Elimination is reduced during infancy, resulting in slower rates of
clearance for many commonly used drugs. Glomerular filtration rate
increases throughout childhood. Use of creatinine clearance as an
estimate of glomerular filtration rate requires different equations than
Adolescence is not simply a link between childhood and adulthood; it is a
distinct period of significant physiologic change. The effects of puberty
can alter the efficacy or toxicity of many drugs administered during this
Although less well understood than pharmacokinetic differences
between children and adults, there are significant age-related effects on
pharmacodynamics as well. Children may exhibit differences in both
therapeutic response and adverse effect profiles.
The differences in pharmacokinetics and pharmacodynamics observed in
children influence the choice of drug dose and dosing interval. For most
dose calculations, weight is used to account for growth and
All pediatric prescriptions and medication orders must be checked for
the appropriateness of the dose, route, and frequency with a pediatric
PREVENTING MEDICATION ERRORS IN CHILDREN
Children are at a greater risk for medication errors than adults, as a
result of the need to calculate drug doses and alter dosage formulations.
Electronic prescribing, standardization of drug doses and concentrations,
and the introduction of smart-pump technology have been shown to
reduce errors in many children’s hospitals. One of the most effective
methods to avoid errors is the inclusion of pediatric pharmacists in the
medication ordering and review process.
INCREASING PEDIATRIC MEDICATION INFORMATION
A number of governmental programs are increasing the availability of
pediatric medication information and improving the ability of pediatric
healthcare professionals to provide safe and effective drug therapy for
Providing care for children can be one of the most challenging, but rewarding,
aspects of pharmacy practice. Although a relatively small number of healthcare
providers pursue specialty training in pediatrics and work exclusively with children,
most clinicians will provide care for children every day in the community or hospital
setting. According to recent population estimates, approximately one-quarter of the
US population is younger than 20 years of age, with 6% younger than 5 years of age.
Although most children are healthy, this segment of the population still uses a
significant amount of healthcare resources. In a recent telephone survey, one in five
parents reported giving their child one or more prescription medications within the
2 A survey conducted in pediatricians’ offices found that 53% of
children left their visit with a prescription.
Pediatrics, as a specialty, encompasses a very diverse patient population. Patients
range in age from premature neonates to adolescents and can vary in weight by 100-
fold, from a 0.5-kg premature neonate to a 50-kg 16-year-old. Further complicating
the care of children is the relative lack of information on drug dosing and monitoring.
Because of the small numbers of children requiring medical treatment and the
difficulty in conducting research in these patients, fewer than half of the drugs
currently available in the United States are approved by the Food and Drug
Administration (FDA) for pediatric use.
4,5 As a result, as many as 60% of all
prescriptions written by pediatricians are for “off-label” uses.
monitoring information for off-label uses is often based on case series and clinical
trials published in the medical literature and may not be readily available in general
Healthcare providers caring for children must be capable of assessing the
appropriateness of drug doses for this diverse population and providing
recommendations for dosage adjustments and patient monitoring with limited
resources. This requires knowledge of the pharmacokinetic and pharmacodynamic
differences between children and adults and how these differences impact both
therapeutic and adverse drug effects.
Premature neonate Born at <36 weeks’ gestational age
Term neonate Born at ≥36 weeks’ gestational age
medication and dosing regimen for C.J.? What medication and dose will you recommend to his parents?
Children undergo considerable physiologic changes between birth and adulthood.
Although many changes are easily observed, such as the ability to walk or the
development of language, others are less evident. C.J.’s analgesic dose will be based
on his age and weight, as estimates of the numerous pharmacokinetic and
pharmacodynamic differences between children and adults. To discuss the changes
that occur with growth and development, pediatric patients are typically grouped by
age (Table 102-1). These definitions are helpful to provide a consistent framework
for dosing recommendations, but it should be kept in mind that they are arbitrary and
can oversimplify the differences among individual patients. Although children tend to
grow and develop in a relatively similar manner, the timing of maturation varies from
child to child. Children do not grow in a predictable, linear fashion, but rather in
periodic bursts, with additional variation caused by differences in genetic
predisposition, nutritional intake, and environment.
growth and development on pharmacokinetics and pharmacodynamics, often referred
to as developmental pharmacology, has grown considerably during the past several
decades, improving our ability to optimize the efficacy of drug therapy in children
while minimizing adverse effects.
