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MajorSideEffectsofNSAIDs&COX2SelectiveInhibitors
Prostanoids are synthesized from arachidonic acid by either COX1 or COX2, and play an important role in
maintaining homeostasis in many body tissues. The expression of COX1 in most tissues is relatively constant
(constitutive),whileCOX2expressionistypicallyminimal,butbecomesselectivelyupregulatedunderinflammatory
conditions.Exceptionstothisgeneralruleincludeendothelialcellsliningthearteriolesinthecardiovascularsystem&
kidney,whereCOX2expressionissignificantevenintheabsenceofinflammation.

TheThreeClassesofNSAIDs
ClinicallyavailableNSAIDscanbeseparatedinto3differentclassesbasedupontheirmechanismofaction:

ASPIRIN: Acts to irreversibly inhibit COX 1 & COX2 by covalent acetylation of serine residues in their
respective active sites. Most notably, low doses of aspirin can suppress platelet COX1 activity by 95% or
more, an effect that is permanent for the lifetime of the platelet, since platelets lack DNA and cannot
synthesize new enzyme. All other NSAIDs interact with COX isoforms reversibly and produce variable COX
inhibition (ranging from 50% to 95%) in a timedependent fashion based upon their pharmacokinetic
properties.
COXIBS:SelectiveCOX2inhibitorsweredesignedandmarketedtoavoidtheGIsideeffectsknowntoresult
fromsuppressionprotectiveprostaglandinssynthesizedbyCOX1intheGImucosa.Theiruseledtothefirst
reported incidence of increased cardiovascular events (myocardial infarction and stroke) in 2004. Rofecoxib
(Vioxx ), one of the most selective COX2 inhibitors was removed from the market because of mounting
evidenceforsignificantCVtoxicity(Drazen,2005).Celecoxib(Celebrex)iscurrentlytheonlyFDAapproved
coxib available in the US. It has a 1020 fold selectivity for COX2 over COX1. Etoricoxib (Arcoxia ) is a
secondcoxibwith~106foldselectivityforCOX2overCOX1thatisavailableoutsideoftheUnitedStates.
NONSELECTIVECOXINHIBITORS:DifferentnonselectiveNSAIDshavevaryinginhibitoryeffectsagainst
COX1&COX2(Figure1).Thetwomostcommonlyusedoverthecounterdrugsinthisgroup(ibuprofen&
naproxen) produce reversible platelet inhibition ranging from 50 to 95% in a reversible timedependent
manner that may be insufficient to provide cardioprotection throughout a commonly used dosing interval
(Reilly & FitzGerald, 1987 Anwar et al, 2015). Ketorolac (Toradol ), an NSAID most commonly used in a
hospitalsetting,isclassifiedasanonselectiveNSAID,althoughitisarguablyveryselectiveforCOX1.

The two most commonly used NSAIDs (ibuprofen & naproxen) are relatively nonselective for inhibiting COX1 vs
COX2,andthereforecanproduceunwantedsideeffectsbyinhibitingbothisoforms(Figure1).

Figure1.RelativeCOX1&COX2selectivityforcommonlyusednonaspirinNSAIDs.Celecoxib(Celebrex)isthe
onlyCOX2selectiveNSAIDonthemarketintheUS.AdaptedfromDanelichetal(2015).

ThreeMajorSideEffectsAssociatedwithNSAIDUse
Assummarizedbelow,NSAIDinducedCOX1inhibitionisassociatedwithGItoxicitybecauseprostaglandinsproduced
byconstitutiveCOX1activityareimportantinmediatinggastricprotection.Incontrast,drugsthatmoreselectively
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inhibit COX2 have relatively few GI side effects, but have a higher incidence of CV toxicity by altering the normal
balanceinproductionofprostacyclinvsthromboxanebydifferentcelltypesintheCVsystem.Thiscanaccountfor
theincreasedincidenceofmyocardial&strokethathasbeenassociatedwiththeuseofNSAIDs&selectiveCOX2
inhibitors.DrugsthatblockeitherCOX1orCOX2canalsointerferewiththeproductionofprostaglandinsthatplay
animportantroleinmaintainingrenalbloodflowinpatientswithcompromisedrenalfunction.

Figure2.MajorphysiologicalrolesforCOX1&COX2,andmechanismsunderlyingdruginducedsideeffects.PGI2:
prostacyclin,TXA2:thromboxane.

