Obat Anaemia, Hematopoetic GF Mei 2012
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Transcript of Obat Anaemia, Hematopoetic GF Mei 2012
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Obat antianemia dan Hematopoietic Growth Factors
Hedi R. Dewoto & Dewi Selvina RDept. Farmakologi & Terapeutik FKUI
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Hematopoiesis Pembentukan eritrosit, lekosit, trombosit dari
stem sel Sumsum tulang : mesin hematopoietik membutuhkan: * besi, vitamin B12, asam folat * hematopoietic growth factors ( protein yg mengatur proliferasi & diferensiasi sel darah)
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• Tdk cukup Anemia, trombositopenia, neutropenia
• Anemia penyebab banyak,diantaranya akibat defisiensi
besi, vitamin B12, atau asam folat
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Akan dibahas :1. Antianemia defisiensi : Besi, vitamin B12, asam folat (folic acid)2. Hematopoietic growth factors : untuk anemia, trombositopenia, neutropenia , dan menunjang transplantasi
stem cell
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I. Besi membentuk inti cicin heme (besi-porfirin), bersama rantai globin hemoglobin. Hemoglobin mengikat oksigen secara reversibelmembawa oksigen dr paru ke jar.
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• Defisiensi besi penyebab plg sering anemia kronik
• Besi kurang eritrosit kecil dg Hb kurang anemia hipokrom mikrositer
• kebutuhan Fe meningkat pada : pertumbuhan, hamil, laktasi menstruasi , perdarahan
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FarmakokinetikAbsorpsi
umumnya butuh 10-15 mg elemen besi/hari N absorpsi 5-10 % 0,5-1 mg / hari
di duodenum, prox. jejunum, juga >distal
Abs. meningkat bila kebutuhan meningkat Mis. Hamil , laktasi
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• Besi pd berbagai makanan, > pd daging
• Besi pd daging > efisien diabs. krn besi heme dpt diabs.utuh.
Besi sayuran sering terikat senyawa organik sulit di abs.
• Besi nonheme pada makanan & garam besi inorganik harus direduksi menjadi ion Fero
(Fe++) seb.diabs.sel mukosa usus.
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• Besi melewati membran mukosa usus halus mel. 2 mekanisme:
1. transport aktif ion Fero oleh DMT (divalent metal transporter) 2. abs.kompleks besi dg heme
• Kecepatan uptake besi oleh sel mukosa tgt pada cadangan besi .Cadangan < abs. >
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• Kelebihan besi pd sel mukosa disimpan sbg ferritin, inti Fe (0H)3 dibungkus apoprotein
• Umumnya bila cadangan besi banyak , kebutuhan rendah besi yg diabs. disimpan sebagai ferritin
• Bila cadangan sedikit dan kebutuhan banyak besi yg diabs. segera dibawa ke sumsum tulang untuk sintesis Hb.
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• Transport besi pd plasma terikat transferrin (-globulin)
reseptor pd membran sel eritroid endocytosis besi dilepaskan u/ sintesis Hb.
transferrin kembali ke darah.
• Anemia defisiensi besi , cadangan besi kurang peningkatan jumlah transferrin
• Meningkatnya eritropoiesis disertai me jumlah reseptor transferrin pd sel eritroid .
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Storage besi
• > sbg ferritin• Selain pd sel mukosa usus halus, juga pd makrofag
di hati ,limpa , tulang, dan pada sel parenkim hati
• Ferritin serum seimbang dg ferritin cadangan pd RES jaringan, u/ mengestimasi cadangan besi
tubuh.
