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Medication Use in Older
Adults
Kimberly Keefer, Pharm.D., BCPS
• Sponsored by The Penn State Site of The Geriatric
Education Center of PA Consortium (Penn State, Univ.
of Pittsburgh, and University of Pittsburgh Medical
Center, in conjunction with The Pennsylvania
Behavioral Health and Aging Coalition and Penn
State College of Medicine
• Supported by funds from the Bureau of Health
Professions (BHPr), Health Resources and Services
Administration (HRSA), Department of Health and
Human Services (DHHS) under grant number
UB4HP19199 “Geriatric Education Center of
Pennsylvania”.
Objectives
• Review pharmacokinetics and
pharmacodynamics as they relate to the
elderly population
• Present common adverse drug reactions
and drug-drug interactions seen
• Manage polypharmacy in the elderly
patient
Aging
• Elderly population is expected to reach
22% in 2050.
• By 2012 10,000 people will turn 65 daily.
• By 2027 Inpatient admissions are
expected to increase by 78%.
Koltz U. Pharmacokinetics and drug metabolism in the elderly. Drug
Metabolism Reviews 2009; 41:67-76.
Medication Use
• Older persons over 65 represent 12% of
population but receive 32% of all
prescription drugs and 40% of all
nonprescription medications
• Average 4 to 5 prescriptions and 2 OTC
drugs at a time
Cusack B. Pharmacokinetics in Older Persons. The American
Journal of Geriatric Pharmacotherapy 2004; vol 2 (number 4):
274-302.
Drugs and the Body
• Pharmacokinetics: how the body handles
the drug
• Pharmacodynamics: how various target
organs respond to the drug
• Changes with aging:
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Drugs having prolonged durations of activity
Greater risks of toxicity
Increased frequency of adverse effects
Different effects than anticipated from a given dose
Catterson M et al. Pharmacodynamic and Pharmacokinetic , Considerations in
Geriatric Psychopharmacology 1997; 20: 205-17.
Drugs and the Body (cont.)
• Differentiate multiple disease states
• Neurologic
• Cardiovascular
• Pulmonary
• Hepatic
• Renal
• Immunologic
• Endocrine
Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr
Med 2007; 23:371-390.
Pharmacokinetics
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•
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Absorption
Distribution
Metabolism
Elimination
Absorption
• Drug absorption
– Passive process (most drugs absorbed in the
small bowel)
• pH
• Drug binding
• Gastric motility
– Delay in absorption: the onset of action will
be delayed but total amount of drug
absorbed not affected
Koltz U. Pharmacokinetics and drug metabolism in the elderly. Drug
Metabolism Reviews 2009; 41:67-76.
Distribution
Koltz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metabolism Reviews 2009; 41:67-76.
Distribution
• Polar drugs (e.g., Lithium, digoxin) ↓
• Lipophilic drugs (e.g., diazepam) ↑
• Albumin (10-20% decline)
• Phenytoin
• Furosemide
• NSAIDs
• Warfarin
Hayes B, Klein-Schwartz W, Barrueto F. Polypharmacy and the
Geriatric Patient. Clin Geriatr Med 2007; 23:371-390.
Metabolism
• Liver by cytochrome P450 (CYP)
• Phase I reactions and/or phase II pathways such
as glucuronidation, acetylation, or sulfatation
• Biosynthesis and degradation of chemicals,
toxins and medications
• Water soluble to facilitate elimination
• CYP3A4, 2D6, 1A2, and 2C9 IMPORTANT!
• Blood flow in the liver can decrease by
up to 40% = ↓ clearance of drugs
Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007;
23:371-390.
Elimination
• Kidney mass and number of glomeruli
decreases by 20-30%
• 1/3 of patients have no decrease in renal function
• Confounding factors: hypertension, chronic heart
diseases, and diabetes
• Half lives of drugs are prolonged
• Drug serum levels ↑
• Decline in renal function is closely related to
the incidence of adverse drug reactions
(ADRs)
Cusack B. Pharmacokinetics in Older Persons. The American Journal of
Geriatric Pharmacotherapy 2004; vol 2 (number 4): 274-302.
Factors Affecting Creatinine Generation
Stevens L et al. N England J Med 2006;354:2473-2483
Which of the following is not true
of Aging?
