1. SEMINAR ON ALTERED KINETICS IN PEDIATRICSBy
RAJANI THOUTREDDY
(M. Pharm I- Sem)
DEPARTMENT OF PHARMACEUTICS
BLUE BIRDS COLLEGE OF PHARMACY
(Affiliated to Kakatiya University)
WARANGAL
2009

2. CONTENTS INTRODUCTION CALCULATION OF CHILD DOSE DRUG ABSORPTION
DRUG DISTRIBUTION
DRUG METABOLISM
DRUG ELIMINATION
THERAPEUTIC DRUG MONITORING
DOSING CONSIDERATIONS
CONCLUSION
REFERENCES

3. Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGY
1. INTRODUCTION
Pediatric population comprises 20-25% of total world population.
Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGY
TERMS
DEFINITION
Gestational Age
Time from the mother’s last menstrual period to the time the baby is born
Postnatal age
Age since birth
Neonate
First 1 month of life
Pre mature neonates
Born at less than 37 weeks gestation
Full term neonates
Born between 37 and 42 weeks gestation
Infant
1 month to 1 year of age
Child
1-12 years of age
Adolescent
12-18 years of age

4. 2. CALCULATION OF CHILD DOSE
Dose for child from adult dose can be calculated by any of the following formulae-
Clark’s Formulae: (For infants and Children)
(Weight in pounds) x (adult dose) 50
Fried’s Formulae: (For infants and children up to 1 to 2 years)
(Age in months) x (adult dose)
150
Young’s Formulae: (For children of 1 to 12 years)
(Age in years) x (adult dose)
Age + 12

5. Based of Surface area
% of Adult dose = Surface area of child x 100 Surface area of adult Table. 2
Age
% of Adult dose
1 Month 10
2 Months 15
4 Months 20
1 Year 25
3 Years 35
5 Years 40
10 Years 60
12 Years 75
16 Years 90

6. 3. DRUG ABSORPTION
3.1 Oral absorption 3.2 Intravenous absorption 3.3 Intramuscular absorption 3.4 Percutaneous /Transdermal absorption 3.5 Rectal absorption

7. 3.1. Oral Absorption Effected by – Gastric emptying and GI motility
Gastric pH
Gastric emptying and GI motility
Absorptive surface area
Pancreatic enzyme activity
Bile Salt production
Underlying disease state

8. 3.2. Intravenous Absorption
Effected by –
Site of injection
IV flow rate
Dose volume
3.3. Intramuscular Absorption
Used when child is unable to take medication orally or when drug is unavailable for oral use.
Surface area available
Blood flow to site of injection
Muscle activity

9. Less desirable because of pain, irritation and decreased drug delivery compared to I.V. administration Pain can be over come by applying topical anesthetic such as lidocaine.

10. l 3.4. Percutaneous /Transdermal Absorption Effected by –
Patient age
Skin hydration
Stratum corneum thickness and intactness
Application site
Drug diffusion by percutaneous absorption is explained by the equation –
J = Km x Dm x Cs l
J – Flux
Km – Partition Co-efficient
Dm – Diffusion constant under specific conditions such as temperature and hydration
Cs – Concentration gradient
l – Length /thickness of stratum corneum

11. 3.5. Rectal Absorption
Used as an alternative to oral, I.V and I.M routes of absorption
Absorption is more in solution from than in the form of suppositories
Not generally preferred due to –
Delay in onset of action
Failure to reach minimum effective concentrations in the plasma.

