Pediatric pharmacotherapy

Pediatric
Pharmacotherapy
Dr. Kaveh Kazemian
Pharm-D
Board Certified of Clinical Pharmacy Specialist
Fellowship Assistant of Critical Care Pharmacotherapy
@pharmacotherapists @pharmacotherapist drkavehkazemian@gmail.com

 Providing care for children can be one of the most challenging, but rewarding, aspects of
pharmacy practice.
 According to recent population estimates, approximately one-quarter of the US population is
younger than 20 years of age, with 7% younger than 5 years of age.
 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
 As a result, as many as 60% of all prescriptions written by pediatricians are for "off-label" uses.“
Dr. Kaveh Kazemian. Pharm-D. BCCP. Fellowship assistant of critical care pharmacotherapy
Ref: Applied Therapeutics , The Clinical Use of Drugs 11th edition

 Health care 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.

GROWTH AND DEVELOPMENT DURING
CHILDHOOD

 Research on the impact of growth and development on pharmacokinetics and
pharmacodynamics, often referred to as developmental pharmacology
 Aspirin is no longer used as an analgesic in children because of its association with Reye
syndrome
 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.
 acetaminophen dose of 10 to 15 mg/kg given every 4 to 6 hours as needed, with no more than
five doses given in a 24-hour period.
 65 mg of the concentrated infant acetaminophen drops by mouth every 6 hours as needed.

 All aspects of pharmacokinetics are affected by growth and physical maturation, beginning
during gestation (pregnancy) and ending in adulthood.
PEDIATRIC PHARMACOKINETIC
DIFFERENCES

Oral
 Enteral absorption of drugs is altered at birth and does not approximate adult patterns for
several months
 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
 Transport of bile acids into the gastrointestinal lumen and pancreatic enzyme production are
also reduced
Drug Absorption

 Amylase activity is minimal at birth and remains low until the third month of life
 Pancreatic lipase activity is detectable by 32 weeks' gestational age, but remains low at birth
and throughout the next 2 to 3 months.
 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
 Gastric emptying time is delayed and intestinal transit time is prolonged at birth, but both
quickly increase within the first few days of life
 Premature infants have delayed development of normal gastric emptying and intestinal
transit

 Adult values for gastric emptying and intestinal transit time are generally reached by 4 to 8
months of age.

 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. Boucher and colleagues 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.

INTRAMUSCULAR DRUG ABSORPTION
 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.
 Disadvantage when rapid absorption is needed and is used as an advantage for the
administration of phytonadione after birth.
 A similar delay in drug absorption may occur with subcutaneous injection because of the
lower percentage of body fat in neonates.

TRANSDERMAL DRUG ABSORPTION
 In contrast to enteral, 1M, and subcutaneous administration, transdermal or percutaneous
administration results in greater drug absorption in neonates than it does in older children
and adults.
 Greater skin to body surface area ratio, approximately three times that of adults, as well as a
thinner stratum corneum, better epidermis hydration, and greater perfusion.
 Resulted in significant toxicity
 Hexachlorophene
 Application of povidone-iodine as a topical disinfectant before surgery
 Frequent use of diaper rash products.

 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
 4% lidocaine and EMLA (eutectic mixture of local anesthetics) cream, which contains
lidocaine and prilocaine
 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.
 After the first year of life, transdermal application becomes a more useful route of
administration for several medications. Methylphenidate and clonidine patches and both
lidocaine and fentanyl patches

RECTAL DRUG ABSORPTION
 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
 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
 Many drug dosing references recommend a slightly higher rectal acetaminophen dose (10-
20 mg/kg) to account for a potentially lower bioavailability.

 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
 The greatest degree of change occurs during the first year of life.
 Empiric antibiotic therapy for sepsis and meningitis typically consists of ampicillin and an
aminoglycoside but not in adults
 Constituting only 2% of total body weight in an adult, the brain makes up 10% to 12% of
the weight of an infant
 In addition, the percentage of systemic blood flow that reaches the cerebral vasculature is
greater.
Drug Distribution

 This can 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.

