Download GNRS4Pharmacotherapy

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PHARMACOTHERAPY
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OBJECTIVES
Know and understand:
• Key issues in geriatric pharmacology
• Effects of age on pharmacokinetics and
pharmacodynamics
• Risk factors for adverse drug events for older
patients and ways to mitigate them
• Principles of prescribing for older patients
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TO P I C S C O V E R E D
• Challenges of Geriatric Pharmacology
• Aging and Pharmacokinetics
• Aging and Pharmacodynamics
• Adverse Drug Events
• Drug-drug and Drug-disease Interactions
• Principles of Prescribing for Older Adults
• Nonadherence
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WHY GERIATRIC PHARMACOTHERAPY
IS IMPORTANT
People 65+
65+ share of prescriptions
People <65
<65 share of presciptions
100
90
80
70
60
50
40
30
20
10
0
Present
2040
Now, people age 65+ are 13% of US population, buy 33% of prescription drugs
By 2040, will be 25% of population, will buy 50% of prescription drugs
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W H Y G E R I AT R I C P H A R M A C O T H E R A P Y
IS CHALLENGING
• More drugs are available each year
• FDA and off-label indications are expanding
• Formularies change frequently
• Knowledge of drug-drug interactions advances
• Drugs change from prescription to OTC
• “Nutraceuticals” (herbal preparations, nutritional
supplements) are booming
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PHARMACOKINETICS
• Absorption
• Distribution
• Metabolism
• Elimination
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AGING AND ABSORPTION
• Amount absorbed (bioavailability) is not
changed
• Peak serum concentrations may be lower and
delayed
• Exceptions: drugs with extensive first-pass
effect (bioavailability may increase and serum
concentrations may be higher because less
drug is extracted by the liver, which is smaller
with reduced blood flow)
FA C TO R S T H AT A F F E C T
DRUG ABSORPTION (1 of 2)
• Route of administration
• What is taken with the drug
• Comorbid illnesses
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FA C TO R S T H AT A F F E C T
DRUG ABSORPTION (2 of 2)
• Divalent cations (calcium, magnesium, iron) can
affect absorption of many fluoroquinolones (eg,
ciprofloxacin)
• Enteral feedings interfere with absorption of some
drugs (eg, phenytoin)
• Increased gastric pH may increase or decrease
absorption of some drugs
• Drugs that affect GI motility can affect absorption
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EFFECTS OF AGING ON
VOLUME OF DISTRIBUTION (VD)
• Age-associated changes in body composition can alter
drug distribution
•  body water  lower VD for hydrophilic drugs
•  lean body mass  lower VD for drugs that bind to
muscle
•  fat stores  higher VD for lipophilic drugs
•  plasma protein (albumin)  higher percentage of
drug that is unbound (active)
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A G I N G A N D M E TA B O L I S M
Metabolic clearance of a drug by the liver may
be reduced because:
• Aging decreases liver blood flow, size and
mass
• The liver is the most common site of drug
metabolism
W H Y T H E M E TA B O L I C
PAT H WAY M AT T E R S
• Phase I pathways (eg, hydroxylation, oxidation,
dealkylation, and reduction) convert drugs to
metabolites with <, =, or > pharmacologic effect than
parent compound
• Phase II pathways convert drugs to inactive
metabolites that do not accumulate
 With few exceptions, drugs metabolized by phase II
pathways are preferred for older patients
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O T H E R FA C TO R S T H AT A F F E C T
D R U G M E TA B O L I S M
• Age and gender (eg, oxazepam is metabolized
faster in older men than in older women;
nefazodone concentrations are 50% higher in
older women than in younger women)
• Hepatic congestion from heart failure (eg, reduces
metabolism of warfarin)
• Smoking (eg, increases clearance of theophylline)
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KEY CONCEPTS ABOUT
D R U G E L I M I N AT I O N
• Half-life: Time for serum concentration of drug
to decline by 50%
• Clearance: Volume of serum from which the
drug is removed per unit of time (eg, L/hour or
mL/minute)
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KIDNEY FUNCTION IS CRITICAL
F O R D R U G E L I M I N AT I O N
• Most drugs exit the body via the kidney
• Reduced elimination  drug accumulation
and toxicity
• Aging and common geriatric disorders can
impair kidney function
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THE EFFECTS OF AGING
