PEDIATRIC PHARMACOLOGY

Iwan Dwiprahasto Dept of Pharmacology & Therapy FK UGM

Main reference
N Engl J Med 2003;349:1157-67 Developmental Pharmacology Drug Disposition, Action, and Therapy in Infants and Children

Gregory L. Kearns, Pharm.D., Ph.D., Susan M. AbdelRahman, 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.

Developmental Pharmacology

Scaling adult doses to infants based on body weight or surface area does not account for developmental changes that affect drug disposition or tissue/organ sensitivity.
Pediatrics does not deal with miniature men and women, with reduced doses and the same class of disease in smaller bodies, but . . . has its own independent range and horizon.
Dr. Abraham Jacobi, the father of American pediatrics,

Tissue and Organ Weight

% of Total Body Weight Fetus Newborn Adult

Skeletal muscle Skin Skeleton Heart Liver Kidneys

25 13 22 0.6 4 0.7

25 4 18 0.5 5 1

40 6 14 0.4 2 0.5

ORAL ABSORPTION
Premature
Reduced gastric acid secretion

Adult values neonatus

3 years

Gastric emptying
Adult values Oral Penisilin

prolonged
6-8 months

Relative Achlorhydria
(pH=4)

Rifampin Phenobarbiton Phenytoin

Need larger dose

Drug absorption in gastrointestinal tract

Neonates > adult Penicillin Ampicilin Nafcilin Erithromycin = adult Phenylbutazon Diazepam Digoxin Cotrimoksazol Sulfonamid Teophyllin < adult Phenytoin Nalidixic acid Paracetamol Rifampin Carbamazepin Chloramphenicol

Oral absorption of drugs for GI tract in neonates & child

pH Bacterial colonisation Gastric & intestinal motility Saturable transport process Intestinal absorption Disease states

Absorption after parenteral administration

Resting muscle blood flow greatest least Deltoid Intermediate in the thigh buttock

Resting muscle blood flow

Varies considerably 2-3 weeks Poorly absorbed from any sites

Phenytoin Digoxin Diazepam

Not to be administered i.m

Factors Affecting Drug Distribution

Physicochemical properties of the drug

Cardiac output/Regional blood flow

Degree of protein/tissue binding

Extracellular water
Body composition Adipose tissue

Factors influencing drug availability after i.v admin

Body composition

Extracellular fluid volume Neonates (50%) Full term infants (45%) Older infants (25%) = adult

Total body water Neonates (92-75%) Adults (50-60%

Fat content: Premature (3%) Full term (12%) 1 year (30%) Adult (18%)

Larger initial doses on a mg/kgbw

Gentamicin: initial 4mg/kgbw, then 1 mg/kgbw (24 hour)

larger extracellular and totalbody water spaces

Neonates

coupled with adipose stores that have a higher ratio of water to lipid

when the drugs are administered in a weight-based fashion

Young child

lower plasma levels of drugs in these compartments

PLASMA PROTEIN BINDING

Plasma protein binding
Availability of binding proteins number of binding sites affinity constant of a drug for the protein pathophysiological condition

In neonatal period: less than adult (lower plasma protein (albumin), for age 10-12 months Higher free fraction of unbound drug

Higher plasma concentration

Hepatic disease, nephrotic synd, CRF, cardiac failure, malnutrition Higher penetration into CSF Salicylate intoxication

Protein Binding in Cord and Adult Plasma

Plasma Protein Binding (%) Cord Acetominophen Chloramphenicol Morphine Phenobarbital Phenytoin Promethazine 36.8 31 46 32.4 74.4 69.8 Adult 47.5 42 66 50.7 85.8 82.7

Kurz et al., Europ J Clin Pharmacol II:463-7, 1977

Plasma Proteins
Change from Adult Values Newborn Total protein Albumin Present Absent Infant = Child = = = Absent =

1-Acid glycoprotein Fetal albumin Globulin

BLOOD BRAIN BARIER

Penetration of drugs into childs brain
Penicillin G Ampicillin Ticarcillin Cefalosporin Rifampin Vancomycin

Degree of immaturity Acidosis Hypoxia Hypothermia Infection

Meningeal inflammation

greater penetration

Chloramphenicol Cotrimoxazole

good penetration

No inflammation

Aminoglycosides Clindamycin poor penetration

Erythromycin
Tetracyclin

Fucidic acid

No or Meningeal inflammation

Drug elimination

Physiological immaturity in the capacity of the liver to metabolise a large number of drug

