Antiviral drugs


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Antiviral Drugs, basics

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  • Trifluridine
  • Fomivirsen : CMV It is an antisense oligonucleotide against CMV m-RNA. It is limited to CMV retinitis who fail to other therapies.
  • Antiviral drugs

    1. 1. Antiviral Drugs basics Dr.T.V.Rao MD11/18/12 Dr.T.V.Rao MD 1
    2. 2. 11/18/12 Dr.T.V.Rao MD 2
    3. 3. Understanding Viruses They are different from other MicrobesViral replication• A virus cannot replicate on its own• It must attach to and enter a host cell• It then uses the host cell’s energy to synthesize protein, DNA, and RNA11/18/12 Dr.T.V.Rao MD 3
    4. 4. Understanding VirusesViruses aredifficult to killbecause they liveinside the cells• Any drug that killsa virus may also killcells11/18/12 Dr.T.V.Rao MD 4
    5. 5. Antivirals available for many viral infectionsViruses controlled by current antiviral therapy• Cytomegalovirus (CMV)• Hepatitis viruses• Herpes viruses• Human immunodeficiency virus (HIV)• Influenza viruses (the “flu”)• Respiratory syncytial virus (RSV) 11/18/12 Dr.T.V.Rao MD 5
    6. 6. Anti-viral drugs• Viruses have no cell wall and made up of nucleic acid components• Viruses containing envelope – antigenic in nature• Viruses are obligate intracellular parasite• They do not have a metabolic machinery of their own – uses host enzymes11/18/12 Dr.T.V.Rao MD 6
    7. 7. Anti-viral drugs• Certain viruses multiply in the cytoplasm but others do in the nucleus• Most multiplication take place before diagnosis is made11/18/12 Dr.T.V.Rao MD 7
    8. 8. Anti-Viral drugs• Many antiviral drugs are Purine or Pyrimidine analogs.• Many antiviral drugs are Prodrugs. They must be phosphorylated by viral or cellular enzymes in order to become active.• Anti-viral agents inhibits active replication so the viral growth resumes after drug removal.11/18/12 Dr.T.V.Rao MD 8
    9. 9. 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 body’s immune system Best responses to antiviral drugs are in patients with competent immune systems A11/18/12 healthy immune systemDr.T.V.Rao MD synergistically with the works 9
    10. 10. Antiviral MedicationsAntiviral drugs  Used to treat infections caused by viruses other than HIVAntiretroviral drugs  Used to treat infections caused by HIV, the virus that causes AIDSHerpes-Simplex Viruses  HSV-1 (oral herpes)  HSV-2 (genital herpes)Varicella Zoster Virus  Chickenpox Shingles 11/18/12 Dr.T.V.Rao MD 10
    11. 11. Antiviral Drugs: Nonretroviral Mechanism of action  Inhibit viral replicationUsed to treat non-HIV viral infections  Influenza viruses  HSV (herpes simplex virus), VZV (vericella zoster virus)  CMV (cytomegalovirus)  Hepatitis A, B, C (HAV, HBV, NCV) Adverse Effects  Vary with each drug  Healthy cells are often killed also, resulting in serious toxicities 11/18/12 Dr.T.V.Rao MD 11
    12. 12. Anti-viral drugs• Current anti-viral agents do not eliminate non-replicating or latent virus• Effective host immune response remains essential for the recovery from the viral infection• Clinical efficacy depends on achieving inhibitory conc. at the site of infection within the infected cells11/18/12 Dr.T.V.Rao MD 12
    13. 13. Anti-viral drugs Stages of viral replication • Cell entry – attachment - penetration • Uncoating • Transcription of viral genome • Translation • Assembly of virion components • Release11/18/12 Dr.T.V.Rao MD 13
    14. 14. 11/18/12 Dr.T.V.Rao MD 14
    15. 15. Anti-viral drugs Anti-herpes virus agents• Acyclovir / Valacyclovir• Famciclovir / Penciclovir• Ganciclovir / Cidofovir• Foscarnet• Trifluridine / Idoxuridine / Vidarabine11/18/12 Dr.T.V.Rao MD 15
