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SEMINAR ON ALTERED KINETICS IN PEDIATRICS

SEMINAR ON ALTERED KINETICS IN PEDIATRICS. By RAJANI THOUTREDDY (M. Pharm I- Sem). DEPARTMENT OF PHARMACEUTICS BLUE BIRDS COLLEGE OF PHARMACY (Affiliated to Kakatiya University) WARANGAL 2009. CONTENTS. INTRODUCTION CALCULATION OF CHILD DOSE DRUG ABSORPTION

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SEMINAR ON ALTERED KINETICS IN PEDIATRICS

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  1. SEMINARONALTERED KINETICS IN PEDIATRICS By 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. 1. INTRODUCTION Pediatric population comprises 20-25% of total world population. Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGY

  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

  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 = 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 0.5 -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 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 10-12 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. Table. 3. Age dependent differences in activity of important drug metabolising phase – I enzymes and drug metabolism

  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

  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

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

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

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

  26. 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

  27. REFERENCES Bauer, 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)

  28. 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)

  29. Thank you

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