Drug Interactions in Older Adults

1. Drug Interactions in Older Adults Joseph T. Hanlon, PharmD, MS

2. Learning Objectives At the conclusion of this talk the participant should be able to: • List the 4 major types of drug interactions that can occur in the elderly • Discuss the epidemiology of the different types of drug interactions in the elderly • Implement strategies to prevent/manage drug interactions in the elderly

3. Types of Drug Interactions • Drug-Drug Pharmacokinetic • Drug-Drug Pharmacodynamic • Drug-Food/Nutrient • Drug-Disease

4. Drug-Drug Interactions Affecting Absorption and Distribution Precipitant Drug(s)Object Drug(s) Outcome Antacids, Iron Tetracycline, Ciprofloxacin  abs. Chloral hydrate Warfarin  PPB • Generally absorption and distribution drug-drug-interactions are not clinically important. Drugs & Aging 1998;12:485-94

5. Phase I (CYP 450) Oxidation hydroxylation dealkylation sulfoxidation Reduction Hydrolysis Phase II Conjugation glucuronidation sulfation glycine acetylation Hepatic Metabolism

6. Cytochrome P450 Phase I Isoenzymes, % Total and Substrate Examples Isoenzymes % Substrate CYP1A2 17 Olanzapine, Theophylline CYP2C9/19 26 Phenytoin, Warfarin CYP2D6 2-4 Codeine, Desipramine, Tramadol CYP2E1 9-10 Chlorzoxazone, Ethanol CYP3A4 35-45 Diazepam, Triazolam, Quinidine, Methadone, Carbamazepine www.drug-interactions.com

7. Inhibitors of Hepatic Cytochrome P450 1A22C9/192D63A4 Fluvoxamine Amiodarone Fluoxetine Erythromycin Cimetidine Fluconazole Paroxetine Azole antifungal Ciprofloxacin Fluvastatin Quinidine Nefazodone Fluoxetine Ritonavir Clarithromycin Isoniazid Bupropion Ritonavir Sertraline Cimetidine Cimetidine Omeprazole Cimetidine www.drug-interactions.com

8. Effect of Age on Theophylline Hepatic Metabolism Inhibition J Pharmacol Exp Ther 1997;280:627-37.

9. Inhibitors Cimetidine Propafenone Mexiletine Propranolol Erythromycin Ciprofloxacin Fluvoxamine Drugs Aging. 2003;20:71-84 Inducers Barbiturates Phenytoin Smoking Rifampin Carbamazepine JAPHA 2004;44:142-51 Drugs That Interact with Theophylline

10. Drug-Drug Interactions With Warfarin Interacting DrugMechanismAnticoagulant Effect Aspirin PD  Barbiturate PK  Cimetidine PK  Dipyridamole PD  Fibrates PD  Fluvoxamine PK  Macrolides PK  Phenytoin PK  Quinolones PK  Rifampin PK  Sulfinpyrazone PK/PD  Thyroid hormones PD  Ticlopidine PD  N Engl J Med. 2003; 14;349:675-83; JAPHA 2004;44:142-51

11. Clinically SignificantDrug-Drug Interactions with AEDs Object Drug Interacting Drug Outcome Carbamazepine Danazol  CBZ level Carbamazepine Diltiazem  CBZ level Carbamazepine Macrolides  CBZ level Carbamazepine Propoxyphene  CBZ level Carbamazepine Verapamil  CBZ level Phenytoin Amiodarone  DPH level Phenytoin Cimetidine  DPH level Phenytoin Fluoxetine  DPH level Phenytoin INH  DPH level Phenytoin Omeprazole  DPH level Neuropharmacology 2002;5:280-9

12. Inducers of Hepatic Cytochrome P450 1A22C9/192D63A4 Smoking Rifampin None Carbamazepine Omeprazole Phenobarbital Phenytoin Phenytoin Phenytoin Phenobarbital Rifampin St. John’s wort www.drug-interactions.com

13. Effect of Age on Theophylline Hepatic Metabolism Induction by DPH Crowley J. J Phamacol Exp Ther 1988;245:513-23.

14. Selected Phenytoin Induction Interactions Object DrugInteracting DrugCYP Isoenzyme Induced Methadone Phenytoin 3A4 Quinidine Phenytoin 3A4 Theophylline Phenytoin 1A2 Warfarin Phenytoin 2C9 Neuropharmacology 2002;5:280-9.

15. Basic (cationic) Agents Amiodarone Cimetidine Digoxin Procainamide Quinidine Ranitidine Trimethoprim Verapamil Acidic (Anionic) Agents Cephalosporins Indomethacin Methotrexate Penicillins Probenecid Salicylates Thiazides Selected Drugs Secreted by Renal Tubules

16. Drug-Drug Interactions With Digoxin Interacting DrugEffect on Levels Amiodarone  Clarithromycin  Propafenone  Quinidine  Verapamil  Drug Saf. 2000;23:509-32; JAPHA 2004;44:142-51

17. Drugs that Interact with Lithium • Diuretics • ACE-I • NSAIDs

18. Pharmacokinetics Pharmacodynamics Dosage Regimen Effects Plasma Concen tration Site of Action

19. Drug-Drug PD Interactions Object Drug Interacting Drug (s) ACE-I K+ & K+ sparing diuretics Beta blockers Verapamil Digoxin Diuretics MAOI SSRI, Dextromethorphan, Pseudoephedrine, Anorexiants Meperidine MAOI Hydroxyine Thioridazine