GI(Stomach)
Inthestomach,COX1mediatedproductionofprostaglandinsPGE 2&PGI2playsanimportantroleinregulatingthe
productionofbicarbonateandmucus,aswellasregulatingnormalbloodflow.Eachoftheseeffectshelpstoprotect
thecellsliningthewallofthestomachfromtheerosiveeffectsofstomachacid(stomachfluidhasanormalpHof
1.53.5)(Wallace,2008Wikipedia:Gastricacid[https://en.wikipedia.org/wiki/Gastric_acid]).

Hence,blockingCOX1mediatedproductionofprostaglandinsinthestomachbyaspirinandothernon
selectiveNSAIDs(e.g.ibuprofen,naproxen)isexpectedtoincreasetheincidenceofpepticulcers(and
associated symptoms including bleeding & pain). The spectrum of peptic ulceration caused by NSAIDs can
rangefromsuperficialtolarge,withacutebleedingbeingrelativelycommon.Evidenceforendoscopiculcershasbeen
observedin1030%ofpatientsonNSAIDs,andseriousulcercomplicationsoccurin12%ofpatients(Conaghan,
2012Seminerioetal,2014).

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Figure3.PathogenesisofgastricdamagebyNSAIDs.Currentevidenceindicatesthatthemajorityofharmfuleffects
mediated by NSAIDs result from inhibition of the synthesis of mucosalprotective prostaglandins produced by
constitutiveCOX1activity.Directdrugmediatedirritanteffectsonepithelialcellsappeartoplayonlyaminorrolein
GItoxicity.ThepresenceofinfectionsbythebacteriumHpylorirepresentsaseparateriskfactorthatincreasesthe
likelihoodofdevelopingduodenalulcers(Feldman,2014).

Kidney

Epidemiology

Adverserenaleventsoccurin1to5percentofpatientstakingNSAIDs.Becauseofthelargenumberofpatientsthat
take NSAIDs (more than 70 million prescriptions and 30 billion overthecounter doses annually) it has been
estimatedthatapproximately2.5millionpatientsexperienceaNSAIDrelatednephrotoxiceventannually(Luciano&
Perazella,2015).

RenalProstaglandinExpression&Function

Renal prostaglandins function primarily as vasodilators in the kidneys. In healthy individuals, the impact of
prostaglandins on renal perfusion is relatively limited. However, in the setting of prolonged renal
vasoconstriction that develops during settings of advanced age, heart failure, and kidney failure, prostaglandin
synthesis is upregulated. Under these conditions when kidney function is compromised, the production of
prostaglandins serves an important role to preserve renal blood flow and protect the glomerular
filtration rate (GFR) by decreasing preglomerular (afferent) arterial resistance (Figure 4 left). In this
setting,evenepisodicuseofNSAIDscandecreasebloodflowthroughtheglomerulus,andincreasetheriskofacute
kidneyinjury(Figure4right)(Luciano&Perazella,2015).

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Figure4.Regulationofrenalbloodflow&glomerularfiltrationinthekidney.Theglomerularfiltrationrate(GFR)is
optimalwhentheintraglomerularpressuregradientismaintainedatnormallevels.Areductioninafferentbloodflow
or pressure due to hypotension, volume loss (blood loss or excessive diuresis), decreased cardiac output or
obstruction (renal artery stenosis) can lower the intraglomerular pressure and result in impaired renal function.
Whennormalrenalfunctionisphysiologicallyimpaired,prostaglandinsynthesisisincreased,suchthat
it plays an increasingly important role in maintaining renal perfusion by causing enhanced pre
glomerularvasodilation(leftpanel).Undertheseconditions,NSAIDs&COX2inhibitorscanadversely
affectrenalfunctionbyblockingtheproductionofautoregulatoryprostaglandins,resultinginadeclineinGFRthat
canultimatelyresultinacutekidneyinjury(rightpanel).TreatmentwithACEinhibitors(whichreducetheeffectof
Ang II to produce efferent vasoconstriction) can also further reduce glomerular perfusion and contribute to renal
failure.AdaptedfromLuciano&Perazella(2015).

