Transcript NSAIDs
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
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
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
Cyclosporine
Methotrexate
Triamterene
Tacrolimus
Aminoglycosides
Increased GI bleed
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