1. 1000 Drug Interactions That You Didn’t Know You Knew Paul Starr, M.D. Department of Family Medicine Louisiana State University

2. Introduction Drug interactions were once thought to represent an insidious threat to public health. Although initial estimates predicted huge numbers of dangerous drug interactions, in practice they do not appear to be as menacing as they once appeared

3. Epidemiology Unknown incidence Still a preventable cause of morbidity

4. Pivot Table Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline Warfarin war tet ter pro phe nif iro flu ery dig cim asp

5. Pivot Table Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline Warfarin war tet ter pro phe nif iro flu ery dig cim asp

6. Pivot Table Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim (Don’t forget to turn the corner!)

7. Learning objectives for improving awareness of drug interactions A. Evaluate medications B. Famous interactions C. Group medications D. Hear your patient

8. Medications for this lecture Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline Warfarin

9. Consider the Medication’s passage through the body

11. Absorption a. Chelation : Divalent cations such as calcium or iron can bind to certain medications and prevent their absorption I. iron with tetracycline (H.C. Heinrich and KH Oppitz, Tetracycline inhibits iron absorption in man. Naturwissenschaften, 60:524, 1973)

12. Absorption b. Absorption pH: Weak acids need to be absorbed at a low pH. Raising the pH with antacid medication considerably hinders absorption. I. iron with cimetidine (R Esposito, Cimetidine and iron-deficiency anaemia. Lancet, 2:1132, 1977) II. cimetidine with aspirin (W Khoury, et.al., The effect of cimetidine on aspirin absorption. Gastroenterology, 76:1169, 1979.

13. Absorption Drug Absorption @ pH=1 @ pH=8 Acids: Salicylic Acid 61% 13% Thiopental 46% 34% Bases: Aniline 6% 56% Quinine 0% 18%

14. Pivot Table Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim A A A

15. Phase 1 (usually inactivated) CYP Enzymes Oxidation Reduction Dealkylation Hydrolysis Phase 2 (“ear-marked for destruction”) Conjugation Glucuronidation Sulfation Methylation Acetylation Protein Binding

16. CYP Enzymes in drug metabolism Substrates Inhibitors Inducers Cyp1A2Coumadin Cimetidine Phenytoin Cyp2B6Bupropion Thiotepa Rifampin Cyp2C9Phenytoin Isoniazid Rifampin Cyp2C19Diazepam Ketoconazole N/A Cyp2D6Metoprolol Cimetidine N/A Cyp2E1Ethanol Disulfiram INH Cyp3A4,5,7Terfenadine Erythromycin Phenytoin (and everything!)

17. CYP Enzyme Table

18. Three Kinds of Metabolic Interactions Substrate (a cyp enzyme simply performs a reaction on a medication Inhibition (a medication binds so strongly to a cyp enzyme that it prevents the enzyme from metabolizing other medications) Induction (the medication interacts with the enzyme in a way that leads to new production of the enzyme; this takes time!)

19. Metabolism Amitriptylline is metabolized by CYP1A2 Cimetidine inhibits CYP1A2 Coadministration results in elevated Amitriptylline levels

20. Michaelis-Menten Model E + SESE + P Enzyme Plus Substrate Enzyme- Substrate Complex Enzyme Plus Product K1 K2 K-1 K1= forward reaction K2= completed reaction K-1= aborted reaction (Pertinent to Substrate and Inhibition)

21. Michaelis-Menten Model E + SESE + P Enzyme Plus Substrate Enzyme- Substrate Complex Enzyme Plus Product K1K2 K-1 K1= forward reaction K2= completed reaction K-1= aborted reaction Km A derivation that describes the completed reaction Ki A derivation that describes an inhibited reaction (Pertinent to Substrate and Inhibition)

22. Ki Ki = _[Inhibitor]_ Km,obs - 1.0 Km Km= (k2+k-1) k1

23. Inhibition Substrates Inhibitors Inducers Cyp1A2Warfarin Cimetidine Phenytoin Cyp2B6Bupropion Thiotepa Rifampin Cyp2C9Phenytoin Isoniazid Rifampin Cyp2C19Diazepam Ketoconazole N/A Cyp2D6Metoprolol Cimetidine N/A Cyp2E1Ethanol Disulfiram INH Cyp3A4,5,7Terfenadine Erythromycin Phenytoin (and everything!)

24. Induction Endoplasmic Reticulum Nucleus CYP1A AhR Activation Arnt + Up-regulation

25. Induction SubstratesInhibitorsInducers Cyp1A2WarfarinCimetidine Phenytoin Cyp2B6BupropionThiotepa Rifampin Cyp2C9PhenytoinIsoniazid Rifampin Cyp2C19DiazepamKetoconazole N/A Cyp2D6MetoprololCimetidineN/A Cyp2E1EthanolDisulfiramINH Cyp3A4,5,7TerfenadineErythromycin Phenytoin (and everything!)

