FARMAKOKINETIK FENITOIN
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FARMAKOKINETIK KLINIKFARMAKOKINETIK KLINIK
PHENYTOINPHENYTOIN DAN DAN ANTIEPILEPSI LAINNYAANTIEPILEPSI LAINNYA
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Antiepileptik
Fenitoin
Karbamazepin
AsamValproat
Fenobarbital
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PHENYTOINPHENYTOIN•• KegunaanKegunaan utamautama sebagaisebagai anticonvulsant.anticonvulsant.•• KadangKadang-- kadangkadang digunakandigunakan untukuntuk pengobatanpengobatan
berbagaiberbagai macammacam penyakitpenyakit aritmiaaritmia JantungJantung
DuaDua PermasalahanPermasalahan UtamaUtama::▫▫ IkatanIkatan phenitoinphenitoin dgndgn protein plasma protein plasma berkurangberkurang
padapada pasienpasien gagalgagal ginjalginjal dandan hipoalbuminemiahipoalbuminemia▫▫ KapasitasKapasitas metabolismemetabolisme untukuntuk fenitoin fenitoin terbatasterbatas
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ADR (REAKSI OBAT YANG MERUGIKAN)•• Gingival hyperplasiaGingival hyperplasia•• FolateFolate deficiencydeficiency•• Peripheral neuropathyPeripheral neuropathy•• FarFar--lateral lateral nystagmusnystagmus (>(>2020mg/L)mg/L)•• Ataxia (>Ataxia (>3030mg/L)mg/L)•• Diminished mental capacity (>Diminished mental capacity (>4040mg/L)mg/L)•• EncephalopathyEncephalopathy
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Karakteristik Farmakokinetik•• BioavailabilitasBioavailabilitas▫▫ Absorpsi sempurna FAbsorpsi sempurna F = = 11..00..▫▫ InjectableInjectable/Capsule consist of the sodium salt (S = /Capsule consist of the sodium salt (S =
00..9292).).▫▫ Chewable tablet and suspension contain the acid Chewable tablet and suspension contain the acid
form (S = form (S = 11..00).).▫▫ PO: PO: KonsentrasiKonsentrasi puncakpuncak 3 3 sampaisampai 12 12 jamjam▫▫ Yang Yang tidaktidak larutlarut air, air, absorbsiabsorbsi lambatlambat▫▫ BioavailabilitasBioavailabilitas berkurangberkurang WaktuWaktu kontakkontak padapada GI GI cepatcepat ((gerakangerakan peristaltikperistaltik ygyg cepatcepat)) NGTNGT
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• Distribusi▫ Sekitar 90 % Phenitoin terikat dengan serum
albumin▫ 10% tidak terikat dan berikatan dengan reseptor
• Metabolisme▫ Kecepatan metabolisme dan atau ekskresi adalah
sebanding dengab konsentrasi plasma.Konsentrasi (mg/L) t½ (Jam)
1 12.810 25.820 40.240 69.0
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Time to Peak Cp
• Dose (mg)• 400• 800• 1600
• Peak Time ( hrs)• 8.4• 13.2• 31.5
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Kondisi yang meyebabkan berkurangnyaIkatan Protein Dari Phenitoin
• Pengurangandalam serum Albumin
• Burns• Hepatic cirrhosis• Nephrotic syndrome• Pregnancy• Cystic Fibrosis
• Penurunan afinitas dari pengokatan dengan albumin
• Renal Failure• Jaundice• Other medications
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Interaksi Obat▫▫ InteraksiInteraksi dengandengan AsamAsam ValproatValproat (displacement (displacement
dandan inhibition inhibition oleholeh CYPCYP450450))▫▫ PhenytoinPhenytoin digantikandigantikan kedudukannyakedudukannya daridari binding binding
sites.sites.▫▫ Reduced (Reduced (~~5050%) total concentration.%) total concentration.▫▫ Increased (Increased (99..6 6 –– 1515..55%) of the unbound %) of the unbound
PhenitoinPhenitoin..
