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Antiretroviral Pharmacology Dept. Pharmacology & Therapeutic
School of Medicine
Universitas Sumatera Utara
Different living organisms Eucaryotes
Mono or polycellular Cell nucleus; DNA May have cell wall Sexual and/or asexual replication Animals Plants Fungi Protocista (protozoea, algea)
Procaryotes
Bacteriea Monocellular, no nucleus – DNA single strand Cell wall, asexual replication
Virus
RNA or DNA + protein coating (not really a cell) Use other organisms ribosomes for protein synthesis
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INFEKSI VIRUS • PELEKATAN VIRUS DAN DINDING SEL (DIHIDROLISA OLEH ENZIM VIRUS) • DNA/RNA MASUK KE DLM SEL SEDANG CAPSID TIDAK • VIRUS SEBAGAI PARASIT, MENGGUNAKAN PROSES ASIMILASI SEL VIRION BARU • ( PERBANYAKAN VIRION SAMPAI PUNCAK GEJALA PENYAKIT )
Antiviral Drugs • Amantadine and analogs • Neuraminidase Inhibitors • Nucleoside analogs - Antimetabolites • Other comp. that interfere with replication • Comp. that interfere with translation (protein synth) • Interferon / interferon inducers Specific retroviral drugs • Reverse transcriptase inhibitors – Nucleosides (NRTIs) – Non-nucleosides (NNRTIs)
• Protease inhibitors
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Klasifikasi Antivirus berdasarkan Antivirus Mekanisme Kerjanya
Mekanisme Kerja Menghalangi penetrasi
γ Globulins
Menghalangi uncoating
Amantadine & Rimantadine
Menghambat sintesis protein awal
Formivirsen
Menghambat sintesis asam nukleat
1. Analog purin & pirimidin (Acyclovir, Valacyclovir, Famciclovir, Penciclovir, Ganciclovir, Idoxurudine, Sorivudine,Trifluridine, Cidofovir, Vidarabine, Ribavirine) 2. Pyrophosphate anorganic (Foscarnet ) 3. NRTI (Zidovudine, Lamivudine, Stavudine Didanosine, Zalcitabine, Abacavir) 4. NNRTI (Nevirapine, Delavirdine, Efavirenz )
Menghambat sintesis protein akhir
Inhibitor protease (Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir)
Menghambat perakitan
Rifampin
Menghambat rilis
Inhibitor neuraminidase (Zanamivir, Oseltamivir)
Menghambat penetrasi, uncoating, sintesis mRNA, translasi, perakitan,rilis
Interferon
Viral zinc-finger nucleocapsid proteins Fusion inhibition
Viral protease
RNA
RNA Proteins
Reverse transcriptase
RT RNA RNA DNA RT
Viral regulatory proteins
DNA DNA
Provirus
Viral integrase
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Antiretroviral Classes NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka “Nukes”)
NNRTIs (Non-Nucleoside Reverse
Transcriptase Inhibitors, aka “Non-Nukes”)
PIs (Protease Inhibitors) Fusion Inhibitors Chemokine Receptor Antagonists Integrase Inhibitors
Mechanism of Action of ARVs Integrase Inhibitor
Protease Inhibitor
Fusion Inhibitor & Chemokine Receptor Antagonist
NNRTI NRTI Illustration by David Klemm
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NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors)
Nucleoside Reverse Transcriptase Inhibitors Nucleoside analogs without 3’ OH - DNA chain termination Pro-drugs - Phosphorylated by kinases in vivo Zidovudine (AZT) Retrovir® Trizivir® Kombi prep.
Stavudine Zerit®
Zalcitabine (ddC)
Lamividine (3TC) Epivir® Trizivir® Compivir ® Kombi prep.
