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Antiviral agents
Pawitra Pulbutr
M.Sc. In Pharm (Pharmacology)
วัตถุประสงค์เชิงพฤติกรรม
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เข้าใจและอธิบายถึงกลไกการออกฤทธิ์, การดื้อยา, เภสัชจลนศาสตร์, อาการไม่
พึงประสงค์ท่เี กิดจากการใช้ยา, การนาไปใช้ประโยชน์ทางคลินิก รวมทัง้ ข้อดี
และข้อเสียของยาต้านไวรัสในกลุม่ ต่างๆได้
Virus
• Intracellular parasite
• Nucleic acid + protein coat
= Nucleocapsid
• Infective particle = Virion
• No metabolic machinery
• Host cells is needed for
viral replication
ชนิ ดของไวรัส
I.DNA virus
1.Poxvirus
2.Herpesvirus
3.Adenovirus
4.Papillomavirus
II. RNA virus
1.Orthomyxovirus
2.Paramyxovirus
3.Rubellavirus
4.Rhabdovirus
5.Picornavirus
6.Retrovirus
7.Arenavirus
8.Hepadenavirus
9.Arbovirus
โรค/ อาการแสดง
Small pox
Chickenpox, Shingles, Cold sores
Sore throat, conjunctivitis
Warts
Influenza
Measles, Mumps
German measles
Rabies
Colds, Meningitis, Poliomyelitis
AIDS
Meningitis, Lassa fever
Serum hepatitis
Arthropod-borne encephalitis
Blocked by
enfuvirtide
Viral replication
(in HIV)
Attachment
• receptor of
NTs, cytokines,
hormones
• HIV … CD4 RC
Early
regulatory
protein =
polymerase
enzyme
Viral DNA/
RNA synthesis
Structural
protein
synthesis
Antiviral agents
Antiherpes & Anticytomegalovirus agents
Antiretroviral agents
Antiinfluenza agents
Antihepatitis virus agents
Antiherpes & Anticytomegalovirus
Acyclovir
• acyclic guanosine derivative
• HSV-1, HSV-2, VZV
• CMV, EBV, HHV
• Mechanism of action
ACV
ACV -P
Viral
thymidine
kinase
ACVPP
Host kinase
ACV-PPP
Active
form
Mechanism of action
o Acyclovir triphosphate
o Inhibit DNA polymerase … competitive
o Incorporate into DNA and Chain termination
Mechanism of resistance
• Alteration of viral thymidine kinase ***
• Cross resistance with valacyclovir,
famcyclovir, ganciclovir
• No cross resistance with foscarnet,
cidofovir, trifluridine
• Alteration of DNA polymerase
Clinical uses
Route of
administration
Oral
Intravenous
Use
Recommended Adult
dosages
Genital herpes treatment
200 mg 5 times daily
or 400 mg q 8 h
HSV proctitis treatment
400 mg q 8 h
Genital herpes
suppression
400 mg q 12 h or 200
mg q 8 h
Varicella
800 mg qid
Zoster
800 mg 5 times daily
Anti-CMV prophylaxis in
organ transplantation
200 mg q 8 h or 800
mg q 12 h
Herpes encephalitis
5 mg/ kg q 8 h
Varicella or zoster in an
immunosuppressed host
10 mg/ kg q 8 h
Topical … Primary HSV infection .. Less effective
Ganciclovir
• Acyclic guanosine analog
• Active in triphosphate form
GAN
GAN-P
• phosphotransferase UL 97 in
CMV infected***
• viral thymidine kinase in
HSV infected
Mechanism of action
• Inhibit DNA polymerase
• Inhibit DNA elongation
 Antiviral activity
 CMV, HSV, VZV, EBV, HHV-8
 Very good activity to CMV***
 Resistance
 UL 97 gene mutation
 DNA polymerase mutation
 thymidine kinase mutation
 Cross resistance with Cidofovir, Acyclovir
P’kinetics
• Low oral bioavailabilty … 6-9%
• Renal excretion
Route of
administration
Clinical uses….CMV
Use
Recommended adult
dosages
IV
CMV retinitis
Induction: 5 mg/ kg q
12 h
Maintenance: 5 mg/ kg
/day
Oral
CMV retinitis
treatment or
prophylaxis
1 g q 8 h
Intraocular
implant
CMV retinitis
1 implant q 5-8 months
Others… CMV colitis, CMV esophagitis, CMV
pneumonitis
ADRs
• myelosuppression*** esp. neutropenia
• CNS S/E… headache, changes in mental
status, seizures
• Mitogenic to mammalian cells
• Carcinogenic & Embryotoxic in animals
Antiretroviral agents
Human Immunodeficiency Virus
(HIV)
RNA virus
AIDS
(Acquired Immune Deficiency Syndrome)
• CD4 infected
• Immune deficiency
AIDS
• Opportunistic infection
• Pneumocystic carinii Pneumonia (PCP)
• Toxoplasma gondii … Toxoplasmosis
• Mycobacterium avium complex (MAC)
• Mycobacterium tuberculosis
• Viral infection … CMV
• Fungal infection … Cyrptococcal meningitis, Oral
candidiasis
• Tumor
• Organ dysfunction … Brain, CVS, Kidney
• Finally … DEATH
Antiretroviral agents
Nucleoside reverse transcriptase
inhibitors (NRTIs)
Non nucleoside reverse
transcriptase inhibitors (NNRTIs)
Protease inhibitors (PIs)
Fusion inhibitors (FIs)
Nucleoside reverse trancriptase inhibitors
Mechanism of action
• Inhibit HIV reverse transcriptase
• Incorporate into viral DNA … Chain
termination
• Active in triphosphate form
• Zidovudine (Azidothymidine, AZT)
• Didanosine (ddI)
• Zalcitabine (ddC)
• Stavudine (d4T)
• Lamivudine (3TC)
• Abacavir (ABC)
• Emtricitabine (FTC)
Thymidine
Adenosine
Thymidine
Cytosine
NRTIs
Cytosine
Guanosine
Tenofovir
Non-nucleoside reverse transcriptase inhibitors
• Nevirapine
• Delavirdine
• Efavirenz
Mechanism of action
• Inhibit reverse transcriptase enzyme at different point
