Presentation on theme: "SEMINAR ON ALTERED KINETICS IN PEDIATRICS"— Presentation transcript:
1 SEMINAR ON ALTERED KINETICS IN PEDIATRICS ByRAJANI THOUTREDDY(M. Pharm I- Sem)DEPARTMENT OF PHARMACEUTICSBLUE BIRDS COLLEGE OF PHARMACY(Affiliated to Kakatiya University)WARANGAL2009
2 CONTENTS INTRODUCTION CALCULATION OF CHILD DOSE DRUG ABSORPTION DRUG DISTRIBUTIONDRUG METABOLISMDRUG ELIMINATIONTHERAPEUTIC DRUG MONITORINGDOSING CONSIDERATIONSCONCLUSIONREFERENCES
3 Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGY 1. INTRODUCTIONPediatric population comprises 20-25% of total world population.Table. 1. PEDIATRIC AGE GROUPS TERMINOLOGYTERMSDEFINITIONGestational AgeTime from the mother’s last menstrual period to the time the baby is bornPostnatal ageAge since birthNeonateFirst 1 month of lifePre mature neonatesBorn at less than 37 weeks gestationFull term neonatesBorn between 37 and 42 weeks gestationInfant1 month to 1 year of ageChild1-12 years of ageAdolescent12-18 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)50Fried’s Formulae: (For infants and children up to 1 to 2 years)(Age in months) x (adult dose)150Young’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. 2Age% of Adult dose1 Month102 Months154 Months201 Year253 Years355 Years4010 Years6012 Years7516 Years90
7 3.1. Oral Absorption Effected by – Gastric emptying and GI motility Gastric pHGastric emptying and GI motilityAbsorptive surface areaPancreatic enzyme activityBile Salt productionUnderlying disease state
8 3.2. Intravenous Absorption Effected by –Site of injectionIV flow rateDose volume3.3. Intramuscular AbsorptionUsed when child is unable to take medication orally or when drug is unavailable for oral use.Surface area availableBlood flow to site of injectionMuscle 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 ageSkin hydrationStratum corneum thickness and intactnessApplication siteDrug diffusion by percutaneous absorption is explained by the equation –J = Km x Dm x CslJ – FluxKm – Partition Co-efficientDm – Diffusion constant under specific conditions such as temperature and hydrationCs – Concentration gradientl – Length /thickness of stratum corneum
11 3.5. Rectal AbsorptionUsed as an alternative to oral, I.V and I.M routes of absorptionAbsorption is more in solution from than in the form of suppositoriesNot generally preferred due to –Delay in onset of actionFailure 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 weight85% in premature infants78% in full term neonatesPercentage of extra cellular water –65% of total body weight premature infants35-44% in full term neonates20% in adultsPercentage of intra cellular water –25% in premature neonates33% in full term neonates40% 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 /adultVd 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 adults4.2. Protein bindingAcidic Drugs – AlbuminBasic Drugs – Alpha1– 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 months of age
14 4.3. Presence of endogenous substances Free fatty acidsUnconjugated bilirubinDrugs 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 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)Phase – I reactions:Oxidation, reduction, hydrolysis, hydroxylation etcCytochrome 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 metabolismEnzymeNeonateInfantChildAdolescentPharmacokinetic ConsequencesCYP2D6Reduced (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.CYP2C19Adult 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 activityCYP2C9Adult 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 maturationCYP3A4Reduced (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 metabolismEnzymeNeonateInfantChildAdolescentPharmacokinetic ConsequencesN-acetyl –transferase – 2Reduced (up to 2 months)Reduced (by age 4-5 months)Adult pattern (present age 1-3 yrs)Adultpattern↓ Acetylation of (sulfa pyridine metabolite) results in ↑ side effects– nausea, headache, abdominal pain in neonates and infantsMethyl-transferaseIncreased (50% higher than adults)Adult patternSpecific example not availableGlucuronosyl transferaseReduced↑ 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 patientsSulfo-tranferaseReduced (10-20% of adult activity)Increased (for specific substances)Increased (for specific substrates)
19 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 –Glomerular filtration30% - 50% of adult value in full term neonates85% adult values by 3-5 months of agePremature infants have reduced filtration rates due to incomplete nephrogenesis.
20 2) Tubular functionIn 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/SCrCrCL is estimated in ml/min/1.73m2, whereL- Body length in CmSCr – Serum creatinine in mg/dLK- 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 year0.33Full term 1 year0.45Children 2-12 years0.55Females yearsMales years0.70
23 Physiologic Variability Pharmacokinetic Consequences Table.6. Age dependent differences in physiologic functions and drug dispositionPhysiologic VariabilityNeonateInfantChildPharmacokinetic ConsequencesAbsorptionGastric pHIncreased(>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. PhenobarbitalGastric and intestinal emptying timeReduced and IrregularIncreased time to achieve peak plasma acetaminophen concentration when administered with meperidine due to decreased gastrointestinal motilityBiliary functionImmatureNear adult patternAdult patternIncreased absorption of fat and fat soluble vitamins D and E in infants and children.Pancreatic functionIncreased hydrolysis and bio-availability of oral liquid ester formulations of dindamycin and chloramphenicol in infants and children
24 Gut microbial colonization ReducedNear Adult patternAdult patternIncreased bio availability of digoxin in infants compared to adults due to lack of microbial gut colonization with a oral digoxin reducing anaerobic bacteria.Intramuscular absorptionVariableIncreasedIncreased to near adult patternBenzathine penicillin G more rapidly absorbed in children compared to adults since no measurable activity was detected in children 18 days after the injectionSkin permeability and percutaneous absorptionNear adult patternEMLA (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 absorptionIncreased 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 NeonateInfantChildPharmacokinetic ConsequencesDistributionTotal Body water (Extra cellular)IncreasedNear Adult patternIncrease 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/KgsTotal body fatReducedIncreased (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 infantsTotal plasma proteinsReduced to near adult patternAdult patternIncrease in Vd and free phenytoin concentration in neonates and children and adults with physiologic/pathologic conditions leading to altered protein concentration
26 Renal EliminationGlomerular FiltrationReduced patternAdult PatternAdultFamotidine – 80% excreted unchanged in the urine in older children and adults; renal clearance equivalent to adults by 1 year of ageTubular secretionReducedNear Adult patternAdult patternPenicillins – 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 reabsorptionSpecific example not available
27 7. THERAPEUTIC DRUG MONITORING Correlation of serum drug concentrations and therapeutic effects.Technical problemsAdverse drug reaction
29 9. CONCLUSION Poorly developed organ functions High risk of toxicity Suboptimal dosage regimen due to altered kineticsDosage requirementsRole of pharmacist in immunizationEducation and Training
30 REFERENCESBauer, 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)