Paediatric pharmacology

Dr.K.Sathishbabu
2nd year PG
Department of Pharmacology
PAEDIATRIC PHARMACOLOGY

OVERVIEW
 Pharmacokinetic process in Paediatric patients
 Pharmacodynamic process in paediatric patients
 Paediatric dosage forms and compliance
 Paediatric drug dosage
 Drug use in Lactation
21/05/2020 2PAEDIATRIC PHARMACOLOGY

INTRODUCTION
• Physiologic processes - influence pharmacokinetic
variables in the infant change significantly in the
first year of life
• Special attention must be paid to pharmacokinetics
• Pharmacodynamic differences between pediatric &
other patients have not been explored and except for
those specific target tissues that mature at birth

Pharmacokinetic
processes

Absorption
1. Blood flow at the site of drug administration :
• Absorption from IM or SC injection in neonates -
rate of blood flow to the muscle or subcutaneous
area injected.
• Physiologic conditions - reduce blood flow
– Cardiovascular shock & Heart failure
– Vasoconstriction due to sympathomimetics21/05/2020 5PAEDIATRIC PHARMACOLOGY

• Sick preterm infants :
– very little muscle mass
– Complicated by diminished peripheral perfusion
to these areas.
• Absorption becomes irregular & difficult to predict :
– Drug may remain in the muscle and be absorbed
more slowly than expected

• If perfusion suddenly improves → sudden and
unpredictable increase in the amount of drug
entering the circulation → high and potentially
toxic concentrations of drug
• Examples :
Cardiac glycosides, Amino glycosides
and Anticonvulsants

2. Gastro intestinal function :
 Gastric acid secretion :
• Full term infants → begins soon after birth
• Preterm infants → occurs more slowly (highest
conc → 4th day of life)
• Drugs – partially / totally inactivated by low pH

 Gastric emptying time : prolonged in 1st day (6-8h)
• Stomach – drug may absorbed more completely
• In small intestine – delayed therapeutic effect
 Peristalsis : In neonates – irregular & slow
• Slow peritalsis  Increased absorption  Toxicity
• Fast peristalsis  Decreased absorption

 Gastro intestinal enzymes : low
 Pancreatic enzymes : low (upto 4 months)
 Bile acids & Lipase : low
Oral drug absorption (bioavailability) of various drugs in the neonate compared with
older children and adults

3. Rectal absorption :
• Faster & more predictable
• Diazepam suppository is given rectally to control
febrile seizures in children < 5yrs
4. Transdermal absorption :
• Faster
• Skin is thin & more permeable

Distribution
• Body weight in the form of water :
Neonate (70–75%) > adult (50–60%)
• ECF : Neonate (40% of BW) > adult (20% of BW)
• Many drugs are distributed through the ECF space
• Volume of the ECF compartment - important in
determining the concentration of drug at receptor
sites21/05/2020 12PAEDIATRIC PHARMACOLOGY

• Total body fat :
 Preterm infants is about 1% of total body weight,
compared with 1.5% in full-term neonates
 Organs accumulate smaller concentrations of lipid
soluble drugs in less mature infants

• Plasma protein binding :
Protein binding is lower because
 Albumin and total protein concentrations are
lower in neonates until 1 year
 Qualitative differences in binding proteins
 Competitive binding by molecules such as
bilirubin and free fatty acids, which circulate in
higher concentrations in neonates and infants

Result may be,
1. Increased free drug concentrations
2. Greater drug availability at receptor sites
3. Higher pharmacologic effects and adverse
effects at lower drug concentrations
Drugs given to a neonate with jaundice → displace bilirubin
from albumin → greater permeability of the neonatal blood-
brain barrier → bilirubin may enter the brain → kernicterus
Example – sulphonamides

Metabolism
• Metabolism of most drugs occurs in the liver
• Drug-metabolizing activities → cytochrome P450
dependent enzymes low in early neonatal life than
later
• Neonates – decreased ability to metabolize drugs
• Glucuronide formation reaches adult values
between the third and fourth years of life

• Many drugs have slow clearance rates and
prolonged elimination half-lives → the neonate is
predisposed to adverse effects from drugs that are
metabolized by the liver
• Example : Chloramphenicol can produce grey
baby syndrome

• Mother receiving drugs (eg, phenobarbital) →
induce early maturation of fetal hepatic enzymes.
↓
• The ability of the neonate to metabolize certain
drugs will be greater than expected
↓
• Less therapeutic effect and lower plasma drug
concentrations (when usual neonatal dose is given)

• During toddlerhood (12–36mon) → the metabolic
rate of many drugs exceeds adult values →
necessitating larger doses per kilogram than later
in life
Comparison of elimination half-lives of various drugs in neonates and adults

Excretion
• Glomerular filtration in neonate :
 30–40% of the adult value (lower in preterm)
 After 3rd week, GFR is 50–60% of adult value
 By 6–12 months, GFR reaches adult values
 During toddlerhood, GFR exceeds adult values →
necessitating larger doses per kg than in adults
Eg : Digoxin21/05/2020 20PAEDIATRIC PHARMACOLOGY

• Drugs that depend on renal function for elimination
are cleared from the body very slowly in the first
weeks of life. Eg : Ampicillin, Aminoglycosides
• Tubular function :
 In infants tubular secretion rates are approx. 20%
 Doesn’t achieve adult values until 6-7months of age
 In neonates tubular reabsorption is decreased

