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PEDIATRIC
PHARMACOLOGY
Iwan
Dwiprahasto
Dept of
Pharmacology
& Therapy FK UGM
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Main reference
Developmental Pharmacology
DrugDisposition, Action, and Therapy
in Infantsand Children
Gregory L. Kearns, Pharm.D., Ph.D., Susan M. Abdel
-
Rahman, Pharm.D., Sarah W. Alander, M.D., Douglas
L. Blowey, M.D., J. Steven Leeder, Pharm.D., Ph.D., and
Ralph E. Kauffman, M.D.
N Engl J Med
2003;349:1157
-
67
http://localhost/var/www/apps/Users/Iwan%20Dwiprahasto/Documents/Developmental%20pharmacology-pediatric%20drug%20disposition,%20absorption.pdfhttp://localhost/var/www/apps/Users/Iwan%20Dwiprahasto/Documents/Developmental%20pharmacology-pediatric%20drug%20disposition,%20absorption.pdfhttp://localhost/var/www/apps/Users/Iwan%20Dwiprahasto/Documents/Developmental%20pharmacology-pediatric%20drug%20disposition,%20absorption.pdfhttp://localhost/var/www/apps/Users/Iwan%20Dwiprahasto/Documents/Developmental%20pharmacology-pediatric%20drug%20disposition,%20absorption.pdfhttp://localhost/var/www/apps/Users/Iwan%20Dwiprahasto/Documents/Developmental%20pharmacology-pediatric%20drug%20disposition,%20absorption.pdfhttp://localhost/var/www/apps/Users/Iwan%20Dwiprahasto/Documents/Developmental%20pharmacology-pediatric%20drug%20disposition,%20absorption.pdf7/22/2019 KP Pediatric Pharmacology
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Developmental Pharmacology
Scaling adult doses to infants based on bodyweight or surface area does not account fordevelopmental changes that affect drugdisposition or tissue/organ sensitivity.
Pediatrics does not deal with miniature men
and women, with reduced doses and the sameclass of disease in smaller bodies, but . . . hasits own independent range and horizon.
Dr. Abraham Jacobi, the father of American pediatrics,
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Tissue and Organ Weight
% of Total Body Weight
Fetus Newborn Adult
Skeletal muscle 25 25 40
Skin 13 4 6
Skeleton 22 18 14
Heart 0.6 0.5 0.4
Liver 4 5 2
Kidneys 0.7 1 0.5
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ORAL ABSORPTION
neonatus
Adult values 3 years
Premature
Reduced gastric acid
secretion
prolonged
Gastric emptying
Adult values
6
-
8 months
RelativeAchlorhydria
Oral Penisilin
Rifampin
PhenobarbitonPhenytoin
Need larger dose(pH=4)
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< adult
Penicillin Phenylbutazon Phenytoin
Ampicilin Diazepam Nalidixic acidNafcilin Digoxin ParacetamolErithromycin Cotrimoksazol Rifampin
Sulfonamid Carbamazepin
Teophyllin Chloramphenicol
Drug absorption in gastrointestinal tract= adult
Neonates > adult
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Oral absorption of drugs for GI tract inneonates & child
pH
Bacterial colonisation
Gastric & intestinal motility
Saturable transport process
Intestinal absorption
Disease states
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Factors Affecting Drug Distribution
Degree of protein/tissue binding
Cardiac output/Regional blood flow
Physicochemical properties of the drug
Body compositionExtracellular water
Adipose tissue
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Factors influencing drug availability after i.v admin
Extracellular fluid volume Neonates (50%) Full term infants (45%) Older infants (25%) = adult
Fat content: Premature (3%) Full term (12%) 1 year (30%) Adult (18%)
Total body water Neonates (92-75%) Adults (50-60%
Body composition
Gentamicin: initial 4mg/kgbw, then 1 mg/kgbw (24 hour)
Larger initial doses on a mg/kgbw
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when the drugs are administered in aweight-based fashion
larger extracellular and total-body water spaces
coupled with adipose stores that have ahigher ratio of water to lipid
lower plasma levels of drugs inthese compartments
Neonates
Young child
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Protein Binding in Cord and Adult Plasma
Plasma Protein Binding (%)
Cord Adult
Acetominophen36.8 47.5
Chloramphenicol 31 42Morphine 46 66
Phenobarbital 32.4 50.7Phenytoin 74.4 85.8
Promethazine 69.8 82.7
Kurz et al., Europ J Clin Pharmacol II:463-7, 1977
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lasma roteinsChange from Adult Values
Newborn Infant ChildTotal protein =
Albumin = =1Acid glycoprotein =
Fetal albumin Present Absent AbsentGlobulin =
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BLOOD BRAIN BARIER
