Pharmacokinetic Considerations

Pharmacokinetic Considerations
in the Elderly
Melanie A. Dodd, Pharm.D., Ph.C., BCPS
Associate Professor of Pharmacy in Geriatrics
College of Pharmacy
The University of New Mexico
At the conclusion of the lecture the student shall be able to:
 Describe the effects of aging on pharmacokinetic
parameters (absorption, distribution, metabolism, and
 Describe the effects of aging on pharmacodynamic
 Discuss basic principles of prescribing for older patients to
avoid adverse drug effects
 Identify potentially inappropriate medications in a given
elderly patient based on the Beers’ criteria
Slide 2
Which of the following principles should NOT
be followed when prescribing new
medication(s) for a geriatric patient?
A. Start with a low dose
B. Start all new medications simultaneously
C. Titrate the dosage upward slowly
D. Use one drug to treat two different conditions,
if possible
Slide 3
Why are geriatric pharmacokinetics
Persons aged 65 and older are prescribed the
highest proportion of medications in relation to their
percentage of the U.S. population
• Now, 13% of total population buy 33% of all
prescription drugs
• By 2040, 25% of total population will buy 50% of all
prescription drugs
Slide 4
Why are geriatric pharmacokinetics
Increased risk of adverse drug reactions
 Multiple medications
• >20% of elderly use 5 or more medications
• Increased frequency of drug-drug interactions
• Decreased medication adherence
 Multiple comorbidities
 Age-related changes in drug pharmacokinetics
 Age-related changes in drug pharmacodynamics
Slide 5
The Burden of Injuries from Medications
 ADEs are responsible for 5% to 28% of
acute geriatric hospital admissions
• ADEs occur in 35% of community-dwelling
elderly persons
• ADEs incidence: 26/1000 hospital beds
• In nursing homes, $1.33 spent on ADEs for
every $1.00 spent on medications
Slide 6
• 6 or more concurrent chronic conditions
• 12 or more doses of drugs / day
• 9 or more medications
• Prior adverse drug reaction
• Low body weight or body mass index
• Age 85 or older
• Estimated CrCl < 50 mL / min
Slide 7
Adverse drug effectmisinterpreted as a new medical
Adverse drug effectmisinterpreted as a new medical condition
Rochon PA, Gurwitz JH. Optimising drug treatment for elderly people: the
prescribing cascade. BMJ. 1997;315(7115):1097.
Slide 8
Principles of prescribing for older patients:
The Basics
• Start with a low dose
• Titrate upward slowly, as tolerated by the
• Avoid starting 2 drugs at the same time
Slide 9
Before Starting a New Medication, Ask:
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?
Slide 10
Slide 11
Aging and Absorption
Clinical significance is not well characterized
 Most drugs absorbed through passive diffusion in
the proximal small bowel
Exception: levodopa
 Threefold increase in bioavailability due to reduced
activity dopa-decarboxylase in the stomach wall
Slide 12
Alterations in GI function
 Decreased gastric parietal cell function
• Decrease in secretion of hydrochloric acid
 Increase in gastric pH
• Ex: tetracycline, Fe, ketoconazole
Decreased rate of gastric emptying
 Ex: anticholinergics, opiates, Fe, anticonvulsants
Drug-drug interactions
 Divalent cations (calcium, magnesium, iron) and
fluoroquinolones (e.g., ciprofloxacin)
Slide 13
Topical absorption (patches, creams,
ointments, etc.)
 Thinning and reduction of absorptive surface
• Skin atrophy and decreased fat content
» Reduction in vascular network and risk of contact
Slide 14
Effects of aging on volume of distribution
Depends mostly on physiochemical
properties of individual medications
t½ = (0.693 x Vd)/Cl
Slide 15
 body water (10-15%)  lower Vd for
hydrophilic drugs
 Ex: warfarin, digoxin, lithium, cimetidine, APAP, ETOH
 lean body mass  lower Vd for drugs that
bind to muscle
 fat stores  higher Vd for lipophilic drugs
 Ex: diazepam, lidocaine, TCAs, propranolol
Slide 16
Protein Binding
Decreased serum albumin
 10 to 20% in hospitalized or poorly nourished pt.
