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Antiretroviral Pharmacology

Dept. Pharmacology & TherapeuticSchool 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 berdasarkanMekanisme KerjanyaMekanisme Kerja Antivirus

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

RT

Provirus

Proteins

RNA

DNA

RNA

DNA

DNA

RT

RNA

RNA

DNA

DNA

DNA

Viral regulatory

proteins

Viral protease

Reverse

transcriptase

Viral integrase

Viral zinc-finger

nucleocapsid

proteins

Fusion

inhibition

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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

NNRTI

NRTI

Protease

Inhibitor

Illustration by David Klemm

Fusion Fusion Fusion Fusion Inhibitor &Inhibitor &Inhibitor &Inhibitor &ChemokineChemokineChemokineChemokineReceptor Receptor Receptor Receptor AntagonistAntagonistAntagonistAntagonistIntegrase

Inhibitor

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NRTIs

(Nucleoside OR Nucleotide

Reverse Transcriptase Inhibitors)

Nucleoside Reverse Transcriptase Inhibitors

Nucleoside analogs without 3’ OH - DNA chain terminationPro-drugs - Phosphorylated by kinases in vivo

HN

N

O

O

O

HO

N3

Zidovudine (AZT)

Retrovir®Trizivir® Kombi prep.

HN

N

O

O

O

HO

Stavudine

Zerit®

N

N

O

O

NH2

HO

Zalcitabine (ddC)

N

N

O

S

O

NH2

HO

Higher bioavail. than ddC

Lamividine (3TC)

Epivir®Trizivir® Compivir ® Kombi prep.

Didanosine (ddI)

Videx®

HN

N N

N

O

OHO

in vivo N

N N

N

NH2

OOPPP

N

N N

N

HN

HO

H2N

Abacavir (ABC)

Trizivir® Kombi prep.

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NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors)

Drug Std Dose Dosage forms Side Effects Elimination

Zidovudine

(ZDV/AZT)

Retrovir

300mg bid* 300mg tab,

100mg cap,

iv, oral soln

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

Renal

Abacavir

(ABC) Ziagen

300mg bid,

600mg qd

300mg tabs, oral

soln

hypersensitivity Hepatic by alcohol

dehydrogenase and

glucuronyl transferase

Tenofovir

(TDF) Viread

300mg qd* 300mg tabs Few SEs,

renal toxicity

Renal

NRTIsMechanism 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)

Efavirenz / Sustiva

Stocrin®

NH

NN

N

MeO

Nevirapin

Viramune®

O

NH

Cl

O

F3C

FDA 1998Already resistance

Binds directly to TR

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 then200 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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NNRTIsMechanism 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 (green) bound to HIV-1 ProteaseHN

NH

OH

PhO

O

N

H

H

O

NH2

NHO

Saquinavir

Fortovase®

Indinavir

Crixivan®

Nelfinavir

Viracept®Amprenavir

Agenerase®

Lopinavir

Kaletra®

O

HN

NH

N

OH

PhO

PhO

NH

O

OH

O

HN

OHPh

N

N

N

O NH

HN

OH

S

Ph

O

OH

H

H

O NH

HN O

OH

PhO

ON

S

O O

Protease Inhibitors

Protease Inhibitors (PIs)Drug Std Dose Dosage forms Side Effects Metabolism

Atazanavir(Reyataz) (1)

400qd or 300/ rtv 100qd

100, 150, 200mg caps

Hyper-bilirubinemia, 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, Pgpsubstrate; 3A4 inducer/Inhibitor

Tipranavir(Aptivus) (1,2)

500/200 RTV mg bid

250mg caps Hepatotoxicity, Increased bleedingcaution with sulfur allergy

3A4, Pgpsubstrate; 3A4, inducer/inhibitor??; Pgpinducer

Darunavir(Prezista) (1)

600/100 RTV mg bid

300mg tabs Diarrhea, nausea, nasopharyngitis

3A4 substrate;3A4 inhibitors

Ritonavir(Norvir) (1,2)

Used as a PK booster 100-200mg

100mg caps; 80mg/mL

Nausea,vomiting, diarrhea, GI upset

2D6, 3A4, Pgpsubstrate; 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.

XHIV

� PIs bind to protease

preventing the

cleavage and inhibiting

the assembly of new

HIV viruses

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 InteractionsDrug Interactions

ARV metabolism, induction, and inhibition

Drug Substrate Inhibits Induces

Efavirenz 2B6, 3A4 3A4 3A4, 2B6

Nevirapine 3A4, 2B6 3A4

Ritonavir 2D6, 3A4, Pgp 3A4, 2D6, Pgp 2D6 (at high doses only)

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 Other enzymes

Darunavir 3A4, Pgp 3A4

Maraviroc 3A4, Pgp

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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 Anti-

depressant

Potential for

Interaction

Effects Management

Amitriptyline ritonavir, lopinavir/r,

amprenavir,

Levels of amitriptyline may be increased

Start with lower dose (50%) of amitriptyline, 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

As above

Sertraline ritonavir, lopinavir/r, all other Pis, efavirenz

Levels of sertraline 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 triazolamlevels 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)

• 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

Nucleotide Reverse Transcriptase Inhibitor

(NRTI)

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• 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

Zidovudine (AZT)

• 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

Didanosine (ddl)

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• 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

Zalcitabine (ddC)

• Bentuk aktif berupa triphosphate

• Bekerja menghentikan rantai DNA

• Diabdsorbsi dengan sangat baik tanpa dipengaruhi

makanan

• SE: periferal neuropati

Stavudine (d4T)

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• Dikombinasikan dengan AZT, tidak boleh digunakan

dengan ddC

• Menyebabkan terminasi sintesis rantai DNA virus

• 3TC dapat mengembalikan sensitiviras terhadap AZT

• Penggunaan secara oral

Lamivudine (3TC)

• Merupakan analog dari guanosine

• Penggunaan secara oral

• SE: gangguan pencernaan, sakit kepala, dan pusing

Abacavir

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• Analog nukleotid

• Menghambat reverse trankriptase

• Dimakan pada saat setelah makan

• SE: mual, muntah, diare

Tenovovir

• Derivatif dari lamivudine

• Menghambat reverse transkriptase

• Dikonsumsi secara oral

• SE: sakit kepala, diare, mual, dan kulit merah gatal

Emtricitabine

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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)