Farmakoterapi Epilepsi

Dr. Diana Laila Ramatillah, M. Farm, Apt

PhD Clinical Pharmacy
Epilepsi
• suatu gangguan saraf kronik, dimana terjadikejang yang
bersifat reccurent
• Kejang : manifestasi klinik dari aktivitas neuron cortical
yang berlebihan di dalam korteks serebral dan ditandai
dengan adanya perubahan aktifitas elektrik pada saat
dilakukan pemeriksaan EEG.
• Manifestasi klinik kejang sangat bervariasi tergantung
dari daerah otak fungsional yang terlibat
Epidemiologi

• Setiap tahun terjadi sekitar 125.000 kasus epilepsi baru

di United States.
• 30%nya terjadi pada usia muda kurang dari 18 tahun
pada saat terdiagnosa.
• Agak sulit mengestimasi jumlah kasus epilepsy  pada
kondisi tanpa serangan, pasien terlihat normal dan
semua data lab juga normal, selain itu ada stigma
tertentu pada penderita epilepsy  malu/enggan
mengakui
Etiologi
• Epilepsi --- gangguan/abnormalitas dari pelepasan
neuron.
• Banyak hal yang bisa menyebabkan terjadinya
abnormalitas pelepasan neuron, seperti :
– Birth trauma
– Cedera kepala
– Tumor otak
– Penyakit cerebrovaskular
– Genetik
– Idiopatik
 Patofisiologi
Kejang disebabkan karena ada
ketidakseimbangan antara pengaruh
inhibisi dan eksitatori pada otak

terjadi karena :
• Kurangnya transmisi inhibitori
– Contoh: setelah pemberian
antagonis GABA, atau selama
penghentian pemberian agonis
GABA (alkohol, benzodiazepin)
• Meningkatnya aksi eksitatori 
meningkatnya aksi glutamat atau
aspartat
Fisiologi Normal
 Diagnosis
• Pasien didiagnosis epilepsi
jika mengalami serangan
kejang secara berulang
• Untuk menentukan jenis
epilepsinya, selain dari gejala,
diperlukan berbagai alat
diagnostik :
– EEG
– CT-scan
– MRI
– Lain-lain
 Klasifikasi epilepsi
• Berdasarkan tanda klinik
dan data EEG, kejang
dibagi menjadi :
– kejang umum (generalized
seizure)  jika aktivasi
terjadi pd kedua hemisfere
otak secara bersama-
sama
– kejang parsial/focal  jika
dimulai dari daerah
tertentu dari otak
Kejang umum terbagi atas:
• Tonic-clonic convulsion = grand mal
– merupakan bentuk paling banyak
terjadi
– pasien tiba-tiba jatuh, kejang, nafas
terengah-engah, keluar air liur
– bisa terjadi sianosis, ngompol, atau
menggigit lidah
– terjadi beberapa menit, kemudian
diikuti lemah, kebingungan, sakit
kepala atau tidur
• Abscense attacks = petit mal
– jenis yang jarang
– umumnya hanya terjadi pada masa anak-anak atau awal remaja
– penderita tiba-tiba melotot, atau matanya berkedip-kedip, dengan
kepala terkulai
– kejadiannya cuma beberapa detik, dan bahkan sering tidak disadari
• Myoclonic seizure
– biasanya tjd pada pagi hari, setelah bangun tidur
– pasien mengalami sentakan yang tiba-tiba
– jenis yang sama (tapi non-epileptik) bisa terjadi pada pasien normal
• Atonic seizure
– jarang terjadi
– pasien tiba-tiba kehilangan kekuatan otot  jatuh, tapi bisa segera
recovered
Kejang parsial terbagi menjadi :
• Simple partial seizures
– pasien tidak kehilangan kesadaran
– terjadi sentakan-sentakan pada bagian
tertentu dari tubuh
• Complex partial seizures
– pasien melakukan gerakan-gerakan tak
terkendali: gerakan mengunyah,
meringis, dll tanpa kesadaran
Sasaran Terapi
• Mengontrol (mencegah dan mengurangi frekuensi)
supaya tidak terjadi kejang - beraktivitas normal lagi
• Meminimalisasi adverse effect of drug

Strategi Terapi
• Mencegah atau menurunkan lepasnya muatan listrik
syaraf yang berlebihan  melalui perubahan pada
kanal ion atau mengatur ketersediaan neurotransmitter
Prinsip pengobatan pada epilepsi
• Monoterapi
– Menurunkan potensi AE
– Meningkatkan kepatuhan pasien
• Hindari / minimalkan penggunaan antiepilepsi sedatif
• Jika monoterapi gagal, dapat diberikan sedatif atau
politerapi
• Pemberian terapi sesuai dengan jenis epilepsinya
• Mulai dengan dosis terkecil (dapat ditingkatkan sesuai
dengan kondisi pasien)
Prinsip pengobatan epilepsi

• Variasi individual -- perlu pemantauan

• Monitoring kadar obat dalam darah - penyesuaian dosis
• Lama pengobatan tergantung jenis epilepsinya, kondisi
pasien dan kepatuhan pasien
• Jangan menghentikan pengobatan secara tiba-tiba
(mendadak)
Penatalaksanaan Terapi
• Non farmakologi :
– Amati faktor pemicu

– Menghindari faktor pemicu (jika ada), misalnya : stress, OR,

konsumsi kopi atau alkohol, perubahan jadwal tidur, terlambat

makan, dll.

