Principles of pharmacotherapy in neonates and paediatric

1. Principles of Pharmacotherapy in
Neonates and Paediatric
Population
Dr Satyabrata Sahoo
DM Clinical Pharmacology Resident
Dept of Clinical & Experimental
Pharmacology, CSTM Kolkata
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2. Introduction
• Differences in physiology in paediatric
populations compared with adults
• That Influence the concentration of drug within
the plasma or tissue
• Paediatric population includes-
1.Preterm & Term neonates(0-27 days)
2.Infants & Toddlers(28 days to 23 months)
3.Children(2 years to 11 years)
4.Adolecsents(12 years to 17 years)
• Partially different from adults according to pk pd
profile
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3. Classification of Pediatric Patients
•Pediatric patients less than 18 years of age.
•Unlike an adult patient, a pediatric patient’s age can be
expressed in days, weeks, months, and years.
• Patients are classified based on age and may be further
described based on other factors, including birth weight and
prematurity status .
Growth and Development
•Children are monitored for physical, motor, cognitive, and
psychosocial development through clinical recognition
•The Centers for Disease Control and Prevention (CDC) Growth
Charts are used to plot head circumference, weight, length or
stature, and body mass index for a graphical representation of a
child’s growth compared to the general pediatric population
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4. Differences in Vital Signs
•Normal values for heart rate and respiratory rate vary
•Heart rates are highest in neonates and infants, ranging from 95 to 180
beats per minute (bpm) and decrease with age, reaching adult rates (60–
100 bpm) around 10 years of age.
•Respiratory rates are also higher in neonates and infants (24–38
breaths/min), decreasing with age to adult rates around 15 years of age
(12–20 breaths/min).
•The American Academy of Pediatrics (AAP) recommends rectal
temperature measurement in children 4 years of age or younger, using a
digital thermometer.
•For children 4 years of age or older, axillary or oral temperature
measurement is appropriate as the child is more able to cooperate when
asked.
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5. Fluid Requirements
Fluid requirement and balance are important to
monitor in pediatric patients, especially in
premature neonates and infants.
Maintenance fluid requirement can be
calculated based on body surface area for
patients greater than 10 kg with a range of
1,500 to 2,000 mL/m2/day.
However, a weight-based method of
determining normal maintenance fluid for
children is often used .
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6. Maintenance Fluid Calculations by Body weight
PATIENT BODY WEIGHT MAINTAINANCE FLUID REQUIREMENT
Less than 10 kg 100 ml/kg/day
11-20 kg 1000ml +50 ml/kg over 10 kg
Greater than 20 kg 1500 ml + 20 ml/kg over 20 kg
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7. Effects Of Pharmacokinetic And Pharmacodynamic Differences
On Drug Therapy
•Drug selection strategy may be similar or different depending on
age and disease state
• Pediatric patients may require the use of different medications
from those used in adults .
• For example, phenobarbital - neonatal seizures, but not often
used for treatment of seizures in adults.
• There also exist commonalties between pediatric and adult
patients, such as therapeutic serum drug concentrations required
to treat certain diseases.
• For example, gentamicin peak and trough serum concentrations
needed to treat Gram-negative pneumonia are the same in children
as in adults.
•The appropriate selection and dosing of drug therapy for a
pediatric patient depends on specific factors such as age, weight,
height, disease being treated, comorbidities, organ function, and
available drug dosage forms.
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8. •Equations proposed to calculate pediatric doses based on
adjusted age or weight such as Clark’s, Fried’s, or Young’s Rule
should not be routinely used to calculate pediatric doses
• Because they account for only one factor of difference, age or
weight, and lack integration of the effect of growth and
development on drug pharmacokinetics and pharmacodynamics
in this population.
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9. Absorption
• Oral absorption may be reduced in premature infants and neonates
due to differences in gastric acid secretion and pancreatic and biliary
function.
• Full-term neonates have a gastric pH of 6 to 8 at birth and pH 1 to 3 by
48 hours of age.