A. Increased body fat
B. Decreased gastric motility causes
decreased total amounts of drug
absorbed
C. Decreased blood flow to the liver
decreases clearance of drugs
D. Decreased total body water
Pharmacodynamics
 Dopaminergic System
 Progressive loss of dopamine D2 receptors
 Increased incidence of extrapyramidal syndromes such as
tardive dyskinesia
 Associated with Parkinson’s disease
 Cholinergic System
 Important in memory and other higher cognitive functions
 Associated with Alzheimer’s dementia
 Adrenergic System
 Reduction of beta-adrenergic and Alpha2 adrenoreceptors
 Response to agents like clonidine is decreased
 Gabaminergic System
 Greater impairment in psychomotor performance with agents
like Benzodiazepines
Catterson M, et al. Pharmacodynamic and Pharmacokinetic. Considerations in
Geriatric Psychopharmacology 1997; 20: 205-17.
Adverse Drug Reactions (ADRs)
• 7 times more common in persons aged
70 to 79 than in those 20 to 29
• Up to 17% of elderly hospital admission
• Antibiotics, anticoagulants, digoxin,
diuretics, hypoglycemic agents,
antineoplastic agents and NSAIDs are
responsible for 60% of ADRs leading to
hospital admission and 70% of ADRs
occurring in hospitals
Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care Clinics 2006;22:
329-45.
ADRs
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Discontinue the drug
Change drug therapy
Modify the dose
Necessitates admission to the hospital
Prolongs stay
Complicates diagnosis
Affects prognosis
Results in harm or death
Routledge P, et al. Adverse drug reactions in elderly patients. British Journal
of Clinical Pharmacology. 2003; 57: 121-126.
Symptoms of ADRs
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 freq of falls
 confusion
Excessive sedation
Constipation
Urinary retention
 oral intake
Failure to thrive
Routledge P, et al. Adverse drug reactions in elderly patients. British Journal of
Clinical Pharmacology. 2003; 57: 121-126.
Incidence and Preventability of Adverse
Drug Events Among Older Persons in the
Ambulatory Setting
• > 65 years of age
• 12 month study ending June 2000
• Ambulatory Setting
• Outcome Measures: Adverse drug events
– Errors in prescribing
– Dispensing
– Patient adherence
– Monitoring
Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older Persons
in the Ambulatory Setting. JAMA 2003; 289: 1107-1116.
Characteristics and Type of Adverse Event
Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older Persons in the
Ambulatory Setting. JAMA 2003; 289: 1107-1116.
Frequency of Event by Drug Class
Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older
Persons in the Ambulatory Setting. JAMA 2003; 289: 1107-1116.
Frequency of Type of Event
Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older Persons in the Ambulatory Setting. JAMA 2003; 289: 1107-1116.
Conclusions from Study
• Preventable efforts for those known adverse drug effects such
as electrolytes/renal, hemorrhagic and metabolic/endocrine
effects.
• Most errors associated with preventable adverse drug events
occurred at the prescribing and monitoring stages
• Active prompting to prescriber to perform follow-up lab
testing
• Anticoagulants
• Thyroid medications
• Anti-seizure medications
• Cardiovascular drugs
• 20% contributed to patient adherence
Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among
Older Persons in the Ambulatory Setting. JAMA 2003; 289: 1107-1116.
ADRs
Drug
Age-Related Effects
NSAIDs (e.g. diclofenac, celecoxib)
Volume overload, hypertension, decline in GFR
NSAIDs, antibiotics, diuretics, H2-blockers
Idiosyncratic acute interstitial nephritis and acute kidney injury
Bisphosphonates
Nephrotoxicity in 17% of elderly
Levofloxacin, moxifloxacin
Confusion, seizures, psychosis
Moxifloxacin
QTc interval prolongation
Anticholinergic drugs (e.g. donepezil)
Cognitive impairment, psychosis
Nondihydropyridine calcium channel blockers (e.g. diltiazem,
verapamil)
Decrease in PR interval without consequences
Dihydropyridine calcium channel blockers
Increased effect
Opioids
Impaired neurotransmitter production, increased receptor affinity
CNS drugs (e.g.benzodiazepines), psychotropic drugs,
anesthetics, antiepileptics (e.g. phenytoin)
Increased sensitivity, tremor, ataxia, cognitive difficulties
Warfarin
Increased sensitivity
Midazolam
Increased sensitivity
Angiotensin Converting Enzyme Inhibitors
Impaired renal clearance
Aymanns C, et al. Review on Pharmacokinetics and Pharmacodynamics and the Aging
Kidney. Clin J Am Soc Nephrol 2010; 5: 314-27.
Avoiding ADRs
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Avoid combinations with toxic effects
Titrate slowly
Monitor levels
Keep drugs to a minimum
Limit number of physicians/pharmacies
Report ADRs
1. Fluoroquinolones
(ciprofloxacin, moxifloxacin, levofloxacin)
2. NSAIDs
3. Warfarin
4. Donepezil
A. Volume overload
B. Acute Interstitial
Nephritis
C. Seizures
D. GI bleed
E. Psychosis
Drug Interactions
• 50% probability for having a drug
interaction when a patient is receiving
five medications
• The probability increases to 100% when
7 drugs are used.
Drug Interactions
Drug or drug class
Precipitant drug or drug class
Interaction
Benzodiazepines
(alprazolam, triazolam)
Azole antifungals (fluconazole,
itraconazole, ketoconazole)
Increased benzodiazepine concentration because of
inhibition of CYP
Carbamazepine
Propoxyphene
Increased carbamazepine concentration because of
decreased hepatic metabolism
Dextromethorphan
MAO inhibitors (phenelzine,
selegiline, tranylcypromine)
Increased risk of serotonin syndrome due to altered
catecholamine uptake and metabolism.
MAO inhibitors
Serotonin syndrome symptoms:
Mental status changes: anxiety, agitation, delirium,
restlessness, and disorientation
Autonomic manifestations: diaphoresis,
tachycardia, hyperthermia, hypertension, vomiting,
and diarrhea
Neuromuscular hyperactivity: tremor, muscle
rigidity, myoclonus, hyperreflexia
Increased risk of serotonin syndrome
SSRIs
Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care
Clinics 2006;22: 329-45.
Drug Interactions (cont.)
Drug or drug class
Meperidine
Precipitant drug or drug
class
MAO inhibitors
Interaction
Nitrates
Sildenafil, tadalafil,
vardenafil
Increased risk for cardiovascular
instability, hyperpyrexia, agitation,
seizures, diaphoresis (unknown
mechanism)
Increased hypotensive effect due to
increased levels of cGMP
Pimozide
Macrolides and azole
antifungals
Increased risk for cardiotoxicity due
to inhibition of CYP3A
Digoxin
Clarithromycin
Increased digoxin toxicity due to
inhibition of p-glycoprotein
Digoxin
Amiodarone
Decreased clearance of digoxin
leading to dig toxicity
Decrease dig dose by 50% when
initiating amiodarone
Theophylline
Fluoroquinolones
Increased concentration of
(ciprofloxacin)
theophylline because of inhibition of
Fluvoxamine
CYP
Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care
Clinics 2006;22: 329-45.
Drug Interactions (cont.)
Drug or drug class
Precipitant drug or drug class
Interaction
Warfarin
NSAIDs
Warfarin
Cimetidine
Increased risk for bleeding because of
gastric erosion and inhibition of platelet
aggregation
Increased warfarin concentration leading
to increased risk of bleeding
Warfarin
Fibric acid (clofibrate,
fenofibrate, gemfibrozil)
Increased risk of bleeding due to unknown
mechanism
Warfarin
Barbiturates
Warfarin
Thyroid hormones
Decreased warfarin concentration due to
increased metabolism.
Increased risk of bleeding because of
increased metabolism of vitamin Kdependent clotting factors. No increased
risk if warfarin is started after patient is on
stable thyroid hormone therapy.
Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care Clinics
2006;22: 329-45.
Avoiding Drug Interactions
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Avoid the combination
Adjust the dose of the object drug
Alter the administration times
Monitor for early detection
Delafuente J. Understanding and preventing drug interactions in elderly patients.
Critical Reviews in Oncology/Hematology. 2003; 48: 133-143.
Which of the following is not true?