• No DNA incorporation*
• No phosphorylation needed
• Use in combination with other group … rapid resistance
• No cross resistance with NRTIs or PIs**
Protease Inhibitors (PIs)
• Inhibit Protease Enzyme … essential for mature
structural protein
• Easy resistance … Use in combination
• *Major ADRs*
• Altered body fat distribution … buffalo
hump, truncal obesity, facial & peripheral
atrophy
• Insulin resistance
• Hyperlipidemia, Hypertriglyceridemia
• Spontaneous bleeding in hemophilia
Protease Inhibitors (PIs)
• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir
• Amprenavir
• Lopinavir … New agents
• Fosamprenavir
• Atazanavir
Fusion inhibitor
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Novel class of ARV use in HIV infection
Enfuvirtide (Fuzeon®, T-20)
Linear 36 aa synthetic peptide
Inhibit HIV fusion with CD4+ cell
Bind to HR1 in gp 41 at viral glycoprotein
envelope
Inhibit conformational change of envelope
Inhibit HIV fusion
No cross resistance with other class
Reserve >>> last option to be used***
HAART; Highly Active AntiRetrovirus Therapy
• 3 Antiretrovirus in combinations
• NNRTIs based regimen
• NNRTIs + 2 NRTIs
• Efavirenz + 2 NRTIs (3TC + AZT/ Tenofovir/ d4T)
• PIs based regimen
• PI + 2NRTIs
• Lopinavir/ RNV (kaletra®)+ 2NRTIs (3TC + AZT/
d4T)
• Triple NRTIs regimen >>> 3 NRTIs
• ABC + 3TC + AZT/ d4T
Four drug regimen
• 3 NRTIs + 1 PIs or NNRTIs
• May be more effective in high viral load > 100,000
GPO vir® in Thailand
S30 = d4T 30 + 3TC 150 + Nevirapine 200 mg
S40 = d4T 40 + 3TC 150 + Nevirapine 200 mg
Factors affecting anti-retroviral regimen
• P’kinetic profile
• Potency
• ADRs
• Tolerability
• Resistance
• Life style
• Drug interaction
• Advantage VS
Disadvantage of
ARV agents
• AZT + Ganciclovir …
bone marrow suppression
• ddI + dapsone …
altered absorption
• Clarithromycin
…Enzyme inhibitor
• Rifampin … Enzyme
inducer
Anti-influenza agents
• M2 Inhibitors
• Amantadine
• Rimantadine
• Neuraminidase inhibitors
• Zanamivir
• Oseltamivir
Amantadine and Rimantadine
• Cyclic amine
• Mechanism of action
• Inhibit viral uncoating
• Bind at M2 protein
• Effective to Influenza A only**
• Easy mutation of M2 protein… drug
resistance
Neuraminidase inhibitors
• Zanamivir & Oseltamivir
• Neuramidinase … essential for viral release & viral
penetration
• Effective both Influenza A & B**
• Zanamivir
• Intranasal powder for inhalation.. Low oral
bioavailability
• Rapid renal clearance
• Oseltamivir
• Oral … prodrug … Activate in gut & liver into
Oseltamivir carboxylate … active form
Viral hepatitis
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Hepatitis
Hepatitis
Hepatitis
Hepatitis
Hepatitis
A
B
C
D
E
Interferon (IFN)
 Peginterferon
 Ribavirin
 Lamivudine (3TC)
 Adefovir
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Anti-hepatitis agents
• Interferons … IFN α, IFN β, IFN γ
.. Endogeneous protein
• IFN  use in chronic hepatitis B &
hepatitis C
• Lamivudine >>> chronic hepatitis B
• Adefovir >>> chronic hepatitis B
• Ribavirin >>> chronic hepatitis C
PEG IFN
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Pegylated interferon 
Conjugated with polyethylene glycol (PEG)
Longer half-life >>> 45 hrs … Once a
week
Less clearance
PEG IFN -2b (PEG Intron®)
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Chronic hepatitis C
Monotherapy
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Combined with ribavirin
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1.0 g/ kg/ wk SC for 1 year
1.5 g/ kg/ wk SC + Ribavirin 800 mg/ day
PEG Intron powder for injection
PEG Intron RedipenTM
Ribavirin (Rebetol®)
• Guanosine analog
• Activate by phosphorylation
• Expected mechanism of action
• Inhibit guanosine triphosphate synthesis
• Inhibit RNA dependent RNA polymerase
• Hep C, Influenza A, B, Parainfluenza,
RSV, Paramyxovirus
Adefovir dipivoxil
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Hepsera®
Diester prodrug of adefovir
Adefovir diphosphate = active
Inhibit HBV DNA polymerase**
Incorporate into DNA & chain termination
Active for HBV including lamivudine
resistance
Clinical use >>> Active chronic hepatitis B
infection in adults
10 mg OD for 1 year
Antiviral agents
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Antiherpes & Anti-CMV
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Antiretrovirus
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NRTIs
NNRTIs
PIs
FIs
Antiinfluenza
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Acyclovir & derivatives
Ganciclovir, Foscarnet
M2 inhibitors
Neuraminidase inhibitors
Antihepatitis
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IFN/ PEG IFN
Ribavirin
Adefovir