BODY WATER
 One of the most significant differences in drug distribution during childhood is the decrease
in total body water content with increasing age
 85% of a premature newborn's
70% to 80% of a term newborn's
60% to 65% in a 1-year-old
 After a year of age, the percentage declines to 50% to 60% and remains relatively constant,
Extracellular water decreases in a similar manner
40% to 45% in the newborn
20% to 25% by the end of the first year of life.
Intracellular water content, however, remains relatively stable.
 These changes result in a much greater distribution of highly water-soluble drugs, such as
the aminoglycosides or linezolid, and a reduced accumulation of highly lipid-soluble drugs,
such as amphotericin, amiodarone, benzodiazepines, or digoxin

 The volume of distribution of dosgentamicin
 As a result of their higher volume of distribution, the weight-based for an infant is often
much higher than a comparable dose in an adult
 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
 Using these same weight-based doses in a 70-kg adult would result in doses much higher
than the typical recommended adult dose

BODY FAT
 The effects of changes in body fat are not yet well understood
 A premature neonate 1% to 2% body fat
Term infant will have closer to 10% to 15% body fat
A 1-year-old will have a body fat of20% 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

PROTEIN BINDING
 Plasma protein binding is reduced in neonates as a result of decreased circulating levels of
both albumin and a1 acid glycoprotein, as well as decreased binding affinity

 Administration of drugs with a high binding affinity for albumin lead to kernicterus,
neurologic damage caused by deposition of bilirubin in the brain
 Ceftriaxone, another possible option also is known to be highly protein bound. Although
approved for use in neonates, it is contraindicated in those with hyperbilirubinemia.

Metabolism
 Much of the research currently being conducted in developmental pharmacology is focused
on changes in metabolic function

GLOMERULAR FILTRATION
 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
 At birth, full-term neonates GFR = 2 to 4 ml/min/1.73 m2
premature infants 0.6-0.8 ml/min/1.73 m2
 There is a rapid rise in GFR during the first 2 weeks of life, with values increasing to 20 to
40 ml/min/l. 73 m2
6 months of age 80 to 110 ml/min/1.73 m2
1 year of age 100 to 120 ml/min/l. 73 m2
Elemination

 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 to determine gentamicin dosing in neonates.

TUBULAR SECRETION
 The elimination of ampicillin is also affected by changes in the rate of tubular secretion.
 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 ftom approximately 30 to 40 hours in a term
neonate to 20 to 25hours in a 1-year-old as renal function matures.
 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

 Ampicillin doses are typically adjusted by lengthening the dosing interval to compensate for
reduced tubular secretion
 Renal function should be closely monitored
 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.
 Urine output is often used as an additional measure of renal function in this population

 After infancy; serum creatinine may be used to estimate clearance. The equations used in
adults, such as Cockroft -Gault,]ellife, or the Modification of Diet in Renal Disease
(MDRD), are not appropriate for patients younger than 18 years of age.
CLCr = (0.48 x Ht)/SCr

Pharmacokinetic Changes During Puberty

Although not as well studied as pharmacokinetics
 Maturational changes in receptor conformation, density, and affinity, as well as signal
transduction
 Although a dopamine infusion of 20mcg/kg/minute will produce an adequate increase in
myocardial contractility and elevate systemic vascular resistance in most children and
adults, infants may not have a significant change in cardiovascular response
 Infants have long been suspected to be relatively resistant to the effects of beta-adrenergic
agonists, including dopamine, dobutamine, and epinephrine. Recent research suggests the
lack of response is related to a relative reduction in adrenergic receptor density or a
downregulation of receptors within the myocardium of premature and critically ill neonates.
PEDIATRIC PHARMACODYNAMIC
DIFFERENCES

