This document discusses drug therapy in children and outlines several key points. It notes that pediatric pharmacokinetics differ from adults due to immature organ systems. Absorption, distribution, metabolism and excretion of drugs is often slower or less developed in children. The document also discusses different pediatric dosage forms and challenges in drug administration for children due to palatability, dosing accuracy and safety concerns. Alternative treatment options are sometimes used but can compromise drug efficacy and safety.

1. DRUG THERAPY IN CHILDREN
By: Dr.Nivedita Mishra
Pediatrics (PGY1),TUTH

2. OBJECTIVES
• To discuss the principles of prescribing in
Pediatric age group.
• To discuss the pharmacokinetic and
pharmacodynamic differences in Pediatric and
adult age groups.
• To describe how efficacies of drugs vary according
to age.
• To describe different Pediatric dosage forms and
compliance in children.
• To discuss important ADRs occuring in Pediatric
age groups.

3. “Pediatrics does not deal with
miniature men and women,with
reduced doses and the same class of
disease in smaller bodies.. But has
its own independent range and
horizon.”
Dr. Abraham Jacobi
(Father of American Pediatrics)

4. PEDIATRIC AGE GROUPS
According to International Conference of Harmonisation :
• Extremely Preterm = 23-38 WOG
• Moderately Preterm = 29-33 WOG
• Late Preterm = 34-37 WOG
• Early Term = 37- 38+6 WOG 1. Newborn=0 to 1 month
• Full Term = 39 – 40+6 WOG
• Late Term = 41 – 41+6 WOG
• Post Term = /> 42 WOG
1. Infant = >1 month to 1 year
2. Toddler = 1year to 23 months
3. Child = 2 to 11 years (According to European Committee for Medicinal
Products for Human Use: Preschool = 2-5 yrs, School = 6-11yrs)
4. Adolescent = 12- 18 years

5. Pediatric Pharmacokinetics
• Immaturity of:
1.Hepatic metabolism- immature microsomal enz.
System.Drugs administered to mother can induce
neonatal enz. activity.(e.g-Barbiturates)
2.Renal excretion- LOW BLOOD FLOW,DRUG EXCRETES
SLOW.
3.Blood brain barrier- more permeable in neonates and
young children.more CNS adv.effects.(e.g-kernicterus)
• GI absorption slower
• I.M/topical absorption unprdictable (diazepam-
rapid,phenobarb- slow)
• Lower vol.of distribution of fat soluble drugs.
• Decr.plasma protein binding in neonates.

6. Pediatric Pharmacokinetics
A= Absorption:
G.I.T-
1.Ph- premature babies have higher ph than mature babies (ACID
LABILE DRUGS INCR CONC.)
2.Rate of gastric emptying is prolonged with irregular
peristalsis(motilin) in neonates and infants.Reaches adult level by
6-8 months
(incr. absorption from stomach than from intestine,
delayed therapeutic effect of drugs absorbed from intestines)
3.G.I enz activity – lower ,decr. Absorption of lipid soluble drugs
4.Surface area available for drug absorption
Skin- incr.absorption(under developed stratum corneum,incr.skin
hydration.
Rectal- absorption similar to upper g.i
I.M – unreliable absorption.

7. Pediatric Pharmacokinetics
D= Distribution: Membrane permeability-
Plasma protein binding – less in newborns
(increase in apparent vol. of distribution)
Total body water- 94% in fetus,85% in
premature babies,78% in full term,60% in adults.
Transporter expression-
M= Metabolism:differences in the pediatric population
compared with adults both for phase I and phase II
metabolic enzymes.
Sulfation is well developed.
Glucuronidation is under developed. (Gray baby syndrome)
Reduced doses reqd. for
theophylline,phenobarbital,phenetoin,diazepam d/t decr.
Metabolism in neonates.

8. Pediatric Pharmacokinetics
E= Excretion:
• Immaturity of glomerular filtration, renal tubular
secretion and tubular reabsorption at birth.
Maturation by 1 year.
In toddlers, renal excretion exceeds adult values
often neccesitating larger doses/kg. (e.g- digoxin
dose in toddlers is higher than in adults)
• Biliary function maturity determines excretion.

