Non-Steroidal Anti-Non-Steroidal Anti-Inflammatory DrugsInflammatory Drugs

Meghin GjerswoldMeghin Gjerswold

12.01.200612.01.2006

UWSOP at GenelexUWSOP at Genelex

ibuprofen

NSAID use NSAID use

NSAIDs are available OTCNSAIDs are available OTC NSAIDs can be toxic on their ownNSAIDs can be toxic on their own People who take NSAIDs (elderly people) People who take NSAIDs (elderly people)

often take many drugs which can lead to often take many drugs which can lead to dangerous interactionsdangerous interactions

NSAIDs are metabolized by multiple NSAIDs are metabolized by multiple hepatic pathways hepatic pathways

Adverse effectsAdverse effects

NephrotoxicNephrotoxic Bleeding problemsBleeding problems Increase blood pressureIncrease blood pressure

FDA requires medication guide be dispensed FDA requires medication guide be dispensed with with everyevery NSAID prescription – NSAID prescription – www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdfwww.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf

FDA fact: FDA fact: >70,000 hospitalizations per year and 10,000->70,000 hospitalizations per year and 10,000-20,000 deaths per year can be associated with 20,000 deaths per year can be associated with NSAID useNSAID use

Potential interaction Potential interaction typestypes

Pharmacokinetic interactions – involve Pharmacokinetic interactions – involve absorption, distribution, eliminationabsorption, distribution, elimination

Pharmacodynamic interactions – involve Pharmacodynamic interactions – involve drug effects and/or toxicitydrug effects and/or toxicity

Pharmacokinetic interactionsPharmacokinetic interactions

AbsorptionAbsorption Protein bindingProtein binding P450 interactions P450 interactions

2D62D6 2C92C9 2C192C19 3A43A4

Renal elimination Renal elimination

Decreased absorption of Decreased absorption of NSAIDsNSAIDs

Sucralfate – coat the stomach to protect from Sucralfate – coat the stomach to protect from bleed/ulcersbleed/ulcers

H2-blockers/antacids – decrease stomach pH H2-blockers/antacids – decrease stomach pH to protect from bleed/ulcersto protect from bleed/ulcers

Bile acid sequesterants – bind to bile acid to Bile acid sequesterants – bind to bile acid to prevent manufacture of cholesterol prevent manufacture of cholesterol

Evidence points to lack of clinically significant Evidence points to lack of clinically significant effect with coadministration of these drugseffect with coadministration of these drugs

Protein bindingProtein binding

Most NSAIDs are greater than 95% Most NSAIDs are greater than 95% protein boundprotein bound

Potential for drug-drug interactions via Potential for drug-drug interactions via competition for protein binding sitescompetition for protein binding sites

Warfarin Warfarin Aspirin Aspirin Digoxin Digoxin

Warfarin protein bindingWarfarin protein binding• Strongly protein bound and only unbound fraction is active• Ketorolac reduces protein binding of warfarin but

apparently has no effect on prothrombin time (PT)• Meloxicam has been shown to increase plasma AUC of s-

warfarin, but again no change in PT

• Most trials and PIs state that NSAIDs have no effect on pharmacokinetics of warfarin, but that patients should still be monitored for bleeding complications Warfarin in its natural habitat

Aspirin protein bindingAspirin protein binding

Common OTC drug that is highly protein bound Common OTC drug that is highly protein bound Used as NSAID and as cardio-protectant and Used as NSAID and as cardio-protectant and

as preventative for strokeas preventative for stroke Aspirin demonstrated to significantly decrease Aspirin demonstrated to significantly decrease

plasma NSAID levels secondary to plasma NSAID levels secondary to displacement from protein binding sitesdisplacement from protein binding sites

Evidence that some NSAIDs may inhibit the Evidence that some NSAIDs may inhibit the anti-platelet activity of aspirinanti-platelet activity of aspirin

