FARKIN~1
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PENYESUAIAN DOSIS PADAPENYAKIT RENAL DAN HEPATIK
(Profesi)
BUDI SUPRAPTI
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Ginjal organ penting –berperan dalamMengatur cairan tubuhKesetimbangan elektrolitPengeluaran sisa metabolikEkskresi obat dari tubuh
Gangguan fungsi ginjalFarmakokinetika ObatPenyesuaian dosis
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GANGGUAN FUNGSI GINJAL-UREMIAGFR turunSekresi aktif turunAkumulasi cairan, produk nitrogen, FFA dalam tubuhGangguan kesetimbangan elektrolit
PERUBAHAN FISIOLOGIK-METABOLIKPERUBAHAN FISIOLOGIK-METABOLIKPERUBAHAN FARKIN-FARDIN
Bioavailabilitas menurunVol. DistribusiIkatan Obat-ProteinEliminasi obat (Biotransformasi, ekskresi renal)Sensitivitas-receptor site
ELIMINASI OBAT MENURUN
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DALAM PRAKTEK KLINIK- Est. Do Obat didasarkanEst. fungsi ginjal yang tersisaPrediksi Klirens total
Tidak mungkin Analisis farkin lengkap pada pasien uremiakondisi uremia tidak stabildapat berubah dengan cepat
Ada berbagai pendekatan –REFERENSIberdasar asumsiketerbatasan
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PENDEKATAN UMUM –PENYESUAIAN DOSISPADA PASIEN – PENYAKIT GINJAL
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PENYESUAIAN DOSIS – KLIRENS OBAT
Untuk mempertahankan kadar tunak yang diinginkan setelah dosis ganda (oral/IV) saat ClT berubah:
Pada kondisi uremia, dosis harus diubah ke Do uremia atau interval uremia
Untuk infusi, laju infusi harus diubah untuk laju infusi uremia
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PENYESUAIAN DOSIS – TETAPAN LAJU ELIMINASIDo turun frekwensi/interval tetapDo tetap frekwensi turun/interval > panjang
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Bila fe diketahui
Lihat latihan hal 690-691692-693Lihat latihan hal 690-691
692-693
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PENGUKURAN GFRKriteria-bahan untuk mengukur GFR
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INULINTidak banyak digunakan di klinikPerlu waktu lama infusi sampai tss
Cl inulin = R/Css
KREATININ (Cr)Bahan endogen – creatin fosfat-metab ototDifiltrasi, tidak direabsorpsi, sedikit sekresi aktif Hasil perhitungan > perhitungan dengan inulin Hasil perhitungan > perhitungan dengan inulinFaktor usia, berat badan, gender
BLOOD UREA NITROGEN (BUN)BUN –meningkat bila fs renal turunDifiltrasi, reabsorpsi sebagianHasil perhitungan < Cl cr atau Cl inulinTidak dapat untuk ukuran kuantitatif fs.ginjalFaktor: intake protein, penurunan aliran darah, shock haemorrhagic,
gastric bleeding
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KLIRENS KREATININ
Normal produksi = ekskresi CCr konstan
Distribusi ke seluruh cairan tubuh
Penurunan GFR akumulasi CCr
Clcr = laju ekskresi Cr / CCr
Clcr normalisasi ke LPT 1,73 m2, BB 70 kg, laki-laki
Perhitungan LBW (!!! Pasien obese)
Clcr Wanita = 80 - 85% Laki-laki
LBW (laki-laki) = 50 kg + 2,3 for each inch over 5 ftLBW (wanita) = 45,5 kg + 2,3 for each inch over 5 ft
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PERHITUNGAN KLIRENS KREATININ
DEWASA
Metoda Crockcroft-Gault (1976)
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PERHITUNGAN KLIRENS KREATININ (Lanjut)
NOMOGRAM SIERBACK-NIELSEN, 1974
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Nomogram Traub & Johnson, 198081 anak, 6 – 12 tahu
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PRACTICE PROBLEM shargel hal 682
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DOSE ADJUSTMENT FOR UREMIC PX
Loading dose = subyek fungsi renal normalVd diasumsikan tidak berubah
Maintenance dose Cl obat pada pasien menurunCl non renal tidak berubah
Cl total – gangguan ginjal
