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Premium member Presentation Transcript Antiviral Drugs basics: Antiviral Drugs basics Dr.T.V.Rao MD 11/17/2012 Dr.T.V.Rao MD 1PowerPoint Presentation: 11/17/2012 Dr.T.V.Rao MD 2Understanding Viruses They are different from other Microbes: 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 cell’s energy to synthesize protein, DNA, and RNA 11/17/2012 Dr.T.V.Rao MD 3Understanding Viruses: Understanding Viruses Viruses are difficult to kill because they live inside the cells Any drug that kills a virus may also kill cells 11/17/2012 Dr.T.V.Rao MD 4Antivirals available for many viral infections: Antivirals available 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 5Anti-viral drugs: 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 enzymes 11/17/2012 Dr.T.V.Rao MD 6Anti-viral drugs: Anti-viral drugs Certain viruses multiply in the cytoplasm but others do in the nucleus Most multiplication take place before diagnosis is made 11/17/2012 Dr.T.V.Rao MD 7Anti-Viral drugs: 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. 11/17/2012 Dr.T.V.Rao MD 8Antivirals how they act : Antivirals how they act Key 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 A healthy immune system works synergistically with the drug to eliminate or suppress viral activity 11/17/2012 Dr.T.V.Rao MD 9Antiviral Medications: 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 11/17/2012 Dr.T.V.Rao MD 10Antiviral Drugs: Nonretroviral : 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 11/17/2012 Dr.T.V.Rao MD 11Anti-viral drugs: 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 cells 11/17/2012 Dr.T.V.Rao MD 12Anti-viral drugs: Anti-viral drugs Stages of viral replication Cell entry – attachment - penetration Uncoating Transcription of viral genome Translation Assembly of virion components Release 11/17/2012 Dr.T.V.Rao MD 13PowerPoint Presentation: 11/17/2012 Dr.T.V.Rao MD 14Anti-viral drugs: Anti-viral drugs Anti-herpes virus agents Acyclovir / Valacyclovir Famciclovir / Penciclovir Ganciclovir / Cidofovir Foscarnet Trifluridine / Idoxuridine / Vidarabine 11/17/2012 Dr.T.V.Rao MD 15Anti-viral drugs: Anti-viral drugs Acyclovir & 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. 11/17/2012 Dr.T.V.Rao MD 16Anti-Viral drugs: Anti-Viral drugs PHARMACOLOGY OF ACYCLOVIR AND CONGENERS Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs. 11/17/2012 Dr.T.V.Rao MD 17Anti-viral drugs: Anti-viral drugs Mechanism 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 inhibited 11/17/2012 Dr.T.V.Rao MD 18Anti-viral drugs: Anti-viral drugs Acyclovir is thus selectively activated in cells infected with herpes virus. Uninfected cells do not phosphorylate acyclovir. 11/17/2012 Dr.T.V.Rao MD 19Mechanism of Action of Acyclovir: Mechanism of Action of Acyclovir 11/17/2012 Dr.T.V.Rao MD 20Anti-Viral drugs: 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 keratoconjunctivitis 11/17/2012 Dr.T.V.Rao MD 21Anti-Viral drugs: Anti-Viral drugs Pharmacokinetics of Acyclovir : Oral bioavailability ~ 20-30% Distribution in all body tissues including CNS Renal excretion: > 80% Half lives: 2-5 hours Administration: Topical, Oral , IV 11/17/2012 Dr.T.V.Rao MD 22Anti-viral drugs: Anti-viral drugs Adverse effects of Acyclovir / Ganciclovir Nausea, vomiting and diarrhea Nephrotoxicity - crystalluria, haematuria, renal insufficiency Myelosuppression – Neutropenia and thrombocytopenia – Ganciclovir 11/17/2012 Dr.T.V.Rao MD 23Anti-viral drugs: 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 11/17/2012 Dr.T.V.Rao MD 24Anti-viral drugs: Anti-viral drugs Cidofovir : 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. 11/17/2012 Dr.T.V.Rao MD 25Anti-viral drugs: Anti-viral drugs PHARMACOLOGY 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 only 11/17/2012 Dr.T.V.Rao MD 26Anti-viral drugs: Anti-viral drugs Vidarabine 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. 11/17/2012 Dr.T.V.Rao MD 27Anti-viral drugs: Anti-viral drugs PHARMACOLOGY 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 Keratitis 11/17/2012 Dr.T.V.Rao MD 28Anti-viral drugs: 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 require phosphorylation for antiviral activity) 11/17/2012 Dr.T.V.Rao MD 29Anti-viral drugs: Anti-viral drugs Foscarnet HSV-1, HSV-2, VZV, CMV and HIV. Oral bioavailability ~ 10-20% Distribution to all tissues including CNS Administration: IV 11/17/2012 Dr.T.V.Rao MD 30Anti-viral drugs: Anti-viral drugs Adverse 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) 11/17/2012 Dr.T.V.Rao MD 31Anti-viral drugs: 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 ) 11/17/2012 Dr.T.V.Rao MD 32Anti-viral drugs: Anti-viral drugs Respiratory viral infections Influenza – Amantadine / Rimantadine Oseltamivir / Zanamavir (Neuraminidase inhibitors) RSV bronchiolitis – Ribavirin 11/17/2012 Dr.T.V.Rao MD 33Anti-viral drugs: Anti-viral drugs Amantadine 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. 