Penicillin G AmpicillinTicarcillin Cefalosporin Rifampin
Vancomycin
Meningealinflammation
greaterpenetration
Chloramphenicol Cotrimoxazole
No inflammation
goodpenetration
Penetration ofdrugs into childsbrain
Degree of immaturity
Acidosis Hypoxia Hypothermia Infection
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Aminoglycosides
Clindamycin
ErythromycinTetracyclin
Fucidic acid No or Meningealinflammation
poor
penetration
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Drug elimination
Longer time to reach steady stateAssociated dicrease/absence of
metabolites
Physiological immaturity in the
capacity of the liver to metabolise alarge number of drug
Longer plasma half-life
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Drug elimination
Longer plasma half-life
GFR low Tubular secretion low
The more premature
The less the ability to excrete
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ceftazidime &famotidine
excreted primarilyby the glomeruli
correlations betweenplasma drug clearance
and normal maturational
changes in renal function
tobramycin
is eliminatedpredominantly by
glomerular filtration
dosing intervals
24 hours in
term newborns
36 to 48 hours in
preterm newborns
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BIOAVAILABILITY
INH RifampinTetracyclin Glibenclamide Glipizid
Low
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Per cutan
Infant & child
Boric acidAniline
Toxic(methemoglobinemia
increased
laceration
Povidone iodineaminoglycocsida+polymixin spray
increased
hexachlorophen
neurotoxic
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HEPATIC METABOLISM
Older child
1. Phenyton2. Theophylin
Increase dose
Metabolism rate >>clearance >>>
Half life
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Drugs Neonates (7
days)Infant
(7-14d)Infant
(> 14d)Adult
AmpisilinBenzilpenisilin
KarbenisilinGentamisin
Metisilin
Tobramisin
4 (4-6)2,5-4,9
(3,8)3-5,7 (5-6)3,4-6,5(4-13,8)1,3-3,33(2,4-3,3)
4,6 (5,6-11,3)
2,81,7-2,6
1,53-5
0,9-3,1
1,71,4-3,8
1,53-5
0,8-1,8
-
1-1,50,7
1-1,52-3
0,5
1-2
Plasma half-lives of different drugs in neonates, infants,children and adults
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Waktu paruh Jam)Obat Newborn Infant Child AdultAcetaminophen 4.9 4.5 3.6Amikacin 5.0-6.5 1.6 2.3
Ampicillin 4.0 1.7 1.0-1.5Amoxicillin 3.7 0.9-1.9 0.6-1.5Carbamazepine 8-25 10-20Cefotaxime 4.0 0.8 1.0 1.1Cefoxitin 3.8 1.4 0.8 0.8
Ceftazidime 4.5 4.5 2.0 1.8Ceftriaxone 17.0 5.9 4.7 7.8Cefuroxime 5.5 3.5 1.2 1.5Cephalothin 0.3 0.6Clindamycin 3.6 3.0 2.4 4.5Cyclosporine 4.8 5.5Diazepam 30 10 25 30Digoxin 18-33 37 30-50Famotadine 11 3.2 3.5
Gentamicin 4.0 2.6 1.2 2-3
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Half life (hour)Obat Newborn Infant Child Adult
Ibuprofen 1.0-2.0 2.0-3.0
Isoniazid 2.9a
2.8a
Mezlocillin 3.7 0.8 1.0Midazolam 6.3 3.1 2.7 4.8Moxalactam 5.4 1.7 1.6 2.2Naproxen 11-13 10-17
Phenobarbital 67-99 36-72 48-120Piperacillin 0.8 0.5 0.4 0.9Quinidine 4.0 5-7Rifampin 2.9 3.3-3.9Sulfadiazine 40 10 10-15
heophylline 30 6.9 3.4 8.1icarcillin 5-6 0.9 1.3obramycin 4.6 1-2 2-3
Valproate 7.0 6-12Vancomycin 4.1-9.1 2.2-2.4 5-6Zidovudine 1.0-1.5 1.6
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Youngs rule =Adult dos x age (in year)
Age + 12
Clarks rule:
Dose = adult dose x weight (kg)/70
Body surface area (BSA)
(neonate BSA/adult BSA) x 100 = % of
adult dose needed
Calculation of pediatric drug dosages
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PROBLEMS WITH DRUGS & DRUG THERAPY
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PROBLEMS WITH DRUGS & DRUG THERAPYIN CHILDREN
Early postnatal period
risk of aspiration/poorabsorptionOral
muscular volumeI.m
risk of ekstravasation --> necrosisI.v
Drug administration
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Early postnatal period
Treatment, dosages, monitoring
Drug with saturable metabolism (phenytoin, theophylin,salycilate)
Narrow therapeutic margin
Non bodyweight basis adjustment (antiepilepsi,
aminoglikosida Preventing ADR (metotreksat)
Organ dysfunction which influence RBF & protein binding
Variability in absorption (siklosporin)
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Early school age
Faster elimination vs adults
Warning: phenobarbital, theophylin,phenytoin) --> higher dose
Oral liquid drug: sukrose, sorbitol
Compliance
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