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Non-Ster oidal Anti-

Inflammator y Dr ugs

ibuprofen Meghin Gjerswold

UWSOP at Genelex

 NSAIDs are available OTC

 NSAIDs can be toxic on their own
 People who take NSAIDs (elderly
people) often take many drugs which can
lead to dangerous interactions
 NSAIDs are metabolized by multiple
hepatic pathways
Adverse effects
 Nephrotoxic
 Bleeding problems
 Increase blood pressure

 FDA requires medication guide be dispensed

with every NSAID prescription –
 FDA fact:
>70,000 hospitalizations per year and 10,000-20,000
deaths per year can be associated with NSAID use
Potential interaction

 Pharmacokinetic interactions – involve

absorption, distribution, elimination

 Pharmacodynamic interactions – involve

drug effects and/or toxicity
 Absorption
 Protein binding
 P450 interactions
 2D6
 2C9
 2C19
 3A4
 Renal elimination
Decreased absorption
 Sucralfate – coat the stomach to protect from
 H2-blockers/antacids – decrease stomach pH to
protect from bleed/ulcers
 Bile acid sequesterants – bind to bile acid to
prevent manufacture of cholesterol

 Evidence points to lack of clinically significant

effect with coadministration of these drugs
Protein binding

 Most NSAIDs are greater than 95%

protein bound
 Potential for drug-drug interactions via
competition for protein binding sites
 Warfarin
 Aspirin
 Digoxin
Warfarin protein
• 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 binding
 Common OTC drug that is highly protein bound
 Used as NSAID and as cardio-protectant and as
preventative for stroke
 Aspirin demonstrated to significantly decrease plasma
NSAID levels secondary to displacement from protein
binding sites
 Evidence that some NSAIDs may inhibit the anti-
platelet activity of aspirin
Digoxin protein binding
 Digoxin is highly protein bound
and is easily displaced by other
 Most studies show that NSAIDs
and digoxin are safe to take
 However, it is well documented
that indomethacin can increase
the plasma levels of digoxin to a
toxic level
 Bottom line: patients on digoxin
should avoid indomethacin Digoxin in its natural habitat
P450 interactions

 Most P450 interactions involve changing

the metabolism of the NSAIDs rather than
the interacting drug
 NSAIDs have wide therapeutic range so
that fluctuations in metabolism rates has
less adverse effect than could otherwise
be expected
 Not as exciting as we might have hoped

 NSAID substrates:
celecoxib, diclofenac, etodolac, ibuprofen,
indomethacin, meloxicam, naproxen,
 NSAID inhibitors:
diclofenac, etodolac*, ketoprofen,

*incredibly weak
 Antifungal agents that inhibit 2C9
 Increase celecoxib plasma concentration times 2
 Significant increases in ibuprofen plasma
 Significance: potential for excessive NSAID
levels that could lead to nephrotoxicity and
increased cardiovascular events

 Anti-tubercular agent that induces 2C9

 Shown to significantly decrease plasma
levels of celecoxib
 Not as immediately scary because levels
will be decreased rather than increased
 Patients may not have adequate pain
control, however
 Anticoagulant metabolized by 2C9
 Competition for metabolism may lead to excessive
anticoagulation – celecoxib clinical trial has shown risk
of excessive bleed in individuals with 2C9*2, *3
 Though several NSAIDs have been implicated in
inhibiting 2C9, studies don’t show pharmacokinetic
effect on warfarin

 Inhibited by celecoxib
 Substrates
 Beta blockers
 Antidepressants/antipsychotics
 Antihistamines
 Opiates
• Clinical significance?

 Inhibited by indomethacin
 Metabolizes carisoprodol, citalopram,
clozapine, diazepam, doxepin, fluoxetine,
phenytoin, propranolol

 Clinical trials are lacking for these

 Metabolizes meloxicam, diclofenac

 Amiodarone, chloramphenicol, clarithromycin,

cyclosporine, ethinyl estradiol, azole antifungals,
grapefruit inhibit
 Barbiturates, carbamazepine, phenytoin, rifampin,
St John’s Wort induce

 Lacking studies!!
Renal elimination
 Probenecid – is a competitive inhibitor of
organic acid transport in the kidney
 Get increased levels of NSAIDs by several fold
 May lead to decreased effect of probenecid
• Methotrexate and Lithium may have decreased
renal clearance in the presence of NSAIDs
though this may be attributable to the
pharmacodynamic effects of the NSAIDs

 Effects on other drugs due to inhibition of

renal prostaglandins
 Increased adverse effects
 Bleeding
 GI toxicity
 Nephrotoxicity
Inhibition of renal
 Loss of BP control with beta blockers,
ACE inhibitors, diuretics
 Toxic levels of methotrexate due to
decreased excretion
 Toxic levels of lithium due to decreased
Increased risk of
 Cyclosporine
 Methotrexate
 Triamterene
 Tacrolimus
 Aminoglycosides
Increased GI bleed

 Salicylates
 Anticoagulants
 H2 blockers
 Bisphosphonates?
NSAID summary
 Interactions possible and dangerous, but some are
rather dubious, allowing many of them to be safe
enough for OTC use
 Most interaction effects are on NSAIDs. This allows for
increased safety in the presence of P450 interactions
due to the wide therapeutic range of many NSAIDs
 It would be interesting to see more clinical trials on the
P450 interactions with NSAIDs, but the drugs are old
and numerous and proven relatively safe, so drug
companies will take their monies eslewhere
Keeping GeneMedRx
 Documentation for 97 new NSAID-drug
interactions were found and added as new
 Documentation for 14 new NSAID class-drug
class interactions were found and added as
new notes
 P450 effects of NSAIDs was updated and
verified to ensure algorithm is working properly
even for potential interactions for which studies
have not been conducted
 Thank you Genelex!

 References available upon request