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eliminasi
• <1mg / hari
• Exfoliasi mukosa intestine ,empedu,urine, keringat
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Farmakologi klinikIndikasi : Pengobatan &pencegahan anemia defisiensi Fe
Umumnya krn • kebutuhan me : bayi prematur, anak dlm masa
pertumbuhan, hamil, laktasi, dan penderita dg peny.ginjal kronik (kehilangan eritrosit selama hemodialisis,o.k eritropoietin)
• Krn abs.tdk cukup: stlh gastrektomi,ggn usus
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• Pd dewasa plg sering blood loss : menstruasi, perdarahan sal.cerna
Pengobatan anemia defisiensi Fe• Preparat Fe oral / suntikan. • Bila tdk ada ggn abs.pd sal. cernaoral, krn umumnya sama cepat dg suntikan• Peny.ginjal kronik berat dg hemodialisis dan th/
eitropoietinkebutuhan Fe besarsuntikan > baik
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Preparat Fe oral
• Ion Fero lebih efisien diabs garam :Fero sulfat, fero glukonat, fero fumarat
• elemen besi bervariasi
• Dibutuhkan 200-400 mg elemen besi/hari untuk memperbaiki dg cepat anemia defisiensi
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Efek samping pemberian oral:• mual,nyeri epigastrium, kram perut, konstipasi,
diare, feces hitam
• umumnya dose related sering kali dpt dikurangi dg <dosis, diminum segera setelah atau waktu makan,
menukar preparat
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Preparat Fe suntikan
• Untuk penderita yg tidak tahan atau tdk dpt mengabsorpsi preparat oral, penderita dg perdarahan hebat yg tdk dpt diatasi dg prepa-rat oral saja
mis: pasca gastrektomi, reseksi usus,sindrom malabsorpsi, peny.ginjal kronik lanjut (hemodialisis, th/eritropoietin)
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Iron dextran :• kompleks Fe (OH)3 dg dextran BM rendah• IM dalam / infus IV • Efek samping IM : nyeri lokal, pewarnaan pd tempat suntik
• Efek samping IV : sakit kepala, demam artralgia, mual, muntah, nyeri punggung, flushing, urticaria, bronchospasme, jarang dpt anafilaksis, kematian
Sebag. krn hipersensitivitas thd dextran • R/ hipersensitivitas mgk delayed: 48-72 jam stlh
obat
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• Kmk hipersensitivitas > : pend.alergi, pernah dapat ion dextran
Iron-sucrose complex,Iron-sodiun gluconate complex• Hanya IV, kmk reaksi hipersensitivitas <
Pemberian parenteral kronik : perlu monitor secara periodik kadar besi cadangan u/menghindarkan keracunan krn kelebihan besi (mekanisme pengaturan uptake spt di usus halus
tdk ada)
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Intoksikasi akut• 10 tabl. dpt letal pd anak kecil• Necrotizing gastroenteritis,dgn nyeri,muntah, diare berdarah, diikuti dg shock, sesak dpt
koma, kematianTh/ • irigasi usus , • pemberian deferoxamine (chelator besi
mengikat besi ,dan me ekskresi)• suportif
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Intoksikasi kronik• Hemochromatosis :kelebihan besi dideposit pd
berbagai organ mis: hati, jantung pankreas kegagalan organ, kematian
• karena bawaan, tranfusi berulang -jangka panjang (talasemia major)
• Th/ flebotomi intermiten bila tidak anemia• Deferoxamine suntikan hanya bila flebotomi tdk
bisa (talasemia major)• Deferasirox: kelator besi per oral, baru
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II. Vitamin B12
• Cofactor bbrp reaksi biokimia• Defisiensi vit. B12 anemia, gejala gastro-
intestinal, dan gangguan neurologik• Defisiensi krn asupan kurang jarang• Relatif sering defisiensi krn gangguan absorpsi
Vit. B12
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• Utk th/: sianokobalamin , hidroksikobalamin
• Bentuk aktif vit. B12 pd manusia: deoksiadenosilkobalamin & metilkobalamin
• Sumber utama vit. B12 pd makanan :
hati, daging , telur, produk susu• tumbuhan vit.B12 neg.• Vegetarian ketat waktu lama mgk def.
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Farmakokinetik• 5-30 mcg / hari Vit.B12 makanan abs.1-5 mcg
• Kebutuhan normal : 2 mcg / hari• Disimpan > di hati : 1-10 mg• Eks.mel.urin feces << • Butuh t lama u/ def. anemia megaloblastik• vit.B12 bentuk kompleks di lambung & duode-
num dg faktor intrinsik (glikoprotein disekresi sel parietal mukosa lambung)
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• abs. di ileum distal
• Transport : berikatan dg transkobalamin II, suatu glikoprotein plasma, ke berbagai sel
• Kelebihan vit. B12 disimpan di hati
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• Penyebab paling sering def.Vit.B12: ggn abs.
anemia perniciosa (akibat ggn sekresi faktor intrinsik oleh sel mukosa lambung) gastrektomi peny.distal ileum : radang,reseksi
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Farmakodinamik
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• Metabolisme vit.B12 & asam folat berhub.
