Nonsteroidal anti-inflammatory drugs and

antihypertensives:how do they relate?

Zovinar Der, Isabel Moreno-Hay, and Reny de Leeuw

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 drug stores

and supermarkets not only in the United States but also

worldwide.

• NSAIDs are very commonly used medications despite

their numerous side effects and drug interactions.

• For instance, the acute administration of NSAIDs can

cause:

• Allergic reactions

• Renal failure

• Coagulation problems

• Worsening of asthma.

Long-term administration

• Gastrointestinal (GI) adverse effects (e.g., bleeding,

ulcers)

• Renal failure

• Congestive heart failure.

Minor side effects, such as nausea, dizziness, or gastric

irritation

• Risk for complications increases in susceptible patients,

for example those who present with a history of ulcers,

cardiovascular disease, diabetes, or renal complications

And also in the elderly people

• According to Seager and Hawkey NSAIDs should be

prescribed to manage conditions that are not life-

threatening.

• NSAIDs also have numerous drug interactions.

• For instance,

• 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 often overlooked 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

• The aim of this article is to increase awareness of the

blood pressure (BP) increasing potential of NSAIDs and

their interference with antihypertensives.

PREVALENCE AND IMPLICATIONS OF

HYPERTENSION• Hypertension is one of the known factors implicated in

CVD, such as stroke, coronary heart disease, and heart

failure,as well as in renal and ocular disease.

• According to the recently published Joint National

Committee (JNC-8) hypertension is

Age Blood pressure

younger than 60 years 140/90mmHg

older than 60 years 150/90 mm Hg

chronic kidney disease 130/80 mm Hg.

• 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.

• 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.

• Both transient and sustained elevations in BP are risk

factors for cardiovascular mortality and morbidity.

• For instance,

• An increase of 5 mm Hg in the diastolic BP (DBP) can

• Increase the risk of stroke by 67%

• Increases risk of Coronary heart disease by 15%.

• From meta-analysis of 61 randomized controlled trials

involving over 1 million participants, 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.

• RCT 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%.

MECHANISM OF ACTION OF PGs

CNS GIT Renal function

CVS Inflammatory process

Fever generation

Secretion of mucus

Controls blood

circulation

Regulates BP by renin

angiotensin pathway

Along with other

mediators cause

vascular permeability and edema

Stimulation of ACTH

hormone

GIT mobility Salt and water excretion

Platelet aggregation

and activation Contraction

and relaxation of vascular

smooth muscle

Furthermore, PGs are also believed to sensitize the free endings of Sensory neurons, inducing hyperalgesic responses in the periphery.

MECHANISM OF ACTION OF NSAIDs• Act by inhibiting the COX enzyme, thus inhibiting the

production of PGs.

Sodium and fluid retention

• PGs are released to promote vasodilation and enhance

renal blood flow.

• By blocking the tubular PGE2, NSAIDs promote sodium

and fluid retention, increasing the tubular reabsorption of

sodium, which may lead to an increase in BP

Renin-angiotensin system

• NSAIDs may reduce BP by inhibiting the production of

renin released by PG.

• This hypotensive effect is due to the combination of 2

processes.

Aldosterone increase sodium

and water reabsorption and

excretion of potassium

Also regulates the

secretion of

antidiuretic hormone

Inhibition of PG vasodilation

• NSAIDs may increase the BP by a direct effect on

vascular smooth muscle.

• 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 resistance responsible for BP

increase.

Cytochrome P-450-dependent monooxygenase system

Arachidonic acid

Prostaglandins

Lipoxygenase P-450 cytochrome

Leukotrienes Metabolites with potential

effects on raising BP.

• Given the aforementioned factors, it isclear that the use

of NSAIDs may raise the BP in some individuals, mostly

through their action on PGs.

• Gaziano 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.

• A meta-analysis 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.

• 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

• Patients with hypertension appear to be more

susceptible than normotensive participants to the BP

increasing effect of NSAIDs.

• A systematic review found an increase of BP 1 mm Hg

BP in normotensive participants taking NSAIDs.

• In patients with controlled hypertension, the increases

were variable, ranging up to14.3 mm Hg for SBP and 2.3

mm Hg for DBP.

• Among the various nonselective NSAIDs,

indomethacin, naproxen, and piroxicam were

associated with the greatest increase in BP in the

hypertensive population.

• 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

MECHANISM OF ACTION OF

ANTIHYPERTENSIVE MEDICATIONS

• BP is regulated through 3 separate mechanisms:

• Baroreflexes that are mediated by the sympathetic

nervous system (SNS)

• Inflammatory mediators

• RAS

• 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.

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

(5) other cardiovascular affecting medications, such as b-

blockers and calcium channel blockers.

• 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

Diuretics

• This class of antihypertensive medication is subdivided

into several classes

Loop diuretics

• The loop diuretics inhibit sodium reabsorption at the level

of the loop of Henle by competing with chloride for the

sodium/potassium cotransporter, 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

Thiazide-type 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.

• Hyperureninemia and hypoaldosteronism induced by

NSAIDs can negate the effect of diuretics, possibly

owing to resulting hyperkalemia.

Potassium-sparing Family

• In this group of antihypertensives, one subclass acts as

competitive antagonist of aldosterone thus effecting

RAS pathway.

• The second subclass, usually used in combination with

thiazide diuretics, can increase renal vascular resistance

• Combination of this potassium-sparing diuretic with

NSAIDs can result in acute renal failure lasting for

several days associated with secretion of PGE2.

Angiotensin system affecting agents

• Angiotensin II increases BP in several ways:

• Through the

• Aldosterone system,

• Increasing the response to catecholamines

• Causing vasoconstriction mediated by release of

PGE2.

• Angiotensin-converting enzyme (ACE) is involved in the

production of angiotensin II; thus, its inhibition will lower

the levels of this hormone.

• 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

• NSAIDs, by virtue of inhibiting the PG synthesis, can

interfere with the vasodilatory effects of bradykinin and

angiotensin II.

Vasodilators

• Vasodilators are rarely used as primary medications to

control hypertension.

• The exact mechanism of vasodilators is unknown, but it

is believed, to be mediated by the PG pathways through

relaxation of smooth muscles in arterioles.

• The relaxation of the smooth muscles decreases

resistance in the arterioles and hence reduces BP.

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

baroreceptor.

• 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

• 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.

• The b-blockers block the action of epinephrine and

norepinephrine at the b-adrenergic receptors.

• These are 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.

• 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.

• NSAIDs block PGI2 synthesis, thus negating the

effectiveness of propranolol at the PGI2 level.

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 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.

• Most major antihypertensives exert their effect,

completely or partially, through the PG-mediated

mechanisms, except for calcium channel blockers and b-

blockers and a2-adrenoreceptor agonists.

• It is likely that NSAIDs’ interference with intrarenal blood

flow through PG inhibition is the main reason for the BP-

raising effect, thus antagonizing the effects of

antihypertensive drugs and consequently increasing

hypertension-related morbidity

• A prospective clinical trial of 88 treated patients with

hypertension found that all antihypertensive medications

except calcium channel blockers are affected by

NSAIDs’ confirming findings in several review articles.

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.

• The trial found stronger effects in hypertensive vs

normotensive participants and found that they were

dose-dependent

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.

• 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

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.

Conclusion

• As 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 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.

REFERENCES • Essentials of medical pharmacology: K D Tripathy

• 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.

• Bjorkman DJ. The effect of aspirin and nonsteroidal anti-

inflammatory drugs on prostaglandins. Am J Med.

1998;105:8S-12S.

Thank you