Farmakologi arv
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Transcript of Farmakologi arv
![Page 1: Farmakologi arv](https://reader033.fdocument.pub/reader033/viewer/2022061505/558e75471a28abdd478b461b/html5/thumbnails/1.jpg)
Farmakologi ARV
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Prinsip Dasar Farmakologi
Clinical Option
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Konsep Steady State
• Suatu kondisi dimana konsentrasi obat menjadi konstan karena pemberian obat yang terus menerus
• Kondisi tercapai setelah +/- 5 half-lives
Clinical Option, University of Alalbama
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Mekanisme kerja ARV
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HIV - Life Cycle
ReverseTranscriptaseInhibitors(10)
ProteaseInhibitors(6)
Fusion/EntryInhibitors
IntegrationInhibitors
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NRTI
– Interfensi enzim DNA polymerase - RNA (reverse transcriptase, RT).
– Intracellular phosphorylation to active metabolite.
– Competitor dengan nucleosides.– Inkorporasi dengan viral DNA yg sedang
berkembang dan mengakibatkan berhentinya rantai DNA.
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Nucleosides of the DNA chain
• Adenine (A)
• Guanine (G)
• Cytosine (C)
• Thymidine (T)
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Nucleoside reverse transcriptase inhibitors (NRTI)
Zidovudine (ZDV) Thymidine analogue
Stavudine (d4T) Thymidine analogue
Zalcitabine (ddC) Cytidine analogue
Lamivudine (3TC) Cytidine analogue
Didanosine (ddI) Adenine analogue
Abacavir (ABC) Guanine analogue
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• NRTIs:
Ph
P PP PPP
PhP P PhP
NRTIs:
NtRTIs (tenofovir):Cellular enzyme
Cellular enzyme
Cellular enzyme
Cellular enzyme
Cellular enzyme
Rate-limiting step
Mekanisme kerja Phosporilasi
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Efek NRTI pada Mitokondria
• Mitokondria → penghasil energy
• NNRTI menghambat DNA polimerase ð
• ATP tidak dapat dihasilkan → mitokondria toxicity
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NNRTI
• Berikatan secara langsung dengan RT pada kantung katalitik sehingga proses katalisasi terhenti
.
NNRTI
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Protease Inhibitor
• Dengan menghambat langsung enzim protease yang diperlukan untuk mengumpulkan informasi genetik dan maturasi
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Aspek pemilihan obat
• Efikasi
• Toksisitas
• Adherence
• Resistensi
• Interaksi Obat
• Rp/$$$$
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Obat yang penetrasi Cairan Cerebrospinal
• Zidovudine
• Stavudine
• Abacavir
• Nevirapine
• Indinavir
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Diminum saat perut kosongDiminum saat perut kosong(1 jam sebelum atau 2 jam
setelah makan)
• Didanosine (kecuali jika dengan tenofovir)
• Indinavir (kecuali jika dengan ritonavir)
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Dengan makananDengan makanan
• Nelfinavir
• Ritonavir
• Lopinavir
• Saquinavir
• Tenofovir
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Dengan atau Tanpa Dengan atau Tanpa MakananMakanan
• ZDV, D4T
• Nevirapine
• Efavirenz: hindari lemak tinggi
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ARV disimpan dengan ARV disimpan dengan RefrigeratorRefrigerator
• RitonavirRitonavir
• Suspensi DDI Suspensi DDI
• D4T solutionD4T solution
• Lopinavir/rit kapsul dan solutionLopinavir/rit kapsul dan solution
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Penyimpanan ARV dalam Penyimpanan ARV dalam botol kacabotol kaca
• ZDV sirop
• D4T sirop
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Zidovudine(ZDV, AZT, Retrovir®)
• Tablet : 300 mg Capsule: 100 mg• Syrup: 10 mg/ml IV: 10 mg/ml• dosis: 300 mg po tiap 12 jam dgn atau tanpa makan.• Duviral® (ZDV 300mg/3TC 150mg/tab)• Duviral 1 tab po tiap 12 jam• Efek samping: mual/muntah, sakit kepala, kembung,
anemia, neutropenia, mialgia, miopati, artralgia, peningkatan transaminase.
• Makan mengurangi mual, monitor Ht (diharapkan MCV meningkat), Lekosit/ANC, tes fungsi hati.
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Didanosine(ddI, Videx®)
• Sediaan enteric coated tablet dpt diberikan dosis tunggal
• Dosis: >60kg, 400 mg PO sekali sehari• Dosis: <60kg, 250 mg PO sekali sehari• Efek samping: diare, neuropati perifer,
pankreatitis!, enzim transaminase , Peripheral neuropathy
• Diberikan dengan perut kosong!monitor LFT, amyl/lipase, hati2 dgn obat yg menyebabkan pankreatitis
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Stavudine(d4T, Zerit®)
• Kapsul: 15, 20, 30, 40mg• Solution: 1mg/ml• dosis: >60kg, 40mg PO tiap 12 jam dengan /
tanpa makanan.• dosis: <60kg, 30mg PO tiap 12 jam• Efek samping: peripheral neuropathy (PN),
enzim transaminase , lactic acidosis, GI. Penyebab utama lipoatrophy
• Tidak aman digunakan dgn ddI, ↓ dosis utk PN menjadi 20mg or 15mg po tiap 12 jam.