Anemia megaloblastik krn defisiensi vit.B12 sebag.dpt diatasi asam folat jumlah relatif besar
• Tetapi asam folat tidak mencegah / mengatasi
manifestasi neurologik• Gangguan neurologik krn akumulasi methylmalonil-
CoA (?), akumulasi metionin (bukti >baru)
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Farmakologi klinik Vit. B12
• u/ pengobatan & pencegahan defisiensi Vit.B12
• Manifestasi defisiensi vit. B12 :
anemia megaloblastik, sindrom neurologik dimulai dg kesemutan dan kelemahan (ggn saraf
perifer), spastik,ataksia, lain ggn CNS• Gambaran patologik khas: degenerasi sarung myelin diikuti degenerasi
akson di cornu dorsalis & lateralis med.spinalis & saraf perifer
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• Pemberian vitamin B12 menghentikan progress ggn neurologik, tapi tdk sepenuhnya mengatasi gejala neurologik yg sdh berlangsung bbrp bln
• Anemia megaloblastik juga dpt krn def. asam folat Diagnosis penyebab perlu ditegakkan, biasanya dpt ditentukan berdasarkan pengukuran kadar serum
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• Penyebab def.vit B12 paling sering krn malabsorpsi dibutuhkan terapi suntikan
• Suntikan:Cyanocobalamin / hidroksokobalamin• Hidroksokobalamin > terikat protein> lama• Dosis awal 100-1000 g IM /hari atau selang sehari
selama 1-2 minggu.• maintenance 100-1000 g 1X / bulan Bila ada gejala neurologis tiap 1-2 minggu selama
6 bulan , selanjutnya 1 X/bulan
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III. Asam folat
• u/ meghasilkan precursor u/ sintesis asam amino, purine , dan DNA
• Defisiensi folatanemia, malformasi kongenital
• = pteroylglutamic acid
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Farmakokinetik• Sumber : > ragi, hati, ginjal ,sayuran hijau
• Abs. umum 50-200 g. Hamil: 300-400 g/ hari
• Cadangan: 5-20 mg di hati, dan jar.lain. Ekskresi : mel urin, feces
• Abs. mudah, sempurna mel. jejunum proks.
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• folat makanan terutama poliglutamat N5-metiltetrahidrofolat
dihidrolisis pd mukosa usus seb.diabsorpsi.
• Monoglutamat N5-metiltetrahidrofolat ditransport ke darah distribusi
• Dlm sel N5-metiltetrahidrofolat mengalami demetilasi , membutuhkan vitamin B12
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Farmakodinamik
• berperan utk menghasilkan dTMP ( 2-deoxy-thyimidine monophosphate) untk sintesis DNA
• Pd jaringan tumbuh cepat dibutuhkan > banyak tetrahidofolat, regenerasi tetrahidrofolat dari dihidrofolat
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Farmakologi klinik
• Defisiensi folat anemia megaloblastik, spt def. vit.B12, tetapi tdk menyebabkan sindrom neurologik spt yg terlihat pd def. vit. B12
• Anemia megaloblastik ukur kadar folat dlm eritrosit atau serum . Dalam eri > baik
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Defisiensi asam folat :• Sering pd alkoholism, penyakit hati• Hamil, anemia hemolitik kebutuhan folat
meningkat• Defisiensi asam folat pd ibu hamil – neural tube
defect (mis. spina bifida) pd fetus• Malabsorpsi
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• Dialisis
• Metotreksat, trimetoprim, pirimetamin hambat dihidrofolat reduktase defisiensi cofactor folat anemia megaloblastik
• Fenitoin jangka lama dpt def. folat, tetapi jarang menyebabkan anemia megaloblastik
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• Oral diabs.baik, jarang dibutuhkan suntikan
• Dosis 1 mg / hari umumnya cukup mengatasi anemia megaloblastik
• Suplementasi asam folat u/ mencegah def. asam folat pd penderita high risk:
wanita hamil, alkoholism, anemia hemolitik, penyakit hati, dialisis
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IV.Hematopoietic growth factors
• Hormon glikoprotein , mengatur proliferasi & diferensiasi sel progenitor hematopoietik dlm sumsum tulang
• efek kompleks termasuk nonhematologik• Kmk kegunaan sbg antikanker, antiinflamasi sdg
diselidiki
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Yg sekarang digunakan di klinik :• erythropoietin (epoetin alfa)• granulocyte colony-stimulating factor (G-CSF)• granulocyte-macrophage colony-stimulaing factor
(GM-CSF)• interleukin -11 (IL-11)
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Erythropoietin
• Glikoprotein, 34-39 kDA• Semula dimurnikan dr urin pend. anemia berat
• Setelah pemberian IV t1/2 serum 4-13 jam pd penderita dg gagal ginjal kronik
• Darbepoetin : bentuk glikosilasi t1/2 2-3 X
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Farmakodinamik
• Menstimulasi proliferasi & diferensiasi erythroid• interaksi dg reseptor erythropoietin pd
progenitor eritrosit• Menginduksi release retikulosit dr sumsum tl• Dlm tubuh : terutama diproduksi oleh ginjal • hipoksia jaringan diproduksi > banyak
perbaikan anemia
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hub.terbalik kadar hematokrit /hemoglobin dg kadar erotropoietin serum
anemia kadar ,kec. anemia pd gagal ginjal kronik
Non anemis : kadar eritropoietin serum < 20 IU/L
Anemia ringan-sedang umumnya 100-500 IU/L
anemia pd GGKkadar eritropoietin rendah (tdk bisa prod) umumnya respons thd eritropoietin eksogen
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• Anemia krn ggn sumsum tulang , anemia def., anemia sekunder umumnya kmk respons thd eritropoietin eksogen <
Indikasi• Anemia pada gagal ginjal kronik Ht dan Hb meningkat dlm 2-6 minggu , me –
ngurangi kmk tranfusi. Umumnya Ht skt 35 % dg dosis 50-150 IU/kg IV
atau SK, 3 X/minggu peningkatan retikulosit dalam 10 hari
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anemia krn ggn sumsum tl primer atau anemia sekunder, bila kadar eritropoietin relatif rendah (<100 IU/L) eritropoietin mgk bermanfaat.
