Non-Steroidal Anti-Inflammatory Drugs

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Non-Steroidal Anti-Inflammatory Drugs
ibuprofen

• Meghin Gjerswold
• 12.01.2006
• UWSOP at Genelex

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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

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Adverse effects

• Nephrotoxic
• Bleeding problems
• Increase blood pressure
• FDA requires medication guide be dispensed with
  every NSAID prescription www.fda.gov/cder/drug/i
  nfopage/COX2/NSAIDmedguide.pdf
• FDA fact
• gt70,000 hospitalizations per year and
  10,000-20,000 deaths per year can be associated
  with NSAID use

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Potential interaction types

• Pharmacokinetic interactions involve
  absorption, distribution, elimination
• Pharmacodynamic interactions involve drug
  effects and/or toxicity

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Pharmacokinetic interactions

• Absorption
• Protein binding
• P450 interactions
• 2D6
• 2C9
• 2C19
• 3A4
• Renal elimination

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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

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Protein binding

• Most NSAIDs are greater than 95 protein bound
• Potential for drug-drug interactions via
  competition for protein binding sites
• Warfarin
• Aspirin
• Digoxin

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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 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
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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

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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
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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

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CYP2C9

• NSAID substrates
• celecoxib, diclofenac, etodolac, ibuprofen,
  indomethacin, meloxicam, naproxen, piroxicam
• NSAID inhibitors
• diclofenac, etodolac, ketoprofen,
• incredibly weak

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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

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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

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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
  2C92, 3 variants
• Though several NSAIDs have been implicated in
  inhibiting 2C9, studies dont show
  pharmacokinetic effect on warfarin

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CYP2D6

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

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CYP2C19

• Inhibited by indomethacin
• Metabolizes carisoprodol, citalopram, clozapine,
  diazepam, doxepin, fluoxetine, phenytoin,
  propranolol
• Clinical trials are lacking for these
  interactions!!

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CYP3A4

• Metabolizes meloxicam, diclofenac
• Amiodarone, chloramphenicol, clarithromycin,
  cyclosporine, ethinyl estradiol, azole
  antifungals, grapefruit inhibit
• Barbiturates, carbamazepine, phenytoin, rifampin,
  St Johns Wort induce
• Lacking studies!!

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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

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Pharmacodynamic

• Effects on other drugs due to inhibition of renal
  prostaglandins
• Increased adverse effects
• Bleeding
• GI toxicity
• Nephrotoxicity

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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

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Increased risk of nephrotoxicity

• Cyclosporine
• Methotrexate
• Triamterene
• Tacrolimus
• Aminoglycosides

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Increased GI bleed

• SSRIs
• Salicylates
• Anticoagulants
• H2 blockers
• Bisphosphonates?

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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

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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

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Questions?

• Thank you Genelex!
• References available upon request