Drug Interactions in Older Adults
Joseph T. Hanlon, PharmD, MS
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
Types of Drug Interactions
1. Drug-Drug Pharmacokinetic
2. Drug-Drug Pharmacodynamic
3. Drug-Food/Nutrient
4. Drug-Disease
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
Hepatic Metabolism
Phase I (CYP 450)
• Oxidation
hydroxylation
dealkylation
sulfoxidation
• Reduction
• Hydrolysis
Phase II
• Conjugation
glucuronidation
sulfation
glycine
acetylation
Cytochrome P450 Phase I Isoenzymes, % Total and Substrate Examples
Isoenzymes % SubstrateCYP1A2 17 Olanzapine, TheophyllineCYP2C9/19 26 Phenytoin, WarfarinCYP2D6 2-4 Codeine, Desipramine, TramadolCYP2E1 9-10 Chlorzoxazone, EthanolCYP3A4 35-45 Diazepam, Triazolam, Quinidine,
Methadone, Carbamazepine
www.drug-interactions.com
Inhibitors of Hepatic Cytochrome P450
1A2 2C9/19 2D6 3A4Fluvoxamine Amiodarone Fluoxetine ErythromycinCimetidine Fluconazole Paroxetine Azole
antifungalCiprofloxacin Fluvastatin Quinidine Nefazodone
Fluoxetine Ritonavir ClarithromycinIsoniazid Bupropion RitonavirSertraline Cimetidine CimetidineOmeprazoleCimetidine
www.drug-interactions.com
J Pharmacol Exp Ther 1997;280:627-37.
Effect of Age on Theophylline Hepatic
Metabolism Inhibition
Drugs That Interact with Theophylline
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
Drug-Drug Interactions With WarfarinInteracting Drug Mechanism Anticoagulant 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
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
Inducers of Hepatic Cytochrome P450
1A2 2C9/19 2D6 3A4Smoking Rifampin None CarbamazepineOmeprazole Phenobarbital PhenytoinPhenytoinPhenytoin Phenobarbital
RifampinSt. John’s
wort
www.drug-interactions.com
Effect of Age on Theophylline Hepatic Metabolism Induction by DPH
Crowley J. J Phamacol Exp Ther 1988;245:513-23.
Selected Phenytoin Induction Interactions
Object Drug Interacting Drug CYP Isoenzyme Induced
Methadone Phenytoin 3A4
Quinidine Phenytoin 3A4
Theophylline Phenytoin 1A2
Warfarin Phenytoin 2C9
Neuropharmacology 2002;5:280-9.
Selected Drugs Secreted by Renal Tubules
Basic (cationic) Agents
• Amiodarone
• Cimetidine
• Digoxin
• Procainamide
• Quinidine
• Ranitidine
• Trimethoprim
• Verapamil
Acidic (Anionic) Agents
• Cephalosporins
• Indomethacin
• Methotrexate
• Penicillins
• Probenecid
• Salicylates
• Thiazides
Drug-Drug Interactions With Digoxin
Interacting Drug Effect on Levels
Amiodarone
Clarithromycin
Propafenone
Quinidine
Verapamil
Drug Saf. 2000;23:509-32; JAPHA 2004;44:142-51
Drugs that Interact with Lithium
• Diuretics
• ACE-I
• NSAIDs
Pharmacokinetics Pharmacodynamics
DosageRegimen Effects
PlasmaConcentration
Site ofAction
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
Drug- TCA PD Interactions
• Concurrent use with any other drugs with antimuscarinic properties
• Concurrent MAOI
• Type I antiarrhythmics
• Clonidine
• Guanadrel
• Guanethidine
Drug-NSAID PD Interactions
Object Drug Interacting Drug Outcome
Antihypertensives NSAIDs BP
Corticosteroids NSAIDs risk of PUD
Diuretics NSAIDs diuretic effect
Triamterene Indomethacin K+
Warfarin NSAIDs anticoagulant
effect
CNS Polypharmacy and Falls in Elderly Persons
1
1.54
2.37
0
1
2
3
4
5A
djus
ted
odds
rat
io
0 1 >2CNS - active medications (n)
Weiner D, et al. Gerontol 1998;44:217-21
Drug-Food/Nutrient Interactions
Drug Effect
Phenytoin ↓ Folate
Isoniazid ↓ Vit B6
Phenytoin ↓ Absorption with NG feedings
Levodopa High protein meals effect blood-brain transport
Captopril Altered taste sensation
Clinically Significant Drug –St. John Wort Interactions
Object Drug OutcomeAntidepressants serotonergic syndromeCyclosporine levels, transplant rejectionDigoxin digoxin levelsEstrogen breakthrough bleedingIndinavir indinavir levelsMethadone withdrawal sx’sTacrolimus levelsTheophylline theophylline levelsWarfarin INR
CPT 2004;75:1-12
Other Clinically Significant Herb- Drug Interactions
Object Drug Interacting Drug OutcomeAnticonvulsants Wormwood seizure thresholdAnticonvulsants Gingko biloba seizure thresholdDigoxin Hawthorne digoxin activitySaquinavir Garlic saquinavir levelsWarfarin Feverfew risk of bleedingWarfarin Garlic risk of bleedingWarfarin Ginger risk of bleedingWarfarin Ginkgo risk of bleedingWarfarin Ginseng anticoagulant
Lancet 2000;355:134-8.
Clinically Important Drug-Disease Interactions Determined by Expert Panel
ConsensusDrug Disease
– 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
Clinically Important Drug-Disease Interactions Determined by Expert Panel
ConsensusDrug Disease
– 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
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
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.
Drug Interactions Are Avoidable
Gosney et al. Lancet 1984;2:564
Previous
adverse reactions
Contraindicated drugs
Drug interactions Totals
Avoidable 7 57 67 131
Probably avoidable
---- ---- 37 37
Uncertain ---- 3 29 32
Total 7 60 133 200
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 prescribingand/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 necessary5. When adding a new drug to regimen, screen for potential
drug-drug interactions.
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
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