12. 4. DRUG DISTRIBUTION 4.1. Volume of distribution
Total body water as a percentage of total body weight
85% in premature infants
78% in full term neonates
Percentage of extra cellular water –
65% of total body weight premature infants
35-44% in full term neonates
20% in adults
Percentage of intra cellular water –
25% in premature neonates
33% in full term neonates
40% in adults

13. Amino glycosides such as gentamycin have extra cellular. volume of 0
Amino glycosides such as gentamycin have extra cellular volume of L/Kg for a neonate but only 0.2 – 0.3 L/Kg for an older child /adult
Vd is decreased for lipid soluble drugs such as diazepam in neonates. Neonates exhibit apparent Vd of 1.4 – 1.8 L/Kg compared to L/Kg in adults
4.2. Protein binding
Acidic Drugs – Albumin
Basic Drugs – Alpha1– acid glycoprotein (AGP)
These proteins are less efficient in neonates in binding drugs such as phenytoin, phenobarbital, chloramphenicol, penicillin, propranolol, lidocaine etc
Adult levels of albumin and AGP occur at approximately months of age

14. 4.3. Presence of endogenous substances
Free fatty acids
Unconjugated bilirubin
Drugs like sulfonamides or ceftriaxome bind to plasma proteins, may displace bilirubin and contribute to high levels of bilirubin in neonate and infants.
Displaced bilirubin can cross the blood brain barrier and deposit in the brain causing an encephalopathy termed “Kernicterus”.
Unconjugated bilirubin normally binds non-covalently to plasma albumin, but binding affinity is reduced in neonates, not approaching adult values until 6 months of age.

15. 5. DRUG METABOLISM
Drug Metabolism occurs primarily in the liver with additional biotransformation occurring in the intestine, lung, adrenal gland and skin.
In liver, metabolism involves –
1) Phase – I reactions (Non Synthetic reactions)
2) Phase – II reactions (Synthetic Reactions)
Phase – I reactions:
Oxidation, reduction, hydrolysis, hydroxylation etc
Cytochrome P450 mono-oxygenase enzymes which are responsible for Phase –I oxidation reactions are 50% of the activity of the adults.

16. Pharmacokinetic Consequences
Table. 3. Age dependent differences in activity of important drug metabolising phase – I enzymes and drug metabolism
Enzyme
Neonate
Infant
Child
Adolescent
Pharmacokinetic Consequences
CYP2D6
Reduced (20% adult activity)
Reduced
Adult pattern (by age 3-5 yr)
Adult pattern
O-demethylation of codeine to morphine ↓ in neonate/infants resulting in lack of efficacy and poor pain control.
CYP2C19
Adult pattern (reached by age 6 months)
Increased (peak activity at age 3-4 years)
Adult pattern (decreases to adult value at puberty)
Diazepam half-life ↑ in neonates/infants (25-100hrs) compared to children (7-37hrs) and adults (20-50 hrs) due to ↓oxidative activity
CYP2C9
Adult pattern ( reached by age 1-6 months)
Increased (peak activity at age 3-10 years)
Phenytoin half life ↓from 80 hrs at 0-2 days, to 15 hrs at 3-14 days, to 6 hrs at days of life due to slow maturation
CYP3A4
Reduced (30-40% of adult activity)
Adult pattern(by age 6 months)
Increased (between age 1-4 years then progressively ↓)
Adult pattern (at puberty)
↑ Metabolism of carbamazepine to its 10,11 epoxide in infants/children with ↑CYP3A4 activity compared to neonates, and adults

17. 2) Phase –II reactions:
Glucuronidation, sulfation, acetylation, glutathione conjugation etc.
Involve the conjugation of active drugs with endogenous molecules to form metabolites that are more water soluble.
Glucoronidation in children reaches adult levels by the age of 2 years.
Sulfate conjugation is fully developed immediately prior to or at the time of birth.
Theophylline is example of drug that is readily metabolized in neonates by N-Methylation to caffeine.
Drugs like cimetidine, erythromycin and ketoconazole inhibit metabolism of other medications in children.