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Lamivudine(3TC, Hiviral®)
• Tablet: 150mg /300mg(HIV), 100mg (hepatitis B)
• 150mg/tab• dosis: 150 mg PO tiap 12 jam or 300 mg
PO sekali sehari, <50kg: 2mg/kg PO tiap 12 jam dengan/ tanpa makanan.
• Obat yg sangat dpt ditoleransi• Dpt digunakan utk hepatitis B. Low barrier
utk resistance (mudah terjadi resisten)!
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EMTRICITABINE (FTC)Mempunyai keuntungan yang melebihi
Lamivudine• half life lebih panjang
• More forgiving
• Kemungkinan timbul resistensi lebih kecil
• Aktif untuk Hepatitis B
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Abacavir(ABC, Ziagen®)
• Tablet: 300 mg• dosis: 300 mg PO tiap 12 jam dengan / tanpa
makanan, atau 600 mg PO sekali sehari.• Efek samping: mual/muntah, diarrhea, abdominal pain• Reaksi hypersensitivity (5%): Perhatikan tanda2
alergi!!!! Demam + mual atau fatigue, +/- rash. Jangan pernah diulangi jika terjadi alergi!!!!!.
• Infokan secara rinci mengenai kemungkinan dan tanda alergi!!! dan lakukan monitoring ketat thd reaksi hypersensitivity .
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Abacavir Hypersensitivity• +/- 5% timbul reaksi alergi pada clinical trials• Onset
– Timbul biasanya dalam 2 minggu pertama; jarang >6 minggu
– Dapat timbul kapan saja dan dapat tiba2 memburuk– Gejala akan hilang dengan cepat jika segera
dihentikan
• Symptom– Sering berupa demam +/- fatigue, atau
mual/muntah/diare, nyeri abdominal . Rash bisa timbul/ tidak
– 20% dari pasien dapat timbul gangguan respirasis– Melibatkan seluruh sistem organ
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Abacavir Hypersensitivity-2
• PF– lymphadenopathy, mucous membrane lesions – Rash: banyak bentuk, biasanya maculopapular
atau urticarial)
• Laboratory – ↑LFTs & CPK, lymphopenia
• Anaphylaxis, liver failure, RF, hypotensi dapat terjadi!
• Penanganan– ABC harus dihentikan & Jangan digunakan lagi!!– Kematian dilaporkan pada penggunaan kembali
(rechallange)!!
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Tenofovir DF (Viread)
• Tablet: 245 mg
• dosis: 245mg PO sekali sehari with or without food.
• Efek samping: Fanconis syndrome dgn disertai renal Toxicity
• Dapat digunakan utk hepatitis B. Kurangi dosis ddi ketika digunakan dengan tenofovir
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NNRTI
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Efavirenz(EFV, Sustiva®, Stocrin®)
• Capsules: 50, 100, 200, 600 mg• dosis: 600 mg PO sekali sehari dengan/tanpa
makanan• Efek samping: CNS (vivid dreams, susah
konsentrasi, dizziness, insomnia, somnolence feelings of detachment), rash (biasanya ringan)
• Comments: gejala CNS biasanya terjadi,tapi akan membaik dalam 7-14 days; T 1/2 40-55 jam; CYP 3A inducer; can treat through rash in some patients
• Jangan diberikan pada wanita hamil
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Nevirapine(NVP, Viramune®)
• Tablets: 200 mg
• dosis: 200 mg PO sekali sehari 14 days, lalu 200 mg PO bid dengan/tanpa makanan
• Efek samping: Rash (dpt severe), demam, HA, GI, ↑transaminase
• Pemberian 200mg single dosis utk 2 mgg pertama mengurangi kemungkinan alergi; periksa LFT tiap 2 minggu utk 2 bln pertama, selanjutnya tiap bulan utk 3 bln berikut; autoinduction of its own metabolism; CYP 3A inducer
• Long acting
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Protease Inhibitor
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Ritonavir boosting pada PI
• Efficacy – ↑• Toxicity – bertambah krn efek samping
dari Ritonavir PLUS Cmax yg ↑• Adherence – ↑ krn jumlah tablet ↓
sehingga dpt diberikan single dosis• Resistance – ↑ barrier thd reistance – tidak
mudah resisten• Drug Interactions – P450 inhibitor• $$
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Nelfinavir mesylate
Sediaan:
dosis:
Administration:
Peyimpanan:
Jalu metabolism :
Efek samping
250 mg tablet
1250 mg (5 tabs) bid
Dengan makanan!!