10. Pediatric Pharmacodynamics
• For the clinician, the consideration of age-dependent differences in
pharmacodynamics is particularly relevant when they are associated with adverse
drug reactions (e.g., higher incidence of valproic acidassociated hepatotoxicity in
young infants; greater frequency of paradoxical CNS reactions to diphenhydramine
in infants; weight gain associated with use of atypical antipsychotic drugs in
adolescents) or when drugs have a narrow therapeutic index.
• This latter situation is exemplified by the immunomodulatory agent cyclosporine
and the anticoagulant warfarin. In children younger than 1 yr old, the mean
concentration of cyclosporine required to inhibit monocyte proliferation and the
expression of the inflammatory cytokine interleukin-2 is less than required in older
children.
• The age-associated pharmacodynamics of warfarin observed in children with
congenital heart disease is, to a great degree, associated with developmental
differences in serum concentrations of vitamin-K dependent coagulation factors (II,
VII, IX, X) between children and adults. Developmental differences in drug action
have also been observed between prepubertal children and adults with regard to
warfarin action. Prepubertal children compared to adults exhibit a more profound
response, demonstrated by lower protein C concentration, prothrombin fragments
1 and 2, and greater rise in international normalized ratio, to comparable doses of
warfarin.
• Thus, when age-dependent pharmacodynamics of a given drug are evident, the
use of simple allometric approaches for “scaling” the pediatric dose from the usual
adult dose may not produce the desired pharmacologic effects.

11. PHARMACOGENETICS
Drug response is a function of the complex interplay among genes involved in
drug transport, drug biotransformation, and receptor and signal
transduction processes
• An information gap currently exists regarding the developmental and
genetic aspects (i.e., the possible role of polymorphisms) of liver enzymes
regulation and its potential effect on pediatric drug therapy
• Human growth hormone can modulate the effect of many general
transcription factors, the demonstrated regulatory role for growth
hormone in the expression of CYP2A2 and CYP3A2 in rats
• Pharmacogenetic differences between patients of the same age can have
profound effects on drug metabolism (and clearance) by producing
quantitatively important differences in the rates and routes of drug
biotransformation.
• Drug biotransformation phenotype may be influenced by disease (e.g.,
infection), environmental factors (e.g., diet and environmental xenobiotics
compounds), and concurrent medications.

12. DOSE CALCULATION
Based on AGE
Young’s rule:
Pediatric dose = (Age * Adult dose)/(Age + 12)
Fried’s rule:
Infant dose = Age*Adult dose/150
Based on WEIGHT
Clark’s rule:
Pediatric dose = Weight * Adult dose/150
Based on BSA
Pediatric dose = BSA of child * Adult dose/1.73m2

13. Disease conditions
• LIVER DISEASE:
• Drugs with high hepatic extraction ratio(>0.7)=
morphine,meperidine,lidocaine,Pprnl.
• Clearance of these drugs are affected by
hepatic blood flow.
• Toxicity may occur if cirrhosis,CHF
• Theophylline clearance decr by 45% in acute
viral hepatitis.

14. Disease conditions
• RENAL DISEASE:
• Sr.drug conc. should be measured for drugs
with narrow therapeutic index and eliminated
largely by kidneys (e.g-
Aminoglycosides,Vancomycin)
• For drugs with wide therapeutic ranges (e.g
penicillins,cephalosporins) dose adjustment is
only reqd. in mod- severe renal faliure.

15. Disease conditions
• Cystic Fibrosis:
• Require increased doses of certain drugs d/t
high clearance –
Gentamucin,Tobramycin,Netilmicin,Amikacin,
Dicloxacillin,Cloxacillin,Piperacillin,Theophyllin
e.
• d/t variations in metabolic activity or
phenotypic distribution of hepatic enzymes.

16. Drug administration
3 criterias for each drug formulation:
1. Product efficacy and ease of use (e.g dose flexibility,
drug acceptability, convenient handling, correct use),
2. Patient safety (eg, bioavailability of active substances,
safety of excipients, medication stability, risk of
medication errors)
3. Patient access (eg, product manufacturability,
affordability, development, production speed).
Ideal pediatric formulation: flexible dosage
increments,minimal excipients,palatable,safe and
easy to administer,stable to light, heat, humidity.