    16. 16. Anti-viral drugsAcyclovir & Congeners :• Valacyclovir is a prodrug of Acyclovir with better bioavailability.• Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability.• Penciclovir is used only topically whereas Famciclovir can be administered orally.11/18/12 Dr.T.V.Rao MD 16
    17. 17. Anti-Viral drugsPHARMACOLOGY OF ACYCLOVIR AND CONGENERS• Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs.11/18/12 Dr.T.V.Rao MD 17
    18. 18. Anti-viral drugsMechanism of action of Acyclovir and congeners :• All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs.• The analog inhibits viral DNA- polymerase• Only actively replicating viruses are inhibited11/18/12 Dr.T.V.Rao MD 18
    19. 19. Anti-viral drugs• Acyclovir is thus selectively activated in cells infected with herpes virus.• Uninfected cells do not phosphorylate acyclovir.11/18/12 Dr.T.V.Rao MD 19
    20. 20. Mechanism of Action of Acyclovir11/18/12 Dr.T.V.Rao MD 20
    21. 21. Anti-Viral drugs Antiviral 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 keratoconjunctivitis11/18/12 Dr.T.V.Rao MD 21
    22. 22. Anti-Viral drugsPharmacokinetics of Acyclovir :• Oral bioavailability ~ 20-30%• Distribution in all body tissues including CNS• Renal excretion: > 80%• Half lives: 2-5 hours• Administration: Topical, Oral , IV11/18/12 Dr.T.V.Rao MD 22
    23. 23. Anti-viral drugs Adverse effects of Acyclovir / Ganciclovir • Nausea, vomiting and diarrhea • Nephrotoxicity - crystalluria, haematuria, renal insufficiency • Myelosuppression – Neutropenia and thrombocytopenia – Ganciclovir11/18/12 Dr.T.V.Rao MD 23
    24. 24. Anti-viral drugsTherapeutic uses :Acyclovir is the drug of choice for:• HSV Genital infections• HSV encephalitis• HSV infections in immunocompromised patientGanciclovir is the drug of choice for:• CMV retinitis in immunocompromised patient• Prevention of CMV disease in transplant patients 11/18/12 Dr.T.V.Rao MD 24
    25. 25. Anti-viral drugsCidofovir :• It is approved for the treatment of CMV retinitis in immunocompromised patients• It is a nucleotide analog of cytosine – no phosphorylation required.• It inhibits viral DNA synthesis• Available for IV, Intravitreal inj, topical• Nephrotoxicity is a major disadvantage.11/18/12 Dr.T.V.Rao MD 25
    26. 26. Anti-viral drugsPHARMACOLOGY OF VIDARABINE• Vidarabine is a nucleoside analog. (adenosine)Antiviral spectrum of Vidarabine : HSV-1, HSV-2 and VZV.Its use is limited to HSV keratitis only11/18/12 Dr.T.V.Rao MD 26
    27. 27. 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.11/18/12 Dr.T.V.Rao MD 27
    28. 28. Anti-viral drugsPHARMACOLOGY OF TRIFLURIDINE• Trifluridine is a Pyrimidine nucleoside analogs - inhibits viral DNA synthesis.Antiviral spectrum Trifluridine :• HSV-1, HSV-2 and VZV.• Use is limited to Topical - Ocular HSV Keratitis11/18/12 Dr.T.V.Rao MD 28
    29. 29. Anti-viral drugsPHARMACOLOGY OF FOSCARNET• Foscarnet is an inorganic pyrophosphate analog  • It directly inhibits viral DNA and RNA -polymerase and viral inverse transcriptase (it does not require phosphorylation for antiviral activity)11/18/12 Dr.T.V.Rao MD 29
    30. 30. Anti-viral drugsFoscarnet• HSV-1, HSV-2, VZV, CMV and HIV.• Oral bioavailability ~ 10-20%• Distribution to all tissues including CNS• Administration: IV11/18/12 Dr.T.V.Rao MD 30
    31. 31. Anti-viral drugsAdverse effects of Foscarnet• Hypocalcemia and hypomagnesemia (due to chelation of the drug with divalent cations) are common.• Neurotoxicity (headache, hallucinations, seizures)• Nephrotoxicity (acute tubular nephrosis, interstitial nephritis)11/18/12 Dr.T.V.Rao MD 31
