SEMINAR ON ALTERED KINETICS IN PEDIATRICS

SEMINARON

ALTERED KINETICS IN PEDIATRICS

DEPARTMENT OF PHARMACEUTICSBLUE BIRDS COLLEGE OF PHARMACY

(Affiliated to Kakatiya University)WARANGAL

2009

ByRAJANI THOUTREDDY

(M. Pharm I- Sem)

CONTENTS1. INTRODUCTION2. CALCULATION OF CHILD DOSE3. DRUG ABSORPTION4. DRUG DISTRIBUTION5. DRUG METABOLISM6. DRUG ELIMINATION7. THERAPEUTIC DRUG MONITORING8. DOSING CONSIDERATIONS9. CONCLUSION

REFERENCES

1. INTRODUCTIONPediatric population comprises 20-25% of total world

population.Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGYTERMS DEFINITION

Gestational Age Time from the mother’s last menstrual period to the time the baby is born

Postnatal age Age since birthNeonate First 1 month of lifePre 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 ageChild 1-12 years of ageAdolescent 12-18 years of age

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)

50Fried’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

Based of Surface area% of Adult dose = Surface area of child x 100

Surface area of adult Table. 2

Age % of Adult dose1 Month 102 Months 154 Months 20

1 Year 253 Years 355 Years 40

10 Years 6012 Years 7516 Years 90

3. DRUG ABSORPTION

3.1 Oral absorption3.2 Intravenous absorption3.3 Intramuscular absorption3.4 Percutaneous /Transdermal absorption3.5 Rectal absorption

3.1. Oral AbsorptionEffected by –

Gastric pH Gastric emptying and GI motility Absorptive surface area Pancreatic enzyme activity Bile Salt production Underlying disease state

3.2. Intravenous AbsorptionEffected by – Site of injection IV flow rate Dose volume

3.3. Intramuscular AbsorptionUsed when child is unable to take medication

orally or when drug is unavailable for oral use.

Effected by – Surface area available Blood flow to site of injection Muscle activity

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.

3.4. Percutaneous /Transdermal AbsorptionEffected 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 – FluxKm – Partition Co-efficientDm – Diffusion constant under specific conditions such as temperature and hydrationCs – Concentration gradientl – Length /thickness of stratum corneum

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.

4. DRUG DISTRIBUTION4.1. 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

• Amino glycosides such as gentamycin have extra cellular volume of 0.5 -1.2 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 2.2 -2.6 L/Kg in adults4.2. Protein binding

Acidic Drugs – AlbuminBasic Drugs – Alpha

1– acid glycoprotein (AGP)

These proteins are less efficient in neonates in binding drugs such as phenytoin, phenobarbital, chloramphenicol, penicillin, propranolol, lidocaine etcAdult levels of albumin and AGP occur at approximately 10-12 months of age

4.3. Presence of endogenous substancesFree fatty acidsUnconjugated 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.

5. DRUG METABOLISMDrug 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)

1) 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.

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 Reduced 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 Reduced Adult pattern ( reached by age 1-6 months)

Increased (peak activity at age 3-10 years)

Adult pattern (decreases to adult value at puberty)

Phenytoin half life ↓from 80 hrs at 0-2 days, to 15 hrs at 3-14 days, to 6 hrs at 14-150 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

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.

Table. 4. Age dependent differences in activity of important drug metabolising Phase – II enzymes and drug metabolismEnzyme Neonate Infant Child Adolescent Pharmacokinetic

ConsequencesN-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 Adult pattern Adult pattern

Specific example not available

Glucuronosyl transferase

Reduced Adult pattern Adult pattern Adult pattern

↑ Ratio of glucuronide to sulfate of acetaminophen with age; newborn 0.34; child (3-10 yrs) 0.8; adolescent 1.61 and adult 1.8 -2.3 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)

Adult pattern

Specific example not available

6. DRUG ELIMINATIONKidney 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 –

1) 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.

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.

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/SCrCrCL is estimated in ml/min/1.73m2, whereL- Body length in CmSCr – Serum creatinine in mg/dLK- constant of proportionality

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 0.45Children 2-12 years 0.55Females 13-21 years 0.55Males 13-21 years 0.70

Table.6. Age dependent differences in physiologic functions and drug disposition

Physiologic Variability Neonate Infant Child Pharmacokinetic Consequences

AbsorptionGastric pH Increased

(>5)

Increased (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 Increased 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

Immature Near adult pattern

Adult pattern

Increased hydrolysis and bio-availability of oral liquid ester formulations of dindamycin and chloramphenicol in infants and children

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

Increased Increased 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 Increased Near Adult pattern

Increased rate and extent of diazepam absorption from rectal solution compound to suppositories, used to prevent and treat febrile seizures in infants and children.

Physiologic Variability Neonate Infant Child Pharmacokinetic Consequences

DistributionTotal Body water (Extra cellular)

Increased

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 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 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

Renal EliminationGlomerular 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

Reduced Near Adult pattern

Adult Pattern

Specific example not available

7. THERAPEUTIC DRUG MONITORING

Correlation of serum drug concentrations and therapeutic effects.

Technical problemsAdverse drug reaction

8. DOSING CONSIDERATIONS

Dosing intervalsDisease statesError in dosage calculations/drug preparation

9. CONCLUSION

Poorly developed organ functionsHigh risk of toxicitySuboptimal dosage regimen due to altered

kineticsDosage requirementsRole of pharmacist in immunizationEducation and Training

REFERENCESBauer, L. A, “ Drug Dosing in Special Populations’’, Applied clinical

pharmacokinetics, (3): 52-68 (2008)

Begg, E. J, “ Dosing in children”, Instant clinical Pharmacology, 34-36 (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): 359-373 (2007)

Perucca, E, “ Drug metabolism in infancy and childhood”, Journal of Pharmacology and Therapeutics, 34(1): 129-143 (1987)

Reed, M. D, “ The ontogeny of drug disposition : Focus on drug absorption, distribution and execution”, Journal of Drug Information, 30: 1129-1134 (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: 673-677 (2004)

Sagraves, R, “ Pediatric Dosing and Dosing Forms”, Encyclopedia of Pharmaceuical Technology, Swarbrick, J, 4(3): 2629-2648 (2000)

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