent metabolites of arachidonic acid in blood pressure 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 COX2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? An updated meta-analysis. J Hypertens. 2009;27: 2332-2341. 39. Wang J, Mullins CD, Mamdani M, Rublee DA, Shaya FT. New diagnosis of hypertension among celecoxib and nonselective NSAID users: a population-based cohort study. Ann Pharmacother. 2007;41:937-943. 40. White WB, West CR, Borer JS, et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am J Cardiol. 2007;99:91-98. 41. Solomon SD, Pfeffer MA, McMurray JJV, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006;114: 1028-1035. 42. Morgan T, Anderson A. The effect of nonsteroidal anti-inflammatory drugs on blood pressure in patients treated with different antihypertensive 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. New York, NY: McGraw-Hill Medical; 2012. 44. Chou CM. Evaluation and treatment of hypertension. Rheum Dis Clin 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: Antihypertensive agents. In: Tintinalli J, Stapczynski J, Ma OJ, Cline D, Cydulka R, Meckler G, eds. Tintinalli’s Emergency Medicine: A
REVIEW ARTICLE Khatchadourian, Moreno-Hay and de Leeuw 703
47.
48.
49.
50.
51.
52.
53.
54.
55. 56.
57.
58.
Comprehensive Study Guide. 7th ed. New York, NY: McGrawHill Medical; 2011. Sica DA. Diuretic therapy in cardiovascular disease. In: Black HR, Elliott WJ, eds. Hypertension: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: Elsevier Health Sciences; 2012. Cooper CL, Shaffer JE, Malik KU. Mechanism of action of angiotensin II and bradykinin on prostaglandin synthesis and vascular tone in the isolated rat kidney. Effect of Caþþ antagonists and calmodulin inhibitors. Circ Res. 1985;56:97-108. Dyer R, Huttner J, Tan S, Mulrow P. Prostaglandin synthesis by vascular smooth muscle cells stimulated by bradykinin, prazosin, and hydralazine. Prog Lipid Res. 1981;20:557-560. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med. 1993;153:477-484. Beckmann ML, Gerber JG, Byyny RL, LoVerde M, Nies AS. Propranolol increases prostacyclin synthesis in patients with essential hypertension. Hypertension. 1988;12:582-588. Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens. 2000;13:1161-1167. Houston MC, Weir M, Gray J, et al. The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Arch Intern Med. 1995;155: 1049-1054. Pavlicevic I, Kuzmanic M, Rumboldt M, Rumboldt Z. Interaction between antihypertensives and NSAIDs in primary care: a controlled trial. Can J Clin Pharmacol. 2008;15:e372-e382. Elliott WJ. Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006;8:731-737. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal antiinflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994;121:289-300. Ishiguro C, Fujita T, Omori T, Fujii Y, Mayama T, Sato T. Assessing the effects of non-steroidal anti-inflammatory drugs on antihypertensive drug therapy using post-marketing surveillance database. J Epidemiol. 2008;18:119-124. Sheridan R, Montgomery AA, Fahey T. NSAID use and BP in treated hypertensives: a retrospective controlled observational study. J Hum Hypertens. 2005;19:445-450.