O O
NH2
HN HN HO
O
NH2
N
N O
HO
O
N O
HO
O
N
N O
HO
N3
O
N O
S Higher bioavail. than ddC
Didanosine (ddI) Videx®
Abacavir (ABC) Trizivir® Kombi prep. NH2
O N
HN
O
N
N
N
N HO
in vivo
P P P O
HN
N
N O
N
N H2N HO
N
N
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NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors) Side Effects
Elimination
Zidovudine (ZDV/AZT) Retrovir
Drug
300mg bid*
Std Dose
300mg tab, 100mg cap, iv, oral soln
Dosage forms
Fatigue, malaise, HA myalgia, anemia, GI
Renal
Lamivudine (3TC) Epivir
150mg bid* or 300mg qd
150, 300mg tab, oral soln
Well tolerated
Renal
Emtricitabine (FTC) Emtriva
200mg qd*
200mg cap
Well tolerated
Renal
Didanosine (ddI) Videx
400mg EC qd (≥ 60kg) 250mg EC qd (<60kg)*
125,200,250, 400mg cap, pwdr for soln
Pancreatitis, peripheral neuropathy, LA/HS
Renal
Stavudine (d4T) Zerit IR
40mg bid (≥ 60kg) 30mg bid (<60kg)
15,20,30,40 mg cap,oral soln
Peripheral neuropathy, Pancreatitis, LA/HS, Lipoatrophy, facial wasting
Abacavir (ABC) Ziagen
300mg bid, 600mg qd
300mg tabs, oral soln
hypersensitivity
Tenofovir (TDF) Viread
300mg qd*
300mg tabs
Few SEs, renal toxicity
Renal
Hepatic by alcohol dehydrogenase and glucuronyl transferase Renal
NRTIs Mechanism of Action Nucleoside analogs (like AZT below) Analog of thymidine, cytosine, adenine, or guanine Triphosphorylated inside lymphocytes to active compound Incorporate into the growing HIV viral DNA strand by reverse transcriptase
Nucleotide analog Currently only tenofovir (TDF) Does NOT need to be tri-phosphorylated only di-phosphorylated to active compound
After incorporation of the NRTI, viral DNA synthesis will be terminated.
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NRTI Class Toxicities • Lactic Acidosis – Damage to mitochondria in cells – Elevated lactate, low pH/bicarbonate, N/V, shortness of breath, if untreated can lead to death – Lactic acidosis can occur with any NRTIs
• Hepatomegaly with Steatosis – Build up of fat droplets inside liver cells – Enlarged liver
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
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Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) Binds directly to TR Nevirapin Viramune®
Efavirenz / Sustiva Stocrin®
N
N
N
F3C NH
Cl
O Me
O
O
N H
FDA 1998 Already resistance
NNRTIs Drug
Std Dose
Dosage forms
Side Effects
Elimination
Delavirdine (DLV) Rescriptor
400 mg tid
100mg tab, 200mg cap
Rash
Potent CYP3A inhibitor; 3A4 substrate
Nevirapine (NVP) Viramune
200 mg qd x 14 d then 200 mg bid
200mg tabs, Oral susp
Rash (SJ), hepatotoxicity
CYP3A inducer, auto inducer; 3A4, 2B6 substrate
Efavirenz* (EFV) Sustiva
600 mg qhs
50, 100, 200mg cap, 600mg tab
Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia
CYP3A, 2B6 inducer; 2B6, 3A4 substrate
*Pregnancy Class D
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NNRTIs Mechanism of Action These agents directly bind to reverse transcriptase to inhibit transcription NNRTIs do not require phosphorylation to be active
RT
Protease Inhibitors (PIs)
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Saquinavir Fortovase®
Protease Inhibitors O
H OH
H
O
NH2 O
H N
Saquinavir (green) bound to HIV-1 Protease
N H
O Ph
NH
N
Lopinavir Kaletra®
Indinavir Crixivan® N
Ph
OH
H N
N
N O
OH
O
NH
OH OH
NH
N
NH O
Amprenavir Agenerase®
H
O
Ph O N H
O Ph
Nelfinavir Viracept®
H
OH
H N
O
H N
OH
N
S O O
O
S Ph
H N O Ph
O O
Protease Inhibitors (PIs) Drug