Efek samping pe Ht & Hb yg cepat hipertensi, trombosis Perlu peningkatan perlahan, monitoring,
pengobatan hipertensi
Reaksi alergi: jarang, ringan
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Myeloid growth factors
• Granulocyte colony-stimulating factor (G-CSF, filgrastim)• Granulocyte-macrophage colony- stimulating
factor (GM-CSF, sargramostim )
• T1/2 serum : 2-7 jam, setelah IV atau SK
Pegfilgrastim t1/2 > panjang 1 X / siklus kemoterapi
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FarmakodinamikG-CSF : • stimulasi proliferasi &diferensiasi sel progenitor
neutrofil
• Mengaktivasi aktivitas fagosit neutrofil & memperpanjang survivalnya dlm sirkulasi
• Mobilisasi stem cells hematopoietik me stem cell darah perifer u/ transplantasi stem cells hematopoietik
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GM-CSF: aktivitas > luas dr G-CSF
• Stimulasi proliferasi & diferensiasi sel progenitor granulosit, eritroid, megakariosit
• Stimulasi fagositosis oleh neutrofil• Stimulasi proliferasi sel T, bersama IL-2 • Berperan di tempat inflamasi• Mobilisasi stem cells haematopietik (<efektif
dibanding G-CSF)
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Indikasi
• Neutropenia akibat kemoterapi kanker lama neutropenia berkurang me kadar neutrofil setelah kemoterapi Terhadap perbaikan klinis (berkurangnya lama demam krn neutropenia, kebutuhan akan AB spektrum luas, lama di RS) hasil bervariasi
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Dosis : G-CSF 5 mg/kg/hari GM-CSF 250 g/m2/hari biasa diberikan 24-72 jam setelah kemoterapi dan diteruskan sampai neutrofil >10.000/ L
Lain indikasiNeutropenia congenital, cyclic neutropenia,anemia aplastikTransplantasi stem cell autolog pd penderita dgkemoterapi dosis tinggi
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• Efek samping G-CSF < nyeri tulang, hilang bila dihentikan GM-CSF > berat, terutama dosis inggi demam, malaise, artralgia,mialgia, kebocoran kapiler (edema perifer, pleural effusion/ pericardial effusion) reaksi alergi, ruptur limpa
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Megakarycyte growth factors• Interleukin-II dan trombopoietin
• Interleukin-II stimulasi pertumbuhan progenitor megaka-riosit
& me trombosit & netrofil darah perifer
• Trombopoietin stimulasi pertumbuhan progenitor megaka-riosit,
juga aktivasi platelet
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Interleukin-IIu/ trombositopenia akibat kemoterapi sitotoksik
• me jumlah tranfusi trombosit yg dibutuhkan• Tdk memiliki efek bermakna thd leukopenia akibat
kemoterapi
• SK,50 mcg/kg/hari,6-24 jam setelah kemoterapi• diberikan selama 14-21 hari atau trombosit
meningkat menjadi > 50.000 sel/l
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• Efek samping Interleukin-II : cape,sakit kepala, pusing, CV
(anemia,sesak,aritmia, hipokalemia) Trombopoietin• sedang diteliti u/ trombositopenia akibat
kemoterapi dan pd transplantasi stem cell hematologik
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