• Farmakologi : menggunakan obat-obat antiepilepsi

Obat-obat yang meningkatkan inaktivasi kanal Na+:
• Inaktivasi kanal Na  menurunkan kemampuan syaraf untuk
menghantarkan muatan listrik
• Contoh: fenitoin, karbamazepin, lamotrigin, okskarbazepin, valproat

Obat-obat yang meningkatkan transmisi inhibitori GABAergik:

• agonis reseptor GABA  meningkatkan transmisi inhibitori dg
mengaktifkan kerja reseptor GABA  contoh: benzodiazepin,
barbiturat
• menghambat GABA transaminase  konsentrasi GABA meningkat
 contoh: Vigabatrin
• menghambat GABA transporter  memperlama aksi GABA 
contoh: Tiagabin
• meningkatkan konsentrasi GABA pada cairan cerebrospinal pasien
 mungkin dg menstimulasi pelepasan GABA dari non-vesikular
pool  contoh: Gabapentin
 glutamat Pre-sinaptik
tiagabin
GAD
-
Berdifusi gabapentin GABA Transporter GABA
menjauh
+

2
GABA-transaminase Re-uptake
Metabolit
GABA
GABA 3
- 1

Post sinaptik
Reseptor GABA
vigabatrin
EFEK DEPRESI CNS
 Partial Generalized Atypical
DRUG Seizure
Tonic- Clonic/ Absence Absence
Grand Mal

Drug of Carbamazepine Valproate

Ethosuximide
Phenytoin Carbamazepine Valproate
Choice Valproate Phenytoin
Valproate

Lamotrigine Lamotrigine
Gabapentine Topiramate Clonazepam
Topiramate Clonazepam Lamotrigine
Alternative Tiagabine
Primidone
Lamotrigine Topiramate
Phenobarbital
Primidone Felbamate
Phenobarbital
Farmakokinetika Obat
Epilepsi pada Kehamilan
– the possibility of increased maternal seizures,
– pregnancy complications,
– adverse fetal outcome.

• Approximately 25% to 30% of women have increased

seizures during pregnancy
• Increased seizure activity may result from either a direct
effect on seizure threshold or a reduction in AED
concentration.
• Barbiturates and phenytoin are associated with
congenital heart malformations, orofacial clefts, and
other malformations.
• Valproic acid and carbamazepine are associated with
spina bifida (neural tube defect) and hypospadias.
• Lamotrigin dan Gabapentin : tidak ditemui
efek teratogen pada hewan uji, tetapi data
pada manusia belum cukup kuat.

• Pemberian suplemen asam folat dan vitamin

K diperlukan selama wanita hamil yang
mengkonsumsi obat-obat antiepilepsi.
• What is Valproic Acid?
Guideline for Pediatric
• If the patient is still seizing
– No IV/IO Access give;
• Midazolam (Versed) 0.1-0.2 mg/kg IN/IM. Max 10 mg.
• May repeat in 5 minutes. Note IN/IM Versed should be 5mg/ml concentration.
• or
• Diazepam (Valium) rectally: 0.5 mg/kg <6 y/o; 0.3mg/kg 6-11 y/o; 0.2mg/kg
>11y/o
• May repeat in 10 minutes for continued seizure give 0.2 mg/kg/dose.
– IV/IO access give;
• Lorazepam (Ativan) 0.05-0.1mg/kg/dose up to 2 mg
• or
• Midazolam (Versed) 0.1-0.2 mg/kg IV. Max 10 mg.
• May repeat in 5 minutes. Note IN/IM Versed should be 5 mg/ml concentration.
• Intermediate agencies may have only one benzodiazepine on formulary
• Continue to monitor airway since respiratory depression can result

Alternative Benzodiazepines
DIAZEPAM
• Diazepam
 Indication:  Status epilepticus
Dosage:  IV: 0.1 mg/kg every 2 minutes. Maximum dose, 0.3 mg/kg
(maximum 10 mg/dose).
Dosage:  Rectal: 0.5 mg/kg up to 20 mg
Note:  Do not give as IM injection.