Temperature ruangan
P450 3A4
Diare
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Nelfinavir
• Diare!
– Sering timbul: setelah dosis awal, dalam bentuk intermiten
– Terbaik diberikan sesudah makan
– Biasanya tidak disertai dengan keluhan yg lain
– Memberikan respon yg baik terhadap loperamide, bisa dicoba diberikan calcium carbonate
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Saquinavir(SQV-HGC, Invirase®; SQV-SGC, Fortovase®
FTV)
• Soft-gel kapsul (Fortovase®) 200 mg• Hard-gel kapsul (Invirase®) 200 mg• dosis: FTV 1200 mg PO tiap 8 jam dgn makanan
atau FTV 1000/RTV 100 tiap 12 jam. Unboosted hard gel tidak direkomendasikan, boosted hard gel : 1000/100mg tiap 12 jam
• Efek samping: GI, nyeri abdominal, rash• Jumlah pil terlalu banyak• Pemberian BID dlm penjajakan, sediaan baru 500 mg
kapsul
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Indinavir• Dosing
– Kapsul: 200, 333, and 400 mg
– IDV/RTV (100rit/800 ind bd)
– Tanpa boosting 800mg/8jam
– Indinavir tanpa boosting diberikan dengan perut kosong
– Hydration!
– Penetrasi ke CNS bagus
• Nephrolithiasis
• “Retinoid Syndrome”
• Hyperbilirubinemia
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Amprenavir(APV, Agenerase®)
• Capsules: 50 and 150 mg (+ Vit E 109 IU/cap)• Oral Solution: 15 mg/ml mengandung propelene glycol• Tdk boleh diberikan pada bumil dan anak < 4thn• dosis: 1200 mg PO tiap 12 jam dengan/ tanpa makan;
600 mg BID dgn RTV 100 mg BID• Efek samping: N/V/D, rash (dpt severe), nyeri
abdominal • Jumlah pil yg banyak dapat dikurangi dgn memberikan
fosamprenavir; Ukuran kapsul sangat besar; RTV dpt mengurangi dosis
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Lopinavir/ritonavir(ABT378/r, LPV/r, Kaletra®)
• Kapsul(lopinavir 133mg & ritonavir 33mg)
• Oral solution (LPV 400mg & RTV 100mg)/5ml
• dosis: 3 kapsul PO tiap 12 jam dengan makanan
• Efek samping: diarrhea, nausea, asthenia, nyeri abdominal ,↑ triglycerides & cholesterol.
• Hati – hati untuk peningkatan lipid
• Respon sangat baik utk naïve pasien
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Fusion Inhibitors
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Fusion Inhibitors
• Mencegah penetrasi sel membran• Digunakan untuk HIV-1 yg resisten dgn golongan
lain• Bekerja diluar sel• “dikabarkan” dapat menekan VL pada highly ART-
experienced patients
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Working model for HIV fusion (1)
1) HIV approaches a host CD4+ T-cell. It’s viral membrane contains trimeric glycoprotein spikes. Each spike contains a gp41 and gp120 subunit.
2) Fusion begins with the binding of gp120 to the CD4 and chemokine receptors on the cell membrane.
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Working model for HIV fusion (2)
3) Binding induces a conformational change in gp120 moving it aside and exposing gp41.
4) Fusion is mediated by gp41, which contains two heptad repeat domains, HR1 and HR2.
gp41
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Working model for HIV fusion (3)
5) As gp41 is exposed, the hydrophobic terminus of gp41 embeds itself into the cell membrane. The HR2 domain (blue) begins to coil into the grooves exposed on the trimeric HR1 domain of gp41 (red). This process, called zipping, destabilizes both cell and viral membranes punching a hole (fusion pore) into both membranes. This allows the HIV capsid to pass through the cell membrane and infection occurs.
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Working model for HIV fusion inhibition
WITHOUT FUZEON: ZIPPING
WITH FUZEON: ZIPPING BLOCKED
Fuzeon
HR2
Fuzeon is a peptide mimic of the HR2 region of gp41. As a result, Fuzeon binds to the HR1 region. Zipping cannot take place, and
so infection is blocked.
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Fusion/binding Inhibitors
Enfuvirtide (T-20)• amino-acid synthetic peptide inhibits HIV-1 gp41
Dosis: 90 mg 2 x sehari sc
Efek samping:
Reaksi pada t4 suntikan (nyeri, discomfort, induration, erythema, nodules & cysts). 3% withdrew
diarre, nausea, sakit kepala, bacterial pneumonia, reaksi hypersensitivity r (JANGAN rechallenge!)
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• Apakah pengenalan profil setiap obat cukup?
• Pengenalan profil obat penting tapi lebih penting lagi mengetahui bagaimana cara melakukan kombinasi atau…..
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