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

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Presentation on theme: "Non-Steroidal Anti- Inflammatory Drugs Meghin Gjerswold 12.01.2006 UWSOP at Genelex ibuprofen."— Presentation transcript:

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

2 NSAID use NSAIDs are available OTC NSAIDs are available OTC NSAIDs can be toxic on their own NSAIDs can be toxic on their own People who take NSAIDs (elderly people) often take many drugs which can lead to dangerous interactions People who take NSAIDs (elderly people) often take many drugs which can lead to dangerous interactions NSAIDs are metabolized by multiple hepatic pathways NSAIDs are metabolized by multiple hepatic pathways

3 Adverse effects Nephrotoxic Nephrotoxic Bleeding problems Bleeding problems Increase blood pressure Increase blood pressure FDA requires medication guide be dispensed with every NSAID prescription – FDA requires medication guide be dispensed with every NSAID prescription – FDA fact: FDA fact: >70,000 hospitalizations per year and 10, ,000 deaths per year can be associated with NSAID use

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

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

6 Decreased absorption of NSAIDs Sucralfate – coat the stomach to protect from bleed/ulcers Sucralfate – coat the stomach to protect from bleed/ulcers H2-blockers/antacids – decrease stomach pH 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 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 Evidence points to lack of clinically significant effect with coadministration of these drugs

7 Protein binding Most NSAIDs are greater than 95% protein bound Most NSAIDs are greater than 95% protein bound Potential for drug-drug interactions via competition for protein binding sites Potential for drug-drug interactions via competition for protein binding sites Warfarin Warfarin Aspirin Aspirin Digoxin 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 Common OTC drug that is highly protein bound Used as NSAID and as cardio-protectant and as preventative for stroke 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 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 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 Digoxin is highly protein bound and is easily displaced by other drugs Most studies show that NSAIDs and digoxin are safe to take together 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 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 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 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 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 Not as exciting as we might have hoped

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

13 Fluconazole/voriconazole Antifungal agents that inhibit 2C9 Antifungal agents that inhibit 2C9 Increase celecoxib plasma concentration times 2 Increase celecoxib plasma concentration times 2 Significant increases in ibuprofen plasma concentrations Significant increases in ibuprofen plasma concentrations Significance: potential for excessive NSAID levels that could lead to nephrotoxicity and increased cardiovascular events Significance: potential for excessive NSAID levels that could lead to nephrotoxicity and increased cardiovascular events

14 Rifampicin Anti-tubercular agent that induces 2C9 Anti-tubercular agent that induces 2C9 Shown to significantly decrease plasma levels of celecoxib Shown to significantly decrease plasma levels of celecoxib Not as immediately scary because levels will be decreased rather than increased Not as immediately scary because levels will be decreased rather than increased Patients may not have adequate pain control, however Patients may not have adequate pain control, however

15 Warfarin Anticoagulant metabolized by 2C9 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 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 dont show pharmacokinetic effect on warfarin Though several NSAIDs have been implicated in inhibiting 2C9, studies dont show pharmacokinetic effect on warfarin

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

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

18 CYP3A4 Metabolizes meloxicam, diclofenac Metabolizes meloxicam, diclofenac Amiodarone, chloramphenicol, clarithromycin, cyclosporine, ethinyl estradiol, azole antifungals, grapefruit inhibit Amiodarone, chloramphenicol, clarithromycin, cyclosporine, ethinyl estradiol, azole antifungals, grapefruit inhibit Barbiturates, carbamazepine, phenytoin, rifampin, St Johns Wort induce Barbiturates, carbamazepine, phenytoin, rifampin, St Johns Wort induce Lacking studies!! Lacking studies!!

19 Renal elimination Probenecid – is a competitive inhibitor of organic acid transport in the kidney Probenecid – is a competitive inhibitor of organic acid transport in the kidney Get increased levels of NSAIDs by several fold Get increased levels of NSAIDs by several fold May lead to decreased effect of probenecid 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 NSAIDsMethotrexate 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 Effects on other drugs due to inhibition of renal prostaglandins Increased adverse effects Increased adverse effects Bleeding Bleeding GI toxicity GI toxicity Nephrotoxicity Nephrotoxicity

21 Inhibition of renal prostaglandins Loss of BP control with beta blockers, ACE inhibitors, diuretics Loss of BP control with beta blockers, ACE inhibitors, diuretics Toxic levels of methotrexate due to decreased excretion Toxic levels of methotrexate due to decreased excretion Toxic levels of lithium due to decreased excretion Toxic levels of lithium due to decreased excretion

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

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

24 NSAID summary Interactions possible and dangerous, but some are rather dubious, allowing many of them to be safe enough for OTC use 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 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 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 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 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 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! Thank you Genelex! References available upon request References available upon request


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