1. Non-Steroidal Anti-Inflammatory Drugs
Focus excludes salicylates.
Class effects is to inhibit prostaglandins by inhibiting cox1/2.
Ibuprofen is my favorite.
ibuprofen
Meghin Gjerswold
UWSOP at Genelex

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
NSAID use is very common
potential is there for many and serious adverse drug interactions.
In addition they have the potential to be toxic on their own though especially in individuals with impaired renal function or pre-existing cardiac problems.

3. 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
Have the ability to cause kidney damage esp in nephro-compromised individuals.
Can cause GI bleed, but also have been shown to increase bleed time by 3-4 minutes.
NSAIDs have always been associated with increased GI bleed and now are associated even more with CV events. With the introduction of the COX2 specific drugs, the CV problems have really come to the fore.
The FDA has gone so far as to regulate that each Rx is dispensed with a med guide that breaks down all of the possible risks.

4. Potential interaction types
Pharmacokinetic interactions – involve absorption, distribution, elimination
Pharmacodynamic interactions – involve drug effects and/or toxicity
There are 2 classifications of drug interactions, but they are linked together insofar as pharmacokinetic interactions can lead to pharmacodynamic effects. NSAIDs can be implicated in both types of interactions though the pharmacodynamic interactions probably tend to be the most significant for the NSAIDs.

5. Pharmacokinetic interactions
Absorption
Protein binding
P450 interactions
2D6
2C9
2C19
3A4
Renal elimination
NSAIDs pharmacokinetics can be interfered with at the level of absorption, protein binding, metabolism, and elimination.
For the NSAIDs, the most significant interactions probably tends to be at the level of the kidney but each stage can have interactions.

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
NSAIDs aren’t likely to affect the absorption of other drugs, but several classes of drugs have the potential to interfere with absorption of NSAIDs.
Because nsaids can cause GI bleed, they are often given with drugs that protect the stomach mucosa. Sucralfate coats the stomach and antacids and H2 blockers decrease the stomach pH.
Because most NSAIDs are acidic moieties, absorption would be expected to change when stomach conditions are changed, but studies are conflicted about the actual effect. Most studies agree that rate of NSAID absorption may be affected, but not extent so usually no clinically significant effect is seen.
The bile acid sequesterants, on the other hand, have been shown to decrease the extent of absorption by binding the NSIAD and causing it to be excreted rather than absorbed.

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
This has the potential to be bad, but nsaids usually have less affinity than the competing drug and often are excreted at the same rate so that there is not actually a net plasma increase of nsaid and sometimes there is actually a decrease in serum nsaid levels due to clearance that keeps up with the displaced NSAID as it enters the blood stream.

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 is highly protein bound as well, but studies show that even though there is the potential for warfarin to be displaced and increase plasma levels, it does not lead to an increase in PT time.
Studies with warfarin focus on bleed time and don’t generally reflect the effect warfarin may have on nsaid levels/effects.
Ketorolac is an example of a drug that has been studied where warfarin protein binding was reduced and ketorolac’s was unaffected. Despite the reduced protein binding of warfarin, PT was not affected.
However, NSAIDs have been shown to increase bleeding time independent of coadministration with anticoagulants so patients still need to be carefully monitored for bleeding events.
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
Aspirin has been demonstrated to displace NSAIDs and lead to decreased NSAID levels.
Evidence also shows that NSAIDs may interfere with aspirin’s ability to prevent platelet aggregation and so block it’s cardio-protectant capabilities.
This is not immediately dangerous, but in the long run coadministration could lead to decreased benefit of asa use.

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
What you guys are really interested in
Most P450 effects are on the NSAIDs themselves, which is not exciting because fluctuation in NSAID levels aren’t as dangerous as with other drugs

12. CYP2C9 NSAID substrates:
celecoxib, diclofenac, etodolac, ibuprofen, indomethacin, meloxicam, naproxen, piroxicam
NSAID inhibitors:
diclofenac, etodolac*, ketoprofen,
*incredibly weak
2C9 is the CYP most involved with NSAIDs.
2C9 interactions with these drugs are most likely to affect the NSAIDs and so can be less dangerous than other combinations.
Though diclofenac and ketoprofen have been shown to inhibit 2C9, there is a lack of studies that show what effect, if any, this has on the metabolism of other 2C9 substrates.
Celecoxib has the most information on it because it is a newer nsaid that had great hopes of being better than the older agents.