• Gastric acid output per kilogram is lower in premature infants and
increases with age to adult levels by 6 months of age.
• Low gastric acid secretion increased serum concentrations of weak
bases and acid-labile medications, such as penicillin, and decreased
serum concentrations of weak acid medications, such as
phenobarbital.
• Additionally, gastric emptying time and intestinal transit time are
delayed in premature infants.
• Pancreatic exocrine and biliary function are also reduced in newborns
• Topical or percutaneous absorption in neonates and infants is
increased due to a thinner stratum corneum.
• Application of topical medications should be limited to the smallest
amount possible.
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10. • Intramuscular absorption in premature and full-term infants can be
erratic
• Rectal absorption can also be erratic and is not a commonly
recommended route of administration if there are other routes
available (e.g., oral).
• This route is useful in cases of severe nausea and vomiting or status
epilepticus.
• Bioavailability increases as the blood supply bypasses the liver from
the lower rectum directly to the inferior vena cava.
• Availability of rectal dosage forms varies, with acetaminophen
suppositories and diazepam gel as examples of medications used by
the rectal route in pediatric patients.
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11. Volume of Distribution
• In pediatric patients, apparent volume of distribution
(Vd) is normalized based on body weight and expressed
as L/kg.
• Neonates and infants have a lower normal range for
serum albumin (2–4 g/dL, 20–40 g/L), reaching adult
levels after 1 year of age.
• This affects highly protein-bound drugs such as
phenytoin, resulting in lower total serum
concentrations needed to achieve therapeutic,
unbound serum concentrations.
•As premature neonates have lower body adipose
composition compared to older children and adults,
they have a decreased Vd for lipid-soluble drugs such as
midazolam and require lower doses by body weight.
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12. Metabolism
• Drug metabolism is slower at birth in full-term infants compared
to adolescents and adults, with further delay in premature
neonates.
• Phase I reactions and enzymes, such as oxidation and alcohol
dehydrogenase, are impaired in premature neonates and infants
• Glucuronidation by the uridine diphosphate glucuronosyl
transferases, on the other hand, is immature in neonates and
infants
• Adverse effects including cyanosis, ash gray color of the skin,
limp body tone, and hypotension, also known as “gray baby
syndrome” with use of chloramphenicol.
• Products containing benzyl alcohol or benzoic acid should be
avoided in neonates due to immature glycine conjugation,
resulting in accumulation of benzoic acid.
• Acetylation via N-acetyltransferase reaches adult maturation at
around 1 year of life.
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13. Elimination
• Renal drug clearance is reduced in infants and slowest in premature neonates
• Glomerular filtration rate (GFR) is lowest in premature neonates
• For example, vancomycin - 18 to 24 hours in a low birth weight (LBW) premature
neonate, every 6 hours in children with normal renal function, and every 8 to 12
hours in adult patients with normal renal function.
• Children with cystic fibrosis also present with greater renal clearance of drugs such
as aminoglycosides
• The use of the Cockroft-Gault or Jelliffe equations for estimating CrCl in adults is
not recommended for patients less than 18 years of age.
• Schwartz’s equation is a common method of estimating pediatric CrCl for LBW
infants up to 21 years of age .
• Urine output is also a parameter used to assess renal function in pediatric
patients, with a urine output of greater than 1 to 2 mL/kg/h considered normal.
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15. Specific Considerations In Drug Therapy
• In addition to differences in pharmacokinetics and
pharmacodynamic parameters, other factors including
dosage formulations, medication administration techniques,
and parent/caregiver education should be considered when
selecting drug therapy
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16. Routes of Administration and Drug Formulations
• Depending on age, disease, and disease severity,
different routes of administration may be
considered.
• When oral drug therapy is needed, one must also
consider the type of dosage form available.
• Most hospitals caring for pediatric patients
compound formulations in their inpatient
pharmacy.
• A list of community pharmacies with
compounding capabilities should be maintained
and provided to the parents and caregivers
before discharge from the hospital.
