1. 1
Clinical Pharmacology in SpecialClinical Pharmacology in Special
PopulationsPopulations
Patty Slattum, PharmD, PhDPatty Slattum, PharmD, PhD
March 31, 2014March 31, 2014

2. 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
2

3. The Clinical Pharmacology Paradigm:
Pharmacokinetics, Pharmacodyamics and
Therapeutics
3
Drug
Concentration
in the
Circulation
PK
•Absorption
•Distribution
•Metabolism
•Excretion
Drug
Effect
PD
•Drug-receptor
interactions
•Concentration at
receptor
•Homeostatic
mechanisms
Desirable
Therapeutic
Outcome
Efficacy
•compliance
•disease
characteristics

4. Clinical Pharmacology in SpecialClinical Pharmacology in Special
Populations: PediatricsPopulations: Pediatrics

5. Definitions
Premature
infant
Gestational age less
than 36 weeks
Full-term
infant
Gestational age 36
weeks to birth
Neonate First month of
postnatal life
Infant 1to 12 months of age
Child 1to 12 years of age
Adolescent 12 to 18 years of age
Adult Greater than 18
years of age

6. 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.

7. 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.

8. Drug Absorption
Population Physiologic
Change
Effect on PK
Neonates, infants,
young children
gastic pH Change in rate of
dissolution and
absorption
Neonates, infants gastric emptying
and GI transit
times, peristalsis
Variable effects on
rate and extent of
absorption
Older infants,
children
 GI transit time
and
 motility
Unpredictable
effects on rate and
extent of
absorption

9. Drug Absorption
Population Physiologic
Change
Effect on PK
Premature infants GI enzyme
activity
Variable effects on
rate and extent of
absorption
Neonates bile salts absorption of
some drugs
Infants Changes in
intestinal microflora
 absorption of
some drugs

10. Drug Absorption
Population Physiologic
Change
Effect on PK
Neonates, infants,
young children
Blood flow (in
newborns and  in
infants and
children),
vasomotor
instability,
insufficient muscle
tone, muscle
oxygenation
Unpredictable
intramuscular
absorption
Neonates, infants skin permeability Increased
absorption through
the skin

11. Examples
• Hydrocortisone
– Systemic absorption and toxicity
• Povidone-Iodine
– Iodine toxicity in neonates

12. 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.

13. Drug Distribution
Population Physiologic Change Effect on PK
Neonates,
infants
total body water
extracellular water
body fat
volume of
distribution for
water soluble drugs
 volume of
distribution for lipid-
soluble drugs

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

15. Drug Distribution
Population Physiologic Change Effect on PK
Neonates,
infants
 albumin levels (80% of
adult value for neonates),
binding capacity,
binding affinity,
competition for binding with
endogenous compounds
such as bilirubin and free
fatty acids
fraction bound
for drugs highly
bound to albumin
Neonates  α1-acid glycoprotein
binding
fraction bound
for drugs highly
bound to α1-acid
glycoprotein

16. 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

17. 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.

18. Drug Metabolism
Population Physiologic
Change
Effect on PK
Premature,
neonates, infants
oxidative enzyme
activity (neonates
have 20-70% of
adult values for
cytochrome p450
activity)
drug metabolism
or use of alternate
routes of
metabolism
Neonates, infants glucuronide
conjugation, but
well-developed
sulfate conjugation
drug metabolism
or use of alternate
routes of
metabolism
Young children enzyme capacity
for methylation
drug metabolism

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

20. 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

21. 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.

22. Renal Elimination
Population Physiologic Change Effect on PK
Neonates,
infants
filtration, reabsorption,
secretion by the kidney
clearance of
renally-excreted
drugs and
metabolites

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

24. Example
• Digoxin

25. 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.

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

27. 27
Clinical Pharmacology in SpecialClinical Pharmacology in Special
Populations: GeriatricsPopulations: Geriatrics

28. INTRODUCTION
 Definition of elderly
 Aging versus disease
 “Usual” versus “Successful” Aging
28

29. 29
http://lydia.bradley
.edu/hilltopics/11wi
nter/feature/

30. Drug Absorption
30
 gastric pH
 GI fluid volume
 GI surface area
 GI transit time
 intestinal/hepatic blood flow
 gut wall enzymes

31. Examples
 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
31

32. Drug absorption
 muscle blood flow
 muscle mass
 skin hydration
 keratinized cells
 thinning of dermis
 abraded areas
 use of occlusive dressings
32

33. 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.
33

34. Drug Absorption:
Take home message
34
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.

35. Distribution
 lean body mass
 total body water
 total body fat
 serum albumin levels (15-20%)
35

36. Examples
 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.
36

37. Distribution:
Take home message
 Distribution may be altered in the elderly due to age-
related 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.
37

38. Renal Excretion
 renal blood flow, glomerular
filtration rate, altered tubular
function
 Glomerular filtration rate
declines about 10% per decade
after age 20
38

39. Examples
 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)
39

40. Renal Excretion:
Take home message
40
Decreased renal elimination of drugs in
the elderly is the most significant age-
related change in PK. It accounts for
the majority of necessary dosage
adjustments.

41. Metabolism
 liver mass/volume
and membrane
permeability
 liver blood flow
(about 40%)
 Phase I metabolism
(oxidation)
 No change in Phase II
(conjugation)
41

42. Examples
 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)
42
http://www.americangeriatrics.org/health_care_professionals/
clinical_practice/clinical_guidelines_recommendations/2012

43. Metabolism:
Take home message
43
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.

44. Pharmacodynamics
 Changes in receptor responsiveness
– receptor number
– receptor affinity
– signal transduction mechanisms
– cellular responses
 Changes in homeostatic regulation
– Decreased physiologic reserve
44

45. Pharmacodynamics:
Take home message
45
Age-related changes in receptors and
homeostatic control may alter an
elderly patient’s response to drug
therapy.

46. Case Study
46

47. Episode 1: Before Hospital Admission
47
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.
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.

48. 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

49. 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
nurse’s visit he had fallen in the bathroom and broken
his wrist. His medications were:
• digoxin
• furosemide
• flurazepam
• a variety of OTCs

50. Episode 2: Hospital Course
50
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.

51. Over the next 4 weeks, the patient’s 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

52. Episode 3: Placement in LTC
52
After the 4-week hospital stay, a conference was held
with the patient’s 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.
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.

53. 53
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.

54. 54
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 short-
term 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.

55. Epilogue
55
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.

56. 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.
56

57. Questions?Questions?