11/17/2012 Dr.T.V.Rao MD 34Anti-viral drugs: Anti-viral drugs Pharmacokinetics of Amantadine Oral bioavailability ~ 50-90% Amantadine cross extensively BBB whereas Rimantadine does not cross extensively . Administration: Oral 11/17/2012 Dr.T.V.Rao MD 35Anti-viral drugs: Anti-viral drugs Neuraminidase 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. 11/17/2012 Dr.T.V.Rao MD 36Anti-viral drugs: Anti-viral drugs Neuraminidase 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. 11/17/2012 Dr.T.V.Rao MD 37Anti-viral drugs: Anti-viral drugs 11/17/2012 Dr.T.V.Rao MD 38Anti-viral drugs: Anti-viral drugs Neuraminidase inhibitors : Influenza Oseltamivir / Zanamavir Oseltamivir is orally administered. Zanamavir is given intranasal. Risk of bronchospasm with zanamavir 11/17/2012 Dr.T.V.Rao MD 39Anti-viral drugs: Anti-viral drugs PHARMACOLOGY OF RIBAVIRIN Ribavirin is a guanosine analog. Inhibition of RNA polymerase Antiviral spectrum : DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus 11/17/2012 Dr.T.V.Rao MD 40Anti-viral drugs: Anti-viral drugs Ribavirin : RSV Distribution in all body tissues, except CNS Administration : Oral, IV, Inhalational in RSV. Anemia and jaundice are adverse effects Not advised in pregnancy. 11/17/2012 Dr.T.V.Rao MD 41Anti-viral drugs: 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 virus infection in immunocompromised patients 11/17/2012 Dr.T.V.Rao MD 42Anti-viral drugs: Anti-viral drugs Hepatic Viral infections : Interferons Lamivudine – cytosine analog – HBV Entecavir – guanosine analog – HBV – lamivudine resistance strains Ribavirin – Hepatitis C (with interferons) 11/17/2012 Dr.T.V.Rao MD 43Anti-viral drugs: Anti-viral drugs Interferons Interferons (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 11/17/2012 Dr.T.V.Rao MD 44Anti-viral drugs: 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 interferons 11/17/2012 Dr.T.V.Rao MD 45Anti-viral drugs: Anti-viral drugs Mechanism of action of Interferons : Induction of the following enzymes: 1) a protein kinase which inhibits protein synthesis 2) an oligo-adenylate synthase which leads to degradation of viral mRNA 3) a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an inhibition of translation 11/17/2012 Dr.T.V.Rao MD 46Anti-viral drugs: Anti-viral drugs Antiviral 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. 11/17/2012 Dr.T.V.Rao MD 47Anti-viral drugs: Anti-viral drugs Pharmacokinetics : Interferons Oral bioavailability: < 1% Administered Intralesionally, S.C, and I.V Distribution in all body tissues, except CNS and eye. Half lives: 1-4 hours 11/17/2012 Dr.T.V.Rao MD 48Anti-viral drugs: 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 fertility 11/17/2012 Dr.T.V.Rao MD 49Anti-viral drugs: Anti-viral drugs Therapeutic 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 11/17/2012 Dr.T.V.Rao MD 50PowerPoint Presentation: Virus Diseases Drug(s) of choice Alternative drugs FLU A Influenza Amantadine Rimantadine RSV Pneumonia, bronchiolitis Ribavirin (aerosol) HSV Genital herpes Acyclovir Foscarnet Keratitis Conjunctivitis Trifluridine Idoxuridine Vidarabine Encephalitis Acyclovir Neonatal HSV infection Acyclovir Vidarabine Herpes infections in immuno- compromised host Acyclovir Foscarnet 11/17/2012 Dr.T.V.Rao MD 51PowerPoint Presentation: VZV In normal host No therapy In immunocompro-mised host, or during pregnancy Acyclovir Foscarnet CMV Retinitis Ganciclovir Foscarnet HIV AIDS HIV antibody positive with CD4 count < 500/mm 3 Zidovudine ± protease inhibitors Didanosine, Stavudine HBV HCV Hepatitis B, C Interferons 11/17/2012 Dr.T.V.Rao MD 52Antiretroviral Drugs: Antiretroviral Drugs HAART - Highly active antiretroviral therapy Includes at least three medications “cocktails” These medications work in different ways to reduce the viral load 11/17/2012 Dr.T.V.Rao MD 53Antiretroviral Drugs: 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) 11/17/2012 Dr.T.V.Rao MD 54Antiretroviral Drugs: Antiretroviral Drugs Protease inhibitors (PIs) Inhibit the protease retroviral enzyme, preventing viral replication Examples: amprenavir (Agenerase) indinavir (Crixivan) nelfinavir (Viracept) ritonavir (Norvir) saquinavir (Invirase) 11/17/2012 Dr.T.V.Rao MD 55Antiretroviral Drugs: Antiretroviral Drugs Fusion inhibitors Inhibit viral fusion, preventing viral replication Newest class of antiretroviral drugs Example: enfuvirtide (Fuzeon) 11/17/2012 Dr.T.V.Rao MD 56Antiretroviral Drugs: 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 11/17/2012 Dr.T.V.Rao MD 57Antiretroviral Drugs: Adverse Effects: 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 illness 11/17/2012 Dr.T.V.Rao MD 58PowerPoint Presentation: Programme Created by Dr.T.V.Rao MD for Medical and Paramedical Students Email email@example.com 11/17/2012 Dr.T.V.Rao MD 59 You do not have the permission to view this presentation. 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