CardiovascularSystem

Coxibs&TheThromboxane/ProstacyclinImbalanceHypothesis:

PreviousresearchindicatesthatintheCVsystem,agreaterinhibitionofCOX2vsCOX1(asproducedbyCOX
2 selective coxibs) can tip the normal balance between the effects produced by prostacyclin & thromboxane,
resulting in an increased likelihood for platelet aggregation and vasoconstriction. These effects can
explainthehigherincidenceofmyocardialinfarctionandstrokeobservedwhenthesedrugshavebeen
usedclinically.ThemechanismsinvolvedareillustratedinFigure5.

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Figure5. COX2 Inhibitors & Cardiovascular Risk. The left graphic illustrates the normal balanced effect between
prostacyclin(PGI2)andThromboxane(TXA2).PGI2isproducedprimarilybyCOX2activityintheendothelialcellwall.
PGI2producesvasodilation,andinhibitsplateletactivation.Incontrast,TXA2isproducedprimarilybyCOX1activity
ofplatelets,andproducesvasoconstrictionandenhancedplateletaggregation.Whentheirisabalancedeffectofboth
PGI2 & TXA2, normal vascular homeostasis is maintained. However, when the balance is tipped in favor of TXA2
formationafterselectiveinhibitionofCOX2(rightgraphic),vasoconstrictionandplateletclumpingaremorelikelyto
occur,andthereisanincreasedriskforcardiovasculareventssuchasmyocardialinfarctionandstroke.

NonselectiveNonAspirinNSAIDs

Evidenceaccumulatingoverthepastdecadeindicatesthattheuseofnonaspirin,nonselectiveNSAIDs(that
include ibuprofen, diclofenac & naproxen) is associated with an increased risk for the development of
myocardial infarction & stroke, similar to that previously documented for COX2 selective drugs (see
FDA Black Box warning below) (Conaghan 2012 Olsen et al, 2014 Anwar et al, 2015). It is hoped that the
1)
conclusion of the currently ongoing PRECISION trail will provide more definitive estimates of the relative
cardiovascularsafetyprofilesforcelecoxib,ibuprofen&naproxen(Beckeretal,2009).

Multiple mechanisms appear to play a role in mediating the increased CV risk associated with NSAID use. They
include:

1.NSAIDInducedElevatedBloodPressure
All NSAIDs in doses adequate to reduce inflammation & pain can increase blood pressure in both
normotensive & hypertensive patients by an average of 3/2 mm Hg (systolic/diastolic) (Pope et al,
1993Johnsonetal,1994Warner&Mitchell,2008Groveretal,2005).
The prohypertensive effect is dosedependent and has been attributed to inhibition of renal COX2,
resultinginreducedNaexcretion,andincreasedintravascularvolume(White2007).
2.IncreasedRiskforKidneyFailure
In patients with underlying kidney disease, renal function becomes dependent upon prostaglandin
formation.InsuchpatientsNSAIDuseisknowntoincreasetheriskforacutedeteriorationofkidney
function, resulting in a reduced GFR, development of sodium retention, edema, hyperkalemia, renal

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papillary necrosis and hypertension (Patak et al, 1975 CatellaLawson, 1999 Breyer et al 2001
Aronowetal,2011).
3.ReducedEffectivenessofAntihypertensiveDrugs
NSAIDs have been observed to reduce the effectiveness of all antihypertensive drugs except calcium
channelblockers(White2007).
Note that low dose aspirin (75 mg) which has little or no COX2 inhibiting effect, does not increase
blood pressure, and does not interfere with the effects of antihypertensive therapy (Zanchetti et al,
2002).Thisconclusionislikelynottrueforhigherdosesofaspirin.
4.NSAIDInterferencewithAspirin'sAntiplateletEffects
NonaspirinNSAIDscaninterferewithaspirin'sabilitytogainaccesstoitsCOX1bindingsitebysteric
2)
interference, thus reducing aspirin's antiplatelet effects when the two drug types are taken
concomitantly(seeaspirin_di).
Whentaken2hourspriortoaspirin,ibuprofeninterfereswithaspirin'sabilitytoinhibittheproduction
ofthromboxaneA2,whereasifibuprofenistaken2hoursafteraspirin,aspirin'santiplateleteffectsare
preserved(CatellaLawsonetal,2001).
Naproxen taken once a day has also been observed to interfere with aspirin's antiplatelet effects
mediatedbyinhibitingCOX1(Caponeetal,2005).
5.IncreasedRiskforAdditionalTypesofCVPathology
In animal models, either druginduced inhibition or genetic deletion of COX2 dependent prostacyclin
formation results in a variety of pathology including disruption of vascular homeostasis, accelerated
atherosclerosis,andincreasedcardiacfibrosis,arrhythmiasandsystolicheartfailure.Sincetherapeutic
levelsofbothCOX2selectivedrugsandnonaspirinNSAIDssuppressprostacyclinproductionbyover
60%,thismechanismcouldalsoplayaroleinthedevelopmentofcardiovasculardiseaseinpatients
takingNSAIDsforlongperiodsoftime(Anwaretal,2015).

