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14. antiviral drugs

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14. antiviral drugs

  1. 1. Anti Viral
  2. 2. Introduction to Viruses • Viruses are composed of nucleic acid, protein capsid, and host membrane containing virus proteins. • Virus are obligate parasite Mammalian  Mammalian virus Insect  arbovirus Plant  Plant virus Bacteria  Bacteriophage
  3. 3. • Viruses live inside host cells and use many host enzymes. • viruses have core genome of nucleic acid either DNA or RNA. •DNA viruses  Adenoviruses (upper respiratory infections)  Hepadnaviruses  Herpes virus(HSV-1,HSV-2,VZV,CMV)  Poxvirus ( small pox)  Papilloma viruses (warts)
  4. 4. •RNA viruses  Arborvirus-yellow fever  Arenaviruses- meningitis  Bunya viruses- encephalitis  Coronaviruses- URI  Influenza A and B  Paramyxoviruses – Measles, mumps  Rhabdoviruses- Rabbies  Human immunodeficiency virus (HIV)
  5. 5. Viral Replication(DNA)
  6. 6. RNA viruses replication RNA viruses  replication in the cytoplasam. Own enzyme to synthesis mRNA mRNA translated as Viral proteins genomic RNA
  7. 7. RNA virus replication (Influenza)
  8. 8. Anti viral therapy • Restricted spectrum • No standardized in-vitro susceptibility tests • Most inhibit replication. • Cure depends on host immune system to eradicate. • If patients are immunocompromized, may have recurrences. • Drugs need to be activated by viral and cellular enzymes before exerting antiviral effect. • Activity of enzymes and concentration of substrates will influence the efficacy.
  9. 9. Mechanisms of Action of Antiviral Drugs •Targets include • Viral penetration • uncoating • Nucleoside analogs • Non-nucleoside polymerase inhibitors • Neuraminidase inhibitors
  10. 10. Classification • DNA polymerase inhibitors ― Purine Nucleoside Analogues: Acyclovir Ganciclovir Famiciclovir Valacyclovir Penciclovir Cidofovir – Pyrimidine Nucleoside Analogues: Idoxuridine – Non nucloside Foscarnet • Inhibitors of viral penetration, uncoating Amantadine Rimantadine • m-RNA Synthesis inhibitors Ribvirin Fomivirsen • Neuraminidase Inhibitors Zanamivir Oseltamivir • Immunomodulators Immunoglobulins Imiquimod Interferns Palivizumab
  11. 11. Nucleoside Analogues General Mechanism of Action 1. Taken up by cells 2. Converted by viral and cellualr enzymes to the triphosphate form 3. The triphosphate form inhibits: • • • DNA polymerase Reverse transcriptase RNA polymerase 4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.
  12. 12. Antiviral Drugs Nucleoside and Nucleotide Analogs
  13. 13. Analogs Block DNA Synthesis Figure 20.16b, c
  14. 14. Acyclovir and Valacyclovir (prodrug, better availability) A Guanine analogue Acyclovir AcycloGMP Thymidine kinase AcycloGTP Cellular kinases Viral 200x affinity of mammalian 1. 2. Inhibits viral DNA polymerase selectively Incorporated into DNA and terminates synthesis Resistance: Toxicity: Use: 1. ↓ activity of thymidine kinase 1. Encephalopathy 1. H. simplez I and II 2. altered DNA polymerase 2. Renal Insuficiency 2. H. zoster and Varicella, not good for CMV
  15. 15. Pharacokinetics • Oral • 20-30% BV highly susceptible infection • Wide distribution • 20% plasma binding • 90% excreted in unchange from in urine • T ½-3-4hr, but in renal failure- 20hrs.
  16. 16. Spectrum and clinical use Highly effective against • HSV-1 • HSV-2 genital herpes • Varicella zoster (Chickenpox) Parenteral  mucocutaneous HSV VZV, H.Simplex encephalitis Ointment  early genital herpes Ophthalmic  herpes keratoconjunctivitis
  17. 17. Adverse effects • Oral 3-6months use headache, diarrhoea, nausea, vomiting. • IV – Phelbitis, rash, mild hypotension • renaltoxicity • DI- Cyclosporine nephro toxicity • Probencid inhibits renal excretion
  18. 18. Acyclovir Ganciclovir Guanine
  19. 19. Ganciclovir: • Hydroxy methylated analogue of acyclovir • Poor BV, IV , t ½- 3-4hrs • Use parenteral serious CMV (accu.100 folds) • ADR:- Myelosupression, neutropenia, anaemia, Teratogenic , carcinogenic
  20. 20. Valacyclovir • L- Valine ester of acyclovir • Mechanism and clinical use same • It require less oral dose • More effective than acyclovir  Zoster • No IV formulation
  21. 21. Idoxuridine • First pyrimidine antimetabolite, used as antiviral drug. • MOA –incorporate in DNA →formed faulty DNA which breaks down easily →synthesis of wronge viral protein.
  22. 22. Use • Only topical ophthalmic use • H. simplex keratoconjunctivitis. • Dose – one drop of 0.1% solution hourly during day time and two hourly during night time. • In acute stage- 0.5% eye ointment four hourly for 3 weeks. • Side effect – ocular irritation, lid odema, photophobia.
  23. 23. Foscarnet • An inorganic pyrophosphate analog • Active against Herpes (I, II, Varicella , CMV), including those resistant to Acyclovir and Ganciclovir. • Direct inhibition of DNA polymerase and RT • Nephrotoxicity (25%) most common ADR • Hypocalcemia (chelates divalent cations) • Others: hypokalemia, hypomagnesemia • Use: CMV retinitis and other CMV infections instead of ganciclovir. H simplex resistant to Acyclovir.
  24. 24. NON-SELECTIVE ANTIVIRAL DRUG RIBAVIRIN• Has broad spectrum antiviral activity. • Oral bioavailability-50% • MAO: Inhibits viral RNAp • USE- 1. Influenza –A,B 2. Measles in immunocompramised pt., • Route  aerosol  to treat Respiratory syncitial virus • DOSE- 200MG/QID
  25. 25. ADVERSE EFFECT • ANAEMIA • HAEMOLYSIS. • IRRITATION TO MUCOSA & BRONCHOSPASM DUE TO AEROSOL.
  26. 26. Inhibitors of viral penetration and uncoating • Amantadine and Rimantadine • Synthetic tricyclic amines • Active against Influenza-A • MAO:- Inhibit viral M2 protein • t ½- 17-25hr.
  27. 27. Neuraminidase inhibitors • Oseltamivir, Zanamivir • Oral  Oseltamivir carboxylate • 80% BV • t ½- 8hrs. • Effective against influenza • ADR: Zanamivir- bronchospasm, Nasal discomfort
  28. 28. Immunomodulators • Interferons:• Enhanced production of cytokines • Glycoprotiens produced by body cells after viral infections. • TYPES : 1. ALPHA (α)Leucocytes 2. BETA (β) fibroblasts 3 . GAMMA (γ)  T-lymphocytes
  29. 29. • IFN- α, β  potent anti viral effects • IFN- γ antiviral & immuno modulatory • IFNs Bind to cell surface receptors  viral penetration , m-RNA synthesis, assembly of virions.

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