Longer plasma half-life

Longer time to reach steady state Associated dicrease/absence of metabolites

Drug elimination

GFR low Tubular secretion low

The more premature

The less the ability to excrete Longer plasma half-life

ceftazidime & famotidine excreted primarily by the glomeruli

tobramycin

is eliminated predominantly by glomerular filtration

correlations between plasma drug clearance and normal maturational changes in renal function

dosing intervals

36 to 48 hours in preterm newborns

24 hours in term newborns

BIOAVAILABILITY

INH Rifampin Tetracyclin Glibenclamide Glipizid

Low

Per cutan
Infant & child

Povidone iodine aminoglycocsida+ polymixin spray

laceration
increased

increased

hexachlorophen Boric acid Aniline Toxic (methemo globinemia

neurotoxic

HEPATIC METABOLISM
PRENATAL
Hepatic immaturity Older child 1. Phenyton 2. Theophylin

Glucoronidase deficiency Glukoronil transferase Uridine diphosphat glucoronic dehydrogenase

Metabolism rate >> clearance >>> Half life <<

Chloram phenicol

Grey baby syndrome

Increase dose

Circulation collapse

Plasma half-lives of different drugs in neonates, infants, children and adults

Drugs Neonates (< 7 days) Infant (> 1 mth) Children (1-15yrs) Adults

Drugs mainly eliminated by hepatic metabolism Carbamazepin Diazepam Ethosuximide Indometasin Salicylate Paracetamol Lidokain Mepivakain Nalidixic acid Pethidin Fenobarbital Fenilbutazon Fenitoin Teofilin Tolbutamid 8-28 22-46 (38-120) 15 (13-24) 4,5-11 2-5 3 9 4 23 70-500 27 30-60 20-35 (14-58) 10-40 10-12 3 20-70 18 2-7 5-6 14-19 15-21 24-41 2 20-80 18-23 2-20 1,4-8 16-36 24-48 40-60 4-11 2-4 2 1-2 2 1,5-2,5 4 60-180 70 20-30 3,5-8 4-10

Plasma half-lives of different drugs in neonates, infants, children and adults

Drugs Ampisilin Benzilpenisilin Karbenisilin Gentamisin Metisilin Tobramisin Neonates (7 days) 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) Infant (7-14d) 2,8 1,7-2,6 1,5 3-5 0,9-3,1 Infant (> 14d) 1,7 1,4-3,8 1,5 3-5 0,8-1,8 Adult 1-1,5 0,7 1-1,5 2-3 0,5 1-2

Obat Acetaminophen Amikacin Ampicillin Amoxicillin Carbamazepine Cefotaxime Cefoxitin Ceftazidime Ceftriaxone Cefuroxime Cephalothin Clindamycin Cyclosporine Diazepam Digoxin Famotadine Gentamicin

Waktu paruh (Jam) Newborn Infant 4.9 5.0-6.5 4.0 1.7 3.7 4.0 3.8 4.5 17.0 5.5 3.6 30 11 4.0 0.8 1.4 4.5 5.9 3.5 3.0 10 18-33 2.6

Child 4.5 1.6

0.9-1.9 8-25 1.0 0.8 2.0 4.7 1.2 0.3 2.4 4.8 25 37 3.2 1.2

Adult 3.6 2.3 1.0-1.5 0.6-1.5 10-20 1.1 0.8 1.8 7.8 1.5 0.6 4.5 5.5 30 30-50 3.5 2-3

Obat Ibuprofen Isoniazid Mezlocillin Midazolam Moxalactam Naproxen Phenobarbital Piperacillin Quinidine Rifampin Sulfadiazine Theophylline Ticarcillin Tobramycin Valproate Vancomycin Zidovudine

Newborn 3.7 6.3 5.4 67-99 0.8 40 30 5-6 4.6 4.1-9.1

Half life (hour) Infant Child 1.0-2.0 2.9a 0.8 3.1 2.7 1.7 1.6 11-13 36-72 0.5 0.4 4.0 2.9 10 6.9 3.4 0.9 1-2 7.0 2.2-2.4 1.0-1.5

Adult 2.0-3.0 2.8a 1.0 4.8 2.2 10-17 48-120 0.9 5-7 3.3-3.9 10-15 8.1 1.3 2-3 6-12 5-6 1.6

Calculation of pediatric drug dosages

Adult dos x age (in year) Age + 12

Youngs rule =
Clarks rule:

Dose = adult dose x weight (kg)/70 Body surface area (BSA) (neonate BSA/adult BSA) x 100 = % of adult dose needed

PROBLEMS WITH DRUGS & DRUG THERAPY IN CHILDREN

Early postnatal period

Drug administration

Oral

risk of aspiration/poor absorption

muscular volume risk of ekstravasation -> necrosis

I.m
I.v

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)

Early school age

Faster elimination vs adults Warning: phenobarbital, theophylin, phenytoin) --> higher dose

Oral liquid drug: sukrose, sorbitol

Compliance