How To Deliver Antiseizure

Drugs in Infant and

Children

DR.Sunarni Zakaria,dr;MKes
Departemen Farmakologi & Terapi
Fakultas Kedokteran
Universitas Airlangga
Universitas Airlangga
Surabaya
 pendahuluan
kejang
etiologi yang
mendasari
,2 demam 2,4 %
Kejang 1. Riwayat kejang
2. ensefalopati-
15% yang menyertai
3. etiologi
2,7% 4. rendahnya
epilepsi
kadar obat anti
epilepsi dalam
plasma
Status epileptikus

Dian Pratamastuti,Darto Saharso,Prastiya I.G,Erny . Tatalaksana Status Epileptikus Pada Anak Media IDI No
1 2015; 39:43-48
 Epidemiology Status epilepticus

• insidens Status Epileptikus 41-61 / 100,000

infant 135-156 /100.000 , children 17-58/100.000

mortalitas Status Epilepticus 19 / 100,000

. Scot RC,Surtees RAH, neville BGR.Status epilepticus:

patophysiology,epidemiology and Outcome.Arch Dis Child 1998;79:73-7
 Mortality After Initial
Pediatric Status Epilepticus
40

30

% 20 30 Days 1
180 Days

10

0
<1 1 to 19

Age (Years)

. Official Journal of the international league Aginst Epilepsy for the ILAE Commission on
Epidemiology Article first published online: 7 SEP 2011
 Pengelompokan populasi
(WHO 2007)

A. Preterm newborn infants (bayi prematur yang baru lahir).

B. Term newborn infants/neonatus (bayi yang baru lahir

umur 0-28 hari).

C. Infants and toddlers (bayi dan anak kecil yang baru

belajar berjalan umur > 28 hari sampai 23 bulan).

D. Children (anak-anak umur 2-11 tahun).

E. Adolescent (anak remaja 12 -16/18 th tergantung daerah)

Problem farmakokinetik pada
infant dan anak
Why children are not little Adults

• Banyak dokter yang tidak tahu batasan dosis

• Secara tradisional karena jarang menggunakan
suatu preparat obat ,dosis untuk bayi dan anak
yang dilakukan ekstrapolasi dosis dari orang
dewasa degan menggunakan Berat Badan dan
luas permukaan tubuh
 problem
• Absorption may be more or less than adult
• Clearance of some drugs in children is affected
by maturation ,as well as size
- cytochrome P450 enzyme system matures
overtime
- glumerular filtration changes over time
• Drug targets may vary with age
 Absorption
• Intraluminal PH changes over time
- High in neonatal period (achlorhydria)
o Increases biavailibility of acid labile
compounds
o weak acids may require larger doses
(phenobarbital )
- Gastric emptying slower in neonatal periode
o “normal” by about 4 months
o Some oral drug slower to reach peak
concentration in neonatus
 Absorption 2
• Villous formation initially limited – less
absorption surface
• Intestinal CYP 1A1 increases with age
• Re : topical skin drugs,thinner skin sand higher
body surface area to volume ratio makes children
susceptible to absorption effects
- steroid use on aczema- growth supression
- PhisoHex soap
 Tabel
Comparative Developmental Alterations Affecting Neonatal
Pharmacokinetics ( oral absorbtion)
Function Maturational Alteration Newborn Function Kinetics Compared with
older Children and
Adults
Oral Absorption Gastric PH Relatively high at birth Decreased bioavailability
and in preterm infants of acid labile drugs
Decrease after 24 hour Increased absorption of
acid-labile drugs
Gastric emptying Feeding dependent and Unpredictible rate of drug
variable delivery to intestinal
mucose
Intestinal motility slower Prolonged time to achieve
maximum plasma
concentration
Lipase levels and bile salt decreased Decreased bioavailability
pool of lipid soluble drugs
Eflux transpoters reduced Altered bioavailability
 Tabel
Comparative Developmental Alterations Affecting Neonatal
Pharmacokinetics ( other absorption)

Function Maturational Alteration Newborn function Kinetic Compared

with Older Children
and Adults
Rectal absorption Permebility and first pass Higher if administered Increased
to portal circulation Into the distal segment bioavailability if drug
of rectum ; if adminis- absorbed into the
tered deep,first pass lower or distal
effect may after segment of rectum
bioavailibity
Intramuscular Perfusion,muscle mass Usually decreased Decreased rate of
absorption ,and activity absorption and
potential local trauma
Transcutaneous Body surfase and Higher Increased absorption
absorption permeability
inhalation Mucosal permeability Increased Systemic exposure
 Distribution
• Neonates and infants have relatively high
propotion of body water
• Plasma protein change (for example ,fetal
albumin has less effinity for weak acids
than adult )
 Tabel
Comparative Developmental Alterations Affecting Neonatal
Pharmacokinetics (distribution)

Function Maturational Newborn function Kinetic Compared

Alteration with Older Children
and Adults
Distribution Total Body Water Increased volume of Reduced peak and
distribution threshold concentra-tions
at weight dosing
Extracellular water increased Further expands volume
of distribution
Body fat composition 1% of adult level in Lower lipophilic drug
preterm and 15% in term disposition
infants
Blood Brain Barrier Blocks water soluble immature Increased potential
compounds unless permeability
diseased
Protein binding Plasma protein decreased Increased free/ unbound
drug availlable to
receptors
Development change TBW
 protein binding

