L-1

Pediatrics
Introduction to
The Course
Presented by:
Hiba A. Moneim
Clinical Pharmacy dep.-NUSU
Learning objectives
• Define the different age groups and corresponding developmental
stages in pediatric patients.
• Describe fundamental differences between pediatric and adult
patients regarding drug therapy
• Define off-label medication use and its implications in pediatric drug
therapy.
• Apply general pharmacotherapeutic concepts and pediatric-specific
factors toward providing care and education to patients and families.
• Pediatrics pharmacy practice focuses on the provision of
safe and effective drug therapy in infants, children, and
adolescents
Childhood be divided into the following age ranges for the
purposes of clinical trials and licensing of medicines:

• Newborn
• Preterm or premature < 36 weeks gestation
• Term > 36 weeks gestation
• Neonate < 1 month
• Infants 1 month–1 year
• Children 1–11 years
• Adolescents 12–16 years
Other classifications..
• Additional classifications are based on other factors such as
birth weight
• “low birth weight” is defined as having a birth weight
between 1500 and less than 2500 g
Growth and development
• Children undergo considerable physiologic changes
between birth and adulthood.

• Although most follow the same general pattern of growth,

the timing of maturation varies from child to child.
• Markers of physical growth include weight, length or height,
head circumference, weight-for-length, and body mass
index (BMI)
• World Health Organization (WHO) growth charts are
recommended to assess these parameters
• Motor and cognitive milestones are also important in child
development
Growth chart
Differences in pediatric patient data

• Vital Signs
• Laboratory Values
• Calculations
Common disorders of concern among children

• Congenital anomalies
• Cancer
• Asthma, eczema and hay fever
• Infections
• Mental health disorders
• Drugs, smoking and alcohol
• Malnutrition
The role of a pediatric pharmacist

• Pharmacists who care for pediatric patients should possess

knowledge regarding disease states and drug therapy as
well as the skills to apply this knowledge to practice.

• Pediatric practice includes a wide range of patient ages,

with conditions varying from lower respiratory tract
infection to trauma. Chronic disease states include lifelong
or long-term diseases, such as type 1 diabetes mellitus,
asthma, or congenital heart disease.
• There is limited information on the selection, dosing, and
monitoring of drugs in this population.
• As a result, most pediatric dosing is considered off-label.
Dosing information typically comes directly from case
reports and small clinical trials published in the medical
literature.
• Use of the medication outside the package insert
recommendations for indication, age, route, dose and
frequency was the most common definition of off-label use.
• Studies further defined off-label as “use of medications that
had no pediatric indication or were contraindicated in
children”
Let’s think…
C.J. is a 7-month-old, 6.5 kg baby boy who has recently
started teething. His parents ask for advice on a medication
to alleviate C.J.’s pain.

• What factors will influence the decision?

• What medication and dosing regimen would be appropriate
for C.J.?
Pharmacokinetic considerations
• Children’s pharmacokinetic parameters change during
maturation from neonates into adolescents
• Each aspect of drug disposition is affected, including
absorption, distribution, metabolism, and elimination.
None of these processes is fully mature at birth, and they
develop at different rates over the first years of life.
• The study of these changes is known as developmental
pharmacology.
 1. Drug absorption
• Gastrointestinal absorption. Oral drug absorption is most
greatly altered during the rst year of life.
• Several aspects of absorption are age dependent, including
• Gastric pH
• Gastric emptying time
• Intestinal motility
• Bile salt production
• Pancreatic enzyme function.
• Elevated gastric pH. At birth, gastric pH is elevated to nearly
neutral. This results from a relative decrease in gastric acid
production and an overall decrease in the volume of gastric
secretions.
• As a result, acid-labile drugs such as penicillin G may have a
greater bioavailability in neonates than in older infants.
• Conversely, drugs that are weak acids such as phenobarbital and
phenytoin may not be as well absorbed.
 Prolonged gastric emptying and intestinal
motility
• Coordination of contractions within the stomach begins to improve
shortly after birth, whereas intestinal peristalsis increases more slowly, over
the rst 4 to 8 months of life. As a result of this, absorption of drugs may
be signi cantly slowed.
• (a) Preterm neonates typically have more delayed gastric emptying
time than term neonates, so that changes in oral absorption may be
most pronounced in these patients.
• (b) Breastfed infants empty their stomachs approximately twice as
fast as formula-fed infants. The increased caloric density of formula
feedings delays gastric emptying
Bile salt and pancreatic enzyme production
• The rate of bile salt synthesis in preterm and term infants is
approximately 50% of adult values.
• Decreased fat absorption from enteral feedings, as well as
decreased drug absorption, can occur. For example, when
lipid-soluble vitamin D is administered to infants,
bioavailability is only 30% as compared with 70% in adults.
• The absorption of lipid-soluble drugs is further reduced due
to lower levels of pancreatic enzymes.
Other factors affecting oral drug absorption
• Reduced splanchnic blood flow in the first month of life and
reduced activity of intestinal metabolic enzymes, which
alters the first-pass effect.
• In addition, neonates lack normal gut microflora. Although
bacterial colonization normally occurs shortly after birth, it
may be significantly delayed in preterm neonates who are
being cared for in the sterile environment of an intensive
care unit.
Percutaneous absorption