A. SSRIs and MAOIs when taken together can lead
to serotonin syndrome
B. Warfarin interacts with NSAIDs by increasing
risk for bleeding because of gastric erosion and
inhibition of platelet aggregation
C. Amiodarone dose needs to be increased by
50% when starting warfarin therapy
D. All of the following are inhibitors of CYP 2c9:
Warfarin, Fluconazole, Amiodarone,
Metronidazole and Bactrim
Polypharmacy
• Definition: refers to problems that can
occur when a patient is taking more
medications than are actually needed
• Adverse drug reactions
• Drug-drug interactions
• Decreased compliance
• Drug expense
Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr Med
2007; 23:371-390.
Factors Leading to Polypharmacy
• Complex medication regimen
• Multiple physicians/pharmacies
• Lack of reporting all
medications/symptoms
• Prescribing without compete diagnosis
• Lack of medication instructions
• Daily activities
Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007;
23:371-390.
Patient Education
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Pill boxes/timers
Medication log
Report missed doses
Avoid skipping pills
Avoid cutting medication in half
Don’t stop medication if they “feel good”
Report adverse effects of medication
Compliance
• Highest rates of Noncompliance
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Elderly living alone
Using > 2 medications
No assistance taking medications
Using more than 1 pharmacy
Women traditionally > men regarding noncompliance
Patient recall/Forgetfulness
Increased number of physicians
Cost of medication
»
»
»
»
Higher monthly cost after insurance reimbursement
Not covered by insurance
Perceived expense
Household income
Warfarin
• Warfarin use is rising
• Aging population
• Increase in atrial fibrillation and venous
thromboembolism
• Narrow therapeutic index
• Risk of bleeding
– Increased sensitivity to warfarin
• Reduced drug clearance
• Lower body weight
• Lower dietary vitamin K intake
– Concurrent use of other drugs
– Co-morbidities that increase bleeding risk
Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr Med
2007; 23:371-390.
Warfarin (cont.)
• Fall risk
• Decline in cognitive function
– Lack of awareness of drug and food
interactions
– Problems administering the medication
Hayes B, et al. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007;
23:371-390.
Monitoring Warfarin
• International Normalized Ratio (INR)
– World Health Organization developed INR with the PT test
for patients who are receiving warfarin
– Calculation that adjusts for changes in the PT reagents and
allows for results from different laboratories to be
compared
• INR will need to be monitored at least once
monthly
– Narrow therapeutic window
– Dose is not fixed but rather based upon INR
• INR below goal -- blood clots cannot be
prevented
• INR above goal -- increased risk of bleeding
Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
Warfarin. LexiComp Online. 2009
Medications that Increase INR/Risk for
Bleeding
Anti-infectives
oFluoroquinolones
oCotrimoxazole
oMacrolides
oMetronidazole
oTriazole antifungals
oAmoxicillin
Cardiovascular
oAmiodarone
oDiltiazem
oFenofibrate
oGemfibrozil
oPropanolol
oStatins
Analgesics
oNSAIDs
oAspirin
oAcetaminophen (≥ 4g chronically)
Herbals/supplements
oFish oil, omega-3, vitamin E
oGinseng, garlic, ginko biloba, ginger
oCoenzyme Q10
oCranberry
Others
oSSRIs
oPhenytoin
oOmeprazole/esomeprazole
oCimetidine
oAllopurinol
oAntineoplastic agents
oCorticosteroids
oProthyroid agents
Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
Warfarin. LexiComp Online. 2009
Medications that Decrease INR
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Rifampin
Carbamazepine
Bile acid sequestrants
Sucralafate
Oral contraceptives
Antithyroid agents
Green tea
St. John’s Wort
Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
Warfarin. LexiComp Online. 2009
Diet
 Significant changes in vitamin K intake can upset
warfarin stability- consistency is key!
o Increased intake- decreased INR
o Decreased intake- increased INR
 Foods high in vitamin K
o Fruits and vegetables
 Especially avocado, mango, broccoli, spinach, cabbage
o
o
o
o
Mayonnaise-based dressings
Chewing tobacco
Anise (Found in some cookies and black licorice)
Oils (Canola, corn, olive, peanut, safflower, sesame seed, soybean, and sunflower)
 Alcohol
o Acute alcohol consumption enhances warfarin's availability, increasing the patient's
risk for hemorrhaging.
o Chronic alcohol consumption reduces warfarin's availability, lessening the patient's
anticoagulation.
Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
Warfarin. LexiComp Online. 2009
Side Effects
• Immediate medical attention should be
sought out for the following:
• Signs of stroke/ intracranial bleeding
• Severe/unusual headache, confusion,
weakness, numbness
• Coughing up large amounts of bright red blood
• Vomiting blood
• Bleeding that will not stop
• Bright red blood in stool
• Fall or injury to head
Dabigatran (Pradaxa®)
• Indications
• Nonvalvular atrial fibrillation (to prevent stroke and
systemic embolism)
• MOA: directly inhibits formation of thrombin
• Dose
• 150mg orally twice daily
• CrCl 15-30mL/min: 75mg orally twice daily
• CrCl < 15mL/min or on dialysis: Not recommended
Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals, Inc,
Ridgefield, CT. 2010.
Advantages of Dabigatran
• Requires no monitoring
• Unaffected by food
• Few Drug-Drug interactions
• Concomitant use of following increase bleeding
risk:
– NSAIDs
– Clopidogrel
– Prasugrel
– Aspirin
• P-glycoprotein inducers (e.g. Rifampin)
• Pregnancy Category C (Warfarin category X)
Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals,
Inc, Ridgefield, CT. 2010.
Dabigatran Pitfalls
• Lack of a way to monitor adherence
• No reversal agent in event of
overdose/severe bleeding
• Cost is > than warfarin
• Lack of coverage by insurance
• Twice daily dosage regimen
• Limited indications
• Capsules must be swallowed whole
• Increased bioavailability of the drug by 75%
Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals, Inc,
Ridgefield, CT. 2010.
Dabigatran Side Effects
• Bleeding
• Should be withheld before invasive or surgical
procedures
• GI:
• Dyspepsia (11.3% vs. 5.8% warfarin)
• Abdominal pain
• GERD
• Gastric hemorrhage
• GI ulcer
Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals, Inc, Ridgefield, CT.
2010.
Conclusions
• Effect of aging on medications for elderly
populations
• Confounding factors such as comorbidities (frailty)
• Drug interactions and adverse drug
effects
• Impairments in organ functions
• Managing older patients with medications
that have a narrow therapeutic index
References
Antithrombotic and Thrombolytic Therapy 8th Ed: ACCP Guidelines
Aymanns C, Keller F, Maus S, et al. Review on Pharmacokinetics and Pharmacodynamics and the Aging
Kidney. Clin J Am Soc Nephrol 2010; 5: 314-27.
Catterson M, Preskorn S, Martin R. Pharmacodynamic and Pharmacokinetic Considerations in Geriatric
Psychopharmacology 1997; 20: 205-17.
Cusack B. Pharmacokinetics in Older Persons. The American Journal of Geriatric Pharmacotherapy 2004;
vol 2 (number 4): 274-302.
Delafuente J. Understanding and preventing drug interactions in elderly patients. Critical Reviews in
Oncology/Hematology 2003; 48: 133-143.
Gurwitz J, Field T, et al. Incidence and Preventability of Adverse Drug Events Among Older Persons in the
Ambulatory Setting. JAMA 2003; 289: 1107-1116.
Hayes B, Klein-Schwartz W, Barrueto F. Polypharmacy and the Geriatric Patient. Clin Geriatr Med 2007;
23:371-390.
Koltz U. Pharmacokinetics and drug metabolism in the elderly. Drug Metabolism Reviews 2009; 41:67-76.
Mann HJ. Drug-Associated Disease: Cytochrome P450 Interactions. Critical Care Clinics 2006;22: 329-45.
Noble R. Drug therapy in the elderly. Metabolism. 2003; 52: 27-30.
Pradaxa® Prescribing Information. Boehringer Ingelhem Pharmaceuticals, Inc, Ridgefield, CT. 2010.
Routledge P, O’Mahony M, Woodhouse K. Adverse drug reactions in elderly patients. British Journal of
Clinical Pharmacology 2003; 57: 121-126.
Stevens L, Coresh J, Greene T, et al. Assessing Kidney Function-Measured and Estimated Glomerular
Filtration Rate. The New England Journal Of Medicine 2006; 354: 2473-83.
Warfarin. LexiComp Online. 2009
QUESTIONS?
Kimberly Keefer, Pharm.D., BCPS
Clinical Internal Medicine Pharmacist
Penn State Milton S. Hershey Medical Center
500 Univesity Drive
P.O. Box 850
Hershey, PA 17033
Tel: 717-531-0003
Ext: 284222
[email protected]