18. Pharmacokinetic Consequences
Table. 4. Age dependent differences in activity of important drug metabolising Phase – II enzymes and drug metabolism
Enzyme
Neonate
Infant
Child
Adolescent
Pharmacokinetic Consequences
N-acetyl –transferase – 2
Reduced (up to 2 months)
Reduced (by age 4-5 months)
Adult pattern (present age 1-3 yrs)
Adult
pattern
↓ Acetylation of (sulfa pyridine metabolite) results in ↑ side effects– nausea, headache, abdominal pain in neonates and infants
Methyl-transferase
Increased (50% higher than adults)
Adult pattern
Specific example not available
Glucuronosyl transferase
Reduced
↑ Ratio of glucuronide to sulfate of acetaminophen with age; newborn 0.34; child (3-10 yrs) 0.8; adolescent 1.61 and adult sulfation compensates for glucuronide so no major consequences for dosage adjustments in pediatric patients
Sulfo-tranferase
Reduced (10-20% of adult activity)
Increased (for specific substances)
Increased (for specific substrates)

19. 6. DRUG ELIMINATION
Kidney is the major route of drug elimination for both water soluble drugs and water soluble metabolites of lipid soluble drugs.
The basic processes in renal elimination –
Glomerular filtration
30% - 50% of adult value in full term neonates
85% adult values by 3-5 months of age
Premature infants have reduced filtration rates due to incomplete nephrogenesis.

20. 2) Tubular function
In infants tubular secretion rates are approximately 20% of adult values and do not achieve adult rates until 6-7 months of age.
Some drugs like penicillin stimulate their own secretion, before secretion is fully mature leading to decreased efficacy.
In neonates tubular reabsorption is decreased, unlike tubular secretion, its development remains poorly understood.
Elimination of amino glycosides (gentamicin, tobramycin, amikacin) and digoxin are effected by renal maturation.
Dosage adjustment for digoxin is necessary as renal function matures in neonates and young infants.
Older infants and children require higher mg/kg doses of digoxin than adults due to decreased digoxin absorption or increased renal elimination.

21. Glomerular filtration rates can be estimated by assessing creatinine clearance.
Estimated by using nomograms or mathematical formulae.
Creatinine clearance (CrCL) in pediatric population can be calculated by using Schwartz formulae.
CrCL = KL/SCr
CrCL is estimated in ml/min/1.73m2, where
L- Body length in Cm
SCr – Serum creatinine in mg/dL
K- constant of proportionality

22. Table.5. Values of K for estimating clearance with the Schwartz formulae
Age Group
k (Mean Value)
Low birth weight infants  1 year
0.33
Full term  1 year
0.45
Children 2-12 years
0.55
Females years
Males years
0.70

23. Physiologic Variability Pharmacokinetic Consequences
Table.6. Age dependent differences in physiologic functions and drug disposition
Physiologic Variability
Neonate
Infant
Child
Pharmacokinetic Consequences
Absorption
Gastric pH
Increased
(>5)
(2-4)
Normal
(2-3)
Increase in bioavailability of acid labile drugs e.g. penicillin G, ampicillin, nafcillin in neonates and infants compared to children and adults, decreased bio-availability of weak organic acids e.g. Phenobarbital
Gastric and intestinal emptying time
Reduced and Irregular
Increased time to achieve peak plasma acetaminophen concentration when administered with meperidine due to decreased gastrointestinal motility
Biliary function
Immature
Near adult pattern
Adult pattern
Increased absorption of fat and fat soluble vitamins D and E in infants and children.
Pancreatic function
Increased hydrolysis and bio-availability of oral liquid ester formulations of dindamycin and chloramphenicol in infants and children

24. Gut microbial colonization
Reduced
Near Adult pattern
Adult pattern
Increased bio availability of digoxin in infants compared to adults due to lack of microbial gut colonization with a oral digoxin reducing anaerobic bacteria.
Intramuscular absorption
Variable
Increased
Increased to near adult pattern
Benzathine penicillin G more rapidly absorbed in children compared to adults since no measurable activity was detected in children 18 days after the injection
Skin permeability and percutaneous absorption
Near adult pattern
EMLA (Eutectic mixture of local anesthetics lignocaine and prilocaine) contraindicated in patients less than 3 months of age due to risk of methemoglobinemia due to increased percutaneous absorption of prilocaine and decreased methemoglobin reductase.
Rectal absorption
Increased rate and extent of diazepam absorption from rectal solution compound to suppositories, used to prevent and treat febrile seizures in infants and children.

