Upload
dwi-febriyanti-totti
View
142
Download
90
Embed Size (px)
DESCRIPTION
Farmakokinetik
Citation preview
FARMAKOKINETIK KLINIKFARMAKOKINETIK KLINIK
PHENYTOINPHENYTOIN DAN DAN ANTIEPILEPSI LAINNYAANTIEPILEPSI LAINNYA
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
Antiepileptik
Fenitoin
Karbamazepin
AsamValproat
Fenobarbital
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
• 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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
Time to Peak Cp
• Dose (mg)• 400• 800• 1600
• Peak Time ( hrs)• 8.4• 13.2• 31.5
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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..
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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)
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
Saturation Pathway for Phenytoin
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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%%
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
•• 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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
•• 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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
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
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
DOSE ADJUSTMENT DOSE ADJUSTMENT UntukUntukVAPROIC ACID VAPROIC ACID dandan CARBAMAZEPINECARBAMAZEPINE
CCaveave = = D .D .
KKee VVdd
= = D .D .CL CL
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)
TERIMA KASIH
Print to PDF without this message by purchasing novaPDF (http://www.novapdf.com/)