 Increase in unbound fraction of highly protein
bound acidic drugs
 Monitor drug levels—free phenytoin level with low
• Ex: warfarin, phenytoin, naproxen
Increased -1 acid glycoprotein
 Decrease in unbound fraction of highly protein
bound basic drugs
• Ex: lidocaine, propranolol, imipramine
Slide 17
Aging and Metabolism
The liver is the most common site of drug metabolism
Metabolic clearance of a drug by the liver may be
reduced because …
 Decrease in liver blood flow
 40 to 45% with aging, related to cardiac function
 Increase in bioavailability
 Decreased 1st pass effect = more parent drug
• Reduce initial dose, then titrate
 Decrease in liver size
20 to 50% decrease in absolute weight up to age 80
Reduction of total amount of metabolizing enzymes
Leads to decrease in Cl and increase in t½
Start with lower dosage
Caution with toxic metabolites
• Ex: meperidine and propoxyphene
Slide 18
Other Factors that Affect Drug Metabolism
Hepatic congestion from heart failure
Slide 19
Mean Age in years
Volume of
distribution (L/kg)
 Based on the above table, which of the following statements
correctly explains the change in volume of distribution for
amitriptyline (a lipophilic drug) with increasing age?
A. An increase in the percentage of lean body mass with age
B. A decrease in the unbound fraction of highly protein bound basic
C. An increase in the unbound fraction of highly protein bound
basic drugs
D. An increase in the percentage of fat body mass with age
Slide 20
Most drugs exit body via kidney
Reduced elimination  drug accumulation and
Aging and common geriatric disorders can
impair kidney function
Slide 21
The Effects of Aging on the Kidney
  kidney size
  renal blood flow
 ~1%/year after age 50
  number of functioning nephrons
  renal tubular secretion
Result: Lower glomerular filtration rate
• ~35% in healthy individuals between ages 20 and 90
• Accumulation
increased risk of toxicity
» Ex: lithium, aminoglycosides, captopril, NSAIDs
Slide 22
Serum Creatinine does NOT reflect
Creatinine Clearance
•  lean body mass  lower creatinine
•  glomerular filtration rate (GFR)
Result: In older persons, serum creatinine
stays in normal range, masking change in
creatinine clearance (CrCl)
Slide 23
How to Calculate Creatinine Clearance
• Measure:
Time-consuming to be accurate
Requires 24-h urine collection
8-h collection may be accurate but not widely
• Estimate:
Cockroft and Gault equation
Slide 24
Cockroft and Gault Equation
(Ideal weight in kg) (140 - age)
_________________________ x (0.85 if female)
(72) (serum creatinine in mg/dL)
Slide 25
An elderly person with a serum creatinine in
the normal range may actually have a
decreased creatinine clearance because they
A. Increased creatinine production and an increased
glomerular filtration rate (GFR)
B. Increased creatinine production and a decreased
C. Decreased creatinine production and a decreased
D. Decreased creatinine production and an increased
Slide 26
• Time course and intensity of pharmacologic effect
of a drug
 Impairment varies considerably from person to person
 All organ systems are affected
 Kidneys, liver, GI, CNS, CV, GU
Slide 27
Altered Pharmacodynamic Mechanisms
Change in receptor numbers
Change in receptor affinity
Postreceptor alterations
Age-related impairment of homeostatic
Slide 28
Changes are significant, yet idiosyncratic
 Decrease in weight and volume of brain
 Alterations in cognition
Increased sensitivity to medications
 Ex: benzodiazepines, opioids, anticholinergics,
Slide 29
Cholinergic blockade results in
 Sedation, confusion, and reduced ability to recall
• Ex: TCAs, diphenhydramine, antispasmodics,
Benzodiazepines can cause severe CNS
 Leads to falls and hip fractures
 Use caution and small dosages
Slide 30
Decreased baroreceptor responsiveness
 Results in orthostatic hypotension
• Ex: Antihypertensives—use caution and counseling
Slide 31
Urinary incontinence
 15 to 30% of community-dwellers
 50% of nursing home residents
 Enlarged prostate, urine retention
• Ex: anticholinergics
Slide 32
Inappropriate Medication Use in Older
Adults (Beers Criteria update)
Fick DM, et al.Arch Intern Med 2003;163:2716-2724.
