kp pediatric pharmacology

7/22/2019 KP Pediatric Pharmacology

1/35

PEDIATRIC

PHARMACOLOGY

Iwan

Dwiprahasto

Dept of

Pharmacology

& Therapy FK UGM


2/35

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.pdf


3/35

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,


4/35

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


5/35

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)


6/35

< adult

Penicillin Phenylbutazon Phenytoin

Ampicilin Diazepam Nalidixic acidNafcilin Digoxin ParacetamolErithromycin Cotrimoksazol Rifampin

Sulfonamid Carbamazepin

Teophyllin Chloramphenicol

Drug absorption in gastrointestinal tract= adult

Neonates > adult


7/35

Oral absorption of drugs for GI tract inneonates & child

pH

Bacterial colonisation

Gastric & intestinal motility

Saturable transport process

Intestinal absorption

Disease states


8/35


9/35

Factors Affecting Drug Distribution

Degree of protein/tissue binding

Cardiac output/Regional blood flow

Physicochemical properties of the drug

Body compositionExtracellular water

Adipose tissue


10/35

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


11/35

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


12/35


13/35

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


14/35

lasma roteinsChange from Adult Values

Newborn Infant ChildTotal protein =

Albumin = =1Acid glycoprotein =

Fetal albumin Present Absent AbsentGlobulin =


15/35

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


16/35

Aminoglycosides

Clindamycin

ErythromycinTetracyclin

Fucidic acid No or Meningealinflammation

poor

penetration


17/35

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


18/35

Drug elimination

Longer plasma half-life

GFR low Tubular secretion low

The more premature

The less the ability to excrete


19/35

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


20/35

BIOAVAILABILITY

INH RifampinTetracyclin Glibenclamide Glipizid

Low


21/35

Per cutan

Infant & child

Boric acidAniline

Toxic(methemoglobinemia

increased

laceration

Povidone iodineaminoglycocsida+polymixin spray

increased

hexachlorophen

neurotoxic


22/35

HEPATIC METABOLISM

Older child

1. Phenyton2. Theophylin

Increase dose

Metabolism rate >>clearance >>>

Half life


23/35


24/35

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


25/35

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


26/35

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


27/35

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


28/35


29/35


30/35


31/35

PROBLEMS WITH DRUGS & DRUG THERAPY


32/35

PROBLEMS WITH DRUGS & DRUG THERAPYIN CHILDREN

Early postnatal period

risk of aspiration/poorabsorptionOral

muscular volumeI.m

risk of ekstravasation --> necrosisI.v

Drug administration


33/35

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)


34/35

Early school age

Faster elimination vs adults

Warning: phenobarbital, theophylin,phenytoin) --> higher dose

Oral liquid drug: sukrose, sorbitol

Compliance


35/35