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

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Types of Drug Interactions

• Drug-Drug Pharmacokinetic
• Drug-Drug Pharmacodynamic
• Drug-Food/Nutrient
• Drug-Disease

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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 199812485-94

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Hepatic Metabolism

• Phase I (CYP 450)
• Oxidation
• hydroxylation
• dealkylation
• sulfoxidation
• Reduction
• Hydrolysis

• Phase II
• Conjugation
• glucuronidation
• sulfation
• glycine
• acetylation

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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

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Inhibitors of Hepatic Cytochrome P450

• 1A2 2C9/19 2D6 3A4
• 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

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Effect of Age on Theophylline Hepatic Metabolism
Inhibition
J Pharmacol Exp Ther 1997280627-37.
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Drugs That Interact with Theophylline

• Inhibitors
• Cimetidine
• Propafenone
• Mexiletine
• Propranolol
• Erythromycin
• Ciprofloxacin
• Fluvoxamine
• Drugs Aging. 20032071-84

• Inducers
• Barbiturates
• Phenytoin
• Smoking
• Rifampin
• Carbamazepine
• JAPHA 200444142-51

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Drug-Drug Interactions With Warfarin

• Interacting 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 14349675-83 JAPHA
  200444142-51

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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 20025280-9

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Inducers of Hepatic Cytochrome P450

• 1A2 2C9/19 2D6 3A4
• Smoking Rifampin None Carbamazepine
• Omeprazole Phenobarbital Phenytoin
• Phenytoin Phenytoin Phenobarbital
• Rifampin
• St. Johns wort
• www.drug-interactions.com

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Effect of Age on Theophylline Hepatic Metabolism
Induction by DPH
Crowley J. J Phamacol Exp Ther 1988245513-23.
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Selected Phenytoin Induction Interactions

• Object Drug Interacting Drug CYP Isoenzyme
  Induced
• Methadone Phenytoin 3A4
• Quinidine Phenytoin 3A4
• Theophylline Phenytoin 1A2
• Warfarin Phenytoin 2C9
• Neuropharmacology 20025280-9.

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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

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Drug-Drug Interactions With Digoxin

• Interacting Drug Effect on Levels
• Amiodarone ?
• Clarithromycin ?
• Propafenone ?
• Quinidine ?
• Verapamil ?
• Drug Saf. 200023509-32 JAPHA 200444142-51

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Drugs that Interact with Lithium

• Diuretics
• ACE-I
• NSAIDs

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Pharmacokinetics
Pharmacodynamics
Dosage Regimen
Effects
Plasma Concen tration
Site of Action
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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

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Drug- TCA PD Interactions

• Concurrent use with any other drugs with
  antimuscarinic properties
• Concurrent MAOI
• Type I antiarrhythmics
• Clonidine
• Guanadrel
• Guanethidine

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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

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CNS Polypharmacy and Falls in Elderly Persons
Weiner D, et al. Gerontol 199844217-21
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Drug-Food/Nutrient Interactions
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Clinically Significant Drug St. John Wort
Interactions

• Object Drug Outcome
• Antidepressants serotonergic syndrome
• Cyclosporine ? levels, transplant rejection
• Digoxin ? digoxin levels
• Estrogen breakthrough bleeding
• Indinavir ? indinavir levels
• Methadone withdrawal sxs
• Tacrolimus ? levels
• Theophylline ? theophylline levels
• Warfarin ? INR
• CPT 2004751-12

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Other Clinically Significant Herb- Drug
Interactions

• Object Drug Interacting Drug Outcome
• 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 2000355134-8.

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Clinically Important Drug-Disease Interactions
Determined by Expert Panel Consensus

• Drug 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 200452S135

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Clinically Important Drug-Disease Interactions
Determined by Expert Panel Consensus

• Drug Disease
• Metoclopramide Parkinsons 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

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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

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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.

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Drug Interactions Are Avoidable

• Gosney et al. Lancet 19842564

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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.

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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

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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