Std Dose
Dosage forms
Side Effects
Metabolism
Atazanavir (Reyataz) (1)
400qd or 300/ rtv 100qd
100, 150, 200mg caps
Hyperbilirubinemia, PR prolongation
3A substrate; 3A and UGT1A1 inhibitor
Fosamprenavir (Lexiva) (1)
1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd
700mg tabs (Agenerase-APV liq available)
Rash, GI intolerance, caution with sulfur allergy
3A4, Pgp substrate; 3A4 inducer/ Inhibitor
Tipranavir (Aptivus) (1,2)
500/200 RTV mg bid
250mg caps
Hepatotoxicity, Increased bleeding caution with sulfur allergy
3A4, Pgp substrate; 3A4, inducer/ inhibitor??; Pgp inducer
Darunavir (Prezista) (1)
600/100 RTV mg bid
300mg tabs
Diarrhea, nausea, 3A4 substrate; nasopharyngitis 3A4 inhibitors
Ritonavir (Norvir) (1,2)
Used as a PK booster 100200mg
100mg caps; 80mg/mL
Nausea,vomiting, diarrhea, GI upset
2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor
(1) Take with Food; (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance
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Protease Inhibitors (PIs): Mechanism of Action Protease enzyme cleaves HIV precursor proteins (gag/pol polyproteins) into active proteins that are needed to assemble a new, mature HIV virus. PIs bind to protease preventing the cleavage and inhibiting the assembly of new HIV viruses
X
HIV
Dose adjustments to consider Renally-eliminated NRTIs (except Abacavir) Adjust for CrCl <50 ml/min or dialysis Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine
Reference: Drug product info and DHHS guidelines (see tables)
Hepatic Metabolism ∼ NNRTIs ∼ PIs Adjust for certain inducers, substrates, or inhibitors of P450 system Adjust for insufficiency Indinavir Fosamprenavir Atazanavir Avoid Amprenavir oral soln Foasmprenavir (+/- ritonavir) Tipranavir
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Fusion Inhibitor • Fuzeon (Enfuvirtide, T-20)
See Kilby and Eron, NEJM 2003;348:2228-38
Fuzeon : Enfuvirtide (T-20) • FDA-approved fusion inhibitor; 36 AA peptide – Requires 106 steps to manufacture
• Dose: 90 mg sq bid • side effects: – injection site rxn, hypersensitivity (rare) • resistance: changes in gp41 (cell surface protein)
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Chemokine Receptor Antagonists • Marviroc (Selzentry®) • CCR5 or CXCR4 receptors on cell surface • Virus will bind to one of the 2 receptors – Some patients’ virus will bind to either receptor
• Marviroc blocks viral entry at CCR5 • Dosed 300mg BID – 150mg BID with P450 inhibitors – 600mg BID with P450 inducers
Integrase Inhibitors • Raltegravir (Isentress™) • Dosed 400mg BID (1 tab BID) • No induction or inhibition on CYP450 enzymes or Pgp • Metabolized by UGT1A1 (glucuronidation) – Only affected by drugs that inhibit or induce UGTs (ie, rifampin)
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Drug Interactions
ARV metabolism, induction, and inhibition Drug
Substrate
Inhibits 3A4
Induces
Efavirenz
2B6, 3A4
3A4, 2B6
Nevirapine
3A4, 2B6
Ritonavir
2D6, 3A4, Pgp
3A4, 2D6, Pgp
Saquinavir
3A4, Pgp
3A4
Nelfinavir
2C19 (M8→3A4)
3A4
Amprenavir
3A4, Pgp
3A4 (in vitro)
3A4 (in vivo)
Fosamprenavir
3A4, Pgp
3A4 (in vitro)
3A4 (in vivo)
Lopinavir/ritonavir
3A4, Pgp
3A4
2C9, 2C19, 1A2
Atazanavir
3A4, Pgp
3A4, UGT, 1A2
Tipranavir
3A4, Pgp
3A4
Darunavir
3A4, Pgp
3A4
Maraviroc
3A4, Pgp
3A4 2D6 (at high doses only)
Other enzymes
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Cytochrome P450: Non-Antiretrovirals Cyp.
