1) Pediatric patients have unique considerations for drug therapy due to ongoing development processes. Their organ systems, especially liver and kidney function, are still maturing and may metabolize and eliminate drugs differently than adults. 2) Some infamous past drug disasters in pediatrics, like the teratogenic effects of thalidomide, helped establish modern drug regulations requiring demonstrated safety and efficacy for pediatric populations. 3) Key pharmacokinetic processes like absorption, distribution, metabolism and elimination vary substantially between pediatric age groups from neonates to adolescents due to developmental differences, necessitating careful study of appropriate dosing.

1. Drug therapy in specific patient groups
By: Tsegaye Melaku
[B.Pharm, MSc, Clinical Pharmacist]
November, 2016
tsegayemlk@yahoo.com or tsegaye.melaku@ju.edu.et +251913765609

2. † Special populations.. Need concern in pharmacotherapy???

3. Chapter 1
Neonates and Pediatrics
Brain storming
† Classify pediatric patients of various age groups?
† What makes them ‘’special populations’’?
† Why worry drug therapy in neonates and pediatrics?

4. “Pediatrics does not deal with miniature men and women, with reduced
doses and the same class of disease in smaller bodies, but… has its
own independent range and horizon.”
- Dr. Abraham Jacobi, the father of American Pediatrics

5. Introduction
† Pediatric patients  those younger than 18 yrs.
Newborn infants born before 37 weeks of GA  premature
Between 1 day and 1 month of age  neonates
1 month to 1 yr  infants
1 to 3 yrs  Toddler
3 to 11 yrs child
12 to 18 yrs adolescents.

6. Infant Mortality
† 200, 75, 6.7 per 1,000 births in the 19th century, 1925, 2006.
respectively in USA.
 This is 2˚ to  improvements in identification, prevention, and
treatment of diseases once common during delivery and the
infancy period.
 Today ??

7. Concern in pediatric pharmacotherapy
† Although most marketed drugs are used in pediatric patients, only ¼
of them approved by FDA.
Children are “therapeutic orphans”
Only 20-30% of approved drugs have pediatric labeling
† Scarce data on PK, PD, efficacy, and safety of drugs   
What’s unique?

8. Drug induced disasters
† Some of the most disastrous therapeutic misadventures occurred
in pediatrics.
Thalidomide 1957
Chloramphenicol 1959
† Directly led to the “modern era” of pharmaceutical regulation with
Kefauver-Harris Drug Amendments of 1962
Requirement for demonstrated efficacy and safety for FDA
approval and USA marketing.

9. a. Gray baby syndrome from Chloramphenicol,
1st reported 2 neonates died after excessive doses of CAF
100 –300 mg/kg/day
Due to lack of the necessary liver enzymes (glucuronnyl
transferase) and inadequate renal excretion of unconjugated
drug
S & Sxs: Abdominal distension, V, D, a characteristic gray color,
respiratory distress, hypotension, and progressive shock.
Cont’d…

10. Cont’d…

11. b. Phocomelia from thalidomide:
Well known for its teratogenic effects.
Cause of multiple congenital fetal abnormalities (particularly
limb deformities),
Also can cause polyneuritis, nerve damage, and mental
retardation.
c. Kernicterus from sulfonamide therapy  displaced bilirubin
hyperbilirubinemia  encephalopathy
Cont’d…

12. Cont’d…

13. † Identifying an optimal dosage ????
Dosage regimens cannot be based simply on body weight or SA.
Bioavailability, PK, PD, efficacy, and safety information ???? 
differences in age, organ function, and disease state.
† Unavailable suitable dosage forms  injectables vs liquid vs solid
For example: Dose of captopril, morphine, etc
† Alteration (dilution or reformulation) of dosage forms   bioavailability,
stability, and compatibility ????
† Pharmacologic or therapeutic research brings up the issue of ethical
justification ????
Cont’d…

14. Overview of PK in pediatrics: Absorption
 Gastrointestinal Tract
2 factors affecting the absorption of drugs from the GIT  pH-
dependent passive diffusion & gastric emptying time.
In a full-term infant, gastric pH ranges from 6 to 8 at birth  declines
to 1 to 3 within 24 hrs.
Remains elevated in premature infants because of immature acid
secretion.
In premature infants, higher serum concentrations of acid-labile drugs
(penicillin, ampicillin, and nafcillin) and lower serum concentrations of
a weak acid (phenobarbital) can be explained by higher gastric pH

15. † Gastric emptying is slow in a premature infant.
 Thus, drugs with limited absorption in adults may be absorbed
efficiently in a premature infant
prolonged contact time with GI mucosa.
 Intramuscular Sites  used rarely in neonates
Altered in premature infants.
Differences in relative muscle mass, poor perfusion to various
muscles, peripheral vasomotor instability, and insufficient
muscular contraction
 Example: Phenobarbital absorbed rapidly, whereas diazepam
absorption delayed.
Cont’d…