17. Drug administration
1.Oral solids:
Risk of choking /chewing
Limited dose flexibility
2.Liquid preparations:
Palatability
Dose uniformity
Age-appropriate dosing volumes to ensure full dose ingestion
Stability (chemical, physical, or microbiological)
Requirement for clean water;
Bulky, impractical, and expensive to ship and store,particularly in lower
income countries with hot and humid climates.
3. Nonoral routes:
Difficult application,
Local irritation,
Fluid overload- I.V in Neonates
Electrolyte imbalance,
Poor drug acceptability

18. Drug administration
• The urgent need to understand these safety concerns has led to a
collaborative effort by the United States and the European Union to create
a STEP (Safety and Toxicity of Excipients for Pediatrics) database. Its aim is
to improve systematic data collection on excipient toxicity and tolerance in
children.
• ESNEE (European Study of Neonatal Exposure to Excipients), has
developed a platform for the systematic assessment of excipients in
neonates.
Excipient Adverse Reaction
Benzyl alcohol Neurotoxicity, metabolic acidosis
Ethanol Neurotoxicity, cardiovascular problems
Propylene glycol Neurotoxicity, seizures, hyperosmolarity
Polysorbate 20 and 80 Liver and kidney failure

19. Drug administration
• Alternative treatment options are often used to make unavailable drugs
accessible for children and/or to adjust drug doses according to individual
patient needs.
• These options include:
1. Modification of administration routes (eg, oral use of parenteral formulations)
2. Manipulation of adult dosage forms (eg, diluting liquid formulations)
3. Segmenting tablets and suppositories,cutting patches and dispersing open
capsules or crushed tablets in water, liquid, or food
4. Extemporaneous dispensing (ie, compounding medicines from ingredients
within pharmacies).
• Administering medicines in this way is difficult and unsafe because limited
data are available to validate stability, bioavailability, pharmacokinetics,
pharmacodynamics, dosing accuracy, tolerability, and reproducibility.
• All these manipulations may compromise drug efficacy and/or safety, as well
as create risks for the environment and individuals handling the dosage
forms, particularly in the case of mutagen and cytotoxic compounds.
• Best Pharmaceuticals for Children Act,
• Pediatric Research Equity Act in the United States,
• Pediatric Regulation in the European Union,
• WHO initiative (“Make Medicines Child Size”)

20. Adverse Drug Reactions
• The World Health Organization defines adverse reactions as harmful and
unintended responses to a drug and which occur with doses normally
used in humans for prophylaxis, diagnosis or treatment of a disease or
modifying a physiological function.
• m/c ADRs: skin (rash, urticaria),gastrointestinal(diarrhea, nausea and
vomiting)
• The drugs most frequently associated with adverse reactions are
vaccines,antibiotics,NSAIDS, corticosteroids,cough and cold remedies.
• Use of off-label drugs exposes the child to a high risk of severe adverse
reactions.
• The risk of medication errors is 3 times higher than those observed among
adults.
• Specific pediatric ADRs:
1.Aspirin-Reye’s syndrome
2. cefaclor- serum sickness
3.lamotrigine- cutaneous eruptions
4.valproate- hepatotoxicity (<2yrs old)
5.Phenobarbitone – paradoxical hyperactivity
6.Corticosteroids – growth suppression
Delayed HSR= Fever, Rash, Lymphadenopathy

21. Compliance
• PEDIATRIC Drug formulations should be adapted to suit
children’s age,size,physiologic condition & treatment
requirements.
• Issues: 1. Difficulty in swallowing conventionally sized
tablets.
2. Safety issues with excipients present in adult
formulations esp.OTC
3. Adherence problems with unpalatable medicines.
Patient & Parent education: dose,timing,route of
administration,duration of treatment,storage,desired
responses, adverse responses.
To promote compliance: use convenient drug forms,select
dosing forms to fit lifestyle of patients,mix drugs with foods
when allowed,returned demonstrations.

22. TOXICITY AND POISONING
• Younger children are at especially high risk of accidental poisoning when
they discover and take caregivers’ vitamins or drugs.
• Infants are also at risk of toxicity from drugs used by adults:
- toxicity can occur prenatally when they are exposed via placental transfer or
postnatally when exposed through breast milk. E.G NEONATAL
ABSTINENCE SYNDROME- maternal opiate use
HYPERSEROTONERGIC STATE- maternal SSRI use
OPIATE TOXICITY- maternal codeine use for pain management.
- skin contact with caregivers who have recently applied certain topical
drugs
- Drug-Drug interactions: Ceftriaxone should be avoided in infants younger
than 28 days of age if they are receiving or are expected to receive
intravenous calcium-containing products because of reports of neonatal
deaths resulting from crystalline deposits in the lungs and kidneys.
- displacement of warfarin plasma protein binding by ibuprofen with
consequent increased hemorrhagic risk inhibition of intestinal CYP3A4
activity by grapefruit juice or St. John’s wort and consequent reduction in
presystemic clearance of CYP3A4 substrates.