Digoxin protein bindingDigoxin protein binding

Digoxin is highly protein bound Digoxin is highly protein bound and is easily displaced by other and is easily displaced by other drugsdrugs

Most studies show that NSAIDs Most studies show that NSAIDs and digoxin are safe to take and digoxin are safe to take togethertogether

However, it is well documented However, it is well documented that indomethacin can increase that indomethacin can increase the plasma levels of digoxin to a the plasma levels of digoxin to a toxic leveltoxic level

Bottom line: patients on digoxin Bottom line: patients on digoxin should avoid indomethacin should avoid indomethacin Digoxin in its natural habitat

P450 interactionsP450 interactions

Most P450 interactions involve changing Most P450 interactions involve changing the metabolism of the NSAIDs rather the metabolism of the NSAIDs rather than the interacting drugthan the interacting drug

NSAIDs have wide therapeutic range so NSAIDs have wide therapeutic range so that fluctuations in metabolism rates has that fluctuations in metabolism rates has less adverse effect than could otherwise less adverse effect than could otherwise be expectedbe expected

Not as exciting as we might have hopedNot as exciting as we might have hoped

CYP2C9CYP2C9

NSAID substrates:NSAID substrates:

celecoxib, diclofenac, etodolac, celecoxib, diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, ibuprofen, indomethacin, meloxicam, naproxen, piroxicamnaproxen, piroxicam

NSAID inhibitors:NSAID inhibitors:

diclofenac, etodolac*, ketoprofen, diclofenac, etodolac*, ketoprofen,

*incredibly weak*incredibly weak

Fluconazole/voriconazoleFluconazole/voriconazole

Antifungal agents that inhibit 2C9Antifungal agents that inhibit 2C9 Increase celecoxib plasma concentration times Increase celecoxib plasma concentration times

2 2 Significant increases in ibuprofen plasma Significant increases in ibuprofen plasma

concentrationsconcentrations Significance: potential for excessive NSAID Significance: potential for excessive NSAID

levels that levels that couldcould lead to nephrotoxicity and lead to nephrotoxicity and increased cardiovascular eventsincreased cardiovascular events

RifampicinRifampicin

Anti-tubercular agent that induces 2C9Anti-tubercular agent that induces 2C9 Shown to significantly decrease plasma Shown to significantly decrease plasma

levels of celecoxiblevels of celecoxib Not as immediately scary because levels Not as immediately scary because levels

will be decreased rather than increasedwill be decreased rather than increased Patients may not have adequate pain Patients may not have adequate pain

control, howevercontrol, however

WarfarinWarfarin

Anticoagulant metabolized by 2C9Anticoagulant metabolized by 2C9 Competition for metabolism may lead to Competition for metabolism may lead to

excessive anticoagulation – celecoxib excessive anticoagulation – celecoxib clinical trial has shown risk of excessive clinical trial has shown risk of excessive bleed in individuals with 2C9*2, *3 variantsbleed in individuals with 2C9*2, *3 variants

Though several NSAIDs have been Though several NSAIDs have been implicated in inhibiting 2C9, studies don’t implicated in inhibiting 2C9, studies don’t show pharmacokinetic effect on warfarinshow pharmacokinetic effect on warfarin

CYP2D6CYP2D6

Inhibited by celecoxibInhibited by celecoxib SubstratesSubstrates

Beta blockersBeta blockers Antidepressants/antipsychoticsAntidepressants/antipsychotics AntihistaminesAntihistamines OpiatesOpiates

• Clinical significance?Clinical significance?

CYP2C19CYP2C19

Inhibited by indomethacinInhibited by indomethacin Metabolizes carisoprodol, citalopram, Metabolizes carisoprodol, citalopram,

clozapine, diazepam, doxepin, fluoxetine, clozapine, diazepam, doxepin, fluoxetine, phenytoin, propranololphenytoin, propranolol

Clinical trials are lacking for these Clinical trials are lacking for these interactions!! interactions!!