25. Physiologic Variability Pharmacokinetic Consequences
Neonate
Infant
Child
Pharmacokinetic Consequences
Distribution
Total Body water (Extra cellular)
Increased
Near Adult pattern
Increase in mean apparent volume of distribution (Vd) for hydrophilic drugs. E.g. gentamicin. Vd<34WK 0.67 ± 0.13 l/kg; Vd34-48WK 0.52 ± 0.10 l/Kgs;Vd1-4.9yrs 0.38±0.16 l/Kgs, Vd5-9.9yrs 0.33±0.14 l/Kgs, Vd10-16yrs, 0.31 ± 0.12 l/Kgs, Vdadult < 0.30 l/Kgs
Total body fat
Reduced
Increased (age 5-10 yrs)
Increase in mean apparent Vd for lipophillic drugs e.g. diazepam 1.6 – 3.2 l/Kg in adults vs 1.3 – 2.6 l/Kg in infants
Total plasma proteins
Reduced to near adult pattern
Adult pattern
Increase in Vd and free phenytoin concentration in neonates and children and adults with physiologic/pathologic conditions leading to altered protein concentration

26. Renal Elimination
Glomerular Filtration
Reduced pattern
Adult Pattern
Adult
Famotidine – 80% excreted unchanged in the urine in older children and adults; renal clearance equivalent to adults by 1 year of age
Tubular secretion
Reduced
Near Adult pattern
Adult pattern
Penicillins – increased elimination half life due to decreased excretion both by glomerular filtration and tubular secretion, therefore increase dosing interval in neonates and infants compared to children and adolescent.
Tubular reabsorption
Specific example not available

27. 7. THERAPEUTIC DRUG MONITORING
Correlation of serum drug concentrations and therapeutic effects.
Technical problems
Adverse drug reaction

28. 8. DOSING CONSIDERATIONS
Dosing intervals
Disease states
Error in dosage calculations/drug preparation

29. 9. CONCLUSION Poorly developed organ functions High risk of toxicity
Suboptimal dosage regimen due to altered kinetics
Dosage requirements
Role of pharmacist in immunization
Education and Training

30. REFERENCES
Bauer, L. A, “ Drug Dosing in Special Populations’’, Applied clinical pharmacokinetics, (3): (2008) Begg, E. J, “ Dosing in children”, Instant clinical Pharmacology, (2003) Danish, M & Kottke, M. K, “ Pediatric and Geriatric Aspects of Pharmaceutics”, Modern Pharmaceutics, Banker, G.S & Rhodes, C. T, (4): 1-18 (2002) Fox, E & Balis, F. M, “ Drug therapy in Neonates and Pediatric patients”, Principles of Clinical Pharmacology, (2): (2007)

31. Perucca, E, “ Drug metabolism in infancy and childhood”, Journal of Pharmacology and Therapeutics, 34(1): (1987) Reed, M. D, “ The ontogeny of drug disposition : Focus on drug absorption, distribution and execution”, Journal of Drug Information, 30: (1996) Sorenson, M. K, Phillips, B. B & Mutnick, A. H, “ Drug Use in special patient populations : Pediatric, Pregnant, Geriatric”, Comprehensive pharmacy review, Shargel, L, Mutnick, A. H, Souney, P. F & Swanson, L. N, 5: (2004) Sagraves, R, “ Pediatric Dosing and Dosing Forms”, Encyclopedia of Pharmaceuical Technology, Swarbrick, J, 4(3): (2000)

32. Thank you