23. CONCERNS IN PEDIATRIC
PHARMACOLOGY
• Children are “therapeutic orphans”
• Inadequate research data for prescribers to ensure safe
dosing d/t inability to get consent,impact of ontogeny on
drug disposition
• FDA Safety and innovation Act 2012:
• 2/3rd of drugs used in pediatrics have never been tested in
pediatric pts.
• 20% of drugs were ineffective for children,even though
they were effective for adults.
• 30% of drugs caused unanticipated side effects,some
potentially lethal.
• 20% of drugs required dosages different from those that
had been extrapolated from adult dosages.

24. CONCERNS IN PEDIATRIC
PHARMACOLOGY
• The pediatric market has focused mostly on only a limited number
of therapeutic areas, such as antiinfectives, hormones, and
medicines for the respiratory and central nervous system.
• Meanwhile, there are hardly any dermal preparations and
medicines specifically aimed at younger age groups for the
cardiovascular system, sensory organs, and cancers. This lack of
pediatric formulations often leaves health care professionals no
alternative but to use adult medicines in an off-label or unlicensed
manner.
• Off-label use is common for cancer, renal ds.,antiarrhythmics,
antihypertensives, proton pump inhibitors, H2-receptor antagonists,
antiasthmatic agents, and some antidepressants.
• In the United States, two-thirds of medicines used in pediatrics are
off-label; worldwide, this proportion is up to three-quarters.

25. SUMMARY
• Children are not just “little adults,” and lack of data on
important pharmacokinetic and pharmacodynamic
differences has led to several disastrous situations in
pediatric care.
• Variations in absorption of medications from the
gastrointestinal tract, intramuscular injection sites, and
skin are important in pediatric patients, especially in
premature and other newborn infants.
• The rate and extent of organ function development
and the distribution, metabolism, and elimination of drugs
differ not only between pediatric versus adult patients but
also among pediatric age groups.
• The effectiveness and safety of drugs may vary among
age groups and from one drug to another in pediatric
versus adult patients.

26. • Concomitant diseases may influence dosage requirements to
achieve a targeted effect for a specific disease in children.
• Use of weight-based dosing of medications for obese
children may result in suboptimal drug therapy.
• The myth that neonates and young infants do not
experience pain has led to inadequate pain management in
this pediatric population.
• Special methods of drug administration are needed for
infants and young children.
• Many medicines needed for pediatric patients are not
available in appropriate dosage forms; thus, the dosage forms
of drugs marketed for adults may require modification for use
in infants and children, necessitating assurance of potency
and safety of drug use.
• The pediatric medication-use process is complex and error-
prone because of the multiple steps required in calculating,
verifying, preparing, and administering doses.

27. References
• Pediatric Drug Formulations: A Review of Challenges and
Progress. pediatrics/aappublications.org Verica Ivanovska, Carin
M.A. Rademaker, Liset van Dijk, Aukje K. Mantel-Teeuwisse
• JCS JOINT WORKING GROUP: 2012 GUIDELINES ON
PEDIATRIC DRUG THERAPY IN CARDIOVASCULAR DISEASES.
• Nelson’s textbook of Pediatrics (1ST SOUTH ASIA EDN.)
• FDA: Development of Drug Therapies for Newborns and
Children The Scientific and Regulatory Imperatives Yeruk (Lily)
Mulugeta, PharmDa, *, Anne Zajicek, PharmD, MDb , Jeff Barrett, PhDc , Hari Cheryl Sachs,
MDa , Susan McCune, MDa , Vikram Sinha, PhDd , Lynne Yao, Mda
• PHARMACOTHERAPY(A PATHOPHYSIOLOGIC APPROACH) 8TH
EDN:Chap. 10: Pediatrics Milap C. Nahata; Carol Taketomo