The most appropriate analgesic for C.J. would be acetaminophen. Aspirin is no
longer used as an analgesic in children because of its association with Reye
syndrome, a rare condition causing mitochondrial damage and resulting in hepatic
failure. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, are not
recommended for use in infants younger than 6 months of age because of an increased
risk for renal impairment. C.J. should receive an acetaminophen dose of 10 to 15
mg/kg given every 4 to 6 hours as needed, with no more than five doses or 75 mg/kg
given in a 24-hour period. Based on his age and weight, an
appropriate recommendation for C.J. would be to give 65 mg (2 mL) of the
acetaminophen 160 mg/5 mL oral suspension by mouth every 6 hours as needed. If
C.J. continues to need medication for more than 24 hours, his parents should contact
C.J.’s primary healthcare provider.
PEDIATRIC PHARMACOKINETIC DIFFERENCES
All aspects of pharmacokinetics are affected by growth and physical maturation,
beginning during gestation (pregnancy) and ending in adulthood. These changes are
complex, and their timing can vary widely from patient to patient.
week of therapy. What factors might explain the lower concentration, and how should A.H. be managed?
Enteral absorption of drugs is altered at birth and does not approximate adult
7,8 Gastric fluid volume is greatly reduced at birth.
Gastric acid production is decreased, giving the neonate a higher, nearly neutral pH
in the stomach. This results in a greater absorption of acid-labile drugs such as
penicillin G and erythromycin, but reduced absorption of weakly acidic drugs such as
phenobarbital and phenytoin. Gastric acid output increases during the first 1 to 2
weeks of life, but only reaches adult values at 2 to 3 years of age. Transport of bile
acids into the gastrointestinal lumen and pancreatic enzyme production are also
reduced, further altering the absorption of pH-sensitive drugs and reducing
enterohepatic recirculation. Amylase activity is minimal at birth and remains low
until the third month of life.
9 Pancreatic lipase activity is detectable by 32 weeks’
gestational age, but remains low at birth and throughout the next 2 to 3 months. In
contrast, gastric lipase is present at birth and accounts for a greater percentage of fat
absorption during early life. In addition to these differences, neonates are also born
with relatively sterile gastrointestinal tracts. Normal bacterial colonization typically
occurs within days for term infants, but may be delayed in premature infants who
reside in the more sterile environment of an intensive care unit. The effectiveness of
drugs that rely on gastrointestinal flora for activation or degradation may be
significantly altered during this period.
Gastric emptying time is delayed and intestinal transit time is prolonged at birth,
but both quickly increase within the first few days of life because contractions in the
stomach become more coordinated and intestinal contractions become more frequent,
stronger, and sustained. Premature infants have delayed development of normal
gastric emptying and intestinal transit, as shown in a study of acetaminophen dosing
in which premature infants at 28 weeks’ gestational age had a 2-hour delay in
absorption compared with older infants.
10 Adult values for gastric emptying and
intestinal transit time are generally reached by 4 to 8 months of age.
For drugs absorbed through passive diffusion, reduced splanchnic blood flow
during the first weeks of life can reduce the rate and extent of absorption by altering
concentration gradients across the intestinal villi.
7 Reduction in blood flow may also
place neonates at risk for damage to the gut lining from hyperosmolar drug
formulations. As a result, many institutions delay use of the enteral route for drug
administration until the patient is receiving at least one-quarter to half of their
nutritional needs through enteral feedings. This allows dilution of drug doses and
may reduce the risk for mucosal damage. Lower levels of metabolic enzyme activity
in the intestine may reduce first-pass metabolism of drugs given enterally.
found that the bioavailability of zidovudine decreased from 89% in
neonates during the first 2 weeks of life to 61% in older infants, reflecting increased
first-pass metabolism in the older patients. Intestinal enzymatic activity does not
approach adult values until 2 to 3 years of age.
The lower phenobarbital serum concentration after A.H. was placed on enteral
therapy is most likely the result of reduced drug absorption in the gastrointestinal
tract, resulting from the higher gastric pH and reduced splanchnic blood flow. The
maintenance phenobarbital dose for A.H. should be increased to achieve a trough
serum concentration within the desired range. An increase of the oral dose to 10 mg
would be appropriate, with a plan to obtain a trough concentration within 3 to 5 days.
Although this value will not yet reflect the steady state concentration, due to the long
half-life of the drug, it will be useful to guide additional dosing changes.
