1. Antiviral agents
Hamzeh Elayan 2015.

2. Viruses are made up of core genome of nucleic acid
contained in a protein shell called Capsid
Surrounded by lipoprotein membrane called envelope (Genome + Capsid + Envelope = Virion)
Viruses are obligate intracellular parasite ie. do not have a metabolic machinery of their own – uses host enzymes.
Viruses have DNA or RNA, never both.
Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly.
Most multiplication take place before diagnosis is made

4. Viral Replication Adsorption to and penetration of susceptible cells.
Synthesis of RNA or DNA.
Synthesis of early, nonstructural proteins.
Synthesis of late, structural proteins
Assembly of viral particles and release

5. General Mechanism of Action
Nucleoside Analogues
General Mechanism of Action
1.Taken up by cells
2. Converted by viral and cellualr
enzymes to the triphosphate form
3. Triphosphate form inhibits:
• DNA polymerase
• Reverse transcriptase
• RNA polymerase
4. Or it may get incorporated
into growing DNA leading to
abnormal proteins or breakage.

6. guanine nucleoside analogs Active against
Acyclovir (ACV)
guanine nucleoside analogs
Active against
HSV-1 (Labial and ocular infection)
HSV-2 (Genital infection)
Varicella -zoster infections
Epstein barr virus
Resistance :
HSV and varicella zoster
-Deficiency in thymidine kinase activity
-Changes in virus directed enzymes

7. Therapeutic uses of Acyclovir
Genital Herpes (HSV–II) Acyclovir 5% ointment. Late & severe cases, orally or Iv infusion
(HSV–I) Mucocutaneous : Remains localized to lips and gums (Acyclovir skin cream)
H.Simplex encephalitis: IV/8h for 10 days.
H. Simplex keratitis: Acyclovir eye ointment.
Chickenpox : Oral 400mg TDS for 7 days
Herpes zoster infections: Acyclovir less active
Adverse Effects:
Oral : Headache, nausea, vomiting, diarrhea, vertigo
IV : Phlebitis, rash , hypotention Nephrotoxicity

8. Valacyclovir
Valacyclovir is a prodrug of Acyclovir with better bioavailability.
A Guanine analogue with antiviral effect for Herpes group only.
Inhibits viral DNA polymerase selectively
Incorporated into DNA and terminates synthesis
Active against
HSV-1 (Labial and ocular infection)
HSV-2 (Genital infection)
Varicella-zoster infections
Epstein barr virus

9. Ganciclovir • Mechanism like Acyclovir
• Active against all Herpes viruses including CMV
• Low oral bioavailability given I.V.
• Drug of choice for Cytomegalovirus (CMV) infections: retinitis, pneumonia, colitis
Adverse effects:
Bone marrow suppression (leukopenia 40%, thrombocytopenia 20%)
CNS effects (headache, behavioral, psychosis, coma, convulsions)
1/3 of patients have to stop because of adverse effects

10. Adefovir - Adenosine analogue Converted by cellular kinases
to active diphosphate
- Inhibits Hepatitis B virus DNA polymerase
- Gets incorporated into DNA causes Chain termination
Use:
Chronic hepatitis B
Adverse effects:
Nephrotoxicity, lactic acidosis, hepatomegaly.

11. Ribavirin Inhibit replication of both DNA and RNA viruses
Triphosphate inhibits RNA polymerase
Adverse Effects:
Anemia due to hemolysis and bone marrow suppression
Uses:
Ribavirin is the drug of choice for:
• RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol)
Ribavirin is an alternative drug for:
• Influenza, Para influenza, Measles virus infection in immunocompromised patients

12. Foscarnet An inorganic pyrophosphate
inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase
• Blocks binding site of pyrophosphate and inhibits cleavage
•Given IV
Uses: HSV, VZV, CMV, Epstein barr virus, Hepatitis B and HIV
Resistance due to mutations in DNA polymerase gene
Adverse Effects:
Nephrotoxicity, Hypocalcemia, Anemia
Acute tubular necrosis, Crystalluria
CNS – tremor, irritability, seizure , hallucinations, Rash, fever, nausea, vomiting

13. Antiviral therapies for Influenza Viral Uncoating Inhibitors Amantadine Rimantadine
• Chemically a tricyclic amine not related to any nucleotide
• Inhibit penetration of virus to cells ,the uncoating of certain virus and viral replication.
• M2 protein which acts as ion is one of the target.
• Prevent diseases caused by influenza A
• Treatment of Parkinson’s disease (Amantadine)
Adverse effects:
• GI upset
• Headache
• Nervousness
• Postural hypotension, ankle edema

14. Oseltamivir orally (oral bioavalibility 80%)
Neuraminidase Inhibitors
Inhibit neuraminidase enzyme of influenza which is essential for release of virus
Zanamivir inhalation
Oseltamivir orally (oral bioavalibility 80%)
Therapeutic Use
Treatment of acute uncomplicated Influenza A (H1N1 virus, swine flu)
Adverse effects
N/V, Bronchospasm and abnormal respiratory function

15. Interferons • Three classes of interferons – α , β, γ
• α and β interferons: produced by all the cells in response to viral infections
• γ interferon : produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects
• γ has less anti-viral activity compared to α and β interferon

16. Toxicity: flu-like syndrome, BM suppression; CNS
Mechanism of Action
Induction of the following enzymes:
A protein kinase which inhibits protein synthesis
An oligo-adenylate synthase which leads to degradation of viral mRNA
A phosphodiesterase which inhibit t-RNA
Induction of these enzymes leads to inhibition of translation
• Interferon prevent spread of viruses to new cells (Viral hepatitis)
• Natural products of the immune system in viral infections
• Antiviral, anticancer and immuno-modulating
Toxicity: flu-like syndrome, BM suppression; CNS
Use: Hepatitis B and C

17. Entecavir
• Guanosine analogue
• Competitively inhibits viral DNA polymerase
• Approved by FDA in march 2005 for treatment of chronic hepatitis B
• Oral bioavailability : 95%
• Adverse Effects : Headach, fatigue, NV
Peramivir
Neuramidase inhibitor
• Approved in For emergency treatment of hospitalised patients of H1N1 infection
Used iv for patients resistant to Oseltamivir, zanamivir Peramivir