WARNING:  There is an increased incidence of apnea when

combined with other sedative agents or when given rapidly.
One must be prepared to provide respiratory support. Monitor
oxygen saturation
Phenobarbital
• Phenobarbital is useful in treating many kinds of
seizures in children. It is often considered the first
choice to treat certain seizures in newborn infants.
Phenobarbital also has been widely used to prevent
seizures that sometimes accompany a high fever in
infants or young children
Seizures for Phenobarbital
• All types of seizure disorders, including partial, tonic-clonic, and myoclonic
seizures
• Adult: 1-3 mg/kg/day oral/intravenous (IV) in 1-2 divided doses initially;
adjust accordingly to maintain within therapeutic serum concentration range
• Neonates (less than 28 days): 3-5 mg/kg/day intravenously (IV)/orally in 1-2
divided doses
• Infants: 5-6 mg/kg/day intravenously (IV)/orally in 1-2 divided doses
• Children 1-5 years: 6-8 mg/kg/day intravenously (IV)/orally in 1-2 divided
doses
• Children 6-12 years: 4-6 mg/kg/day intravenously (IV)/orally in 1-2 divided
doses
• Children over 12 years: 1-3 mg/kg/day intravenously (IV)/orally in 1-2
divided doses, OR 50-100 mg two or three times daily
Status Epileptikus for Phenobarbital
• Typically used after benzodiazepines and phenytoin fail to abort
status epilepticus
• Adult: 15-18 mg/kg intravenous (IV) loading dose infused at 25-60
mg/min; prepare to support ventilation; may repeat in 20-minute
intervals as needed; not to exceed 30 mg/kg
• Infants and children: 15-20 mg/kg IV infused at a rate not to exceed
2 mg/kg/min; not to exceed 1000 mg/dose
• Children under 60 kg: IV rate at less than 30 mg/min
• May repeat with 5-10 mg/kg bolus dose after 15-30 min as needed;
not to exceed cumulative dose of 40 mg/kg
Phenitoin
• Phenytoin is an anti-epileptic drug, also called an
anticonvulsant. It works by slowing down impulses in the
brain that cause seizures. Phenytoin is used to control
seizures.
• Phenytoin is indicated for use as an anticonvulsant drug
in people of all ages. Evidence supporting efficacy of
phenytoin as an anticonvulsant was derived from active
drug-controlled studies that enrolled patients with the
following seizure types: Partial seizures. Primary
generalized tonic-clonic seizures (grand mal)
 Loading Dose Phenitoin

Phenytoin sodium IV 18mg/kg (see Table 1 below). Ensure ECG, blood pressure and respiratory function are monitored
throughout the duration of the infusion.
Table 1 - IV phenytoin loading dose

Volume of IV phenytoin (ml) (vial =

Weight (kg) IV Loading Dose (mg)
250mg/5ml)
35-44 700 14
45-54 900 18
55-64 1100 22
65-74 1250 25
75-84 1450 29
85-94 1600 32
>94 1800 36
Phenytoin IV administration
• Phenytoin IV administration
• Give phenytoin over 30-40 minutes (rate <50mg/minute). In patients who are elderly,
or have pre-existing cardiac disease, give phenytoin over 60 minutes. N.B.
Adminstration should commence immediately after the mixture has been prepared
and completed within 1 hour.
• Ideally, administer undiluted via a syringe pump through a large gauge needle or IV
catheter into a large forearm vein.
• If dilution is essential, mix with 100–250ml sodium chloride 0.9% to a final
concentration of <10mg/ml, and administer by infusion pump.
• Use the solution immediately, ideally with a 0.2–0.5micron in-line filter.
• To avoid local venous irritation, inject sterile sodium chloride 0.9% through the vein or
catheter before and after each phenytoin infusion.
• Do not administer as a continuous infusion.
• Continuous ECG and blood pressure monitoring is essential during infusion.
Maintenance Dose Phenitoin

• Phenytoin typical doses are 3–5mg/kg/day. The first dose should be given 12–24
hours after the loading dose.
• Oral or nasogastric administration should be used, whenever possible. Only use
intravenous administration when these options are not feasible and where cardiac
monitoring is available.
• Notes
• Phenytoin sodium 100mg capsules / tablets / injection = 15ml (90mg) suspension
(6mg/ml).
• There are many drug interactions with phenytoin (consult the BNF Appendix 1 or your
clinical
• pharmacist).
• Phenytoin concentrations increase disproportionately with dose; toxicity may occur if
the maintenance dose is increased by more than 25–50mg per day. Table 3 below
may help with dosage adjustment. Based on the patient's current dose and the
measured concentration (columns 1 and 2), column 3 gives a rough guide to
interpretation of the result and possible dosage adjustment.
Table 3 - Phenytoin maintenance dose adjustment

Measured concentration Current dose Maximum dose increase

<4.5mg/kg/day 100mg
< 5mg/L
4.5–6mg/kg/day Check compliance

4.5–6 mg/kg/day 50mg

5–10mg/L
>6mg/kg/day Check compliance

10–20mg/L - 25mg
TDM Phenytoin

4. Therapeutic Drug Monitoring of Phenytoin

Target concentration range: 5–20mg/L
TERIMAKASIH