Clinical Pharmacology in Special

Populations

Learning Objectives

Define pharmacokinetics and pharmacodynamics

Define older adult
Describe physiologic changes associated with aging and
their potential impact on PK and PD of drugs in older
adults.
Define the stages of early human development important
for determining doses in pediatric patients.
Describe physiologic changes associated with growth
and development and their potential impact on the PK/PD
of drugs in children

The Clinical Pharmacology Paradigm:

Pharmacokinetics, Pharmacodyamics and
Therapeutics

Drug

PK

PD

Concentration
in the
Circulation

Drug

Absorption
Distribution
Metabolism

Excretion

Effect
Drug-receptor

interactions
Concentration at
receptor
Homeostatic
mechanisms

Efficacy
Desirable
Therapeutic
Outcome
compliance
disease

characteristics

Clinical Pharmacology in Special

Populations: Pediatrics

Definitions
Premature
infant
Full-term
infant
Neonate
Infant
Child
Adolescent
Adult

Gestational age less

than 36 weeks
Gestational age 36
weeks to birth
First month of
postnatal life
1to 12 months of age
1to 12 years of age
12 to 18 years of age
Greater than 18
years of age

Introduction
By their first 5 years of life, 95% of children
have been prescribed medications.
The greatest number of prescriptions is given
to children between 7 and 12 months of age.
Only recently have pediatric clinical
pharmacology studies been expected by the
FDA to support new drug approvals.
PK studies are difficult to perform in children
due to ethical concerns and limited volume and
number of blood samples that can be obtained.

Developmental Changes in Physiologic Factors That Influence Drug Disposition in Infants,

Children, and Adolescents.

Kearns GL et al. N Engl J Med 2003;349:1157-1167.

Drug Absorption

Drug Absorption

Drug Absorption

Examples
Hydrocortisone
Systemic absorption and toxicity

Povidone-Iodine
Iodine toxicity in neonates

Absorption:
Take home message
Most drugs are well absorbed in pediatric patients.
The rate of absorption may be delayed, but the
extent is not significantly changed for most drugs.
Physiologic changes as well as concurrent diseases
(Ex: inflammatory bowel disease, prolonged
diarrhea, gastroenteritis, malabsorption syndrome,
congenital heart disease) are responsible for the
increased variability in drug absorption observed in
pediatric patients.

Drug Distribution

Kearns GL, et al., NEJM 2003;349:1157-1167.

Drug Distribution

Examples:
Trimethoprim/Sulfamethoxazole
Sulfamethoxazole displaces bilirubin from protein
binding sites

Digoxin
Myocardial-to-plasma digoxin concentration:
2-3 times adult values
Increased distribution to heart tissue has to be accounted for
in dosing

Gentamicin
Larger weight-based doses needed because gentamicin
distributes in body water

Drug Distribution:
Take home message
Distribution of drugs may be altered
in pediatric patients not only due to
age-related physiologic changes, but
due to concurrent diseases as well.
The clinical significance of these
changes depends on the drug under
consideration.

Drug Metabolism

Kearns GL, et al., NEJM 2003;349:1157-1167.

Examples
CYP1A2 and caffeine
Approximately 50% reduction in neonates
Approximately 50% higher doses than adults for
children 2-10 years of age
Adolescents similar to adult doses

Chloramphenicol
Glucuronidation 10% of adult values until 2-4 years
of age
Gray baby syndrome

Drug Metabolism:
Take home message
In general, hepatic oxidative drug
metabolism is decreased in neonates and
infants. There is generally an increase in
drug clearance in children under 10 years
of age compared to adults. The effects of
development may be compounded by
diseases such as heart failure which can
reduce liver blood flow.

Renal Elimination

Kearns GL, et al., NEJM 2003;349:1157-1167.

Example
Digoxin

Renal Elimination:
Take home message
Decreased renal clearance of drugs in
pediatric patients is an important
age-related change in PK, and may be
due to changes in filtration,
reabsorption, or secretion.

Pharmacodynamics
Much less is known about PD changes
in pediatric patients. Receptor
binding or the function of
homeostatic mechanisms may be
altered.