Obat Neonatus Infant > 24 jam adult

< 24 j

Diazepam 84-86 % 10-12 % 18-30%

Lorazepam 93-95 % 15-20 % 20-30%

Midazolam 86-89% 10-13 20-25%

Phenobarbital 20-25% 28-36 % 45-50%

Phenytoin 70-80% 80-89% 90-93%

 metabolism

.Two phass of hepatic metabolism

- Phase I – Oxidation
- Phase II – conjugation
- Phase I done by Cytochrome P-450 (CYP)
- Cyp 3A7 very high in fetal liver,gone in adulthood-
detoxifies anabolic steroids & retinoic acid
breakdown products (which happen to be
teratogenic
 Metabolism (2)

CYP enzymes
• CYP isoforms vary with age
• For example, clearance of midazolam by
CYP 3 A4 and 3A5 goes from 1.2
ml/min/kg to 9 ml/min/Kg over first few
month of live
• Carbamezapine ( 3A4) clearance faster in
children than adults – requires higher
doses
 Tabel
Comparative Developmental Alterations Affecting Neonatal Pharmacokinetics
(metabolism)

Function Maturational Newborn function Kinetic Compared

Alteration with Older
Children and
Adults
Metabolism Biotransformation Decreased Drug dependent
primarily involving renders some drugs
hepatic enzymes more active and
some less
active.often affects
clearance
Hepatic blood flow Extraction or Increased cardiac Increased clearance
removal of active output to liver of drugs with high
drug by metabolism increases hepatic intrinsic hepatic
and increased flow clearance
hepatic clearance
 Elimination phase

drug Elimination Cytochrome

Diazepam Oksidasi CYP2C19
Lorazepam Oksidasi CYP3A4
Midazolam Oksidasi CYP3A4
Phenytoin Oksidasi CYP3A4,CYP2C9,CYP2C19,
CYP1A2
Phenobarbital Oksidasi, Konyugasi CYP2C9,
CYP2C19,CYP3A4,CYP1A2
 Renal clearance
• GFR increases until around 8-12 months
of life
• Tubular secretion reaches adult capacity
during first year of life
• As a result of the low initial GFR,renally
excreted drugs are dosed less frequently
 Tabel
Comparative Developmental Alterations Affecting Neonatal Pharmacokinetics
(clearance)

Function Maturational Newborn function Kinetic Compared

Alteration with Older Children
and Adults
Renal elimination Glumerular Dependent on renal -
filtration blood flow,reduced
in less mature infant
Tubular secretion Reduced active Delayed excretion
secretion and prolonged half-
life
Tubular reduced Dependent on renal
reabsorption blood flow,
GFR,urine PH,
clearance Multisystem reduced Accumulation
function
 Terapi SE

Drug terapi akut Terapi RSE

Diazepam + -
Lorazepam + -
Midazolam + +
Phenytoin/Fosfo + +
phenytoin
Phenobarbital + +
Valproate + +
Sodium
 bioavailibilitas

drug Bioavailibiltas (%)

oral I.M I.V Rectal
Diazepam 100 60 96 100
lorazepam >90 >90 96 -
midazolam 30 >90 100 -
phenytoin 90-100 >80 90-100 -
phenobarbital 95-100 >95 82-90 90

valproate 90 78 76 84
 T max
Obat Tmax (jam)/Peak concentration
oral I.M I.V rectal
Diazepam 3-5 0.5-1.5 0.5-1 5-15
menit
lorazepam 1-2 1-2 1-1.2 0.5-2
midazolam 0.5 0.5 0.24-0.57 0.5-2
phenytoin 3-12 3-6 2-4 0.5-2
phenobarbit 0.5-4 2-8 2-4 2.1-4.4
al
valproate 2-4 4-5 3-7 2-4
 Delivery intra nasal

1.Fisiologi penghidu
 eksitasi pada sel
olfaktory
2.Receptor penghidu terdapat
pada septum superior
mambran olfaktoria
3. Mol penghidu adalah silia
sel olfaktoria yang
dilapisi oleh mukosa
 Syarat odoron
• Larut udara  supaya mudah dihirup
• Larut air/hidrofilik  dapat melarutkan
mukosa silia  berikatan dengan silia sel
olfactoria
• Larut lemak/lipofillik
Midazolam im,iv,intranasal
 Intervensi bedah saraf
• pada kasus SE yang sulit diatasi dengan obat-obat
medikamentosa
• Penelitian retrospektif :
- semua px menunjukkan lokasi epilepsi
di extratemporal  80% menjalani
hemipherectomy
- dari 5 px yang dioperasi 4 orang tidak pernah kejang
dan px ke 5 sembuh 90 %.
 kesimpulan
1>Untuk pemilihan OAE pada bayi dan anak- pilihan utama
adalah golongan Benzodiazepin
•  diazepam,lorazepam,midazolam
• Onset paling cepat : diazepam IV, diazepam rektal
• Duration lebih lama : lorazepam IV
2> pilihan ke 2 Phenytoin IV ( tp hanya untuk orang
dewasa) data utk keberhasilan utk anak masih sedikit.
pilhan ke 2 setelah phenytoin adalah phenobarbital bisa
diberikan pada anak-anak tp efek sampingnya depresi
nafas dan hipotensi.
 Pilihan SE
• 1> terapi pilihan pertama Benzodiazepin
•  diazepam IV,IM,rektal,nasal dan bukal
• paling disukai pemberian per rektal
• lorazepam ( tidak ada di Indonesia)
• midazolam IM
 RSE
• Obat pilihan fenobarbital bolus dan
dilanjutkan IV
•  perlu pemantaun EEG karena efek
samping obat hipotensi dan depresi
miokard
• midazolam