48 medications or classes to avoid in older adults
20 diseases/conditions and medications to avoid in
older adults with these diseases
“Medications to be used with caution in the elderly: a
statewide clinical recommendation on potentially
inappropriate medications”
Inappropriate Drug Therapy based on Beers’
Goulding MR
Zhan et al. 2001
Ambulatory care
dwelling elderly
Prevalence of
7.8% of visits
21.3% of patients
Simon SR, et al.
Elderly in managed 28.8% of patients
Golden et al. 1999 Nursing home39.7% of patients
NM Medicare
Advantage plans
New Mexico
Medicare patients
21.5% of patients
Slide 34
Beers’ Criteria: Independent of Diagnosis
 Meperidine (long t1/2 metabolite, CNS)
 Non-steroidal anti-inflammatory drugs
 Indomethacin (CNS)
 Ketorolac-immediate and long-term use (GI bleeds)*
 Non-COX selective NSAIDs, longer t1/2-long-term use (GI
bleeds, renal failure)*
 Propoxyphene
 Pentazocine (CNS)
Slide 35
Beers’ Criteria: Independent of Diagnosis
 Amitriptyline/doxepin (anticholinergic)
 Daily fluoxetine (CNS)*
 Long-acting benzodiazepines-chlordiazepoxide,
flurazepam (sedation/fractures)
 Doses of short-acting benzodiazepines
 Meprobamate (addiction/sedation)
 Thioridazine (CNS/EPS)*
 Mesoridazine (CNS/EPS)*
Slide 36
Beers’ Criteria: Independent of Diagnosis
 Ticlopidine (no better than aspirin)
 Disopyramide (negative inotrope/anticholinergic)
 Amiodarone (QT interval/torsades de pointes)*
 Methyldopa (bradycardia/depression)
 Clonidine (CNS/orthostatic hypotension)*
 Doxazosin (hypotension/dry mouth)*
 Short-acting nifedipine (hypotension/constipation)*
 Ethacrynic acid (HTN, fluid imbalances)*
Slide 37
Beers’ Criteria: Independent of Diagnosis
Antihistamines (anticholinergic)
Diphenhydramine (confusion/sedation)
Stimulant laxatives, long term use: e.g.,
bisacodyl (bowel dysfunction)
Cimetidine (CNS, confusion)*
Chlorpropamide (hypoglycemia/SIADH)
Slide 38
Beers Criteria
Considering Diagnosis
Heart failure-disopyramide (negative inotropic
Gastric or duodenal ulcers-NSAIDs and aspirin
>325 mg (exacerbate existing ulcers or produce
new ulcers)
Epilepsy-clozapine, chlorpromazine (may lower
seizure threshold)
Insomnia-decongestants, theophylline,
methylphenidate (CNS stimulants)
Slide 39
Beers Criteria
Considering Diagnosis
 Depression-long-term benzodiazepines (exacerbate
 Syncope or falls-TCAs and short to intermed acting
benzodiazepines (may produce syncope/additional
 Chronic constipation-CCBs, anticholinergics, TCAs
Slide 40
Alternatives to Beers criteria
Stefanacci RG, Cavallaro E, Beers MH, Fick
DM. Developing explicit positive beers criteria
for preferred central nervous system
medications in older adults. Consult Pharm.