FDABlackBoxWarning

FDAWarning:NonAspirinNSAIDsIncreasedChanceofHeartAttackorStroke(7/9/15)

Baseduponnewsafetyinformation,theFDAhasstrengthenedanexistingwarning
labelthatnonaspirinNSAIDsincreasethechanceofaheartattackorstroke.
Theriskofheartattackorstrokecanoccurasearlyasthefirstweeksof
usinganNSAID.TheriskmayincreasewithlongeruseoftheNSAID.
Theriskappearsgreaterathigherdoses.
It was previously thought that all NSAIDs may have a similar risk. Newer
informationmakesitlessclearthattheriskofheartattackorstrokeissimilarforall
NSAIDshowever,thisnewerinformationisnotsufficientforustodeterminethat
theriskofanyparticularNSAIDisdefinitelyhigherorlowerthanthatofanyother
particularNSAID.
NSAIDscanincreasetheriskofheartattackorstrokeinpatientswithor
without heart disease or risk factors for heart disease. A large number of
studies support this finding, with varying estimates of how much the risk is
increased,dependingonthedrugsandthedosesstudied.
Ingeneral,patientswithheartdiseaseorriskfactorsforithaveagreater
likelihood of heart attack or stroke following NSAID use than patients
withouttheseriskfactorsbecausetheyhaveahigherriskatbaseline.
PatientstreatedwithNSAIDsfollowingafirstheartattackweremorelikelytodiein
thefirstyearaftertheheartattackcomparedtopatientswhowerenottreatedwith
NSAIDsaftertheirfirstheartattack.
ThereisanincreasedriskofheartfailurewithNSAIDuse.
For more information, see the online FDA Safety Announcement
[http://www.fda.gov/Drugs/DrugSafety/ucm451800.htm]from7/9/15.

AHARecommendationonNSAIDUse:
TheAmericanHeartAssociationcurrentlyrecommendsthatwhenNSAIDtherapyisneeded:

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NSAIDsshouldbeusedattheirlowesteffectivedose
NSAIDsshouldbeavoidedinpatientswithcardiovascularriskfactorsincluding:
hypertension
hypercholesterolemia
angina
edema
recentcardiacbypasssurgery
ahistoryofmyocardialinfarctionorotherCVevents

References:

Anwar A et al (2015): Elevation of cardiovascular risk by nonsteroidal antiinflammatory drugs. Trends