CYP3A4CYP3A4

Metabolizes meloxicam, diclofenacMetabolizes meloxicam, diclofenac

Amiodarone, chloramphenicol, clarithromycin, Amiodarone, chloramphenicol, clarithromycin, cyclosporine, ethinyl estradiol, azole cyclosporine, ethinyl estradiol, azole antifungals, grapefruit inhibit antifungals, grapefruit inhibit

Barbiturates, carbamazepine, phenytoin, Barbiturates, carbamazepine, phenytoin, rifampin, St John’s Wort inducerifampin, St John’s Wort induce

Lacking studies!!Lacking studies!!

Renal eliminationRenal elimination

Probenecid – is a competitive inhibitor of Probenecid – is a competitive inhibitor of organic acid transport in the kidneyorganic acid transport in the kidney Get increased levels of NSAIDs by several foldGet increased levels of NSAIDs by several fold May lead to decreased effect of probenecidMay lead to decreased effect of probenecid

• Methotrexate and Lithium may have decreased Methotrexate and Lithium may have decreased renal clearance in the presence of NSAIDs renal clearance in the presence of NSAIDs though this may be attributable to the though this may be attributable to the pharmacodynamic effects of the NSAIDspharmacodynamic effects of the NSAIDs

PharmacodynamicPharmacodynamic

Effects on other drugs due to inhibition of Effects on other drugs due to inhibition of renal prostaglandinsrenal prostaglandins

Increased adverse effectsIncreased adverse effects Bleeding Bleeding GI toxicityGI toxicity NephrotoxicityNephrotoxicity

Inhibition of renal Inhibition of renal prostaglandinsprostaglandins

Loss of BP control with beta blockers, Loss of BP control with beta blockers, ACE inhibitors, diureticsACE inhibitors, diuretics

Toxic levels of methotrexate due to Toxic levels of methotrexate due to decreased excretiondecreased excretion

Toxic levels of lithium due to decreased Toxic levels of lithium due to decreased excretionexcretion

Increased risk of Increased risk of nephrotoxicitynephrotoxicity

CyclosporineCyclosporine MethotrexateMethotrexate TriamtereneTriamterene TacrolimusTacrolimus AminoglycosidesAminoglycosides

Increased GI bleedIncreased GI bleed

SSRIsSSRIs SalicylatesSalicylates AnticoagulantsAnticoagulants H2 blockersH2 blockers Bisphosphonates? Bisphosphonates?

NSAID summaryNSAID summary

Interactions possible and dangerous, but some are Interactions possible and dangerous, but some are rather dubious, allowing many of them to be safe rather dubious, allowing many of them to be safe enough for OTC useenough for OTC use

Most interaction effects are on NSAIDs. This allows for Most interaction effects are on NSAIDs. This allows for increased safety in the presence of P450 interactions increased safety in the presence of P450 interactions due to the wide therapeutic range of many NSAIDsdue to the wide therapeutic range of many NSAIDs

It would be interesting to see more clinical trials on the It would be interesting to see more clinical trials on the P450 interactions with NSAIDs, but the drugs are old P450 interactions with NSAIDs, but the drugs are old and numerous and proven relatively safe, so drug and numerous and proven relatively safe, so drug companies will take their monies eslewherecompanies will take their monies eslewhere

Keeping GeneMedRx Keeping GeneMedRx CurrentCurrent

Documentation for 97 new NSAID-drug Documentation for 97 new NSAID-drug interactions were found and added as new interactions were found and added as new notesnotes

Documentation for 14 new NSAID class-drug Documentation for 14 new NSAID class-drug class interactions were found and added as class interactions were found and added as new notesnew notes

P450 effects of NSAIDs was updated and P450 effects of NSAIDs was updated and verified to ensure algorithm is working properly verified to ensure algorithm is working properly even for potential interactions for which studies even for potential interactions for which studies have not been conductedhave not been conducted

Questions?Questions?

Thank you Genelex!Thank you Genelex!

References available upon requestReferences available upon request