2009 Aug;24(8):601-10.
Slide 41
STOPP and START Criteria
Screening Tool of Older Persons’ Prescriptions
Screening Tool to Alert doctors to Right
Treatment (START)
Gallagher P, Ryan C, Byrne S, Kennedy J, O’Mahony
D. STOPP and START. Consensus validation. Int J
Clin Pharmacol Ther 2008;46:72-83.
Slide 42
Age alters pharmacokinetics (drug absorption,
distribution, metabolism, and elimination)
Age alters pharmacodynamics
ADEs are common among older patients
Successful drug therapy means:
 Choosing the correct dosage of the correct drug for
the condition and individual patient
 Monitoring the therapy
Slide 43
References/Additional Reading
 Cusack BJ. Pharmacokinetics in older persons. Am J Geriatr
Pharmacother. 2004;2:274-302.
 Fick DM, et al. Arch Intern Med 2003;163:2716-2724. (Beers’
 Gallagher P, et al. STOPP and START. Consensus validation.
Int J Clin Pharmacol Ther 2008;46:72-83.
 Golden AG, et al. J Am Geriatr Soc 1999;47(8):948-53.
 Goulding MR. Arch Intern Med 2004 164(3):305-12.
 Levy HB, et al. Ann Pharmacother 2010;44:xxxx.
 Simon SR, et al. J Am Geriatr Soc 2005;53(2):227-32.
 Stefanacci RG, et al. Consult Pharm. 2009;24(8):601-10.
 Zhan C, et al. JAMA 2001;286(22):2823-9.
Slide 44
Case: AB 81 year-old female
Problem List
1. CVA X 6
2. Carotid stenosis
3. Right endarterectomy in
4. Osteoarthritis
5. Chronic constipation
6. Diabetes
7. Peripheral neuropathy
8. Coronary artery disease
9. Hypertension
10. Hypothyroidism
11. Hypercholesterolemia
12. Osteopenia
13. Urinary incontinence
14. Recurrent pyelonephritis
15. Atrophic vaginitis
16. Reactive airway disease
Slide 45
1. levothyroxine 75 mcg daily
2. lovastatin 10 mg, 2 tablets at
3. clopidogrel 75 mg daily
4. nitroglycerin SL tabs 0.4mg prn
5. amlodipine 10 mg daily
6. furosemide 20 mg daily
7. potassium 10 mEq, 2 tablets twice
8. clonidine 0.2 mg, 2 tablets twice
9. metoprolol 50 mg twice daily
10. Novolin 70/30, 25 units qam, 15
units qpm
11. glipizide extended release 10 mg
twice daily
12. conjugated estrogen vaginal cream
twice weekly
13. gabapentin 300 mg tid for
neuropathy in feet
14. amitriptyline 10 mg at bedtime
15. hydrocodone/ acetaminophen 5/325
mg, 1 tab every 4-6 hours prn pain
(uses 3-4 tabs/day)
16. alendronate 70 mg po weekly
17. tolterodine (Detrol LA) 4 mg qhs
18. albuterol MDI with chamber once
Slide 46
19. docusate 100 mg bid
20. mineral oil prn constipation
21. glycerin suppositories prn
constipation (uses about
22. aspirin 81 mg daily
23. diphenhydramine 25 mg at
bedtime for sleep (uses 3-4
24. calcium 500 mg with vitamin
D bid
25. glucosamine 2 caps qd
Slide 47
Vital Signs:
BP 168/63 HR 79
RR 24 Temp. 97.8˚F
Weight 177.9 lbs.
 Pain 1/10
Lab Values:
Na 140
K 4.8
Cl 104
BUN 25
Scr 1.3
HbA1c 6.8%
 Mean blood glucose 164.8
 TSH 5.680
TC 144
TG 258
HDL 39
LDL 53
Slide 48

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