• Absorption of drugs through the skin is enhanced in infants

and young children owing to better hydration of the
epidermis, greater perfusion of the subcutaneous layer, and
the larger ratio of total body surface area to body mass
compared to adults.
• In preterm neonates, the stratum corneum is also thinner,
further increasing the potential for the absorption of topical
products.
• This route of administration should be used with caution in
infants and young children to avoid overdosage. There are
numerous accounts of toxicity resulting from percutaneous
absorption.
• Repeated use of the skin cleanser hexachlorophene has
resulted in seizures in preterm neonates and application of
povidone–iodine to prepare the skin for surgery or sterile
procedures has caused iodine toxicity in infants.
• Repeated applications of topical hydrocortisone cream for
diaper rash or eczema can produce adrenal axis suppression
after as little as 2 weeks of use in an infant.
Intramuscular absorption

• Reduced blood flow to skeletal muscles and weak or erratic

muscle contractions in neonates may result in reduced drug
distribution.
• Intramuscular administration of drugs is generally
discouraged in the pediatric population because of the pain
associated with the injection and the risk of nerve damage
from inadvertent injection into nerve tissue.
• This route is generally reserved for the administration of
vitamin K where it produces a longer lasting depot-like
effect to prevent hemorrhagic disease of the newborn,
vaccines, and occasionally antibiotics when intravenous
access is not available.
• If it is used, the volume should not exceed 0.5 mL for infants
and younger children and 1.0 mL for older children.
Rectal administration.
• Absorption by this route is fairly reliable, even for preterm
neonates.
• Administration may be complicated in infants; however, by
the increased number of pulsatile contractions in the rectum
compared to adults, making expulsion of a suppository more
likely.
Pulmonary administration
• Inhalation of medications is increasingly being used in
infants and older children to avoid systemic exposure.
• Although developmental changes in the pulmonary
vasculature and respiratory mechanics likely alter the
pharmacokinetics of drugs given by inhalation, little is
known about the effects of growth and maturation on this
route of drug administration.
 2. Drug distribution
• Growth and maturation affect many of the factors that
determine drug distribution.
• Body water content, fat stores, plasma protein
concentrations, organ size and perfusion, hemodynamic
stability, tissue perfusion, acid–base balance, and cell
membrane permeability all undergo significant changes
from infancy to adolescence.
• Total body water content decreases with increasing age.
This is primarily the result of a larger extracellular body
water content in neonates and young infants that decreases
with age.
• Conversely, body fat increases with age from 1% to 2% in a
preterm neonate to 10% to 15% in a term neonate and 20%
to 25% in a 1-year-old. Lipophilic drugs, such as diazepam
(Valium), have a smaller volume of distribution in infants
than in older children and adults.
• Protein binding. Acidic drugs bind to albumin, whereas basic
substances bind primarily to 1-acid glycoprotein (AGP).
• The quantity of total plasma proteins, including both of
these substances, is reduced in neonates and young infants.
In addition, the serum albumin of newborns may have a
reduced binding affinity
• These two factors result in an increase in the free fraction of
many drugs.
• Protein-bound drugs with a high free fraction in neonates
• The increase in the free fraction may result in enhanced
pharmacological activity for a given dose.
• Drugs that are highly bound to albumin, such as the
sulfonamides, may displace bilirubin from its binding sites
and allow deposition in the brain, referred to as kernicterus.
As a result, these drugs are contraindicated in the first 2
months of life.
 3. Metabolism
• Developmental changes have been identified for many
phase I (oxidation, reduction, hydroxylation, and hydrolysis)
and phase II ( conjugation) reactions.

• The maturation of metabolic function results in the need for

age-related dosage alterations for many common therapies
and may explain the increased risk for drug toxicity in infants
and young children.
 Phase I reactions
• Enzymes associated with the metabolism of many common
drugs, including CYP3A4, CYP2C9, and CYP2C19, appear
within the first weeks of life, but their levels increase slowly.
The last of the enzymes to develop, CYP1A2, is present by 1
to 3 months of life.
• By 3 to 5 years of age, most patients have CYP isoenzyme
activity levels similar to that of adults.
• Alcohol dehydrogenase activity is only 3% to 4% of adult
values at birth and does not achieve adult values until
approximately 5 years of age. Because of this, newborns
have a reduced ability to detoxify benzyl alcohol, a
preservative found in many injectable products.

• Newborns exposed repeatedly to these products will

accumulate benzyl alcohol, which may lead to a potentially
fatal condition referred to as “gasping syndrome,” with
metabolic acidosis, respiratory failure, seizures, and
cardiovascular collapse
 Phase II reactions
• glucuronidation is decreased in neonates
• sulfation develops in utero and is well developed in the
neonate
• Ex: In early infancy, acetaminophen is converted primarily
through formation of sulfate conjugates; but with increasing
age, glucuronidation becomes the predominate form of
metabolism.
 4. Elimination
• Immature renal function results in significant alterations in
the elimination of many drugs.
• A rapid rise in glomerular filtration rate (GFR) occurs during
the first 2 weeks of life with continual increases until it
approaches adult values by 1 year of age.
• Tubular secretion gradually increases during the first year of
life.
• To account for the reduced ability of a neonate to eliminate
these drugs, longer dosing intervals are often required
• Blood urea nitrogen and serum creatinine values are not
always useful indicators of renal function in children.
• Adult equations to estimate creatinine clearance are not
appropriate for patients younger than 18 years of age
Several
examples
with their
validated
age ranges
are shown
below: