Non-Steroidal AntiInflammatory Drugs
ibuprofen
Meghin Gjerswold
12.01.2006
UWSOP at Genelex
NSAID use
 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 –
www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.pdf
 FDA fact:
>70,000 hospitalizations per year and 10,00020,000 deaths per year can be associated with
NSAID use
Potential interaction types
 Pharmacokinetic interactions – involve
absorption, distribution, elimination
 Pharmacodynamic interactions – involve
drug effects and/or toxicity
Pharmacokinetic interactions
 Absorption
 Protein binding
 P450 interactions
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2D6
2C9
2C19
3A4
 Renal elimination
Decreased absorption of
NSAIDs
 Sucralfate – coat the stomach to protect from
bleed/ulcers
 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 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 swarfarin, 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
drugs
 Most studies show that NSAIDs
and digoxin are safe to take
together
 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
CYP2C9
 NSAID substrates:
celecoxib, diclofenac, etodolac,
ibuprofen, indomethacin, meloxicam,
naproxen, piroxicam
 NSAID inhibitors:
diclofenac, etodolac*, ketoprofen,
*incredibly weak
Fluconazole/voriconazole
 Antifungal agents that inhibit 2C9
 Increase celecoxib plasma concentration times
2
 Significant increases in ibuprofen plasma
concentrations
 Significance: potential for excessive NSAID
levels that could lead to nephrotoxicity and
increased cardiovascular events
Rifampicin
 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
Warfarin
 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
variants
 Though several NSAIDs have been
implicated in inhibiting 2C9, studies don’t
show pharmacokinetic effect on warfarin
CYP2D6
 Inhibited by celecoxib
 Substrates
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Beta blockers
Antidepressants/antipsychotics
Antihistamines
Opiates
• Clinical significance?
CYP2C19
 Inhibited by indomethacin
 Metabolizes carisoprodol, citalopram,
clozapine, diazepam, doxepin, fluoxetine,
phenytoin, propranolol
 Clinical trials are lacking for these
interactions!!
CYP3A4
 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
Pharmacodynamic
 Effects on other drugs due to inhibition of
renal prostaglandins
 Increased adverse effects
 Bleeding
 GI toxicity
 Nephrotoxicity
Inhibition of renal
prostaglandins
 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
excretion
Increased risk of
nephrotoxicity
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Cyclosporine
Methotrexate
Triamterene
Tacrolimus
Aminoglycosides
Increased GI bleed
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SSRIs
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
Current
 Documentation for 97 new NSAID-drug
interactions were found and added as new
notes
 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
Questions?
 Thank you Genelex!
 References available upon request