) given intramuscularly (IM) to prevent vitamin K-deficiency bleeding of the newborn. C.B.’s
giving phytonadione IM rather than orally?
In the United States, phytonadione is typically given by IM injection after birth.
Drug administration by IM injection typically results in a delay in time to reach peak
serum concentrations in neonates. This delay is related to reduced muscle size,
weaker muscle contractions, and an immature vasculature resulting in more erratic
blood flow to and from the muscle.
7,8 Although considered a disadvantage when
rapid absorption is needed, such as with antibiotic administration, the delay in
systemic absorption after IM injection is used as an advantage for the administration
infant’s dietary intake is adequate to maintain necessary vitamin K serum
13 A similar delay in drug absorption may occur with subcutaneous
injection because of the lower percentage of body fat in neonates. The delay in
absorption seen with IM and subcutaneous administration becomes negligible after
the first months of life. When counseling C.B.’s parents, it will be important to stress
the benefit of the slower absorption of vitamin K with IM administration compared
with the rapid absorption and clearance of a single
oral dose. A single IM injection of vitamin K will protect their son from bleeding
until he is approximately a month old, when he should be taking in enough breast milk
or infant formula to maintain adequate vitamin K concentrations.
In contrast to enteral, IM, and subcutaneous administration, transdermal or
percutaneous administration results in greater drug absorption in neonates than it
does in older children and adults. Enhanced absorption results from a greater skin to
body surface area ratio, approximately 3 times that of adults, as well as a thinner
stratum corneum, better epidermis hydration, and greater perfusion.
degree of percutaneous absorption in infants has resulted in significant toxicity.
Hexachlorophene, when used routinely to bathe infants, has resulted in seizures and
is now considered contraindicated in this age range. Application of povidone–iodine
as a topical disinfectant before surgery has been linked to neonatal thyroid
dysfunction and, as a result, is now used only in limited quantities for brief periods to
limit percutaneous iodine absorption. In spite of the knowledge of this adverse effect,
cases continue to be reported in the medical literature.
topical products can produce systemic toxicity. Frequent use of diaper rash products
containing hydrocortisone can produce suppression of the hypothalamus–pituitary–
adrenal axis in as little as 2 weeks.
Cleaning and disinfecting the skin before surgery in a neonate requires special
attention to the selection of agent, surface area affected, and the length of skin contact.
For C.B., a 10% povidone–iodine solution should be gently applied to the penis and
surrounding skin immediately before surgery and removed as soon as the 5- to 10-
minute circumcision has been completed to minimize the risk for systemic toxicity
resulting from enhanced percutaneous iodine absorption.
CASE 102-3, QUESTION 3: Are transdermal anesthetics an appropriate option for use before C.B.’s
Both 4% lidocaine and eutectic mixture of local anesthetics (EMLA) cream, which
contain lidocaine and prilocaine, are widely used as topical anesthetics for infants
and children before venipuncture, IV catheter placement, or circumcision. Both have
been shown in clinical trials to be safe and effective.
15 The low concentration of the
active ingredients and the limited duration of contact, 30 to 60 minutes, prevent
excessive systemic absorption when applied to intact skin. Either analgesic cream
would be appropriate for C.B. EMLA should be applied an hour before the start of
the circumcision, whereas 4% lidocaine cream should be applied 30 minutes before
the procedure. A thin layer of cream should be applied, without an occlusive
dressing, and the baby diapered until the start of the procedure. The cream should be
completely removed before the application of the 10% povidone–iodine solution.
Other transdermal medications should be avoided or used with caution for only
limited periods in infants. After the first year of life, transdermal application
becomes a more useful route of administration for several medications.
Methylphenidate and clonidine patches are used in the treatment of attention deficit
hyperactivity disorder (ADHD) in school-aged children, and both lidocaine and
fentanyl patches are used for the treatment of older children and adolescents with
CASE 102-3, QUESTION 4: A week after C.B.’s discharge from the hospital, he is brought into the
acceptable option for C.B. in the hospital after he has been stabilized?
Rectal administration is a useful route of drug delivery for many pediatric patients.
Most drugs are well absorbed by this route, but the strong rectal contractions in
infants can result in an inability to retain suppositories for the length of time needed
to achieve optimal absorption.
7,8 Gels and liquid dosage preparations that do not
require an extended time for dissolution are better options. Rectal diazepam gel is
often used by parents of children with seizure disorders to provide rapid control of
worsening seizures while awaiting emergency medical personnel. In an observational
trial of 358 children, the median time from administration of rectal diazepam by a
parent to cessation of seizures was 4.3 minutes.
Rectal acetaminophen would be a viable option for C.B. It is rapidly absorbed
through this route. Many drug dosing references recommend a slightly higher rectal
acetaminophen dose (10–20 mg/kg) to account for a potentially lower
Growth and development also affect drug distribution. Organ size, body water
content, fat stores, plasma protein concentrations, acid–base balance, cardiac output,
and tissue perfusion all change throughout childhood, altering the pattern of
distribution and extent of drug penetration.
7 The greatest degree of change occurs
during the first year of life.
CASE 102-3, QUESTION 5: In the emergency department, C.B. is refusing to breast-feed and is having
Heart rate, 202 beats/minute (normal 107–182 beats/minute)
Blood pressure, 85/62 mm Hg (normalsystolic 70–75 mm Hg, diastolic 50–55 mm Hg)
would you select and what doses would you recommend?
Empiric antibiotic therapy for sepsis and meningitis for C.B. typically consists of
ampicillin and aminoglycoside. Although not commonly used in adults because of the
relatively low degree of penetration across the blood–brain barrier, this combination
is very effective in the neonatal period when drug distribution into the central
nervous system is higher. Constituting only 2% of total body weight in an adult, the
brain makes up 10% to 12% of the weight of an infant. As a result, the brain serves
as a much larger potential compartment for drug distribution. In addition, the
percentage of systemic blood flow that reaches the cerebral vasculature is greater.
These factors, along with a potential for greater passive diffusion of drugs across the
blood–brain barrier, can result in higher drug concentrations within the central
nervous system of infants compared with older children and adults.
produce both benefit and risk to the infant. Drugs given to treat meningitis or seizures
are more likely to achieve therapeutic concentrations within the central nervous
system, but there is also a greater potential risk for drug-induced neurotoxicity.
One of the most significant differences in drug distribution during childhood is the
decrease in total body water content with increasing age. Approximately 85% of a
premature newborn’s weight and 70% to 80% of a term newborn’s weight are body
water, compared with only 60% to 65% in a 1-year-old.
percentage declines from 50% to 60% and remains relatively constant. Extracellular
water decreases in a similar manner, from 40%–45% in the newborn to 20%–25%
by the end of the first year of life. Intracellular water content, however, remains
of highly lipid-soluble drugs, such as amphotericin, amiodarone, benzodiazepines, or
The pharmacokinetic profile of gentamicin has been well described in infants and
children as a result of its role in empiric antibiotic therapy for neonatal sepsis and
meningitis. The volume of distribution of gentamicin in premature neonates ranges
from 0.5 to 0.7 L/kg, reflecting the higher extracellular water content at this age. This
value falls to 0.4 L/kg by the end of the first year of life and further declines from 0.2
17 As a result of their higher volume of distribution, the
weight-based dose for an infant is often much higher than a comparable dose in an
adult. Based on C.B.’s age and weight, the Pediatric Dosage Handbook,
most widely used pediatric drug references, recommends an ampicillin dose of 170
mg (50 mg/kg) given IV every 6 hours and a gentamicin dose of 8.5 mg (2.5 mg/kg)
given IV every 8 hours, or if using extended-interval dosing, 13.6 mg (4 mg/kg) every
24 hours. Using these same weight-based doses in a 70-kg adult would result in
doses much higher than the typical recommended adult dose.
Whereas the effects of growth and development on changes in body water content are
well defined and typically require adjustments in drug dosing only during infancy, the
effects of changes in body fat are not yet well understood. Body fat increases
throughout gestation and infancy. A premature neonate may have as little as 1% to 2%
body fat, whereas a term infant will have closer to 10%–15% body fat. A 1-year-old
will have a body fat of 20% to 25%, similar to that of an adult. Children following
normal growth patterns have relatively little change in their body fat percentage
between the second year of life and the onset of puberty. However, the increasing
rate of childhood obesity has generated concern about the efficacy and safety of
current weight-based dosing strategies.
