1
4) synthesis of RNA or DNA
5) synthesis of structural proteins
6) assembly of viral particles
7) release from host cell
ANTIVIRAL AGENTS
Steps for Viral Replication
1) adsorption and penetration into cell
2) uncoating of viral nucleic acid
3) synthesis of regulatory proteins
Antiherpesvirus agents
• Gancyclovir – CMV infections
• Foscarnet – CMV and HSV infection in
gancyclovir-resistant and acyclovir-resistant
patients
• Cidofovir – CMV retinitis, HSV: acyclovirresistant mucocutaneous HIV infection, others:
adenovirus disease in transplant recipients,
molluscum contagiosum in HIV patient
• Famciclovir – HSV and VZV infections
• Idoxouridine – HSV keratitis, herpes labialis,
genitalis and zoster
• Trifluridine – HSV keratoconjuctivitis and
keratitis
Spectrum
• Herpesviruses – acyclovir, cidofovir,
famcyclovir, foscarnet, gancyclovir,
idoxouridine, trifluridine
• CMV – gancyclovir, fomivirsen, foscarnet,
trifluridine, cidofovir
Therapeutic use
• Acyclovir – HSV: genital HSV infections,
primary herpetic gingivostomatitis, herpes
labialis, mucocutaneous HSV infection in
immunocompromised patients, VZV: varicella
PARAMETER
Oral abs.
ACYCLOVIR FAMCICLOVIR
(PENCICLOVIR)
low-moderate satisfactory
GANCICLOVIR
CIDOFOViR
low
low
=
negligible
Intracel. T1/2
absorption
short
short-moderate
absorption
moderate
CSF pentr.
satisfactory
uncertain
satisfactory
uncertain
Renal excr.
60%-90%
70%
>90%
>90%
Effect of meals
PARAMETER
CIDOFOViR
FOSCARNET
Fomivirsen
Oral abs.
low
low-moderate
intravitreally
Effect of meals
=
-
-
Intracel. T1/2
moderate-long
not applicable
-
CSF penetr.
uncertain
satisfactory
-
Renal excr.
>90%
>80%
-
Adverse effects
• Acyclovir
• Foscarnet
• Ganciclovir
• Cidofovir
- GI, rashes, neurotoxiciy, nephrotoxicity
- Nephrotoxicity, hypocalcemia
- Myelosupression
- Nephrotoxicity, hypersensitivity
moderate-long
2
Antiretroviral agents
Nucleoside RT inhibitors
Nonnucleoside RT inhibitors
HIV protease inhibitors
Entry inhibitors
Fusion inhibitors
Integrase inhibitors
Nucleoside RT inhibitors – bind to the catalytic site of the enzyme
ZIDOVUDINE LAMIVUDINE STAVUDINE DIDANOSINE
Oral bioavailability
satisfactory
excellent
excellent
satisfactory
Effect of meals
 (high fat)


(acidity)
Intracellular T1/2
3-4
12
3.5
8-24
Metabolism
intensive
moderate
intensive
moderate
Renal excr. %
15
70
40
20-50
ABACAVIR
ZALCITABINE TENOFOVIR EMTRICITABE
Oral bioavailability
good
excellent
acceptable
excellent
Effect of meals


 (fat)