Reprint requests: Isabel Moreno-Hay, DDS, PhD 740 S Limestone St Room E214 Kentucky Clinic Lexington KY 40536-0284 USA [email protected]
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) are widely available as over-the-counter medications in drugstores and supermarkets not only in the United States but also worldwide. In 2010, an estimated US $1.1 billion were spent on nonnarcotic analgesic drugs in the United States.1 NSAIDs are very commonly used medications despite their numerous side effects and drug interactions. For instance, the acute administration of NSAIDs has been associated with serious adverse outcomes, such as allergic reactions, renal failure, coagulation problems, and worsening of asthma. Furthermore, the long-term administration of NSAIDs can cause serious gastrointestinal (GI) adverse effects (e.g., bleeding, ulcers), renal failure, and congestive heart failure.2-4 Minor side effects, such as nausea, dizziness, or gastric irritation, have also been reported.4-6 Several studies have found that the risk for complications increases in susceptible patients, for example those who present with a history of ulcers, cardiovascular disease, diabetes, or renal complications.7,8 The risk of deleterious effects with NSAID use is increased in the elderly population,4,5,9 yet Seager and Hawkey9 found in their study that over half of 24 million NSAID prescriptions written in a year in the United Kingdom were prescribed to the elderly population. Owing to the *These authors have equally contributed to the article. a Faculty Lecturer, Montreal General Hospital, Faculty of Dentistry, McGill University. b Resident, Orofacial Pain Center, College of Dentistry, University of Kentucky. c Professor and Chief, Division of Orofacial Pain, University of Kentucky. Received for publication Jul 30, 2013; returned for revision Feb 4, 2014; accepted for publication Feb 21, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.02.028
deleterious effects of NSAIDs, Seager and Hawkey9 debated whether NSAIDs should be prescribed to manage conditions that are not life-threatening. Often overlooked is the fact that long-term use of NSAIDs can cause hypertension.10 NSAIDs also have numerous drug interactions. For instance, most NSAIDs affect platelet function, leading to increased risk of bleeding, when administered with other drugs that impair hemostasis, such as warfarin and selective serotonin reuptake inhibitors. NSAIDs also displace many other drugs, including warfarin and anticonvulsants, from albumin, thus leading to increased risk of bleeding and potentially toxic levels of the displaced drugs. Other oftenoverlooked interactions of NSAIDs follow from their reduction of the renal sodium excretion and inhibition of prostaglandin (PG) synthesis. These actions attenuate the effects of several classes of antihypertensive medications.11,12 The aim of this article is to increase awareness of the blood pressure (BP)eincreasing potential of NSAIDs and their interference with antihypertensives. First we provide an overview of the prevalence of hypertension and the effect it may have on cardiovascular disease (CVD). We then discuss the mechanisms of action of NSAIDs, with emphasis on their potential to increase BP. Finally, we discuss the most common antihypertensive medications and describe how NSAIDs may interfere with their actions.
Statement of Clinical Relevance Dentists should be aware that NSAIDS can increase blood pressure, especially in patients with hypertension. In addition, NSAIDs can interfere with the blood pressureelowering mechanisms of antihypertensives. 697
ORAL MEDICINE 698 Khatchadourian, Moreno-Hay and de Leeuw
PREVALENCE AND IMPLICATIONS OF HYPERTENSION Hypertension is one of the known factors implicated in CVD, such as stroke, coronary heart disease, and heart failure,13,14 as well as in renal and ocular disease.14 According to the recently published Joint National Committee (JNC-8) recommendations for the management of high BP in adult populations, hypertension is defined as an average BP 140/90 mm Hg in the general population younger than 60 years, whereas in patients older than 60 years, BP 150/90 mm Hg is defined as hypertension15; for those with diabetes or chronic kidney disease, the recommended BP is 130/80 mm Hg.16 Hypertension is very common in the United States, affecting over 65 million adults.17 The American Heart Association estimates that 25% of the overall population, and 55% to 60% of those aged between 65 and 74 years, have hypertension.18 A study based on the NHANES database (National Health and Nutrition Examination Survey) performed in 2003 and 2004 found that 24.3% of the hypertensive population was unaware of their condition, and of those that were aware, only 53.7% were receiving proper treatment.19 Thus, over 60% of adults with hypertension living in the United States have uncontrolled hypertension and thus are at risk for CVD complications. Both transient and sustained elevations in BP are risk factors for cardiovascular mortality and morbidity.20 For instance, an increase of 5 mm Hg in the diastolic BP (DBP) can increase the risk of stroke by 67% and the risk of events associated with coronary heart disease by 15%.21 From a meta-analysis of 61 randomized controlled trials involving over 1 million participants,22 it was concluded that for every incremental increase of 20 mm Hg in systolic BP (SBP) and 10 mm Hg in DBP, starting with a BP of 115/75 mm Hg, the risk of CVD doubled. Randomized controlled trials have also found that lowering SBP by 10 mm Hg (and 5 mm Hg for DBP) can reduce the risk of stroke by 40% and that of ischemic heart disease by 30%.23-25 Even smaller reductions in BP can have a positive effect.18,22 Pain can also increase BP.26 MECHANISM OF ACTION OF PGs PGs are produced through oxygenation of arachidonic acid by cyclooxygenase (COX).27,28 There are 2 varieties (isoenzymes) of the COX enzyme: COX-1 and COX-2. COX-1 is constitutive and present in most normal tissues, whereas COX-2 is inducible during inflammatory processes but is constitutive to the brain and kidneys. The constitutive COX-1 enzyme plays a key role in the integrity of the GI mucosal barrier, in kidney function, in maintenance of the vascular tone, and in platelet function. PGs have many physiologic actions in the brain, the GI tract, the kidneys, and the cardiovascular system. They also play a role in bone resorption, pain, and
OOOO June 2014
inflammatory responses.29 The effects of PGs on the kidneys and cardiovascular system are most important for this review and are described in more detail than the other physiologic effects. In the central nervous system, prostaglandin E2 (PGE2) is involved in fever generation and stimulates the secretion of adrenocorticotropic hormone. It has been proposed as a sleep inducer.29 In the GI tract, PGs regulate secretion of mucus and affect GI motility. In renal function, PGs are responsible for the modulation of blood circulation and of salt and water excretion. Solute homeostasis is maintained in part by PGs, such as PGE2, which decreases the sodium resorption. In the cardiovascular system, PGs regulate BP by modulating the renin-angiotensin system (RAS). Renin is an enzyme secreted by juxtaglomerular cells; it is responsible for converting angiotensin I into angiotensin II. PGI2 stimulates the release of renin and therefore the production of angiotensin II, which has a potent vasoconstrictor effect leading to an increase in BP. In addition, angiotensin II also promotes the production of aldosterone from the adrenal cortex. Aldosterone is a steroid hormone that acts on the nephron and elevates BP by water and sodium reabsorption and potassium secretion.30 PGs further contribute to the regulation of the cardiovascular system by eliciting the contractile (PGI2) and relaxing (thromboxane A2 [TxA2]) vascular smooth muscles and by inhibiting (PGI2) or inducing (TxA2) platelet activation and aggregation. It has been proposed that the balance of the PGI2 and TxA2 systems is important for maintaining vascular homeostasis.29,31 PGs are involved in the inflammatory process along with other mediators, such as histamine and bradykinin, which are responsible for vascular permeability and edema. Furthermore, PGs are also believed to sensitize the free endings of sensory neurons, inducing hyperalgesic responses in the periphery.29 Different side effects will be produced by the selective or nonselective inhibition of the COX enzymes and thus production of PGs.32
MECHANISM OF ACTION OF NSAIDs The main mechanism of action by which NSAIDs exert their effect is by means of inhibiting the COX enzyme, thus inhibiting the production of PGs. The analgesic and anti-inflammatory effects of NSAIDs are based on the inhibition of PGs. NSAIDs may thus affect all of the aforementioned systems. There are several proposed mechanisms by which NSAIDs, by virtue of their actions on some of these systems, could raise BP. Sodium and fluid retention PGs are released to promote vasodilation and enhance renal blood flow. By blocking the tubular PGE2,
OOOO Volume 117, Number 6
NSAIDs promote sodium and fluid retention, increasing the tubular reabsorption of sodium, which may lead to an increase in BP.30,33,34 It appears that sodium retention is mostly mediated by COX-2.31,34 Renin-angiotensin system In some cases, NSAIDs may reduce BP by inhibiting the production of renin released by PG. This hypotensive effect is due to the combination of 2 processes. First of all, the aldosterone released by PGs causes increased sodium and water reabsorption and excretion of potassium, thereby increasing BP. In addition, the RAS also regulates the secretion of antidiuretic hormone. Experimental studies, under well-controlled conditions, have found selective inhibition of COX-2 to inhibit the RAS and reduce hypertension.34 Moreover, the hyporeninemia and hypoaldosteronism induced by NSAIDs may manifest as hypercalcemia due to a decrease in potassium excretion. This hypercalcemia can cause cardiac arrhythmias.30 Armstrong and Malone35 proposed that this hypercalcemic condition, although infrequent, may contribute to hypertension independently of hemodynamic and electrolyte balance. Inhibition of PG vasodilation NSAIDs may increase the BP by a direct effect on vascular smooth muscle.36 PGI2 is synthesized by prostacyclin synthase and has vasodilatory effects. The administration of NSAIDs inhibits COX-2 production of PGI2, resulting in an increase in peripheral resistance34 responsible for BP increase. Animal model studies found that the infusion of PGE2 evoked hypotension in mice. Interestingly, PGE2 was produced and increased in urinary secretion when animals were fed a high-salt diet, possibly to downregulate the BP.29 Cytochrome P-450-dependent monooxygenase system By inhibition of COX enzymes, the metabolism of the arachidonic acid is forced through alternative pathways. Examples are the lipoxygenase and P-450 cytochrome nicotinamide adenine dinucleotide phosphateedependent monooxygenase pathways. In recent years, it has been found that the metabolism of arachidonic acid by cytochrome P-450 results in the production of metabolites with potential effects on raising BP.33,34 Animal studies have found that the metabolites epoxyeicosatrienoic acid, hydroxyeicosatetraenoic acid, and 20carboxyl arachidonic acid, produced through this “third” pathway, are involved in the pathogenesis of hypertension by modification of renal function. However, data for humans in this regard are limited.37
REVIEW ARTICLE Khatchadourian, Moreno-Hay and de Leeuw 699
Given the aforementioned factors, it should be clear that the use of NSAIDs may raise the BP in some individuals, mostly through their action on PGs. Gaziano36 found that the acute effect of NSAIDs appears to cause a slight short-term increase in BP and that this is likely to be reversible. However, the effect on chronic hypertension due to the deleterious effects on the kidneys induced by the long-term use of NSAIDs is not clear and requires further research.36 A meta-analysis38 published in 2009 compared the effects of different types of NSAIDs on BP, and the authors found that a few selective COX-2 inhibitors were associated with an elevation in BP compared with placebo or nonselective NSAIDs.38 However, these selective COX-2 inhibitors are no longer on the market. The meta-analysis,38 along with other recent studies,39,40 found no differences in the incidence of hypertension between celecoxib and nonselective NSAIDs. However, a long-term study found that patients treated with celecoxib, 200 mg or 400 mg, for the prevention of colorectal adenomas had an increase in the SBP of 2 mm Hg and 2.9 mm Hg, respectively, after 1 year and 2.6 mm Hg and 5.2 mm Hg, respectively, after 3 years. These results indicate a dose-dependent and possibly increasing rise of BP with the long-term use of such medications.41 Patients with hypertension appear to be more susceptible than normotensive participants to the BPincreasing effect of NSAIDs. A systematic review found an increase of þ1.1 mm Hg BP in normotensive participants taking NSAIDs. In patients with controlled hypertension, the increases were variable, ranging up to þ14.3 mm Hg for SBP and þ2.3 mm Hg for DBP.33 Among the various nonselective NSAIDs, indomethacin, naproxen, and piroxicam were associated with the greatest increase in BP in the hypertensive population.33 A review article by Morgan and Anderson concluded that salt-sensitive patients with hypertension were more likely to be affected by the use of NSAIDs.42 Frishman34 concluded that the incidence for increased BP related to NSAIDs intake was low and that increases were usually less than 5 mm Hg. However, he stated that certain patients are at a higher risk for BP increase with concomitant use of NSAIDs, such as patients with hypertension, those treated with antihypertensives, those with a history of cardiovascular disease, or those with renal or liver disease.34
MECHANISM OF ACTION OF ANTIHYPERTENSIVE MEDICATIONS BP is regulated through 3 separate mechanisms: by baroreflexes that are mediated by the sympathetic nervous system (SNS), by inflammatory mediators, and by the RAS.43 These mechanisms can affect BP on their own as well as in synchrony with each other, depending
ORAL MEDICINE 700 Khatchadourian, Moreno-Hay and de Leeuw
on the level of BP fluctuations. The baroreflexes are activated when the BP is decreased beyond a certain level, which results in the SNS increasing cardiac output and peripheral vascular resistance to counteract the reduced BP. Inflammatory cytokines will cause vasodilatation, leading to edema of tissues and decreased BP. The RAS regulates BP through water and sodium reabsorption and secretion of antidiuretic hormone. The effect of NSAIDs on the RAS is responsible for an increase in total peripheral resistance, and this negates the BP-reducing effect of all antihypertensive medications in a general fashion.
INTERACTION OF ANTIHYPERTENSIVES WITH NSAIDs In addition to raising the BP by themselves, NSAIDs can also negate the BP-lowering effects of many medications used to treat hypertension, again mostly by counteracting the PG effect of such medications. There are different modalities for the treatment of hypertension. Nonpharmacologic therapy includes lifestyle changes to promote weight loss (through diet and exercise) and to promote healthy dietary changes, including reduction in caffeine, sodium, fat, and alcohol intake and increase in fruit, fish, lean protein, and fiber intake.27,28 Another therapy for hypertension is pharmacotherapy.44 Antihypertensives are widely prescribed in the United States and elsewhere, with an estimated cost of more than US $8 million in the United States, based on a 2001 study performed by Hodgson and Cai.45 There are 5 major different classes of antihypertensives: (1) diuretics; (2) those affecting the RAS, such as the angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and renin inhibitors; (3) vasodilators; (4) sympatholytic agents; and (5) other cardiovascular affecting medications, such as b-blockers and calciumchannel blockers.46 Often, hypertension is controlled using multiple antihypertensive agents at the same time. Each agent will decrease BP through one or more mechanisms. The JNC-8 recommends as first-line treatment the following classes of medications: thiazide-type diuretics, ACEIs, ARBs, and calcium channel blockers. It recommends further that medication classes such as the a-blockers and b-blockers, the aldosterone antagonists, and the loop diuretics should only be considered as later-in-line alternatives.15 Diuretics This class of antihypertensive medication is subdivided into several classes; the loop and thiazide-type diuretics are 2 major classes commonly prescribed to treat hypertension.18 The loop diuretics inhibit sodium reabsorption at the level of the loop of Henle by competing with chloride for the sodium/potassium cotransporter,
OOOO June 2014
consequently inhibiting sodium and chloride reabsorption. Loop diuretics can also stimulate renal PG synthesis, particularly of PGE2, which is a vasodilator. Thus, the NSAIDs, by virtue of blocking renal PGE2 synthesis, will increase sodium reabsorption and reduce the effect of loop diuretics. The thiazide-type diuretics exert their effect in the distal convoluted tubule, where the reabsorption of sodium and chloride is inhibited. These agents also reduce calcium and uric acid excretion. Hyperreninemia and hypoaldosteronism induced by NSAIDs can negate the effect of diuretics,18,35 possibly owing to resulting hyperkalemia. Another category of diuretics prescribed for hypertension is the potassium-sparing family. In this group of antihypertensives, one subclass acts as competitive antagonist of aldosterone, whereas another one is independent of aldosterone function. The first subclass can be affected by NSAIDs’ effect at the RAS level. The second subclass, usually used in combination with thiazide diuretics, can increase renal vascular resistance; thus combination of this potassium-sparing diuretic with NSAIDs can result in acute renal failure lasting for several days associated with secretion of PGE2.47 Angiotensin systemeaffecting agents Angiotensin II increases BP in several ways: through the aldosterone system, by increasing the response to catecholamines, and by causing vasoconstriction mediated by release of PGE2.48 Angiotensin-converting enzyme (ACE) is involved in the production of angiotensin II; thus, its inhibition will lower the levels of this hormone.11 Consequently, there is a decrease in aldosterone and an activation of bradykinin (a potent vasodilator), which further reduces BP. The ARBs will antagonize the effects of angiotensin II by blocking its action at the receptor level. Renin blockers will inhibit the production of angiotensin I, a precursor to angiotensin II, once again affecting the RAS system. ACEIs, ARBs, and renin inhibitors increase levels of bradykinin in the system. Bradykinin will contribute to the vasodilatory effects of these antihypertensive medications, and this effect is mediated through stimulation of PGE2 synthesis, as seen in animal studies.48 NSAIDs, by virtue of inhibiting the PG synthesis, can interfere with the vasodilatory effects of bradykinin and angiotensin II. This effect is more pronounced in individuals with hypertension who have low renin levels.18 Vasodilators Vasodilators are rarely used as primary medications to control hypertension. The exact mechanism of vasodilators is unknown, but it is believed, based on animal experiments, to be mediated by the PG pathways49 through relaxation of smooth muscles in arterioles. The relaxation of the smooth muscles decreases resistance in
OOOO Volume 117, Number 6
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 with NSAIDs.18 Their vasodilatory effect may be inhibited through the inhibition of the RAS by NSAIDs. Sympatholytic agents Agents in this group modulate BP centrally by exerting their agonistic action at the a2-adrenoreceptor, or peripherally by blocking the a-adrenoreceptor or badrenoreceptor. These are G-protein coupled receptors that block calcium influx. The centrally acting agents reduce the release of catecholamines; consequently, there is a failure to activate the sympathetic reflex arc pathway at the brain stem vasomotor center, which is associated with aortic baroreceptors involved in BP homeostasis. There is reduced sympathetic flow to the peripheral cardiovascular system, which decreases cardiac output. The sympatholytic agents are rarely used in hypertension therapy because of their systemic widespread undesirable effects. Nevertheless, clonidine is still prescribed for patients having drug-resistant hypertension. These medications are not directly affected by concomitant use of NSAIDs.18 The peripherally acting a1-adrenoreceptor antagonists exert a vasodilatory effect on arterioles and venules, which consequently reduces the peripheral vascular resistance. The peripherally acting a1-adrenoreceptor antagonist also reduces sodium reabsorption in the kidneys, thus promoting excretion of fluids. Consequently, the NSAIDs will affect this class of medication by inhibiting PGE2 in the renal tubules, which promotes sodium reabsorption and fluid retention.21,50 The b-blockers block the action of epinephrine and norepinephrine at the b-adrenergic receptors. The antihypertensive effects are primarily through stimulation of b1 receptors found in the myocardium and the kidney. At the cardiovascular level, these agents lower cardiac output and inhibit release of renin, which consequently affects the RAS by lowering production of angiotensin and aldosterone. NSAIDs inhibit renin release as well. With less renin in the system, the effect of b1 selective blockers is blunted.18 Propranolol is a nonselective b-blocker, acting on b1 and b2 receptors. Propranolol has been found to stimulate PGI2 synthesis, which in turn promotes vasodilation.51 NSAIDs block PGI2 synthesis, thus negating the effectiveness of propranolol at the PGI2 level.34 Calcium channel blockers Calcium channel blockers inhibit calcium influx in smooth muscle cells, resulting in vasodilation of arteries and reduced cardiac output. Morgan and Anderson (2003) performed a double-blind crossover study
REVIEW ARTICLE Khatchadourian, Moreno-Hay and de Leeuw 701
comparing use of indomethacin in patients taking either calcium channel blockers or ACEIs. They concluded that indomethacin had less effect on calcium channel blocking agents than on ACEIs.52 Similarly, in another randomized controlled trial, Houston et al.53 found no significant differences in BP when naproxen or ibuprofen were added to the regimens of patients with well-controlled hypertension taking verapamil. Most major antihypertensives exert their effect, completely or partially, through the PG-mediated mechanisms, except for calcium channel blockers52 and possibly b-blockers and a2-adrenoreceptor agonists.18 It is likely that NSAIDs’ interference with intrarenal blood flow through PG inhibition is the main reason for the BP-raising effect,34 thus antagonizing the effects of antihypertensive drugs and consequently increasing hypertension-related morbidity.14,18 A prospective clinical trial of 88 treated patients with hypertension54 found that all antihypertensive medications except calcium channel blockers are affected by NSAIDs’ vasoconstrictive effect, confirming findings in several review articles.18,44,55 The trial found stronger effects in hypertensive vs normotensive participants and found that they were dose-dependent, similar to results found in a review article35 and 2 meta-analyses of clinical data.50,56 On the other hand, a recent cohort study compared the effect of NSAIDs on different antihypertensive drugs, including ACEIs, calcium channel blockers, b-blockers, a-blockers, and diuretics. This study found that diuretics, ACEIs, and calcium channel blockers were affected by NSAIDs, whereas b-blockers were not.57 A review article published in 2006 ranked the effect of NSAIDs on antihypertensive drugs in the following order of severity of interaction: ACEIs/ARBs, diuretics, b-blockers, and calcium antagonists or a-blockers.55 Sheridan et al.58 stated that nonpharmacologic confounding factors, such as sodium intake and exercise, affect the BP readings and are hard to account for. They concluded that the effect of NSAIDs on increasing BP significantly is debatable. Moreover, other potential confounding factors should be controlled in patients with inadequately controlled hypertension.