ON THE KIDNEY
 kidney size
 renal blood flow
 number of functioning nephrons
 renal tubular secretion
Result: Lower glomerular filtration rate
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S E R U M C R E AT I N I N E D O E S N O T
R E F L E C T C R E AT I N I N E C L E A R A N C E
 lean body mass  lower creatinine production
and
 glomerular filtration rate (GFR)
Result: In older people, serum creatinine stays in
normal range, masking change in creatinine
clearance (CrCl)
T W O WAY S TO D E T E R M I N E
C R E AT I N I N E C L E A R A N C E
Measure
• Time-consuming
• Requires 24-hour urine collection
• 8-hour collection may be accurate but not
widely accepted
Estimate
• Usually done with the Cockroft-Gault equation
(see next slide)
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C O C K R O F T- G A U LT E Q U AT I O N
(Ideal weight in kg) (140 – age)
_________________________ x (0.85 if female)
(72) (serum creatinine in mg/dL)
L I M I TAT I O N S O F T H E
C O C K R O F T- G A U LT E Q U AT I O N
• In patients without a significant age-related decline in
renal function, the equation underestimates CrCl
• In patients with muscle mass reduced beyond normal
aging, the equation overestimates CrCl
• Modification of Diet in Renal Disease (MDRD) is
another method for estimating GFR
 Not validated in adults ≥70 years old or in racial or
ethnic groups other than white and black Americans
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PHARMACODYNAMICS
• Definition: Time course and intensity of the
pharmacologic effect of a drug
• May change with aging, for example:
 Benzodiazepines may cause more sedation and
poorer psychomotor performance in older adults
(likely cause: reduced clearance of the drug and
resultant higher plasma levels)
 Older patients may experience longer pain relief
with morphine
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SUCCESSFUL PHARMACOTHERAPY
• Uses the correct drug
• Prescribes the correct dosage
• Targets the correct condition
• Is appropriate for the patient
Failure in any one of these
can result in adverse drug events (ADEs)
THE BURDEN OF INJURIES
FROM MEDICATIONS (1 of 3)
ADEs are responsible for 5% to 28% of
acute geriatric hospital admissions
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THE BURDEN OF INJURIES
FROM MEDICATIONS (2 of 3)
Incidence of ADEs in
hospitals: 26/1000 beds
(2.6%)
ADEs occur in 35% of
community-dwelling
older adults
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THE BURDEN OF INJURIES
FROM MEDICATIONS (3 of 3)
1.4
1.2
1
0.8
0.6
0.4
0.2
0
In nursing homes, $1.33 is spent on ADEs
for every $1.00 spent on medications
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M E D I C AT I O N S M O S T
C O M M O N LY I N V O LV E D I N A D E s
• Cardiovascular drugs, diuretics, NSAIDs,
hypoglycemics, and anticoagulants
• Medications with a narrow margin of safety
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OPTIMIZING PRESCRIBING (1 of 2)
• Achieve balance between over- and underprescribing
of beneficial therapies
• >20% of ambulatory older adults receive at least one
potentially inappropriate medication
• Nearly 4% of office visits and 10% of hospital
admissions result in prescription of medications
classified as never or rarely appropriate
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OPTIMIZING PRESCRIBING (2 of 2)
• Underprescribing can result from thinking that older
adults will not benefit from:
 Medications intended as primary or secondary
prevention
 Aggressive treatment of chronic conditions
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BEERS CRITERIA
• Originally developed in 2003 and updated in 2012 by the
American Geriatrics Society
• Intend to improve drug selection and reduce exposure to
potentially inappropriate medications in older adults
• Recommendations are evidence-based and in 3
categories:
 Drugs to avoid
 Drugs to avoid in patients with specific diseases or syndromes
 Drugs to use with caution
• Available at AGS web site: www.americangeriatrics.org
COMMONLY OVERPRESCRIBED AND
INAPPROPRIATELY USED DRUGS
• Anti-infective agents
• Anticholinergic agents
• Urinary & GI
antispasmodics
• Antipsychotics
• Benzodiazepines
• Digoxin for diastolic
dysfunction
• Dipyridamole
•
•
•
•
•
•
•
H2 receptor antagonists
Laxatives & fecal softeners
NSAIDs
Proton-pump inhibitors
Sedating antihistamines
Tricyclic antidepressants
Vitamins and minerals
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COMMONLY
UNDERPRESCRIBED DRUGS
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•
ACE inhibitors for patients with diabetes and proteinuria