Substrate
Inhibitor
Inducer
3A4
Macrolides,cyclosporine, CCB, statins, azoles, PDE5 inhibitors, aprepitant, midazolam, triazolam
Cimetidine, Macrolides, FQs, SSRIs, CCB, azoles, aprepitant
rifamycins, phenytoin, CBZ, St. John’s wort, aprepitant, garlic
2D6
nortriptyline, amitriptyline, tramadol, trazodone, opiates, paroxetine, metoprolol, propranolol, carvedilol
Haldol, SSRIs, cimetidine, amiodarone
rifamycins, phenytoin, CBZ, St. John’s wort
1A2
Amitriptyline, clozapine, caffeine, clozapine, imipramine, R-warfarin, theophylline, proprnaolol
FQs, azoles, macrolides,
rifamycins, phenytoin, CBZ, smoking, St. John’s wort
2C19
Omeprazole, phenytoin
SSRIs, azoles, fluvastatin, omeprazole, topiramate
rifamycins, CBZ, phenytoin
2C9
S-warfarin, sulfonylureas, phenytoin, carvedilol
Amiodarone, SSRIs, azoles, amiodarone
Phenytoin, CBZ, rifammycins, aprepitant
Protease Inhibitors and Acid Suppression • Do Not combine Atazanavir and Proton Pump Inhibitors – May Combine ATV and Famotidine but dose adjustments are REQUIRED
• May use Indinavir with PPIs but ONLY if coadministered with RTV • May use Fosamprenavir with Esomeprazole – Separate FPV from H2 blockers if used concomitantly
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Important Drug Interactions • Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV • Do NOT combine Rifampin with PIs – LPV/RTV may be dose increased and combined with Rifampin – Conflicting data with EFV and NVP • Use other P450 inducers with CAUTION when combining with PIs and NNRTIs • Do NOT use Fluticasone or Alfuzosin with Ritonavir • Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, when combined with PIs • Avoid Herbal Products with Known or Suspected Interactions • When combining Protease Inhibitors, Often Dose Adjustments are Necessary
PI/ NNRTI/ Antidepressant Drug Interactions Antidepressant
Potential for Interaction
Effects
Management
Amitriptyline
ritonavir, lopinavir/r, amprenavir,
Levels of Start with lower dose amitriptyline may be (50%) of amitriptyline, increased adjust dose when addIng ritonavir. Monitor for side effects
Fluoxetine
ritonavir, lopinavir/r, all other PIs, efavirenz
Levels of both fluoxetine and ARVs may be increased
Sertraline
ritonavir, lopinavir/r, all other Pis, efavirenz
Levels of sertraline As above may be increased. ARV levels not likely to change.
As above
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PI Drug Interactions • All PIs are metabolized all or in part by the CYP3A4 enzyme system • All PIs can inhibit CYP3A4 enzymes – Ritonavir most potent inhibitor – Saquinavir least potent inhibitor
• Ritonavir can also induce CYP1A2
ARV Interactions with Recreational Drugs Effect
Comments
Alcohol
Abacavir AUC ↑ 41%
Clinical significance unknown
Amphetamines
RTV may ↑ amphetamine levels
Potential amphetamine toxicity
Barbiturates
Potential ↓ levels of PIs and NNRTIs
Potential virologic failure/resistance
Benzo-diazepines
↑ Midazolam and triazolam levels with PIs and delavirdine (levels of alprazolam and clonazepam may ↑)
Potential benzodiazepine toxicity
λ-hydroxybutyrate (GHB)
Potential ↑ GHB levels
Potential GHB toxicity
Heroin
Potential enhanced heroin effect
Clinical significance unknown
Marijuana
Minimal effect on IDV and NFV
Interaction with ARVs unlikely
3,4-MDMA (Ecstasy)
Potential ↑ ecstasy levels
Potential ecstasy toxicity
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Dirgahayu negeriku Dirgahayu FK USU
KEBANGGAAN INDONESIA UNTUK DUNIA
ANTIRETROVIRAL
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ARV dibagi dalam 6 kelas: • Nucleoside reverse transcriptase inhibitors (NRTIs) • Nonnucleoside reverse transcriptase inhibitors (NNRTIs) • Protease inhibitors (PIs) • Integrase inhibitors (IIs) • Fusion inhibitors (FIs) • Chemokine receptor antagonists (CRAs)
Nucleotide Reverse Transcriptase Inhibitor (NRTI)