20. Drug- TCA PD Interactions • Concurrent use with any other drugs with antimuscarinic properties • Concurrent MAOI • Type I antiarrhythmics • Clonidine • Guanadrel • Guanethidine

21. Drug-NSAID PD Interactions Object DrugInteracting DrugOutcome Antihypertensives NSAIDs  BP Corticosteroids NSAIDs  risk of PUD Diuretics NSAIDs  diuretic effect Triamterene Indomethacin  K+ Warfarin NSAIDs  anticoagulant effect

22. CNS Polypharmacy and Falls in Elderly Persons Weiner D, et al. Gerontol 1998;44:217-21

23. Drug-Food/Nutrient Interactions

24. Clinically Significant Drug –St. John Wort Interactions Object DrugOutcome Antidepressants serotonergic syndrome Cyclosporine  levels, transplant rejection Digoxin  digoxin levels Estrogen breakthrough bleeding Indinavir  indinavir levels Methadone withdrawal sx’s Tacrolimus  levels Theophylline  theophylline levels Warfarin  INR CPT 2004;75:1-12

25. Other Clinically Significant Herb- Drug Interactions Object DrugInteracting DrugOutcome Anticonvulsants Wormwood  seizure threshold Anticonvulsants Gingko biloba  seizure threshold Digoxin Hawthorne  digoxin activity Saquinavir Garlic  saquinavir levels Warfarin Feverfew  risk of bleeding Warfarin Garlic  risk of bleeding Warfarin Ginger  risk of bleeding Warfarin Ginkgo  risk of bleeding Warfarin Ginseng  anticoagulant Lancet 2000;355:134-8.

26. Clinically Important Drug-Disease Interactions Determined by Expert Panel Consensus DrugDisease • Anticholinergics BPH, constipation, dementia • Antiarrhythmics (Type 1A) CHF (systolic dysfunction) • Amphetamines HTN, insomnia • Aspirin PUD • Atypical antipsychotics DM • Barbiturates Depression • Benzodiazepines COPD,dementia, falls • Beta-blockers COPD, DM, syncope • CCB 1st generation CHF (systolic dysfunction) • Chlorpromazine Postural hypotension, seizures • Clozapine Seizures • Corticosteroids DM, PUD • Decongestants Insomnia • Digoxin Heart block Lindblad C, Hanlon J et al. (abstract) J Am Geriatr Soc 2004;52:S135

27. Clinically Important Drug-Disease Interactions Determined by Expert Panel Consensus DrugDisease • Metoclopramide Parkinson’s disease • Nitrofurantoin Chronic renal failure • Non-aspirin NSAIDs CRF, CHF, HTN • Non-aspirin, non-COX II NSAIDs PUD • Opioid analgesics BPH, constipation, dementia • Sedative/hypnotics Falls • Skeletal muscle relaxants BPH • SSRIs Falls • Theophylline Insomnia • Thioridazine Postural hypotension, seizures • Thorazine Seizures • Tricyclic antidepressants Arrhythmias, BPH, constipation dementia, falls, heart block postural hypotension • Typical antipsychotics Falls

28. Learning Objectives At the conclusion of this talk the participant should be able to: • List the 4 major types of drug interactions that can occur in the elderly • Discuss the epidemiology of the different types of drug interactions in the elderly • Implement strategies to prevent/manage drug interactions in the elderly

29. Epidemiology of Drug-Drug or Drug-Disease Interactions • Incidence of potential drug-drug interactions ranges from 2-17% of all Rx's and up to 6-42% of elderly patients. • Incidence of potentially clinically significant drug interactions is low in the elderly (usually must involve narrow therapeutic range drug and inhibitor/inducer of drug metabolism or renal excretion) • There is evidence suggesting that adverse health outcomes associated with drug-drug interactions is infrequent. • Drug-disease interactions occur in 6.2-40% of elderly patients • Drug disease interactions may result in higher risk of adverse outcomes (e.g., decline in functional status and increased health services use) due to alterations in homeostatic mechanisms and diminished functional reserve.

30. Drug Interactions Are Avoidable Gosney et al. Lancet 1984;2:564

31. Strategies to Prevent/Manage Drug Interactions 1. Encourage patients to report all prescription, over-the- counter and complementary and alternative drugs at every health care encounter. 2. Support the implementation of electronic prescribing and/or the use by patients of one pharmacy with updated drug interaction software. 3. Work with pharmacists and be familiar with drug interaction information sources 4. Consider whether drug therapy is necessary 5. When adding a new drug to regimen, screen for potential drug-drug interactions.

32. Strategies to Prevent/Manage Drug Interactions 6. When adding a new drug to regimen in a patient, screen for potential drug-disease interaction. 7. If drug interaction can not be avoided, adjust doses and or/dosage intervals for affected medication and monitor the patient closely. 8. Carefully monitor other drug therapy when withdrawing a drug that can inhibit or induce hepatic metabolism. 9. Regularly review the need for chronic medications- reduce polypharmacy

33. Learning Objectives At the conclusion of this talk the participant should be able to: • List the 4 major types of drug interactions that can occur in the elderly • Discuss the epidemiology of the different types of drug interactions in the elderly • Implement strategies to prevent/manage drug interactions in the elderly