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SEMINAR ON ALTERED KINETICS IN PEDIATRICS DEPARTMENT OF PHARMACEUTICS BLUE BIRDS COLLEGE OF PHARMACY (Affiliated to Kakatiya University) WARANGAL 2009.

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Presentation on theme: "SEMINAR ON ALTERED KINETICS IN PEDIATRICS DEPARTMENT OF PHARMACEUTICS BLUE BIRDS COLLEGE OF PHARMACY (Affiliated to Kakatiya University) WARANGAL 2009."— Presentation transcript:

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

2 CONTENTS 1.INTRODUCTION 2.CALCULATION OF CHILD DOSE 3.DRUG ABSORPTION 4.DRUG DISTRIBUTION 5.DRUG METABOLISM 6.DRUG ELIMINATION 7.THERAPEUTIC DRUG MONITORING 8.DOSING CONSIDERATIONS 9.CONCLUSION REFERENCES

3 1. INTRODUCTION Pediatric population comprises 20-25% of total world population. Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGY TERMSDEFINITION Gestational AgeTime from the mother’s last menstrual period to the time the baby is born Postnatal ageAge since birth NeonateFirst 1 month of life Pre mature neonates Born at less than 37 weeks gestation Full term neonates Born between 37 and 42 weeks gestation Infant1 month to 1 year of age Child1-12 years of age Adolescent12-18 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 Month10 2 Months15 4 Months20 1 Year25 3 Years35 5 Years40 10 Years60 12 Years75 16 Years90

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 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. Effected by –  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 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 = K m x D m x C s l J – Flux K m – Partition Co-efficient D m – Diffusion constant under specific conditions such as temperature and hydration C s – 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 L/Kg for a neonate but only 0.2 – 0.3 L/Kg for an older child /adult V d is decreased for lipid soluble drugs such as diazepam in neonates. Neonates exhibit apparent V d of 1.4 – 1.8 L/Kg compared to L/Kg in adults 4.2. Protein binding Acidic Drugs – Albumin Basic Drugs – Alpha 1 – 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) 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.

16 Table. 3. Age dependent differences in activity of important drug metabolising phase – I enzymes and drug metabolism EnzymeNeonateInfantChildAdolescent Pharmacokinetic Consequences CYP2D6Reduced (20% adult activity) ReducedAdult pattern (by age 3-5 yr) Adult patternO-demethylation of codeine to morphine ↓ in neonate/infants resulting in lack of efficacy and poor pain control. CYP2C19ReducedAdult 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 CYP2C9ReducedAdult pattern ( reached by age 1-6 months) Increased (peak activity at age 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 days of life due to slow maturation CYP3A4Reduced (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 Table. 4. Age dependent differences in activity of important drug metabolising Phase – II enzymes and drug metabolism EnzymeNeonateInfantChildAdolescent 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 Adult pattern Specific example not available Glucuronosyl transferase ReducedAdult 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 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

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 – 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.

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/1.73m 2, 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 Groupk (Mean Value) Low birth weight infants  1 year 0.33 Full term  1 year 0.45 Children 2-12 years0.55 Females years0.55 Males years0.70

23 Table.6. Age dependent differences in physiologic functions and drug disposition Physiologic Variability NeonateInfantChildPharmacokinetic Consequences Absorption Gastric pHIncreased (>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 time to achieve peak plasma acetaminophen concentration when administered with meperidine due to decreased gastrointestinal motility Biliary function ImmatureNear adult pattern Adult pattern Increased absorption of fat and fat soluble vitamins D and E in infants and children. Pancreatic function ImmatureNear adult pattern Adult pattern Increased hydrolysis and bio-availability of oral liquid ester formulations of dindamycin and chloramphenicol in infants and children

24 Gut microbial colonization ReducedNear 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. Intramuscula r absorption VariableIncreasedIncreased 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 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 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.

25 Physiologic Variability NeonateInfantChildPharmacokinetic Consequences Distribution Total Body water (Extra cellular) Increase d 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; Vd 34-48WK 0.52 ± 0.10 l/Kgs;Vd 1-4.9yrs 0.38±0.16 l/Kgs, Vd 5-9.9yrs 0.33±0.14 l/Kgs, Vd 10-16yrs, 0.31 ± 0.12 l/Kgs, Vd adult < 0.30 l/Kgs Total body fat Reduced Increa sed (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 ReducedReduced 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 AdultFamotidine – 80% excreted unchanged in the urine in older children and adults; renal clearance equivalent to adults by 1 year of age Tubular secretion ReducedNear 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 ReducedNear Adult pattern Adult Pattern 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)

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