CardiovascMedMarch12(epubaheadofprint)doi:10.1016/j.tcm.2015.03.006
Aronow WS et al (2011): ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly.
Circulation.123:24342506.doi:10.1161/CIR.0b013e31821daaf6.
BeckerMCetal(2009):Rationale,design,andgovernanceofProspectiveRandomizedEvaluationofCelecoxib
IntegratedSafetyversusIbuprofenOrNaproxen(PRECISION),acardiovascularendpointtrialofnonsteroidal
antiinflammatory agents in patients with arthritis. Am Heart J 157(4):606612.
doi:10.1016/j.ahj.2008.12.014
BreyerMDetal(2001):Cyclooxygenase2selectiveinhibitorsandthekidney.CurrOpinCritCare7:393400.
CaponeMLetal(2005):Pharmacodynamicinteractionofnaproxenwithlowdoseaspirininhealthysubjects.
JAmCollCardiol45(8):12951301.
CatellaLawson F et al (1999): Effects of specific inhibition of cyclooxygenase2 on sodium balance,
hemodynamics,andvasoactiveeicosanoids.JPharmacolExpTher289:735741.
CatellaLawsonFetal(2001):Cyclooxygenaseinhibitorsandtheantiplateleteffectsofaspirin.NEnglJMed
345(25):18091817.
Conaghan PG (2012): A turbulent decade for NSAIDs: an update on current concepts of classification,
epidemiology, comparative efficacy, and toxicity. Rheumatol Int 32:14911502. doi 10.1007/s00296011
22636
Danelich IM et al (2015): Safety of Nonsteroidal Antiinflammatory Drugs in Patients with Cardiovascular
Disease.Pharmacotherapy.35(5):520535.doi10.1002/pharm.1584
DrazenJM(2005):Cox2inhibitorsalessoninunexpectedproblems.NEnglJMed352:11311132.
FeldmanM(2014):NSAIDs(includingaspirin):pathogenesisofgastroduodenaltoxicity.In:UpToDate,Basow,
DS(Ed),UpToDate,Waltham,MA.Cited7/13/15.
Furst DE, Ulrich RW, Prakash S (2012) [http://libproxy.tulane.edu:2048/login?
url=http://www.accessmedicine.com/content.aspx?aID=55827148]: Nonsteroidal AntiInflammatory Drugs,
DiseaseModifying Antirheumatic Drugs, Nonopioid Analgesics & Drugs Used in Gout. In: Basic & Clinical
Pharmacology,KatzungBG,MastersSB,TrevorAJ(Eds).McGrawHill/Lange12e(Chp36).
GroverSAetal(2005):Treatingosteoarthritiswithcyclooxygenase2specificinhibitors:whatarethebenefits
ofavoidingbloodpressurestabilization?Hypertension45(1):9297.
HilalDandan R (2011) [http://libproxy.tulane.edu:2048/login?
url=http://www.accessmedicine.com.libproxy.tulane.edu:2048/content.aspx?aID=16667251]:ReninandAngiotensin
Chapter26.In:Goodman&Gilman'sThePharmacologicalBasisofTherapeutics.BruntonLL(Ed)McGrawHill
12e.
HollerT:CardiologyEssentials.Jones&Bartlett,SudburyMass.2008.
Johnson AG et al (1994): Do nonsteroidal antiinflammatory drugs affect blood pressure? A metaanalysis.
AnnInternMed121(4):289300.
LucianaR,PerazellaMA(2015):NSAIDs:acutekidneyinjury(acuterenalfailure).In:UpToDate,Basow,DS
(Ed),UpToDate,Waltham,MA.Cited7/13/15.
PatakRVetal(1975):Antagonismoftheeffectsoffurosemidebyindomethacininnormalandhypertensive
man.Prostaglandins10:649659.
Pope JE et al (1993): A metaanalysis of the effects of nonsteroidal antiinflammatory drugs on blood
pressure.ArchInternMed153(4):477484
Reilly IA, FitzGerald GA (1987): Inhibition of thromboxane formation in vivo and ex vivo: implications for
therapywithplateletinhibitorydrugs.Blood69:180186.
SchmiederRE,BakrisG,WeirMR(2011:Telmisartaninincipientandovertdiabeticrenaldisease.JNephrol
24(3):263273.

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4/4/2017 nsaid_side_effects[TUSOM|Pharmwiki]

SeminerioJetal(2014):MedicationassociatedlesionsoftheGItract.GastrointestinalEndoscopy79(1):140
150.PMID:24119504.
SinghH,MarrsJC:HeartFailure.In:AppliedTherapeutics.TheClinicalUseofDrugs.9thEdition.Lippincott
Williams&Wilkins.KodaKimbleMAetal(Editors).BaltimoreMD,2009.pg1838.
WallaceJL(2008):Prostaglandins,NSAIDs,andGastricMucosalProtection:WhyDoesn'ttheStomachDigest
Itself?PhysiologicalReviews88(4:15471565DOI:10.1152/physrev.00004.2008
WarnerTD,MitchellJA(2008):COX2selectivityalonedoesnotdefinethecardiovascularrisksassociatedwith
nonsteroidalantiinflammatorydrugs.Lancet371:270273.doi:10.1016/S01406736(08)601373.
WhiteWB(2007):Cardiovasculareffectsofthecyclooxygenaseinhibitors.Hypertension49(3):408418.
Zanchetti A et al (2002): Lowdose aspirin does not interfere with the blood pressurelowering effects of
antihypertensivetherapy.JHypertens20(5):10151022.

1)
ProspectiveRandomizedEvaluationofCelecoxibIntegratedSafetyversusIbuprofenOrNaproxen
2)
2drugscan'toccupythesameactivesiteatthesametime
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