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Parameter Penting
•• Target Target KonsentrasiKonsentrasi 10 10 –– 20 20 mg/Lmg/L•• FF 11..00•• SS 00..9292•• VVdd 00..65 65 L/kg BBL/kg BB•• CLCL -- VVmaxmax77..2 2 mg/kg/mg/kg/harihari
-- KKmm 44..4 4 mg/Lmg/L
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HYPOALBUMINEMIA CORRECTIONHYPOALBUMINEMIA CORRECTION• Hypoalbumin saja:
CCppnormalnormal = = CCpp
patientpatient ..00..9 9 ((AlbAlbpatientpatient//44..44) + ) + 00..1 1
• Hypoalbumin dengan gagal ginjal:CCpp
normalnormal = = CCpppatientpatient ..
00..4848((00..99)()(AlbAlbpatientpatient//44..44) + ) + 00..11
**AlbAlbpatientpatient dalamdalam g/g/dLdL
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Konsentrasi Steady State
• Vmax= maximum kecepatan metabolisme phenytoin dalam mg/day
• Km: the concentration at which the rateof metabolism is half maximal ( mg/liter )
Css= Km-Dose(day)/Vmax-Dose(day)
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Perkiraan Loading Dose dari Phenytoin
• LD= Vd (C diinginkan – C diamati)/S*F• Dimana:
Vd = volume of distribution (0.65L/kg)
S=salt factor ( 0.92)F= fraction absorbed ( 1 )Cdiinginkan=10 sampai 20 mg/L
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Estimating Maintenance Dose
• Km untuk pasien dewasa: 5.8 mg/L ( 0.1-27) dan 5.3 mg/l untuk pasien anak2
Vmax untuk pasien dewasa :8mg/kg/day, untuk pasien anak2 12 mg/kg/day
Dose/hari= Vmax*Css/Km+Css
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Saturation Pathway for Phenytoin
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Kondisi yang mempengaruhi fenitoin
Kondisi atau penyakit
Example
Vmax ↑ Induksi enzim Pemberian bersama phenobarb/Carbazepine
Vmax ↓ Cirrhosis Penurunan aktivitas enzim
Km ↑ Hambatan kompetitif
CimetidineatauChloramphenicol
Km ↓ Penurunan ikatan protein
Pe ↓ albumin :Valproic acid
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ANTIEPILEPTICS Yang LainnyaASAM VALPROIC (VPA)
•• KarakteristikKarakteristik FarmakokinetikaFarmakokinetika▫▫ Dalam berbagai formulasiDalam berbagai formulasi▫▫ VariasiVariasi Diurnal Diurnal padapada absorbsiabsorbsi: AUC : AUC padapada malammalam
harihari untukuntuk tablet tablet salutsalut enterikenterik adalahadalah 3232% % lebihlebihrendahrendah daridari siangsiang harihari
▫▫ CLCLVPAVPA meningkatmeningkat oleholeh CBZ, PHB, PHT CBZ, PHB, PHT dandan PRI.PRI.▫▫ Protein binding Protein binding 90 90 –– 9595%%
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Parameter Parameter PentingPenting▫▫ Target concentrationTarget concentration 50 50 –– 100 100 mg/Lmg/L▫▫ FF 11..00▫▫ SS 11..00▫▫ VVdd ~~00..2 2 L/kgL/kg▫▫ CLCL -- ChildrenChildren 13 13 ml/kg/Jamml/kg/Jam
-- AdultsAdults 8 8 ml/kg/Jamml/kg/Jam▫▫ t½t½ -- ChildrenChildren 6 6 –– 8 8 JamJam
-- AdultsAdults 10 10 –– 12 12 JamJam
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•• Dose Requirement:Dose Requirement:▫▫ Maintenance DoseMaintenance Dose
AdultsAdults 10 10 –– 45 45 mg/kg/day POmg/kg/day POChildrenChildren 10 10 –– 60 60 mg/kg/day POmg/kg/day PO