CONCLUSION Most studies have found that short-term use of NSAIDs does not pose a major risk for hypertension or increase in CVD. It is likely that NSAIDs’ interference with RAS is the main reason for the BP-raising effect, and the extent is variable. Patients with hypertension appear to be more susceptible than normotensive participants to the BP-increasing effect of NSAIDs. Given that the elderly are more likely to use NSAIDs and that they have a higher prevalence of hypertension than the younger population, this group should be considered
ORAL MEDICINE 702 Khatchadourian, Moreno-Hay and de Leeuw
more susceptible to this effect as well. Of all the BP medications, the calcium channel blockers and bblockers seem to be least affected by the concomitant use of NSAIDs. Sympatholytic agents are also among the least affected drugs; however, they are not often used for BP control. Of all the NSAIDs, piroxicam, naproxen, and indomethacin seem to have the highest hypertensive effect, especially in patients with hypertension. Celecoxib has a similar hypertensive effect as nonselective NSAIDs in short-term studies but may have an increased effect on hypertension when used over longer periods. A dentist must weigh the benefits and disadvantages of using NSAIDs in patients taking antihypertensive drugs. Conservative, short-term therapy should not be an issue for most of these patients. Caution is also recommended when prescribing NSAIDs in patients with a history of GI disease, CVD, diabetes, or renal or hepatic impairment. For those who may be at a greater risk, careful selection of the class of NSAID and close monitoring are appropriate measures, especially if long-term use is anticipated. Other classes of analgesics may also be considered, such as opioids and acetaminophen. As dentists, we belong to the health care team responsible for the overall management of health issues in our patients. We thank Ms Aline Shogher Markarian, BPharm, DESS, for her comments and critical review of this publication.
REFERENCES 1. IMS Health. Top 20 Global Therapeutic Classes. 2010 ed. Danbury, 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 general practice: determinants and consequences. Aliment Pharmacol Ther. 1997;11:293-298. 4. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med. 2000;160:777-784. 5. Garcia Rodriguez LA, Hernandez-Diaz S. Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure. Epidemiology. 2003;14:240-246. 6. Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP. Risk factors for NSAID-associated upper GI clinical events in a long-term prospective study of 34 701 arthritis patients. Aliment Pharmacol Ther. 2010;32:1240-1248. 7. Cangiano JL, Figueroa J, Palmer R. Renal hemodynamic effects of nabumetone, sulindac, and placebo in patients with osteoarthritis. Clin Ther. 1999;21:503-512. 8. Forrest JB, Camu F, Greer IA, et al. Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery. Br J Anaesth. 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.
OOOO June 2014 10. Aw TJ, Haas SJ, Liew D, Krum H. Meta-analysis of cyclooxygenase-2 inhibitors and their effects on blood pressure. Arch Intern Med. 2005;165:490-496. 11. Katzung BG, Masters SB, Trevor AJ. Basic and Clinical Pharmacology. 12th ed. New York, NY: McGraw Hill Medical; 2012. 12. White WB. Hypertension associated with therapies to treat arthritis and pain. Hypertension. 2004;44:123-124. 13. Turnbull F, Neal B, Ninomiya T, et al. Effects of different regimens to lower blood pressure on major cardiovascular events in older 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-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. 16. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint 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 to 2000: a rising tide. Hypertension. 2004;44:398-404. 18. Ruoff GE. The impact of nonsteroidal anti-inflammatory drugs on hypertension: 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. Prevalence, awareness, treatment, and control of hypertension among United States adults 1999-2004. Hypertension. 2007;49:69-75. 20. Grossman E, Messerli FH. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med. 2012;125:14-22. 21. Johnson AG. NSAIDs and blood pressure: clinical importance for older patients. Drugs Aging. 1998;12:17-27. 22. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies [Erratum appears in Lancet 2003;361:1060]. Lancet. 2002;360:1903-1913. 23. Collins R, MacMahon S. Blood pressure, antihypertensive drug treatment and the risks of stroke and of coronary heart disease. Br Med 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, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827-838. 26. Brand HS, Abraham-Inpijn L. Cardiovascular responses induced by dental treatment. Eur J Oral Sci. 1996;104:245-252. 27. Livingston A. Mechanism of action of nonsteroidal anti-inflammatory drugs. Vet Clin North Am Small Anim Pract. 2000;30: 773-781, vi. 28. Bjorkman DJ. The effect of aspirin and nonsteroidal anti-inflammatory drugs on prostaglandins. Am J Med. 1998;105:8S-12S. 29. Narumiya S, Sugimoto Y, Ushikubi F. Prostanoid receptors: structures, properties, and functions. Physiol Rev. 1999;79:1193-1226. 30. Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-70S:discussion 70S-71S.