Intracell. T1/2
3
2-3
11-49
39
Metabolism
intensive
mild
negliglible
negliglible
Renal excr. %
<5
70
80
80
Adverse effects
• Zidovudine - anemia, granulocytopenia, malaise, myalgia, nausea, insomnia, hyperpigmentation, lactic
acidosis-steatosis syndrome
• Didianosine, stavudine - neuropathy, pancreatitis, diarrhea
• Zalcitabine
- nephropathy
• Lamivudine
- well tolerated
• Abacavir
- hypersensistivity
• Tenofovir
- well tolerated, flatulence
3
Nonnucleoside RT inhibitors - bind to the site distant from the catalytic site of the enzyme
PARAMETER
NEVIRAPINE EFAVIRENZE
DELAVIRDINE
Oral bioavailability
Plasma protein binding, %
Metabolism
Renal excretion (%)
excellent
60
Extensive
Negliglible
satisfactory
99
Extensive
Negliglible
excellent
98
Extensive
Negliglible
Adverse effects
Rashes, sedation, hepatotoxicity
Attention: cytochrome P450
HIV protease inhibitors
• Saquinavir, ritonavir, indinavir, nelfinavir,
amprenavir, lopinavir, atazanavir
• Active against HIV-1 and HIV-2
• Mechanism: inhibit protease which is responsible for
cleaving precursor molecules necessary to produce
final structural proteins of the virion core
• Pharmacokinetics: bioavailability depends on
preparation, high protein-bound, metabolized in the
liver, CNS penetration (indinavir)
• Adverse effects: altered body fat distribution, insulin
resistance, dyslipidemia, liver function impairement,
GI symptoms, nephrolithiasis (Indinavir), skin rashes
Fusion inhibitors - enfuvirtide
Blocks gp 41 subunit of the viral envelope
glycoprotein – involved in fusion
Active: against HV-1
Pharmacokinetics: given parenterally only
Adverse effects: injection-site reactions
Integrase inhibitors - Raltegravir
Immune reconstitution syndrome - patients treated
with combination antiretroviral therapy, which may
include raltegravir-containing regimens.
During the initial phase of treatment, a patient whose
immune system improves may develop an
inflammatory response to indolent or residual
opportunistic infections (e.g., Mycobacterium avium,
cytomegalovirus, Pneumocystis pneumonia,
tuberculosis, varicella zoster virus), which may
necessitate further evaluation and treatment
Entry inhibitors - Maraviroc
Inhibitor of CCRT coreceptor
Caution: patients with liver dysfunction (CYP2A4) and
at increased risk of cardiovascular events
Antiinfluenza Agents
AMANTADINE RIMANTADINE ZANAMIVIR
OSELTAMTViR
Type of influenza A
Route
Oral
A
Oral
A,B
Inhaled
A,B
Oral
Oral abs.
moderateexcellent
excellent
negliglible
very good
Metabolism
< 10%
~75%
Negligible
Negligible
Renal excr. %
50%-90%
~25%
100%
95%
Neuraminidase inhibitors
• Active against influenza virus A and B
• Mechanism: inhibit neuraminidase which is an essential viral glycoprotein for replication and release
• Adverse effects: well tolerated
• Therapeutic use: uncomplicated influenza infection, given intranasally (z) or orally (o)
4
Anti-hepatitis agents
Lamivudine -Nucleoside Reverse Transcriptase
Inhibitor (NRTI)
Adefovir -Nucleotide Inhibitor
Interferon Alfa
Pegylated Interferon Alfa
Ribavirin
Interferon Alfa
Intracellular effects
1. Transcription inhibition (inhibits Mx protein and
mRNA synthesis)
2. Translation inhibition: activated 2’-5’oligoadenylate [2-5(A)] synthetase – vRNA cleaved,
protein kinase - intiation of mRNA inhibited,
phosphodiesterase – tRNA function blocked
3. Proteins posttranslational modyfication glycosylation of proteins inhibited
4. Inhibition of virus maturation – glycoproteins
maturation inhibited, changes in membrane – budding
inhibited
Spectrum - Most of viruses except few of DNA types
Pharmacokinetics - parenerally only, given 3-times
weekly, pegIFN (polyethylene glycol) once a week,
steady-state levels 5-8 weeks after initiation of weekly
dosing, eliminated by the liver and/or kidneys (endstage renal disease)
Therapeutic uses - chronic hepatitis type C and B
Adverse effects
•
Influenza-like symptoms
•
Bone marrow depression
•
Autoimmune effects: hypothyreosis
•
Neurotoxicity: somnolence confusion,
behavioral disturbances, neurasthenia,
depression
•
Hair loss
•
Nephritis
•
Cardio, - hepatotoxicity
•
Impaired fertility
Ribavirin
Mechanism of action: intracellulary phosphorylated
• Inhibits inosine-5’-dehydrogenase – synthesis
of GTP
• Inhibits GTP-dependent 5’capping of viral
mRNA
• Inhibits influenza virus transcriptase
• Enhances viral mutagenesis – lethal
mutagenesis
Spectrum: Influenza and parainfuenza viruses, RSV,
HCV, adenoviruses, paramyxoviruses, arenaviruses,
bunyaviruses, flaviviruses
Pharmacokinetics: well absorbed, large volume of
distribution, hepatic metabolism and renal elimination
Therapeutic use: chronic HCV infection, RSV
bronchiolitis and RSV pneumonia in children
(aerosol), in immunocompromised patients,
occasionaly – influenza, vaccinia, parainfuenza,
measles, Lassa fever, SARS, Congo hemorrhagic fever
Adverse effects: irritation, wheezing, anemia
(hemolysis and bone marrow depression), nausea,
insomnia, depression, embryotoxic, teratogenic and
oncogenic (cat. X)
Adefovir
Spectrum – HBV
•
inhibits DNA polymerase and reverse
transcriptases, serves as chain terminator
Pharmacokinetics: well absorbed, small volume of
distribution, eliminated by the kidneys
Adverse effects: nephrotoxicity, diarrhea, hepatitis
exacerbation, genotoxic, embryotoxic
Therapeutic use: chronic HBV infections
Imiquimod
• Topical treatment of condylomata acuminata
(genital and perisanal warts)
• Induces cytokines with antivirial and
immunomodulatory effects
• Skin irritations