Dm diturunkanInterval ditingkatkanubah dosis dan interval
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EXTRACORPOREAL REMOVAL OF DRUG
Tx suportif hilangkan akumulasi obat-metabolit
HemoperfusiHemofiltrasidialysis
DIALYSISDIALYSIS
Obat/ sisa metab dihilangkan dg difusi dari tubuhcairan dialisis
Peritoneal dialisis (CAPD)Hemodialisis
Dialisat: air, dektrose, elektrolit, elemen lain serupacairan tubuh normal, tidak toksik serpa cairan tubuh normal
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PERITONEAL DIALISIS
FILTER- membran peritoneal dalam abdomen, 1-2 m2Permeabel - obat BM < 30.000 Da
Aliran splanisch 1200 mL/menit 70 mL/menit kontak peritoneal 70 mL/menit kontak peritoneal
CAPD-peritoneal catether2 L cairan dialisis setiap 4-6 jam
tidak memerlukan heparindapat dilakukan dirumah
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HEMODIALISIS
Mesin dialisisMembran artifisial – hollow fiber – ribuan kapiler halus
karakteristik permeabilitas membranluas permukaan membran determinan difusi dan ultrafiltrasi
Akses ke pembuluh darah arteri – venaDiperlukan heparin
Darah dipompa ke mesin dialiser – laju 300-450 mL/menitDarah dipompa ke mesin dialiser – laju 300-450 mL/menitdarah arteri mesin dialisis vena
2-3 x seminggu – 2-4 jam fs. Renal yang tersisa
komplikasi pasienukuran berat badanefisiensi dialisis
Pendosisan obat Dializer sifat fisiko kimia obat
CL selama HD???
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0( )a v
D ava T D
Q C C F DC l C
C C l C l
DIALISIS
Ca – kons. Obat dalam darah arteri (masuk mesin ginjal)Ca – kons. Obat dalam darah arteri (masuk mesin ginjal)Cv – kons. Obat dalam darah vena (darah meninggalkan mesin)Q – laju alir darah ke mesin ginjalClD – DIALYSANCE
klirens dialisis
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DIALISIS
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F raksi oba t h ilang selam a H D
e
Latihan Hal 699-700
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LATIHAN
Seorang laki-laki dewasa, 73 tahun, 65 kg dengan DM menjalani HDClCr < 5 mL/menitPasien mendapat tobramisin 1 mg/kg BB, IV bolusTobramisin ekskresi urin 90%, ikatan protein 10%,
t1/2 normal 2,2 jamDiket. t1/2 elim. interdialisis 50 jam,
t1/2 elim. Selama dialisis 8 jam,t1/2 elim. Selama dialisis 8 jam,Vd = 0,33 L/kg
Hitung:a. Konsentrasi obat awal setelah dosis pertamab. Konsentrasi obat tepat sebelum dialisis (48 jam setelah dosis awal)c. Konsentrasi obat pada akhir dialisis 4 jamd. Jumlah obat yang hilang dari tubuh setelah dialisis.e. Dosis tobramisin yang perlu diberikan pada pasien paska HD
(Replenishment dose)
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PENGARUH PENYAKIT HEPATIK-FARMAKOKINETIKA
GANGGUAN LIVERAkumulasi obatGagal membentuk metabolit aktif/inaktifbioavailabilitas oral meningkatperubahan ikatan obat-proteinPerubahan fungsi ginjal
KESULITAN EST.KLIRENS HEPATIKKompleksitas dan stratifikasi sistem dalam liverTidak ada uji yang akurat untuk tetapkan fs.liverAST/ALT deteksi kerusakan liver, daripada fungsi liverBilirubin obstruksi bilier, aliran bilier
??? PENDOSISANEnzyme dependent drug half-doses or lessFlow dependent clearance avoided Starting therapy with low dose monitoring response/plasma level
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DETERMINANTS OF A DOSAGE REGIMEN
DOSAGE DOSAGE REGIMENTATIONREGIMENTATION
ACTIVITY-TOXICITYTher. WindowSide effectsToxicityC – Rx relationship
PHARMACOKINETICSAbsorptionDistributionMetabolismExcretion
CLINICAL FACTORSSTATE OF PATIENT MANAG. OF THER.Age Multiple drug Ther.Condt. Being treated Convenience of reg.Existence of other Compliance of Px
disease states
REGIMENTATIONREGIMENTATION
OTHER FACTORRoute of AdmDosage formTolerance-DependencePharmacogenetic- IdiosyncrasyDrug InteractionsCost
35