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
(-) celecoxib AUC 64%
Inadequate pain control may lead to use of OTC NSAIDs in addition to celecoxib which could lead to nephrotoxicity

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
Though clinical trial has shown that celecoxib has no effect on PT with warfarin, another trial has shown significant effect on individuals with specific variants.

16. CYP2D6 Inhibited by celecoxib Substrates Clinical significance?
Beta blockers
Antidepressants/antipsychotics
Antihistamines
Opiates
Clinical significance?
Though celecoxib has the potential to decrease the metabolism of these drugs, it is difficult to say the clinical significance.
The anti-HTN effect of beta-B can be attenuated by NSAIDs but this may antagonize the potential for increased levels with celecoxib.
Increased levels of antidepressants and antipsychotics likewise may not be clinically significant because patients may not become toxic with the amount these drugs may be elevated.
Ketorolac has been reported to cause hallucinations with antidepressants and has been withdrawn from the French market though that may or may not mean anything in terms of 2D6.
Opiates may be given with celecoxib for increased pain control, but 2D6 is responsible for converting the opiates to their active form so rather than becoming toxic, a patient may lose pain control and/or have severe n/v esp in patients who are already poor metabolizers.
There are not specific studies examining these effects.

17. CYP2C19 Inhibited by indomethacin
Metabolizes carisoprodol, citalopram, clozapine, diazepam, doxepin, fluoxetine, phenytoin, propranolol
Clinical trials are lacking for these interactions!!
Interesting note: though interactions with these drugs aren’t document in clinical trial with humans, a study with mice showed that indomethacin inhibits GABA uptake and increased psychomotor dysfunction which could be potentially dangerous in combination with the drugs listed on this slide.
A clinical trial between indomethacin and men demonstrated that there was no difference in the subjective effects of diazepam vs diazepam + indomethacin.

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!!
Cyclosporine has been clinically shown to significantly increase diclofenac levels which can be exceedingly dangerous because cyclosporine has been shown to increase risk of nephrotoxicity in NSAIDs even without inhibition of their respective metabolisms.
Note: algorithm did predict interactions for these drugs when substrate/inhibitor/inducer info was available

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
Probenecid can lead to increased indomethacin, ketoprofen, ketorolac, naproxen, etc. This is significant and is a class effect. MTX and Li are odd. There is a great deal of case reports of toxicity with NSAIDs, but not controlled trials. The mechanism isn’t exactly known, but it is possibly due to reduction in clearance of these drug due to inhibition of renal prostaglandins.

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
This is sort of a mixed reaction. Pharmacodynamic effects of NSAIDs interfere with the pharmacodynamic effects of anti-htns, but interfere with the pharmacokinetic properties (maybe) of lithium and methotrexate.
MTX and Li are odd. There is a great deal of case reports of toxicity with NSAIDs, but not controlled trials.
The mechanism isn’t exactly known, but it is possibly due to reduction in clearance of these drug due to inhibition of renal prostaglandins.

22. Increased risk of nephrotoxicity
Cyclosporine
Methotrexate
Triamterene
Tacrolimus
Aminoglycosides
All of these drugs run the risk of causing kidney damage individually. When any of them are given concurrently, the kidneys may be in extreme danger!!

23. Increased GI bleed SSRIs Salicylates Anticoagulants H2 blockers
Bisphosphonates?
SSRIs apparently increase risk of GI bleed by their actions of HT3 in the stomach.
H2 blockers seem to mask symptoms of GI bleed which can be exceedingly dangerous because they are often used to heal ulcers which may have been caused in conjunction with NSAID use.
Bisposphonates temporarily make the stomach extremely acidic. So acidic, that patients who cannot sit or stand for at least 30 minutes after taking them are contraindicated for their use. Despite this, clinical trial has shown that patients taking bisphosphonates and nsaids are not at increased risk of gi bleed compared to those taking NSAIDS alone.

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
There is a huge variety of NSAIDs on the market. For most people they are safe to use even in combination with possibly interacting drugs. However, a few people are always going to be at more risk for others and so individuals should always discuss OTC drug use with their prescribing doctors.

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