# Presentation: 056432

## 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

- Drug-Drug Pharmacokinetic
- Drug-Drug Pharmacodynamic
- Drug-Food/Nutrient
- 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 __	__%     __	__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

## 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

## Effect of Age on Theophylline Hepatic 

- 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 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; 14;349:675-83; JAPHA 2004;44:142-51

## Clinically SignificantDrug-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_    		 _3A4_
- Smoking	Rifampin	None		Carbamazepine
- Omeprazole	Phenobarbital			Phenytoin
- Phenytoin	Phenytoin			Phenobarbital
- 							Rifampin
- 							St. John’s wort
- www.drug-interactions.com

## Effect of Age on Theophylline Hepatic Metabolism Induction by DPH 

- 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

- Dosage
- Regimen

- Effects

- Plasma
- Concen
- tration

- Site of
- Action

## 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

- 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_    			_Outcome_
- 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

## 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 2000;355:134-8.

## 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 2004;52:S135

## Clinically Important Drug-Disease Interactions Determined by Expert Panel Consensus

- 		_Drug_					_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 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.

## 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