    32. 32. Anti-viral drugsTherapeutic uses of Foscarnet• It is an alternative drug for• HSV infections (acyclovir resistant / immunocompromised patient )• CMV retinitis (ganciclovir resistant / immunocompromised patient )11/18/12 Dr.T.V.Rao MD 32
    33. 33. Anti-viral drugsRespiratory viral infectionsInfluenza –• Amantadine / Rimantadine• Oseltamivir / Zanamavir (Neuraminidase inhibitors)RSV bronchiolitis –• Ribavirin11/18/12 Dr.T.V.Rao MD 33
    34. 34. Anti-viral drugsAmantadine and Rimantadine : Influenza• Prevention & Treatment of influenza A• Inhibition of viral uncoating by inhibiting the viral membrane protein M2• Influenza A virus• Amantadine has anti-parkinsonian effects. 11/18/12 Dr.T.V.Rao MD 34
    35. 35. Anti-viral drugsPharmacokinetics of Amantadine• Oral bioavailability ~ 50-90%• Amantadine cross extensively BBB whereas Rimantadine does not cross extensively .• Administration: Oral11/18/12 Dr.T.V.Rao MD 35
    36. 36. Anti-viral drugsNeuraminidase inhibitors : Influenza Oseltamivir / Zanamavir• Influenza contains an enzyme neuraminidase which is essential for the replication of the virus.• Neuraminidase inhibitors prevent the release of new virions and their spread from cell to cell.11/18/12 Dr.T.V.Rao MD 36
    37. 37. Anti-viral drugsNeuraminidase inhibitors : Influenza Oseltamivir / 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 and acute treatment.11/18/12 Dr.T.V.Rao MD 37
    38. 38. Anti-viral drugs11/18/12 Dr.T.V.Rao MD 38
    39. 39. Anti-viral drugsNeuraminidase inhibitors : Influenza Oseltamivir / Zanamavir• Oseltamivir is orally administered.• Zanamavir is given intranasal.• Risk of bronchospasm with zanamavir11/18/12 Dr.T.V.Rao MD 39
    40. 40. Anti-viral drugsPHARMACOLOGY OF RIBAVIRIN• Ribavirin is a guanosine analog.• Inhibition of RNA polymeraseAntiviral spectrum : DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus11/18/12 Dr.T.V.Rao MD 40
    41. 41. Anti-viral drugsRibavirin : RSV• Distribution in all body tissues, except CNS• Administration : Oral, IV, Inhalational in RSV.• Anemia and jaundice are adverse effects• Not advised in pregnancy.11/18/12 Dr.T.V.Rao MD 41
    42. 42. Anti-viral drugsTherapeutic uses RibavirinRibavirin is the drug of choice for:• RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol)• Lassa feverRibavirin is an alternative drug for:• Influenza, parainfluenza, measles virus infection in immunocompromised patients11/18/12 Dr.T.V.Rao MD 42
    43. 43. Anti-viral drugsHepatic Viral infections :• Interferons• Lamivudine – cytosine analog – HBV• Entecavir – guanosine analog – HBV – lamivudine resistance strains• Ribavirin – Hepatitis C (with interferons)11/18/12 Dr.T.V.Rao MD 43
    44. 44. Anti-viral drugsInterferonsInterferons (IFNs) are natural proteins produced by the cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells.• Antiviral, immune modulating and anti-proliferative actions• Three classes of interferons – α , β, γ 11/18/12 Dr.T.V.Rao MD 44
    45. 45. Anti-viral drugs Interferons • α and β interferons are produced by all the cells in response to viral infections • γ interferons are 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 interferons11/18/12 Dr.T.V.Rao MD 45
    46. 46. Anti-viral drugsMechanism of action of Interferons :• Induction of the following enzymes:1) a protein kinase which inhibits protein synthesis2) an oligo-adenylate synthase which leads to degradation of viral mRNA3) a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an inhibition of translation 11/18/12 Dr.T.V.Rao MD 46
    47. 47. Anti-viral drugsAntiviral spectrum : Interferon α• Includes HBV, HCV and HPV.• Anti-proliferative actions may inhibit the growth of certain cancers - like Kaposi sarcoma and hairy cell leukemia.11/18/12 Dr.T.V.Rao MD 47