Pharmaco dynamic process
• Appropriate use of drugs has made possible the
survival of neonates with severe abnormalities
Indomethacin – Rapid closure of PDA
Prostaglandin E1 – Ductus remain open in TGA
• Neonates → more sensitive to the central
depressant effects of opioids → necessitating
extra caution on exposure to some narcotics

• At birth, the function of drug transporters may be
very low
• Eg : P-glycoprotein (pumps morphine from the
blood-brain barrier back to the systemic
circulation) → neonates are substantially more
sensitive to the CNS depressant effects of
morphine

ELIXIRS SUSPENSIONS
Flavoured solutions of drug in sugar
syrup or glycerol along with higher
proportion of alcohol
Liquid medicament containing insoluble
substances which are homogenously
distributed throughout vehicle with or
without help of suspending agents.
Drug molecules are dissolved & evenly
distributed ; Shaking not required
Undissolved particles and uneven
Distribution ; Shaking required
First dose from the bottle and the last
dose should contain equivalent amounts
of drug
First doses from the bottle may contain
less drug than the last doses → less than
the expected plasma concentration or
effect of the drug may be achieved
Eg. Vit B - complex elixir Eg. Milk of magnesia, phenytoin susp.
Paediatric dosage form

COMPLIANCE
Reasons for non
compliance :
Measuring errors
Spilling
Spitting out
Discontinuation of
antibiotics after
feeling better
Measuring compliance :
Random pill counts
Measurement of
serum concentrations
Use of computerized
pill containers

Paediatric drug dosage &
Calculation
• Most reliable paediatric dose information –
provided by the manufacturer in the package
insert
• In absence of explicit paediatric dose
recommendations , an approximation can be made
by methods based on age, weight or surface area

• Rules regarding this aren’t precise and should not
be used if the manufacturer provides a paediatric
dose
• When paediatric doses are calculated (either from
one of the methods set forth below or from a
manufacturers dose), the paediatric dose should
never exceed the adult dose

Age, Weight & Surface area
• Calculations of dosage based on age or weight are
conservative and tend to underestimate the
required dose
Clark’s rule (Weight): Dose = Adult dose  Weight (kg)
70
OR
Dose = Adult dose  Weight (lb)
150
Young rule (Age) : Dose = Adult dose  Age (years)
Age +12

• Catzel Rule :
= surface area of the child (in m2) x Adult dose
1.76 m2
 Doses based on surface area are more likely to be adequate

Monitoring parameters
• It give an idea about therapy management in
prolonged treatment
• Pediatric vital signs, biochemical and Hematology
parameters change through childhood

Drug use in Lactation
Most drugs administered to lactating women are
detectable in breast milk.
Fortunately, the concentration of drugs achieved
in breast milk is usually low
The total amount the infant would receive in a
day is substantially less than “therapeutic dose”
21/05/2020 PAEDIATRIC PHARMACOLOGY 32

Optimal time to take medication: 30–60 minutes
after nursing and 3–4 hours before the next
feeding
This may allow time for drugs to be partially
cleared from the mother’s blood, and the
concentrations in breast milk will be relatively
low

Milk is slightly more acidic (pH 7.0) than plasma
→ weak bases that become more ionised.
Non-electrolytes like alcohol (ethanol) can readily
enter into the milk independently of the pH.
Majority of the drugs get into the milk by passive
diffusion although active transport may occur in a
few cases. Eg. Iodide

 The amount of a drug transferred into the milk
depends on various factors.
 Maternal volume of distribution :
o lipid soluble drugs > water soluble drugs
o Results in low plasma levels relative to the dose.
 Plasma protein binding :
o Only unbound drug in the plasma is able to diffuse
into the milk.
o Highly protein bound drugs cannot be detected in
breast milk

Drugs Effects on infant
Choral hydrate Drowsiness if infant is fed at peak conc. in milk
Heroin,
Morphine
Prolong Neonatal narcotic dependence
Iodine
(radioactive)
Thyroid suppression in infants
Glucocorticoids
affect the growth and development due to
premature fusion of epiphysis
Methadone
Prolong Neonatal narcotic dependence
Signs of opioid withdrawal in infants if mother
stops taking methadone or stops breast feeding
abruptly
Phenobarbital Sedation
Tetracycline Discoloration of teeth

Summary
• There are many pharmacokinetic and pharmaco
dynamic changes as a child develops.
• Caution is particularly needed in the premature and
term neonatal population to avoid pharmacological
errors
• Pharmacological variation amongst neonates and
infants emphasize the need to titrate many drugs to
effect

• Physiological and Pathological factors can alter
drug handling
• Hepatic metabolism is determined by developing
hepatic enzyme systems and by blood flow
• Enzyme systems in the developing child are
variable and complex. This gives reduced
predictability of how a drug will affect a young
child

• Paediatric patient’s ability to clear a drug changes
rapidly in the first few months of life; often a
child can clear drugs faster than an adult
• Oral administration is far more acceptable to
children compared to the intramuscular route

References
• Bertram G Katzung. Special Aspects of Perinatal
& Pediatric & Geriatric Pharmacology. Basic &
clinical pharmacology.13th edition. Pg – 1390-
1417
• Felix Bochner. Medication during Pregnancy,
Lactation, Chlidren & Elderly. Handbook of
clinical pharmacology; 2nd edition. Pg – 43-64

• Sumner J. Yaffe Neonatal and Pediatric
Pharmacology: Therapeutic Principles in Practice
2010
• R.S.Satoskar. Drugs, Pregnancy and Infant;
Pharmacology and Pharmacotherapeutics; 24th
edition. Pg – 1694 – 1705

Paediatric pharmacology

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