•• EfekEfek--efekefek Toxic Toxic Gastric irritation, nausea, vomitingGastric irritation, nausea, vomiting PertambahanPertambahan BeratBerat BadanBadan Sedation, stupor, tremorSedation, stupor, tremor ThrombocytopeniaThrombocytopenia HepatotoxicityHepatotoxicity, pancreatitis, pancreatitis HyperammonemiaHyperammonemia
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ANTIEPILEPTICS YANG LAINNYAANTIEPILEPTICS YANG LAINNYA
CARBAMAZEPINECARBAMAZEPINE•• TidakTidak LarutLarut dalamdalam air.air.•• KelembabanKelembaban akanakan mengurangimengurangi dissolution.dissolution.•• AutoinductionAutoinduction is concentration dependent: is concentration dependent:
increase Dincrease DMM dandan CL CL daridari obatobat bebasbebas..WaktuWaktu tt½ (Jam)½ (Jam)
SetelahSetelah initial dose initial dose ~~3535SetelahSetelah 3 3 –– 4 4 mingguminggu ~~1212
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KarakteristikKarakteristik FarmakokinetikaFarmakokinetika
▫▫ Dimetabolisme menjadi bentuk aktif:Dimetabolisme menjadi bentuk aktif: CBZ CBZ epoxideepoxide▫▫ InteraksiInteraksi ObatObat: CYP: CYP450 450 inhibitors inhibitors egeg. .
Erythromycin, Erythromycin, FluoxetineFluoxetine, , PropoxyphenePropoxyphene, VPA , VPA and and VerapamilVerapamil..
▫▫ Terikat pada Terikat pada --acid glycoprotein.acid glycoprotein.▫▫ 11% % dieksresikan dalam bentuk tidak berubah di dieksresikan dalam bentuk tidak berubah di
urinurin
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Parameter Parameter PentingPenting▫▫ Target concentrationTarget concentration 4 4 –– 12 12 mg/Lmg/L▫▫ FF 00..88▫▫ SS 11..00▫▫ VVdd 11..4 4 L/kgL/kg▫▫ CLCL -- MonotherapyMonotherapy 00..064 064 L/kg/JamL/kg/Jam
-- PolytherapyPolytherapy 00..1 1 L/kg/JamL/kg/Jam▫▫ tt½½ -- MonotherapyMonotherapy 15 15 JamJam
-- PolytherapyPolytherapy 10 10 JamJam
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•• Dose Requirement:Dose Requirement:▫▫ Maintenance DoseMaintenance Dose
AdultsAdults 10 10 –– 45 45 mg/kg/day POmg/kg/day POChildrenChildren 10 10 –– 60 60 mg/kg/day POmg/kg/day PO
•• EfekEfek--efekefek Toxic Toxic Gastric irritation, nausea, vomitingGastric irritation, nausea, vomiting PertambahanPertambahan BeratBerat BadanBadan Sedation, stupor, tremorSedation, stupor, tremor ThrombocytopeniaThrombocytopenia HepatotoxicityHepatotoxicity, pancreatitis, pancreatitis HyperammonemiaHyperammonemia
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Dose Requirement:Dose Requirement:AnticonvulsantAnticonvulsant
AdultsAdults 5 5 –– 25 25 mg/kg/day POmg/kg/day POChildrenChildren 5 5 –– 30 30 mg/kg/day POmg/kg/day PO
Trigeminal neuralgiaTrigeminal neuralgiaAdultsAdults 3 3 –– 20 20 mg/kg/day POmg/kg/day PO
EfekEfek--EfekEfek Toxic Toxic DiplopiaDiplopiaHyponatremiaHyponatremia, water intoxication, water intoxicationSeizuresSeizuresArrhythmiasArrhythmias
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DOSE ADJUSTMENT DOSE ADJUSTMENT UntukUntukVAPROIC ACID VAPROIC ACID dandan CARBAMAZEPINECARBAMAZEPINE
CCaveave = = D .D .
KKee VVdd
= = D .D .CL CL
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TERIMA KASIH
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