    48. 48. Anti-viral drugsPharmacokinetics : Interferons• Oral bioavailability: < 1%• Administered Intralesionally, S.C, and I.V• Distribution in all body tissues, except CNS and eye.• Half lives: 1-4 hours11/18/12 Dr.T.V.Rao MD 48
    49. 49. Anti-viral drugs Adverse effects of Interferons • Acute flu-like syndrome (fever, headache) • Bone marrow suppression (granulocytopenia, thrombocytopenia) • Neurotoxicity (confusion, seizures) • Cardiotoxicity - arrhythmia • Impairment of fertility11/18/12 Dr.T.V.Rao MD 49
    50. 50. Anti-viral drugsTherapeutic uses Interferons• Chronic hepatitis B and C (complete disappearance is seen in 30%).• HZV infection in cancer patients (to prevent the dissemination of the infection)• CMV infections in renal transplant patients• Condylomata acuminata (given by intralesional injection). Complete clearance is seen ~ 50%.• Hairy cell leukemia (in combination with zidovudine)• AIDS related Kaposi’s sarcoma 11/18/12 Dr.T.V.Rao MD 50
    51. 51.   Drug(s) of Alternative Viru Diseases drugs choice      s FLU   Rimantadine A Influenza Amantadine Pneumonia, Ribavirin RSV   bronchiolitis (aerosol)   HSV Genital herpes Acyclovir Foscarnet   Keratitis Idoxuridine Trifluridine   Conjunctivitis Vidarabine Encephalitis Acyclovir     Neonatal HSV Acyclovir Vidarabine   infection Herpes infections in Acyclovir Foscarnet   immuno-11/18/12 compromised hostDr.T.V.Rao MD 51
    52. 52.   In normal host No therapy  VZV  In immunocompro- mised host, or during Acyclovir Foscarnet pregnancyCMV Retinitis Ganciclovir Foscarnet AIDS Zidovudine ± Didanosine,HIV HIV antibody protease Stavudine positive with CD4 inhibitors count < 500/mm3HBV Hepatitis B, C Interferons  HCV 11/18/12 Dr.T.V.Rao MD 52
    53. 53. Antiretroviral Drugs HAART - Highly active antiretroviral therapy• Includes at least three medications – “cocktails”• These medications work in different ways to reduce the viral load11/18/12 Dr.T.V.Rao MD 53
    54. 54. Antiretroviral Drugs• Reverse transcriptase inhibitors (RTIs) – Block activity of the enzyme reverse transcriptase, preventing production of new viral DNA• Reverse transcriptase inhibitors (RTIs) – Nucleoside RTIs (NRTIs) – Nonnucleoside RTIs (NNRTIs) – Nucleotide RTIs (NTRTIs)• Examples abacavir (Ziagen) delavirdine (Rescriptor) didanosine (Videx) lamivudine (Epivir) stavudine (Zerit) tenofovir (Viread) 11/18/12 Dr.T.V.Rao MD 54
    55. 55. Antiretroviral Drugs • Protease inhibitors (PIs) – Inhibit the protease retroviral enzyme, preventing viral replication – Examples: amprenavir (Agenerase) indinavir (Crixivan) nelfinavir (Viracept) ritonavir (Norvir) saquinavir (Invirase)11/18/12 Dr.T.V.Rao MD 55
    56. 56. Antiretroviral Drugs • Fusion inhibitors – Inhibit viral fusion, preventing viral replication – Newest class of antiretroviral drugs – Example: enfuvirtide (Fuzeon)11/18/12 Dr.T.V.Rao MD 56
    57. 57. Antiretroviral Drugs• Combinations of multiple antiretroviral medications are common• Adverse effects vary with each drug and may be severe−monitor for dose- limiting toxicities• Monitor for signs of opportunistic diseases 11/18/12 Dr.T.V.Rao MD 57
    58. 58. Antiretroviral Drugs: Adverse Effects Numerous and vary with each drug Drug therapy may need to be modified because of adverse effects Goal is to find the regimen that will best control the infection with a tolerable adverse effect profile Medication regimens change during the course of the illness11/18/12 Dr.T.V.Rao MD 58
    59. 59. • Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students • Email • doctortvrao@gmail.com11/18/12 Dr.T.V.Rao MD 59