Non-Steroidal Anti-Inflammatory Drugs

1. Non-Steroidal Anti-Inflammatory Drugs Meghin Gjerswold 12.01.2006 UWSOP at Genelex ibuprofen

2. 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

3. 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 10,000-20,000 deaths per year can be associated with NSAID use

4. Potential interaction types • Pharmacokinetic interactions – involve absorption, distribution, elimination • Pharmacodynamic interactions – involve drug effects and/or toxicity

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

6. 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

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

8. 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

9. 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

10. 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

11. 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

12. CYP2C9 • NSAID substrates: celecoxib, diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, naproxen, piroxicam • NSAID inhibitors: diclofenac, etodolac*, ketoprofen, *incredibly weak

13. 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

14. 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

15. 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

16. CYP2D6 • Inhibited by celecoxib • Substrates • Beta blockers • Antidepressants/antipsychotics • Antihistamines • Opiates • Clinical significance?

17. CYP2C19 • Inhibited by indomethacin • Metabolizes carisoprodol, citalopram, clozapine, diazepam, doxepin, fluoxetine, phenytoin, propranolol • Clinical trials are lacking for these interactions!!

18. 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!!

19. 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

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

21. 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

22. Increased risk of nephrotoxicity • Cyclosporine • Methotrexate • Triamterene • Tacrolimus • Aminoglycosides

23. Increased GI bleed • SSRIs • Salicylates • Anticoagulants • H2 blockers • Bisphosphonates?

24. 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

25. 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

26. Questions? • Thank you Genelex! • References available upon request