OOOO Volume 117, Number 6 31. Hermann M, Ruschitzka F. Coxibs, non-steroidal antiinflammatory drugs and cardiovascular risk. Intern Med J. 2006;36:308-319. 32. Johnson DL, Hisel TM, Phillips BB. Effect of cyclooxygenase-2 inhibitors on blood pressure. Ann Pharmacother. 2003;37: 442-446. 33. Snowden S, Nelson R. The effects of nonsteroidal anti-inflammatory drugs on blood pressure in hypertensive patients. Cardiol Rev. 2011;19:184-191. 34. Frishman WH. Effects of nonsteroidal anti-inflammatory drug therapy on blood pressure and peripheral edema. Am J Cardiol. 2002;89:18D-25D. 35. Armstrong EP, Malone DC. The impact of nonsteroidal antiinflammatory drugs on blood pressure, with an emphasis on newer agents. Clin Ther. 2003;25:1-18. 36. Gaziano JM. Nonnarcotic analgesics and hypertension. Am J Cardiol. 2006;97:10-16. 37. Rahman M, Wright JT Jr, Douglas JG. The role of the cytochrome P450-dependent metabolites of arachidonic acid in blood pressure 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 COX2 inhibitors raise blood pressure more than nonselective NSAIDs and placebo? An updated meta-analysis. J Hypertens. 2009;27: 2332-2341. 39. Wang J, Mullins CD, Mamdani M, Rublee DA, Shaya FT. New diagnosis of hypertension among celecoxib and nonselective NSAID users: a population-based cohort study. Ann Pharmacother. 2007;41:937-943. 40. White WB, West CR, Borer JS, et al. Risk of cardiovascular events in patients receiving celecoxib: a meta-analysis of randomized clinical trials. Am J Cardiol. 2007;99:91-98. 41. Solomon SD, Pfeffer MA, McMurray JJV, et al. Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas. Circulation. 2006;114: 1028-1035. 42. Morgan T, Anderson A. The effect of nonsteroidal anti-inflammatory drugs on blood pressure in patients treated with different antihypertensive 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. New York, NY: McGraw-Hill Medical; 2012. 44. Chou CM. Evaluation and treatment of hypertension. Rheum Dis Clin 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: Antihypertensive agents. In: Tintinalli J, Stapczynski J, Ma OJ, Cline D, Cydulka R, Meckler G, eds. Tintinalli’s Emergency Medicine: A
REVIEW ARTICLE Khatchadourian, Moreno-Hay and de Leeuw 703
47.
48.
49.
50.
51.
52.
53.
54.
55. 56.
57.
58.
Comprehensive Study Guide. 7th ed. New York, NY: McGrawHill Medical; 2011. Sica DA. Diuretic therapy in cardiovascular disease. In: Black HR, Elliott WJ, eds. Hypertension: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: Elsevier Health Sciences; 2012. Cooper CL, Shaffer JE, Malik KU. Mechanism of action of angiotensin II and bradykinin on prostaglandin synthesis and vascular tone in the isolated rat kidney. Effect of Caþþ antagonists and calmodulin inhibitors. Circ Res. 1985;56:97-108. Dyer R, Huttner J, Tan S, Mulrow P. Prostaglandin synthesis by vascular smooth muscle cells stimulated by bradykinin, prazosin, and hydralazine. Prog Lipid Res. 1981;20:557-560. Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med. 1993;153:477-484. Beckmann ML, Gerber JG, Byyny RL, LoVerde M, Nies AS. Propranolol increases prostacyclin synthesis in patients with essential hypertension. Hypertension. 1988;12:582-588. Morgan TO, Anderson A, Bertram D. Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens. 2000;13:1161-1167. Houston MC, Weir M, Gray J, et al. The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Arch Intern Med. 1995;155: 1049-1054. Pavlicevic I, Kuzmanic M, Rumboldt M, Rumboldt Z. Interaction between antihypertensives and NSAIDs in primary care: a controlled trial. Can J Clin Pharmacol. 2008;15:e372-e382. Elliott WJ. Drug interactions and drugs that affect blood pressure. J Clin Hypertens (Greenwich). 2006;8:731-737. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal antiinflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med. 1994;121:289-300. Ishiguro C, Fujita T, Omori T, Fujii Y, Mayama T, Sato T. Assessing the effects of non-steroidal anti-inflammatory drugs on antihypertensive drug therapy using post-marketing surveillance database. J Epidemiol. 2008;18:119-124. Sheridan R, Montgomery AA, Fahey T. NSAID use and BP in treated hypertensives: a retrospective controlled observational study. J Hum Hypertens. 2005;19:445-450.
Reprint requests: Isabel Moreno-Hay, DDS, PhD 740 S Limestone St Room E214 Kentucky Clinic Lexington KY 40536-0284 USA [email protected]