In a 2010 retrospective study of 699
children between 5 and 12 years of age admitted to a children’s hospital during a 6-
month period, overweight children (defined as having a body mass index greater than
the 85th percentile for age) accounted for 33% of the admissions.
their medication orders revealed that 8.5% of the doses ordered were for less than
the recommended dose, whereas 2.8% were for an excessive dose. The need to make
dosage adjustments in these children remains controversial; only limited research is
available documenting the effects of childhood obesity on the pharmacokinetics and
pharmacodynamics of commonly used pediatric medications.
recommendation be for C.B.’s continuing treatment?
Many of the drugs that would treat C.B.’s infection are highly protein bound.
Plasma protein binding is reduced in neonates as a result of decreased circulating
-acid glycoprotein, as well as decreased binding
7,8,11 With the known susceptibilities and their long history of efficacy and
safety, continuing C.B.’s current ampicillin and gentamicin regimen for 7 to 10 days
would be an appropriate choice. Although ampicillin is known to be present in higher
unbound concentrations in infants compared with adults (Table 102-2), use of
standard dosing recommendations for C.B. based on age should be adequate to
prevent toxicity. Sulfamethoxazole-trimethoprim would not be appropriate.
Administration of drugs with a high binding affinity for albumin, such as the
sulfonamides, during the neonatal period can result in competition with bilirubin for
binding sites. The resulting increase in unbound bilirubin can lead to kernicterus,
neurologic damage caused by deposition of bilirubin in the brain, primarily in the
20 For this reason, sulfonamides are not recommended for neonates and
are not approved by the FDA for use in infants younger than 2 months of age.
Ceftriaxone, another possible option for C.B., also is known to be highly protein
bound. Although approved for use in neonates, it is contraindicated in those with
hyperbilirubinemia. As a precaution, many hospitals restrict its use in the neonatal
population to only those patients who have infections resistant to other antibiotics.
The clinical impact of changes in protein binding can be difficult to predict.
Separation and measurement of the unbound (free) fraction can be used to guide
blood sample volumes may also be required, which can lead to excessive blood loss
in premature infants. An estimation of the unbound concentration can be made from
total serum drug concentrations, but may not be accurate in infants. Methods to
estimate unbound serum valproic acid concentrations from total concentrations that
were developed for adults have been found to be ineffective in predicting free levels
Examples of Drugs Present in Greater Unbound Concentrations in Neonates
Much of the research currently being conducted in developmental pharmacology is
focused on changes in metabolic function.
7,8,11,22–49 Our understanding of the ontogeny
of metabolic enzymes is improving rapidly, because in vitro data gathered from
studies quantifying hepatic microsomal proteins and determining levels of enzymatic
activity are combined with information obtained through pharmacokinetic and
pharmacogenomic research. It is clear that the onset of function varies among
enzymes; whereas some exhibit metabolic activity in utero, others demonstrate
activity only after several months of life. The development of metabolic enzyme
function continues during the first years of life and does not appear to be complete
until after puberty. There appears to be considerable interpatient variability. Enzyme
development can be affected by the underlying health of the child, nutritional status,
and exposure to substrate. Metabolic activity also reflects genetic polymorphisms,
QUESTION 1: N.M. is a 1.38-kg, 3-week-old girl who was born at 28 weeks’ gestational age. She has
the ability of N.M. to metabolize this drug? What dose of erythromycin would you recommend for N.M.?
Phase I reactions, which include oxidation, reduction, hydroxylation, and hydrolysis,
develop at varying rates during childhood, resulting in the wide range of half-lives
reported for many drugs. The cytochrome P-450 (CYP) 3A enzymes, which play a
major role in drug metabolism, including that of erythromycin, develop early in
7,8,11,22–27 The earliest isozyme in this group to show activity is CYP3A7, the
primary metabolic enzyme present in utero. It has been found on the endoplasmic
reticulum of fetal hepatocytes by the end of the first trimester and serves a role in the
transformation of fetal dehydroepiandrosterone and the detoxification of retinoic acid
derivatives transferred from maternal serum across the placenta.
activity of CYP3A7 declines rapidly after birth, with a 50% reduction during the first
month of life. Levels continue to decline at a slower rate through the next 6 months
and are typically undetectable after 1 year of age. As levels of CYP3A7 decline,
CYP3A4 and CYP3A5 levels rise. Although present during fetal development, the
level of CYP3A4 activity is nearly 100-fold less than that of CYP3A7 until after
Increases in CYP3A4 occur over the first months of life, often reaching
levels of enzymatic activity higher than that seen in adults during early childhood.
Development of CYP3A5 function is highly variable among infants and children and
does not appear to be related to patient age.
It can be anticipated that N.M. will have a slower rate of erythromycin metabolism
as a result of lower levels of CYP3A4 activity, so a more conservative approach to
dosing is often used. An oral erythromycin dose of 7 mg (5 mg/kg) given every 8
hours would be an appropriate starting dose for N.M. In addition to increasing the
risk for adverse effects, higher serum erythromycin concentrations can lead to greater
inhibition of CYP3A4. This may place N.M. at risk for toxicity from accumulation of
other drugs metabolized via CYP3A4, such as fentanyl and midazolam.
Upregulation of CYP2D6 appears to begin in the last stage of gestation as a part of
the complex transition of the baby to extrauterine life.
samples obtained early in gestation, CYP2D6 activity has been reported to be only
22 Earlier studies suggested that levels of enzymatic activity
remained low during infancy, but more recent research has demonstrated that
CYP2D6 activity increases rapidly during the third trimester, and by the second week
of life, values are similar to values in adults.
23 CYP2D6 levels remain relatively
constant throughout childhood. The impact of genetic polymorphisms of CYP2D6 on
elimination half-life in children is comparable to that demonstrated in adults and
appears to play a greater role in determining metabolic function than ontogeny.
A study of atomoxetine response in children and adolescents with ADHD found that
CYP2D6 poor metabolizers had greater increases in heart rate and blood pressure
and impaired weight gain compared with extensive metabolizers taking comparable
doses, reflecting higher serum concentrations with the poor metabolizer phenotype.
The enzymatic activity of CYP2C9 and CYP2C19 develops throughout
22,23,30 Studies of fetal hepatocytes demonstrated CYP2C9 activity at only
1% of adult values from 8 to 24 weeks’ gestation, with an increase from 10% to 20%
between 25 and 40 weeks. Enzyme activity continues to increase after birth, reaching
25% of adult values by approximately 5 months of age. Unlike other enzymes,
CYP2C9 activity remains at only 50% of adult values until after puberty. The
development of CYP2C9 activity is illustrated by the change in the rate of
metabolism of phenytoin with advancing age. The apparent (calculated Michaelis–
Menten) half-life of phenytoin in premature infants is approximately 75 hours,
compared with 20 hours in a term neonate and 8 hours in a 2-week-old.
Development of CYP2C19 function also occurs in utero, with enzyme activity 10%
to 20% that of adults at birth.
23 Enzymatic activity increases gradually during the first
3 months of life to near full adult values. As with CYP2D6, genetic polymorphisms
for CYP2C9 and CYP2C19 play an important role in determining individual patient
response. Population modeling of pantoprazole pharmacokinetics in term neonates
and premature infants revealed a longer elimination half-life than that reported in
adults, supporting the lower levels of CYP2C19 activity in this age group.
study also demonstrated significantly greater drug concentrations in the patients who
had the poor metabolizer genotype.
The ontogeny of CYP2E1 has been studied in conjunction with the ability of infants
to metabolize acetaminophen. Fetal hepatic CYP2E1 concentrations are typically
undetectable during the first trimester, but begin to increase during the second
33 Levels are approximately 10% to 20% of adult values at birth. Enzyme
concentrations continue to increase at a more gradual pace, until by 3 months of age,
CYP2E1 expression becomes similar to that in adults. The increase in CYP2E1
metabolic capacity, along with maturation of glucuronidation, is responsible for the
changing patterns of acetaminophen metabolite formation during infancy.
CASE 102-4, QUESTION 2: N.M. is now tolerating her enteral feedings and was recently extubated.
present in premature newborns, during the past 2 days. Based on current dosing guidelines, you have
mg/kg given once daily to treat her apnea.
34 While reviewing the dosing information, you note that the
The changing elimination half-life of caffeine reflects the onset and maturation of
CYP1A2 activity. The metabolism of caffeine during infancy has been extensively
many neonates are exposed in utero as a result of maternal intake and premature
infants often receive caffeine for the treatment for apnea.
22–23,34,35 Studies have shown
that CYP1A2 activity is negligible in fetal liver tissue and in newborns who were not
35 The lower levels of enzymatic activity result in a longer
caffeine half-life and allow once-daily dosing.
In contrast, newborns exposed to
caffeine during gestation have higher levels of CYP1A2 activity at birth. Enzymatic
activity rises progressively during the first months of life. By 6 months of age, it may
exceed adult values, giving the infant a caffeine half-life of only 4 to 5 hours and
necessitating more frequent dosing.
she was sedated with an infusion of midazolam. Many IV products, including some brands of midazolam,
restricting the use of benzyl alcohol in the neonatal population?
Alcohol dehydrogenase, another Phase I enzyme, is present in utero, but in
concentrations less than 5% of adult values.
23 Enzymatic activity does not approach
functional maturity until approximately 5 years of age. The lack of alcohol
dehydrogenase activity has a profound impact on the ability of newborns to
metabolize benzyl alcohol, a common preservative in injectable drug products. In
1982, five neonates died after developing gasping respirations that progressed to
respiratory failure, severe metabolic acidosis, renal and hepatic failure,
thrombocytopenia, and cardiovascular collapse.
37 All of the infants had been
repeatedly exposed to benzyl alcohol as a preservative in IV flush solutions. This
toxicity, termed gasping syndrome, resulted from accumulation of the parent
compound, as well as the benzoic acid metabolite. Another series of ten patient
deaths was reported from a second institution.
38 From these case series, the threshold
for toxicity was estimated to be a total daily exposure of 99 mg/kg/day. Within
months of these reports, the FDA issued a safety alert calling attention to this reaction
and recommending use of preservative-free products or preparations with alternative
39 This change in practice led to the virtual elimination of
gasping syndrome and brought to light the significance of differences in neonatal
metabolism on drug toxicity. Pediatric clinicians continue to be vigilant for benzyl
alcohol exposure, because several drugs routinely used in premature and critically ill
neonates are not available in preservative-free preparations.
Phase II reactions, including glucuronidation, sulfation, and acetylation, also undergo
change throughout childhood. Present in low levels in fetal hepatic and renal tissues,
the uridine 5'-diphosphate glucuronosyltransferase (UGT) enzymes responsible for
the glucuronidation of both drugs and endogenous substances have minimal metabolic
activity. A gradual increase in UGT expression occurs in the first 6 months of life,
but still remains lower than that of adults for the first 2 to 3 years of life. Genetic
polymorphisms produce additional variation in UGT expression.
reduced ability of infants to perform glucuronidation has been known for many years
as a result of the chloramphenicol “gray baby syndrome.” Chloramphenicol was a
widely used antibiotic during the 1950s. Within several years of its introduction,
case reports began to appear in the medical literature describing emesis, abdominal
distension, and cyanosis followed by cardiovascular collapse in infants given the
46 The mechanism for this toxic effect was later found to be reduced activity of
UGT2B7, the primary enzyme responsible for chloramphenicol metabolism, that
allowed accumulation of the parent compound.
CASE 102-4, QUESTION 4: N.M. also received morphine as an infusion during mechanical ventilation.
Careful attention is needed when administering opioids to neonates to avoid drug accumulation. What
Glucuronidation of morphine to morphine-6-glucuronide and morphine-3-
glucuronide via UGT2B7 can be demonstrated in premature neonates born as early as
24 weeks’ gestational age, but at a much slower rate than that of term
23,43,47,48 Studies of fetal liver microsomes have confirmed the presence of
UGT2B7, with a rate of enzymatic activity only 10% to 20% of adult values.
Morphine metabolism increases rapidly during the last trimester of intrauterine life
and the first weeks after birth. Clearance has been estimated to increase fourfold
between 24 and 40 weeks’ postconceptional age, but remains substantially slower
than that of adults until approximately 3 years of age.
Sulfation is a more important pathway in the metabolism of morphine during early
infancy than later in life. Unlike UGT enzymes, sulfotransferases (SULTs) develop
extensively in utero, reaching levels of enzyme activity similar to that of adults at
Intrauterine expression of SULT1A1, which is responsible for fetal
metabolism of thyroid hormones, SULT2A1, the enzyme that metabolizes steroid
hormones, and SULT1A3, which metabolizes catecholamines, occurs early in
gestation and remains relatively constant thereafter. Not all SULT enzyme
development takes place in the liver. Expression of SULT2A1 occurs primarily in the
The reliance on sulfation during infancy is found with several drugs besides
morphine, including catecholamines, thyroid hormones, theophylline, and
acetaminophen. Glucuronidation of acetaminophen via UGT1A6 and UGT1A9 is
decreased in infants, and as a result, the primary route of acetaminophen metabolism
is formation of sulfate conjugates for the first year of life.
begin to predominate later in infancy and eventually surpass sulfation as the
predominate route for acetaminophen metabolism.
Because of the slower rate of morphine clearance in neonates, particularly those
born prematurely, morphine should be initiated at lower doses than those
recommended for older infants and children. An appropriate starting dose for N.M.’s
morphine infusion would be 0.005 to 0.01 mg/kg/hour. N.M. should be closely
monitored for adverse effects, including hypotension, respiratory depression after
Like the liver, the kidneys are not fully developed at birth. The ability to filter,
excrete, and reabsorb substances is not maximized until 1 year of age.
average glomerular filtration rate (GFR) of only 2 to 4 mL/minute/1.73 m2
premature infants, the value may be even lower (0.6–0.8 mL/minute/1.73 m2
is a rapid rise in GFR during the first 2 weeks of life, with values increasing from 20
to 40 mL/minute/1.73 m2 as a result of increased renal blood flow, increased function
of the existing nephrons, and the appearance of additional nephrons, all of which may
be timed to coincide with birth.
51 GFR increases from 80 to 110 mL/minute/1.73 m2
by 6 months of age and continues to increase in a linear manner until it approaches
adult values of 100 to 120 mL/minute/1.73 m2 by 1 year of age. The impact of this
increase in GFR can be seen in the neonatal dosing recommendations for many
renally eliminated drugs, including the aminoglycosides and vancomycin. To account
for reduced renal function, most pediatric references use a combination of patient
weight and age (postnatal, postconceptional, or postmenstrual) to determine
gentamicin dosing in neonates.
17 As a premature newborn, E.C. is likely to have
significantly reduced glomerular filtration. E.C.’s gentamicin regimen will consist of
the standard neonatal dose (2.5 mg/kg) given at a less frequent interval than that of 2-
month-old N.M. to compensate for her renal insufficiency.
The elimination of ampicillin is also affected by changes in the rate of tubular
7,8,50 Like GFR, tubular secretion is reduced immediately after birth, but
gradually increases during the first year of life. In addition to the penicillins, a
reduction in tubular secretion also results in a prolonged elimination half-life for
cephalosporins, furosemide, and digoxin. Digoxin has been used for many years in
the management of supraventricular tachycardia in neonates. The half-life of digoxin
decreases from approximately 30–40 hours in a term neonate to 20–25 hours in a 1-
year-old as renal function matures. Selection of a digoxin dose must take into account
the difference in elimination. The recommended oral digoxin maintenance dose for a
neonate is 5 mcg/kg/day, whereas a 2-year-old would need to receive twice that
amount to achieve target serum digoxin concentrations.
typically adjusted by lengthening the dosing interval to compensate for reduced
tubular secretion. E.C. (a newborn delivered at 30 weeks’ gestation) would be dosed
every 12 hours, whereas an older child such as N.M. would be expected to clear
ampicillin more rapidly and would be dosed every 6 hours.
CASE 102-5, QUESTION 2: How should renal function be assessed in E.C. and N.M.?
As with adults, renal function should be closely monitored in children and drug
doses adjusted accordingly. Unlike adults, blood urea nitrogen and serum creatinine
values are not always useful as indicators of renal function. In the first days after
birth, serum creatinine values reflect maternal creatinine transferred through the
placenta and may appear falsely elevated. After the first week, serum creatinine
values are typically low as a result of less muscle mass, especially in premature
neonates, and may not accurately represent renal function.
as an additional measure of renal function in this population. Diaper weights can be
used to estimate output in E.C. and N.M., with values greater than 1 mL/kg/hour
considered adequate renal function. At the time of initiation of therapy, if both babies
are maintaining urine output values greater than 1 mL/kg/hour, the dosing regimens
recommended in the Pediatric Dosage Handbook
17 can be used without further
alteration. If urine output falls, the dosing intervals of both antibiotics may require
adjustment. A trough serum gentamicin concentration should be obtained to further
creatinine is 0.5 mg/dL (normal for age 0.5–1.5 mg/dL). Determine H.G.’s creatinine clearance.
After infancy, serum creatinine may be used to estimate clearance. The equations
used in adults, such as Cockroft–Gault, Jellife, or the Modification of Diet in Renal
Disease (MDRD), are not appropriate for patients younger than 18 years of age.
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