 A higher dopamine infusion rate, up to 40 mcg/kg/minute, may be necessary to achieve an
adequate blood pressure. If the dopamine is increased extremities must be closely monitored
for any signs of excessive peripheral vasoconstriction.
 Supplemental therapy with hydrocortisone, at a dose ofo.? mg (1 mg/kg) IV every 8 hours,
may also be used to manage his hypotension.
 Differences in pharmacodynamics resulting from growth and development can alter more
than just therapeutic response. A drug's adverse effect profile may be distinctly different
during childhood.
 classic example of this phenomenon is the higher incidence of serious dermatologic
reactions, including toxic epidermal necrolysis, in children taking lamotrigine compared
with that of adults.
 The slower dose escalation, now recommended for pediatric patients, is starting E.S. 's
lamotrigine dose at 0.15 mglkglday and increasing by 0.15- to 0.3-mg/kg/day increments
every 2 weeks, should reduce the likelihood for these reactions.

 Some investigators have suggested that this is a dose-related toxicity more evident in
children who have a limited capacity to metabolize lamotrigine through glucuronidation to
its inactive metabolites.
 This theory, however, does not explain why other patient groups known to have higher
serum lamotrigine concentrations during treatment, such as the elderly, are not at increased
risk
 Others have speculated that this represents an immune-mediated hypersensitivity response,
as many of the affected patients reported have had previous reactions with other
antiepileptic drugs." Children with refractory seizures, such as those with Lennox-Gastaut
syndrome, who are often treated with multiple agents beginning in the first years of life may
be more likely to develop hypersensitivity
 Although the mechanism underlying the age-related difference in the incidence of
lamotrigine-associated rashes is not yet well understood, the importance of patient
counseling is clear. The caregivers of all children receiving larnotrigine should be made
aware of the risk and the need to seek medical care as soon as any signs of rash or erythema
are noted

 The differences in pharmacokinetics and pharmacodynamics observed in children influence
the choice of dose and dosing interval
 Weight has traditionally been chosen as the single best estimate of growth.
 Among the exceptions to this are chemotherapeutic agents, which are dosed by body surface
area
 Age can be an important variable, especially for premature infants
 For example, neonatal gentamicin dosing is often based on a rubric of gestational or
postconceptional age, postnatal age, and weight.
MEDICATION DOSING IN CHILDREN

 A recent study of clonidine clearance in the early postnatal period suggests that both age and
weight should be used to optimize clonidine doses in newborns being treated for neonatal
abstinence syndrome.

 Medication errors pose a significant risk for infants and children
 Whereas the rate of medication errors reported in studies of adults is approximately 5%,
rates in many pediatric studies have ranged from 10% to 15%.
 The need to calculate weight-based doses can lead to mathematical errors
 Unit conversions and decimal point errors are particularly dangerous in pediatrics, because a
lO-fold overdose of a drug with a narrow dosing range such as clonidine, digoxin,
morphine, or fentanyl can be fatal.
 Oral liquid medications also present a risk for administration errors.
PREVENTING MEDICATION ERRORS IN
CHILDREN

Ref: Applied Therapeutics , The Clinical Use of Drugs 11th
edition

 Use of standard concentrations for IV products and oral liquids, smart pump technology,
barcoding, and electronic prescribing with clinical decision support tools have been found to
significantly reduce errors in pediatric hospitalS
 In the outpatient setting, medication errors can be reduced by the inclusion of patient-
specific information on prescriptions, including diagnosis and patient weigh
 Caregivers should have access to the appropriate tools for measuring liquid medications,
such as oral dosing spoons or syringes, and the opportunity to practice preparing a dose
under the supervision of a health care provider to ensure that they are able to prepare the
dose correctly
 One of the most effective methods to prevent medication errors has been to include clinical
pharmacists in the medication ordering and review process

Thanks
Ref: Applied Therapeutics , The Clinical Use of Drugs 11th edition

Pediatric pharmacotherapy

Empfohlen

Empfohlen

Weitere ähnliche Inhalte

Was ist angesagt?

Was ist angesagt? (20)

Ähnlich wie Pediatric pharmacotherapy

Ähnlich wie Pediatric pharmacotherapy (20)

Mehr von Kaveh Kazemian

Mehr von Kaveh Kazemian (7)

Kürzlich hochgeladen

Kürzlich hochgeladen (20)

Pediatric pharmacotherapy