•
Angiotensin-receptor blockers
•
Anticoagulants
•
Antihypertensives and diuretics for uncontrolled hypertension
•
β-blockers for patients after MI or with heart failure
•
Bronchodilators
•
Proton-pump inhibitors or misoprostol for GI protection from NSAIDs
•
Statins
•
Vitamin D and calcium for patients with or at risk of osteoporosis
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R I S K FA C TO R S F O R A D E s
• 6 or more concurrent chronic conditions
• 12 or more doses of drugs/day
• 9 or more medications
• Prior adverse drug event
• Low body weight or low BMI
• Age 85 or older
• Estimated CrCl < 50 mL/min
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ADE PRESCRIBING CASCADE
Drug 1
Adverse drug effect—
misinterpreted as a new medical condition
Drug 2
Adverse drug effect—
misinterpreted as a new medical condition
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DRUG-DRUG INTERACTIONS
• May lead to ADEs
• Risk increases as number of medications
increases
• Most common: cardiovascular and psychotropic
drugs
K E Y FA C T S A B O U T
DRUG-DRUG INTERACTIONS
• Absorption can be  or 
• Use of drugs with similar or opposite effects
can result in exaggerated or diminished effects
• Drug metabolism may be inhibited or induced
• Herbal preparations may also interact
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C Y TO C H R O M E P - 4 5 0 A N D
DRUG INTERACTIONS
• Effects of aging and clinical implications are still
being researched
• CYP3A4 is involved in more than 50% of drugs on
the market
• CYP3A4 is:
 Induced by rifampin, phenytoin, and carbamazepine
 Inhibited by macrolide antibiotics, nefazodone,
itraconazole, ketoconazole, and grapefruit juice
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MOST COMMON ADVERSE EFFECTS
OF DRUG-DRUG INTERACTIONS
• Confusion/delirium
• Cognitive impairment
• Hypotension
• Acute renal failure
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COMMON DRUG-DRUG INTERACTIONS
Risk
Combination
ACE inhibitor + diuretic
Hypotension, hyperkalemia
ACE inhibitor + potassium
Hyperkalemia
Antiarrhythmic + diuretic
Electrolyte imbalance, arrhythmias
Benzodiazepine + antidepressant,
antipsychotic, or benzodiazepine
Confusion, sedation, falls
Calcium channel blocker + diuretic
or nitrate
Hypotension
Digitalis + diuretic
Arrhythmias
COMMON DRUG-DISEASE
INTERACTIONS
• Obesity alters VD of lipophilic drugs
• Ascites alters VD of hydrophilic drugs
• Dementia may  sensitivity, induce paradoxical
reactions to drugs with CNS or anticholinergic activity
• Renal or hepatic impairment may impair detoxification
and excretion of drugs
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PRINCIPLES OF PRESCRIBING
F O R O L D E R PAT I E N T S : T H E B A S I C S
• Start with a low dose
• Titrate upward slowly, as tolerated by the
patient
• Avoid starting 2 drugs at the same time
BEFORE PRESCRIBING
A NEW DRUG, CONSIDER:
• Is this medication necessary?
• What are the therapeutic end points?
• Do the benefits outweigh the risks?
• Is it used to treat effects of another drug?
• Could 1 drug be used to treat 2 conditions?
• Could it interact with diseases, other drugs?
• Does patient know what it’s for, how to take it,
and what ADEs to look for?
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PRINCIPLES OF PRESCRIBING
A N N U A L LY
• Ask patient to bring in all medications (prescribed,
OTC, supplements) for review
• Ask about side effects and screen for drug and
disease interactions
• Look for duplicate therapies or pharmacologic
effect
• Eliminate unnecessary medications and simplify
dosing regimens
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NONADHERENCE
• May be as high as 50% among older patients
• May result from clinician’s failure to consider
patient’s financial, cognitive, functional status
• May result from patient’s beliefs and
understanding of drugs and diseases
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S U M M A RY
• Successful prescribing means choosing the correct
dosage of the correct drug for the condition and
individual patient
• Age alters pharmacokinetics (drug absorption,
distribution, metabolism, and elimination)
• ADEs are common but can be minimized with strict
attention to risk factors, drug-drug interactions, and
drug-disease interactions
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CASE 1 (1 of 4)
• A 77-year-old woman comes to the clinic because she
has daytime somnolence and occasional dizziness.
• History includes osteoporosis (hip fracture 1 year ago),
type 2 diabetes mellitus, hypertension, frequent falls,
and post-herpetic neuralgia that is controlled.