Clinical Pharmacology in Special

Populations: Geriatrics

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INTRODUCTION

Definition

of elderly
Aging versus disease
Usual versus Successful Aging

28

http://lydia.bradley
.edu/hilltopics/11wi
nter/feature/

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Drug Absorption

30

gastric pH

GI fluid volume

GI surface area

GI transit time

intestinal/hepatic blood flow

gut wall enzymes

Examples

31

Alendronate, NSAIDS: Should ensure that immobile

patients are sitting up for at least 30 minutes after
dosing
Vitamin D, folate and B12 absorption may be
decreased in elderly
Levodopa bioavailability increased by three-fold due
to reduction in gastric wall content of dopa
decarboxylase in older adults

Drug absorption

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muscle blood flow

muscle mass

skin hydration

keratinized cells

thinning of dermis

abraded areas

use of occlusive dressings

Examples
There

may be reduced absorption rate of

some antibiotics from the site of an
intramuscular injection in the elderly
With topical steroids such as fluocinonide,
systemic absorption is more likely to occur
when used on large surfaces, with occlusive
dressings, or with age-related changes in the
skin.
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Drug Absorption:
Take home message
Most drugs are well-absorbed in the
elderly. The rate of absorption may be
delayed for some drugs in some
patients, but the extent is not
significantly changed. Age-related
changes as well as concurrent
diseases result in increased variability
in drug absorption in the elderly.
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Distribution

35

lean body mass

total body water
total body fat
serum albumin levels (15-20%)

Examples

36

Ethanol distributes in body water. Volume of

distribution decreases by about 20% in the elderly.
Diazepam distributes in body fat. Its volume of
distribution increases and is correlated with age.

Distribution:
Take home message

37

Distribution may be altered in the elderly due to agerelated physiologic changes and concurrent diseases.
Lipid-soluble drugs may show an increased volume of
distribution and water-soluble drugs may show a
decreased volume of distribution in older patients
related to these changes in body composition.
Age-related changes in protein binding do not generally
result in clinically significant changes in drug therapy
for elderly patients.

Renal Excretion
renal blood flow, glomerular
filtration rate, altered tubular
function

Glomerular filtration rate

declines about 10% per decade
after age 20

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Examples

39

Allopurinol (dose based on CrCl: 140 ml/min = 400

mg qd; 20 ml/min = 100 mg qd)
Amantidine (half-life = 2-7 hr for normal renal
function, 24-29 hr in the elderly)
Digoxin (half-life = 38-48 h in normal renal function,
69 h on average in the elderly)
Ceftazidime (dose based on renal function and not
more frequently than every 12 h in the elderly)
Nitrofurantoin (less effective when CrCl < 60 ml/min)

Renal Excretion:
Take home message
Decreased renal elimination of drugs in
the elderly is the most significant agerelated change in PK. It accounts for
the majority of necessary dosage
adjustments.

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Metabolism

41

liver mass/volume and

membrane permeability
liver blood flow (about
40%)
Phase I metabolism
(oxidation)
No change in Phase II
(conjugation)

Examples

42

For drugs which undergo oxidative metabolism,

decrease dose by 30%.
(Ex: phenytoin, midazolam)
For drugs which are eliminated following conjugation,
no change in dose is needed based on PK
Lorazepam and oxazepam are preferred over
diazepam and flurazepam in the elderly (Beers
criteria)

http://www.americangeriatrics.org/health_care_professionals/
clinical_practice/clinical_guidelines_recommendations/2012

Metabolism:
Take home message
Drugs metabolized exclusively by Phase II mechanisms
are preferred in the elderly. For oxidatively metabolized
drugs, dosages should generally be reduced. After initial
dosing, doses can be adjusted based on patient
response and tolerability. The potential for significant
drug interactions, particularly resulting from hepatic
enzyme inhibition in elderly patients on multiple
medications, must be carefully considered.

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Pharmacodynamics
Changes

receptor number
receptor affinity
signal transduction mechanisms
cellular responses

Changes

44

in receptor responsiveness

in homeostatic regulation

Decreased physiologic reserve

Pharmacodynamics:
Take home message
Age-related changes in receptors and
homeostatic control may alter an
elderly patients response to drug
therapy.