26. Metabolism Amitriptylline is metabolized by CYP1A2 Cimetidine inhibits CYP1A2 Coadministration results in elevated Amitriptylline levels Ranitidine inhibits CYP1A2 BUT to a much lesser degree (lower Ki)

27. Metabolism Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim A A A M MM M

28. Target 1. If two medications make it past the hepatic enzymes, there is potential for interaction at the site of action, or at sites of major side effects. Propranolol with nifedipine (A-V conduction disturbances and sinus bradycardia U Elkayam et al, Effects of nifedipine on hemodynamics and cardiac function in patients with normal left ventricular ejection fraction already treated with propranolol. Am J Cardiol, 58:536, 1986 Warfarin with aspirin (RA O’Reilly et al, Impact of aspirin and chlorthalidone on the pharmacodynamics of oral anticoagulants in man. Ann NY Acad Sci, 179:173, 1971.)

29. Target Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim A A A M M M M T T

30. Elimination Certain medications can compete for excretion Digoxin with erythromycin (H Wakasugi et al, Effect of clarithromycin on renal excretion of digoxin; interaction with P-glycoprotein. Clin Pharmacol Ther, 64:123, 1998) Although this report was regarding clarithromycin, the caution was extended to all macrolides. Interestingly, there are other digoxin/macrolide interactions including hepatic metabolism, and a unique mechanism in which gut flora which inactivate digoxin can be eliminated with oral antibiotics!

31. Elimination Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim A A A M MM M T T E

32. Famous Interactions Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim A A A M MM M T T E

33. Famous Interactions Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro flu ery dig cim A A A M MM M T T E MM? AM M MMMM ? M ? ? MM ?M ?

34. Grouping Medications Metabolic effects Chemical family Having memorized the above famous interactions, you can expand your knowledge dramatically by remembering a few rules regarding the drug families to which the medications belong. They can be grouped by:

35. Potent Inhibitors Fluoroquinolones (ie: ciprofloxacin) H2Blockers (ie: most notably cimetidine) Imidazoles (ie fluconazole) INH Ritonavir Mnemonic: “cip, cim, con, INH, and rit”

36. Potent Inducers Neuroleptics: Carbamazepine Phenobarbital Phenytoin AND: Rifampin Mnemonic: “carb, barb, pheny, and rif”

37. H1 Blockers Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Nifedipine Phenytoin Propranolol Terfenadine Astemizole Loratadine Tetracycline war tet ter ast lor pro phe nif iro flu ery dig cim A A A M M M T T E M M? A M M M MM M ? ? M M ? ? M M M M M

38. Divalent Cations Aspirin Cimetidine Digoxin Erythromycin Fluconazole Iron Calcium Magnesium Nifedipine Phenytoin Propranolol Terfenadine Tetracycline war tet ter pro phe nif iro ca ma flu ery dig cim A M MM M T T E MM? AM M MMMM ? M ? ? M M ?M ? A A

39. H2 Blockers H2Blockers follow the same rules as H1Blockers; Cimetidine is the most potent inhibitor, ranitidine to a lesser degree, and famotidine slightly lesser. Mnemonic: “cim>ran>fam”

40. Beta Blockers BetaBlockers knowing that propranolol contributes significantly to heart block in the presence of nifedipine, it is interesting to note that metoprolol and atenolol appear to be relatively safe. Mnemonic: “pro>aten>meto”

41. Macrolides Macrolide antibiotics are aggressively metabolized by cyp3A4 with the exception of azithromycin which is metabolized by a different mechanism. Clarithromycin is one of the most potent utilizers of Cyp3A4 and entertains vast potential for competitive inhibition with many other medications. Mnemonic: “clar>ery>azith”

42. Antifungals Antifungals of the imidazole class are metabolized with varying affinities for the cyp enzymes. Fluconazole turns out to be one of the more benign medications whereas ketoconazole is a very potent inhibitor of cyp3A4. Mnemonic: “keto>itra>flu”

43. Calcium Channel Blockers Calcium channel blockers like betablockers vary in their ability to cause heart block. Mnemonic: “ver>nif>car”

44. Conclusion Examining medications encourages careful review of medications Famous interactions should be memorized and form the basis of a broader understanding of drug interactions in general Grouping medications allows one to extrapolate known data to a certain extent across a drug groups Hearing patient’s complaints can help alert the physician to identifying previously unreported reactions