• Medications include glipizide 5 mg q12h, extendedrelease metoprolol 50 mg/day, amlodipine 10 mg/day,
pregabalin 200 mg q12h, alendronate 70 mg/week
(started 1 year ago), vitamin D supplement 800 IU/day,
calcium carbonate 500 mg q8h, and a multivitamin.
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CASE 1 (2 of 4)
• On examination, weight is 62 kg (137 lb). Blood
pressure is 140/75 mmHg.
• Over the past 3 months, blood pressure has ranged
from 140 to 150 mmHg systolic and from 70 to 80
mmHg diastolic, with no orthostatic changes.
• Estimated creatinine clearance is 35 mL/min; it has
declined over the past 2 years but has been stable for
the past 6 months.
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CASE 1 (3 of 4)
Which of the following would address the
patient’s most immediate need?
A. Reduce pregabalin to 150 mg q12h.
B. Start lisinopril 2.5 mg/day.
C. Discontinue alendronate.
D. Start aspirin 81 mg/day.
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CASE 1 (4 of 4)
Which of the following would address the
patient’s most immediate need?
A. Reduce pregabalin to 150 mg q12h.
B. Start lisinopril 2.5 mg/day.
C. Discontinue alendronate.
D. Start aspirin 81 mg/day.
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CASE 2 (1 of 4)
• An 88-year-old man is brought to the clinic by his wife
because he has decreased appetite and progressive
weight loss. Over the past 2 months, he has not eaten
his favorite foods and has lost 3.6 kg (8 lb).
• History includes advanced Alzheimer disease, difficulty
swallowing, and aspiration pneumonia, as well as
hypertension, CAD, hearing loss, and anemia.
• Medications include aspirin, losartan
hydrochlorothiazide, metoprolol, simvastatin, iron,
multivitamins, donepezil, and memantine.
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CASE 2 (2 of 4)
• He requires assistance with all activities of daily living
and speaks only one or two words over 24 hours.
• His wife is tearful and states that she is not ready to lose
him; she wants all recommended treatments for him.
• Physical examination and laboratory tests are
unchanged.
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CASE 2 (3 of 4)
Which of the following is the most appropriate next step
in management of this patient?
A. Refer wife to psychiatry for possible depression.
B. Start mirtazapine to treat patient for depression.
C. Discontinue iron and donepezil and taper
memantine off.
D. Place feeding tube.
E. Start megestrol for appetite stimulation.
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CASE 2 (4 of 4)
Which of the following is the most appropriate next step
in management of this patient?
A. Refer wife to psychiatry for possible depression.
B. Start mirtazapine to treat patient for depression.
C. Discontinue iron and donepezil and taper
memantine off.
D. Place feeding tube.
E. Start megestrol for appetite stimulation.
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CASE 3 (1 of 4)
• A 77-year-old man comes to the office because he
has had increased difficulty with urination, including
straining to void and occasional urinary incontinence.
• History includes benign prostatic hyperplasia,
depression, seasonal allergies, type 2 diabetes
mellitus, and peripheral neuropathy.
• Medications include tamsulosin 0.4 mg at bedtime,
metformin 1,000 mg q12h, fluticasone inhaler 2
sprays in each nostril daily, diphenhydramine 25 mg
q12h as needed, and aspirin 81 mg/day.
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CASE 3 (2 of 4)
• His peripheral neuropathy improved with initiation 3
weeks ago of duloxetine 60 mg/day; he had
experienced intolerable adverse effects with
gabapentin and pregabalin.
• His allergies have been worse over the past month,
and he has been taking a dose of diphenhydramine
at bedtime with excellent symptom control.
• On physical examination, the prostate is not
enlarged. Urinary analysis is normal.
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CASE 3 (3 of 4)
Which of the following is the most appropriate
management for this patient?
A. Discontinue diphenhydramine.
B. Discontinue duloxetine.
C. Begin extended-release tolterodine.
D. Obtain postvoid residual urine level.
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CASE 3 (4 of 4)
Which of the following is the most appropriate
management for this patient?
A. Discontinue diphenhydramine.
B. Discontinue duloxetine.
C. Begin extended-release tolterodine.
D. Obtain postvoid residual urine level.
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GNRS4 Teaching Slides Editor:
Barbara Resnick, PhD, CRNP, FAAN, FAANP, AGSF
GNRS4 Teaching Slides modified from GRS8 Teaching Slides
based on chapter by Todd P. Semla, MS, PharmD
and questions by Shelly L. Gray, PharmD, MS
Managing Editor:
Andrea N. Sherman, MS
Copyright © 2014 American Geriatrics Society