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17. Common Errors in Pediatric Drug Therapy
• Prevention of errors in pediatric drug therapy
begins with identification of possible sources.
• Decimal errors
• The use of the “rule of six” was previously used
to calculate infusions of medication such as
inotropes for critically ill patients in hospitals.
• Prevention of medication errors is a joint effort
between health care professionals and
parents/caregivers.
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18. CAM and OTC Medication Use
• An estimated 31% to 84% of children with cancer, 74% with autism
spectrum disorder, 71% with asthma, and 15% seen in the
emergency department utilize CAM or other OTC products.
• It is critical to realize that there are limited data establishing efficacy
of various CAM therapies in children. Example-Colic
• Symptoms of excessive crying usually improve by the third month
of life and often resolve by 9 months of age.
• No medication has been approved by the FDA for this condition.
This condition is self-limiting and infants will outgrow it as they age.
• Clinicians should respect parents’/caregivers’ beliefs in use of CAM
and OTC products and encourage a discussion with the intention of
providing information regarding their risks and benefits to achieve
desired health outcomes as well as optimize medication safety.
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19. Off-Label Medication Use
• Pharmacotherapy in pediatric patients often
includes use of approved and unapproved
(off-label) drugs.
• This includes the use of a medication in the
treatment of illnesses not listed on the
manufacturer’s package insert
• Such off-label use in infants and children is
frequently based on limited data.
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20. • Currently, there is a lack of pediatric dosing,
safety, and efficacy information for over 75%
of drugs approved in adults.
• Off-label use occurs in both outpatient and
inpatient settings.
• About 80% of hospitalized pediatric patients
receive at least one off-label medication.
• FDA regulatory changes, such as patent
exclusivity, provide incentives for a
pharmaceutical manufacturer to market drugs
for pediatric patients.
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21. Medication Administration to Pediatric Patients
and Caregiver Education
• Considering the challenges in cooperation from infants
and younger children, medication administration can
become a difficult task for any parent or caregiver.
• The means or devices for measuring and administering
medications by the caregivers should also be closely
considered.
• Oral syringes are accurate and offered at most
community pharmacies for measurement of oral liquid
medications.
• Oral droppers
• Comprehensive and clear parent/caregiver education
improves medication adherences, safety, and therapeutic
outcomes.
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22. Summary
• There are less Clinical trials in paediatric population
especially neonates and infants due to ethical issues
• There is not much data published.
• Off label use of drugs in paediatric population
increasing day by day
• Pharmcokinetic and pharmacodynamic profile varies
• Paediatric physician should prescribe rationally for
benefit of patients
• Paediatric populations should be included more and
more in clinical trials for rational treatment in future
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23. References
1. Hamilton BE, Martin JA, Ventura SJ. Births: Preliminary data for 2006. National vital
statistics reports; vol 56 no 7. Hyattsville, MD: National Center for Health Statistics.
2007.
2. Committee on the Future of Emergency Care in the United States Health System.
Emergency Care for Children, Growing Pains. Executive Summary. The Institute of
Medicine, 2007, http://books.nap.edu/catalog/11655.html.
3. Cherry DK, Woodwell DA, Rechtsteiner EA. National Ambulatory Medical Care
Survey: 2005 Summary. Advance data from vital and health statistics; no. 387.
Hyattsville, MD: National Center for Health Statistics. 2007.
4. Kozak LJ, DeFrances CJ, Hall MJ. National Hospital Discharge Survey: 2004 annual
summary with detailed diagnosis and procedure data. National Center for Health
Statistics. Vital Health Stat 13(162). 2006.
5. American Academy of Pediatrics, Committee on Fetus and Newborn. Age
terminology during the perinatal period. Pediatrics 2004;114: 1362–1364.
6. Center for Disease Control Growth Charts, 2000. Developed by the National Center
for Health Statistics in collaboration with the National Center for Chronic Disease
Prevention and Health Promotion. http://www.cdc.gov/growthcharts.
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24. THANK YOU
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