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