• Difosforilasi oleh enzim seluler untuk menjadi bentuk aktif • NRTI toksik terhadap hati kecuali Lamivudine dan Abacavir • Secara umum bekerja untuk menghentikan pembentukan rantai DNA virus • Monitoring kepada toksisitas oleh karena obat
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Zidovudine (AZT) • Bentuk aktif berupa azido-deoxythymidine monophosphate (AZT-MP) • Bekerja menghalangi sintesis DNA • Obat diserap dengan baik melalui oral, dapat menembsu sawar otak • SE: toksisitas sumsum tulang, sakit kepala • Resistensi jarang terjadi
Didanosine (ddl) • Bentuk aktif berupa dideoxyadenosine monophosphate • Sama dengan AZT, ddl juga bekerja pada rantai DNA • Makan saat puasa,saat kondisi basa • Dapat juga memasuki CSF, ttapi tidak seluas AZT • SE: pancreastitis • Resistensi terjadi pada terapi yang panjang
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Zalcitabine (ddC) • • • •
Digunakan bersama AZT Bentuk aktif berupa triphosphate Bekerja pada rantai DNA Penggunaan secara oral, hindari penggunaan bersama antasida • SE: Rash dan stomatitis, periferal neuropati • Tidak boleh digunakan bersama pentamidine, dapat menyebabkan pankreatitis
Stavudine (d4T) • Bentuk aktif berupa triphosphate • Bekerja menghentikan rantai DNA • Diabdsorbsi dengan sangat baik tanpa dipengaruhi makanan • SE: periferal neuropati
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Lamivudine (3TC) • Dikombinasikan dengan AZT, tidak boleh digunakan dengan ddC • Menyebabkan terminasi sintesis rantai DNA virus • 3TC dapat mengembalikan sensitiviras terhadap AZT • Penggunaan secara oral
Abacavir • Merupakan analog dari guanosine • Penggunaan secara oral • SE: gangguan pencernaan, sakit kepala, dan pusing
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Tenovovir • • • •
Analog nukleotid Menghambat reverse trankriptase Dimakan pada saat setelah makan SE: mual, muntah, diare
Emtricitabine • • • •
Derivatif dari lamivudine Menghambat reverse transkriptase Dikonsumsi secara oral SE: sakit kepala, diare, mual, dan kulit merah gatal
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• Tn H, harus segara cuci tangan debgan air dan sabun serta melaporkan diri ke pihak rs dan segera mengeluasi pajanan. Kode pajanan 3 dan status 2 dan diperlukan profilaksis obat AZT Zidovudin (3 kali sehari 200mg ) dan dikombinasi dgn lamivudin 300mg/hari dan Idanavir 3 kali sehari 800mg per oral dan nelvinapir 3 kali sehari 800 mg per oral.Tn H harus lakukan follow up 3 bulan dan 6 bulan pasca pajanan.
Nucleoside Reverse Transcriptase Inhibitors
Abacavir (ABC, Ziagen) Didanosine (ddI, Videx) Emtricitabine (FTC, Emtriva) Lamivudine (3TC, Epivir) Stavudine (d4T, Zerit) Tenofovir (TDF, Viread) Zalcitabine (ddC, Hivid; no longer available in the United States) Zidovudine (ZDV, Retrovir; formerly azidothymidine [AZT]) Mekanisme kerja NRTIs menghambat replikasi HIV melalui inhibisi secara kompetitif HIV reverse transcriptase dan terminasi rantai DNA.
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Therapy of HIV Infection •
Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). – These drugs inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and are incorporated into viral DNA (they are chain-terminating drugs). – Zidovudine (AZT = ZDV, Retrovir) first approved in 1987 – Didanosine (ddI, Videx) – Zalcitabine (ddC, Hivid) – Stavudine (d4T, Zerit) – Lamivudine (3TC, Epivir)
•
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). – In contrast to NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV replication directly by binding non-competitively to reverse transcriptase. – Nevirapine (Viramune) – Delavirdine (Rescriptor)
•
Protease Inhibitors. – These drugs are specific for the HIV-1 protease and competitively inhibit the enzyme, preventing the maturation of virions capable of infecting other cells. – Saquinavir (Invirase) first approved in 1995 – Ritonavir (Norvir) – Indinavir (Crixivan) – Nelfinavir (Viracept)
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