16.  Skin
Percutaneous absorption may be increased substantially in newborns
An underdeveloped epidermal barrier (stratum corneum) and
increased skin hydration.
Topical application of gel containing a standard dose of
theophylline to control apnea in premature neonates
A transdermal patch of methylphenidate for attention-
deficit hyperactivity disorder (ADHD).
Examples
Cont’d…

17. b) Distribution
Determined by the physicochemical properties of the drug itself
(molecular weight, partition coefficient) and the physiologic factors
specific to the patient.
Although the physicochemical properties of the drug are constant, the
physiologic functions often vary in different patient populations.
Patient-specific factors  extracellular and total body water, protein
binding, and presence of pathologic conditions
Cont’d…

18. † Plasma proteins binding is decreased in newborn infants because of:
Decreased plasma protein concentration,
Lower binding capacity of protein,
Decreased affinity of proteins for drug binding, and
Competition for certain binding sites by endogenous compounds
such as bilirubin.
Less in neonates (e.g. phenobarbital, salicylates, and phenytoin)
† The decrease in plasma protein binding of drugs can increase their
apparent volumes of distribution premature infants require a larger
loading dose
Cont’d…

19. † The amount of body fat is substantially lower in neonates than in adults,
which may affect drug therapy.
Certain highly lipid-soluble drugs are distributed less widely in
infants than in adults. Example: Diazepam
Cont’d…

20. Metabolism
† Drug metabolism is substantially slower in infants than in older children and
adults.
† Maturation of various pathways of metabolism ??
Sulfation pathway is well developed but the glucuronidation
pathway is undeveloped in infants.
 Example: Acetaminophen metabolism (glucuronidation is
impaired in infants), it is partly compensated by sulfation
pathway.
Tragic CAF-induced gray baby syndrome decreased metabolism
to the inactive glucuronide metabolite

21. Higher serum concentrations of morphine are required to
achieve efficacy in premature infants
They are not able to metabolize morphine adequately to its
active 6-glucuronide metabolite
† Oxidation also is impaired in newborn infants
Theophylline clearance is not fully developed for several months
(CYP1A2).
Premature infants receiving theophylline, a significant amount of
its active metabolite may be present.
Cont’d…

22. PK Pathway
Metabolism:
Phase I
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
3–5 mo.
Late infant-
toddler
6 – 24 mo.
Older child
CYP1A2      Scale BW3/4  Scale BW3/4
CYP2E1      Scale BW3/4  Scale BW3/4
CYP A      Scale BW3/4  Scale BW3/4
CYP3A7      
Other CYPs      Scale BW3/4  Scale BW3/4
ADH      Scale BW3/4  Scale BW3/4
Cont’d…

23. PK Pathway
Metabolism:
Phase Ii
Premature
Neonates
Neonatal
< 1 mo.
Early
infant
Mid-Infant
3–5 mo.
Late infant-
toddler
6 – 24 mo.
Older child
Glucuonidation      
N-acetylation      
Cont’d…

25. Elimination
† Drugs and their metabolites are often eliminated by the kidney.
GFR may be as low as 0.6 to 0.8 mL/min per 1.73 m2 in
preterm infants and 2 to 4 mL/min per 1.73 m2 in term infants.
Premature infants require a lower daily dose of drugs eliminated
by the kidney during the first week of life;
The dosage requirement then increases with age.

26. Acquisition of Renal Function
0
20
40
60
80
100
120
140
160
1-2
days
2-4 wk 2 mo 6 mo 1 yr 2 yr 6 yr 12 yr
Age
GFR/RelPAHClroGFR
Glomerular
Filtration Rate
PAH Clearance

27. Criteria for Using a Drug in a Child or Infant
† Has there been documented efficacy for the medication for the
disorder in newborn or older infants/children.
– Is the data from adequate clinical trials (randomized,
controlled, size, power, similar age/maturity)?
† Has the safety been established for pediatric population?

28. † Has the pathway of drug clearance been established in
children/infants?
† Is that pathway established in the child/infant you are treating
(based on maturity or physical state)?
† Is there reason to believe that pathway may be compromised in the
specific child/infant (genetics, disease state, concomitant therapy)?
† Have the pharmacokinetics been established in similarly aged
children?
Criteria for Using a Drug in a Child or Infant

29. † Is there a safe route to administer the drug? (intact GI tract, central
access, intact skin, nontoxic solvent)
† Is displacement an issue for albumin binding or bilirubin
displacement?
† Are there technical issues surrounding administration, e.g. solvents,
preservatives, volume?
† Is there an established dose and interval appropriate for age and
disease state of the child?
† Have a plan for monitoring for appropriate response to the agent.
† Look for adverse effects of the agent.
Criteria for Using a Drug in a Child or Infant

30. Cont’d…

31. Thank you