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Case Study

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Episode 1: Before Hospital Admission

You are a member of the Geriatric Management Team
asked to provide consultation on OM, a resident of a LTC
facility.
OM is an 86 yo male referred to LTC from a local
hospital. OM was admitted to the hospital after falling on
the steps of the hospital on the way to an outpatient clinic
visit.

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After his fall, he was taken to the ER, where he was found
to have an extensive bruise on the right elbow and could
not give a clear account of how he fell. He was confused
and restless, so he was admitted to the hospital.

Before his admission, he had been seen in his home

by a visiting nurse: He lived with his wife in an
apartment for at least the previous 8 years. She had
severe arthritis, and required assistance with ADLs
(provided by OM). A visiting homemaker came twice
a week to help in maintaining the apartment. Medical
history included:

prostatic hypertrophy and transurethral resection

hospitalization 5 years age for abdominal pain

bouts of constipation/diarrhea for years

difficulty falling asleep for several years

For many years, OM enjoyed social contacts with

friends. In recent months he noticed that his walking
was becoming less steady. Six months before the
nurses visit he had fallen in the bathroom and broken
his wrist. His medications were:

digoxin

furosemide

flurazepam

a variety of OTCs

Episode 2: Hospital Course

On admission to the hospital, OM was described as
confused, agitated, and demanding to be released. The
admitting physician wrote that he was in incipient heart
failure based on 1 to 2+ pitting edema and possible
rales.
In the days following admission he became more restless,
confused, and agitated; restraints had to be used. He
seemed unable to walk independently, had a shuffling gait
and looked as though he would fall. His sight was
impaired, in part due to a cataract.

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Over the next 4 weeks, the patients condition

remained unchanged, and it was judged that he
could not return to his apartment, especially because
his wife required considerable care.
Medications:

Theragran-M qd

Slow K 2 tabs QID

Digoxin 0.125 mg daily

Flurazepam 30 mg hs

Imodium 1 cap q6h prn

Kaopectate 6 TBSP after each loose bm, prn

Haldol 2 mg tid

Furosemide 40 mg daily in the am

Episode 3: Placement in LTC

After the 4-week hospital stay, a conference was held
with the patients son, and he stated that he could not
accommodate his parents in his home. The family
arranged for his wife to live with a married daughter in
another city and institutional care was arranged for OM.

52

Approximately 2 weeks after entering the nursing home,

OM was referred for Geriatric Team evaluation. The
team prepared a problem list and a plan of action. One
primary objective was to determine the degree to which
each of his medications were useful or indicated. A
referral for cardiac evaluation was carried out.

Cardiac evaluation indicated that the digoxin level

was 1.5 ng/mL. The patient showed no overt signs of
cardiac decompensation. The digoxin was d/cd.
Shortly after admission to LTC, the flurazepam was
reduced by half and then tapered down gradually
over the next 4 weeks. OM was involved in social
and recreational activities as much as possible, and
daytime napping was discouraged.

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In the following weeks, OM became increasingly

coherent and had less difficulty walking. One
month later he was alert and oriented and had no
difficulty with ambulation. He had mild shortterm memory impairment, but his mental status
exam was essentially normal. Although he was
actively involved with the other patients, he
longed to resume his former life with his wife
and friends.

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Epilogue
And now, what for OM? He no longer justified
nursing home placement or skilled care. He received
limited assistance from his children and obtained the
assistance of social workers in obtaining housing for
the well aged. His personal resources had been
exhausted and the profound changes in his life, most
of which were directly related to the medically
prescribed drugs, had become essentially irreversible.

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References
Bowie

MW, Slattum PW. Pharmacodynamics in

the elderly: A review. Am J Geriatr
Pharmacother 2007;5: 263-303.
Cusack BJ. Pharmacokinetics in older persons.
Am J Geriatr Pharmacother 2004;2:274-302.
Hilmer SN, McLachlan AJ, Le Couteur DG.
Clinical Pharmacology in the geriatric patient.
Fund Clin Pharmacol 2007;21:217-30.
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Questions?