antiviral drugs medical students
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Antiviral Drugs
basicsDr.T.V.Rao MD
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Understanding Viruses
They are different from other Microbes
Viral replication
A virus cannot replicate on its own
It must attach to and enter a host
cell
It then uses the host cells energy tosynthesize protein, DNA, and RNA
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Understanding Viruses
Viruses are
difficult to kill
because they liveinside the cells
Any drug that kills
a virus may also kill
cells
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Antiviralsavailable for many viral infections
Viruses controlled by current antiviral therapy
Cytomegalovirus (CMV)
Hepatitis viruses Herpes viruses
Human immunodeficiency virus (HIV)
Influenza viruses (the flu)
Respiratory syncytial virus (RSV)11/17/2012 Dr.T.V.Rao MD 5
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Anti-viral drugs
Viruses have no cell wall and made up ofnucleic acid components
Viruses containing envelope antigenic innature
Viruses are obligate intracellular
parasite They do not have a metabolic machinery
of their own uses host enzymes
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Anti-viral drugs
Certain virusesmultiply in thecytoplasm but
others do in thenucleus
Most multiplication
take place beforediagnosis is made
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Anti-Viral drugs Many antiviral drugs arePurine or
Pyrimidine analogs.
Many antiviral drugs are Prodrugs.
They must be phosphorylated by viralor cellular enzymes in order tobecome active.
Anti-viral agents inhibits activereplication so the viral growth
resumes after drug removal.11/17/2012 Dr.T.V.Rao MD 8
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Antivirals how they actKey characteristics of antiviral drugs
Able to enter the cells infected with virus
Interfere with viral nucleic acid synthesis and/or regulation
Some drugs interfere with ability of virus to bind to cells
Some drugs stimulate the bodys immune system
Best responses to antiviral drugs are in patients withcompetent immune systems
A healthy immune system works synergistically with the
drug to eliminate or suppress viral activity11/17/2012 Dr.T.V.Rao MD 9
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Antiviral Medications
Antiviral drugsUsed to treat infections caused by viruses other than HIV
Antiretroviral drugs
Used to treat infections caused by HIV, the virus thatcauses AIDS
Herpes-Simplex Viruses
HSV-1 (oral herpes)
HSV-2 (genital herpes)
Varicella Zoster Virus
Chickenpox
Shingles11/17/2012 Dr.T.V.Rao MD 10
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Antiviral Drugs: Nonretroviral
Mechanism of action
Inhibit viral replication
Used to treat non-HIV viral infections
Influenza virusesHSV (herpes simplex virus), VZV (vericella zoster virus)
CMV (cytomegalovirus)
Hepatitis A, B, C (HAV, HBV, NCV)
Adverse EffectsVary with each drug
Healthy cells are often killed also, resulting in serious toxicities
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Anti-viral drugs
Current anti-viral agents do not eliminatenon-replicating or latent virus
Effective host immune response remainsessential for the recovery from the viralinfection
Clinical efficacy depends on achievinginhibitory conc. at the site of infectionwithin the infected cells
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Anti-viral drugs
Stages of viral replication
Cell entry attachment
- penetration Uncoating
Transcription of viral genome
Translation
Assembly of virion components
Release
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Anti-viral drugsAnti-herpes virus agents
Acyclovir / Valacyclovir
Famciclovir / Penciclovir
Ganciclovir / Cidofovir
Foscarnet Trifluridine / Idoxuridine /Vidarabine
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Anti-viral drugsAcyclovir & Congeners : Valacyclovir is a prodrug of Acyclovir with
better bioavailability.
Famciclovir is hydrolyzed to Penciclovirand has greatest bioavailability.
Penciclovir is used only topically whereas
Famciclovir can be administered orally.
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Anti-Viral drugs
PHARMACOLOGY OFACYCLOVIR ANDCONGENERS
Acyclovir, Valacyclovir,Ganciclovir,Famciclovir,Penciclovir all are
guanine nucleosideanalogs.
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Anti-viral drugs
Mechanism of action of Acyclovir andcongeners :
All drugs are phosphorylated by a viralthymidine-kinase, then metabolized byhost cell kinases to nucleotide analogs.
The analog inhibits viral DNA-polymerase
Only actively replicating viruses are
inhibited11/17/2012 Dr.T.V.Rao MD 18
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Anti-viral drugs
Acyclovir is thusselectively
activated in cellsinfected withherpes virus.
Uninfected cellsdo notphosphorylate
acyclovir.11/17/2012 Dr.T.V.Rao MD 19
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Mechanism of Action of Acyclovir
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Anti-Viral drugsAntiviral spectrum :
Acyclovir: HSV-1, HSV-2, VZV, Shingles.
Ganciclovir / Cidofovir : CMV Famciclovir : Herpes genitalis and shingles
Foscarnet : HSV, VZV, CMV, HIV
Penciclovir : Herpes labialis Trifluridine : Herpetic keratoconjunctivitis
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Anti-Viral drugs
Pharmacokinetics of Acyclovir :
Oral bioavailability ~ 20-30%
Distribution in all body tissuesincluding CNS
Renal excretion: > 80%
Half lives: 2-5 hours
Administration: Topical, Oral , IV
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Anti-viral drugs
Adverse effects of Acyclovir /Ganciclovir
Nausea, vomiting and diarrhea Nephrotoxicity - crystalluria,
haematuria, renal insufficiency
Myelosuppression Neutropeniaand thrombocytopenia
Ganciclovir11/17/2012 Dr.T.V.Rao MD 23
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Anti-viral drugs
Therapeutic uses :Acyclovir is the drug of choice for:
HSV Genital infections
HSV encephalitis HSV infections in immunocompromised patient
Ganciclovir is the drug of choice for:
CMV retinitis in immunocompromised patient Prevention of CMV disease in transplant patients
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Anti-viral drugs
Cidofovir :
It is approved for the treatment ofCMVretinitis in immunocompromised patients
It is a nucleotide analog of cytosine nophosphorylation required.
It inhibits viral DNA synthesis
Available for IV, Intravitreal inj, topical Nephrotoxicity is a major disadvantage.
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Anti-viral drugs
PHARMACOLOGY OFVIDARABINEVidarabine is a nucleoside analog.
(adenosine)
Antiviral spectrum of Vidarabine :
HSV-1, HSV-2 and VZV.
Its use is limited to HSV keratitis only
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Anti-viral drugsVidarabine The drug is converted to its triphosphate
analog which inhibits viral DNA-
polymerase. Oral bioavailability ~ 2% Administration: Ophthalmic ointment Used in HSV keratoconjunctivitis in
immunocompromised patient. Anemia and SIADH are adverse
effects.
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Anti-viral drugs
PHARMACOLOGY OF TRIFLURIDINE
Trifluridine is a Pyrimidine nucleosideanalogs - inhibits viral DNA synthesis.
Antiviral spectrum Trifluridine :
HSV-1, HSV-2 and VZV.
Use is limited to Topical - Ocular HSVKeratitis
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Anti-viral drugs
PHARMACOLOGY OF FOSCARNET
Foscarnet is an inorganic
pyrophosphate analog It directly inhibits viral DNA and RNA
-polymerase and viral inverse
transcriptase (it does not requirephosphorylation for antiviral activity)
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Anti-viral drugs
Foscarnet
HSV-1, HSV-2, VZV, CMV and
HIV.
Oral bioavailability ~ 10-20%
Distribution to all tissuesincluding CNS
Administration: IV11/17/2012 Dr.T.V.Rao MD 30
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Anti-viral drugs
Adverse effects of Foscarnet
Hypocalcemia and hypomagnesemia (dueto chelation of the drug with divalent
cations) are common. Neurotoxicity (headache, hallucinations,
seizures)
Nephrotoxicity (acute tubular nephrosis,interstitial nephritis)
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Anti-viral drugs
Therapeutic uses of Foscarnet
It is an alternative drug for
HSV infections (acyclovir resistant/ immunocompromised patient )
CMV retinitis (ganciclovir resistant/ immunocompromised patient )
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Anti-viral drugs
Respiratory viral infections
Influenza
Amantadine / Rimantadine Oseltamivir / Zanamavir
(Neuraminidase inhibitors)
RSV bronchiolitis
Ribavirin
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Anti-viral drugs
Amantadine and Rimantadine :Influenza
Prevention & Treatment of influenza A
Inhibition of viral uncoatingbyinhibiting the viral membrane proteinM2
Influenza A virus
Amantadine has anti-parkinsonian
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Anti-viral drugs
Pharmacokinetics of Amantadine
Oral bioavailability ~ 50-90%
Amantadine cross extensivelyBBB whereas Rimantadine
does not cross extensively .Administration: Oral
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Anti-viral drugs
Neuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir
Influenza contains an enzymeneuraminidasewhich is essential for thereplication of the virus.
Neuraminidase inhibitors prevent therelease of new virions and their spreadfrom cell to cell.
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Anti-viral drugs
Neuraminidase inhibitors : InfluenzaOseltamivir / Zanamavir
These are effective against both types of
influenza A and B. Do not interfere with immune response to
influenza A vaccine.
Can be used for both prophylaxis andacute treatment.
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Anti-viral drugs
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Anti-viral drugsNeuraminidase inhibitors :
Influenza
Oseltamivir / Zanamavir Oseltamivir is orally administered.
Zanamavir is given intranasal. Risk of bronchospasm with
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Anti-viral drugs
PHARMACOLOGY OF RIBAVIRIN
Ribavirin is a guanosine analog.
Inhibition of RNA polymerase
Antiviral spectrum : DNA and RNA
viruses are susceptible, includinginfluenza, parainfluenza viruses,RSV, Lassa virus
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Anti-viral drugsRibavirin :RSV
Distribution in all body tissues, except
CNSAdministration : Oral, IV, Inhalational
in RSV.
Anemia and jaundice are adverseeffects
Not advised in pregnancy.11/17/2012 Dr.T.V.Rao MD 41
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Anti-viral drugs
Therapeutic uses Ribavirin
Ribavirin is the drug of choice for:
RSV bronchiolitis and pneumonia in
hospitalized children (given by aerosol) Lassa fever
Ribavirin is an alternative drug for:
Influenza, parainfluenza, measles virusinfection in immunocompromised patients
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Anti-viral drugs
Hepatic Viral infections :
Interferons
Lamivudine cytosine analog HBV Entecavir guanosine analog HBV lamivudine resistance strains
Ribavirin Hepatitis C (withinterferons)
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Anti-viral drugs
InterferonsInterferons (IFNs) are natural proteins
produced by the cells of the immune
systems in response to challenges by foreignagents such as viruses, bacteria, parasitesand tumor cells.
Antiviral, immune modulating andanti-proliferative actions
Three classes of interferons , ,
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Anti-viral drugs
Interferons and interferons are produced by
all the cells in response to viralinfections interferons are produced only by T
lymphocyte and NK cells in response to
cytokinesimmune regulating effects has less anti-viral activity compared
to and interferons
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Anti-viral drugsMechanism of action of Interferons : Induction of the following enzymes:1) aprotein kinasewhich inhibits protein
synthesis2) anoligo-adenylate synthasewhich leads to
degradation of viral mRNA3) aphosphodiesterasewhich inhibit t-RNA
The action of these enzymes leads toaninhibition of translation
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Anti-viral drugs
Antiviral spectrum :Interferon
Includes HBV, HCV
and HPV. Anti-proliferative
actions may inhibitthe growth of certain
cancers - like Kaposisarcoma and hairycell leukemia.
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Anti-viral drugs
Pharmacokinetics :Interferons
Oral bioavailability: