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Antivirals

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

Antivirals Antivirals Presentation Transcript

  • DR.RAHUL 10/5/2013 DR RAHUL KUNKULOL 1
  • 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 10/5/2013 2
  • • Certain viruses multiply in the cytoplasm but others do in the nucleus • Some viruses have unique enzymes for DNA/RNA synthesis or protein cutting in virus assembly. • Most multiplication take place before diagnosis is made 10/5/2013 3
  • • DNA viruses • Adenoviruses (upper respiratory infections) • Herpes simplex (genital herpes) • Hepadna virus (hepatitis B) • Cytomegalovirus (CMV) • Varicella (chickenpox) and varicella-zoster • Smallpox • RNA viruses : Influenza A and B • RNA retroviruses : Human immunodeficiency virus (HIV) 10/5/2013 4
  • Adsorption to and penetration of susceptible cells. Synthesis of early, nonstructural proteins. Synthesis of RNA or DNA. Synthesis of late, structural proteins Assembly of viral particles and release 10/5/2013 5
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  • 10/5/2013 8 Viral uncoating Nucleoside analogs Non-nucleoside polymerase inhibitors Non-nucleoside reverse transcriptase inhibitors Protease inhibitors Neuraminidase inhibitors
  • 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 The viral growth resumes after drug removal. 10/5/2013 9
  • 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 10/5/2013 10
  • :(Herpes, CMV, HIV, R.Syncitial)  Purine analogues Acyclovir Valacyclovir Ganciclovir Valganciclovir Penciclovir Famciclovir Cidofovir (c) Adefovir (a) Vidarabine (a)  Pyrimidine analogues  Idoxuridine  Trifluridine 10/5/2013 11
  • Foscarnet (Direct inhibitor of DNA polymerase and RT) Ribavirin Fomivirsen (Influenza) Amantadine Rimantadine Zanamavir Oseltamivir Interferon-alpha (Hepat. B&C, Herpes) 10/5/2013 12
  • Figure 20.16a 10/5/2013 13
  • • 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. • All are guanine nucleoside analogs. 10/5/2013 14
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  • 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. 10/5/2013 16
  • A Guanine analogue with antiviral for Herpes group only Acyclovir AcycloGMP AcycloGTP Thymidine kinase Cellular kinases Viral 200x affinity of mammalian 1. Inhibits viral DNA polymerase selectively 2. Incorporated into DNA and terminates synthesis 10/5/2013DR RAHUL KUNKULOL 17
  • 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 10/5/2013DR RAHUL KUNKULOL 18
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  • • Primary disease : • Acyclovir 5% ointment 6 times a day for 10 days • Late & severe cases: 400 mg TDS orally for 10 days • Recurrent disease: • Iv infusion 5mg/kg over 1 hr repeated 8 hrly for 10 days • Followed by suppressive treatment with oral acyclovir 10/5/2013 20
  • 10/5/2013 21 • Mucocutaneous : • Remains localized to lips and gums (Acyclovir skin cream) • H.Simplex encephalitis • 10 mg /kg /8hr iv acyclovir for 10 days • H. Simplex keratitis (HSV–I) • Acyclovir eye ointment 5 times a day for 3days
  • 10/5/2013 22 Chickenpox : Oral 400mg TDS for 7 days Herpes zoster infections Acyclovir less active
  • • Oral : • Headach, N/v, diarrhea, vertigo • IV : • Phlebitis, rash , hypotention • Nephrotoxicity • Reversible neurological manifestations 10/5/2013 23
  • • Mechanism like Acyclovir • Active against all Herpes viruses including CMV • Low oral bioavailability given I.V. • Drug of choice for CMV infections: retinitis, pneumonia, colitis… 10/5/2013 24
  • 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 10/5/2013 25
  • Guanine Acyclovir Ganciclovir 10/5/2013 DR RAHUL KUNKULOL 26
  • Approved for the treatment of CMV retinitis in immunocompromised patients Nucleoside analog of cytosine  Gets converted to only cidofovir diphosphate and inhibit viral DNA polymerase  It inhibits viral DNA synthesis Available for IV, Intravitreal inj, Topical Nephrotoxicity is a major disadvantage. Uses : CMV retinitis 10/5/2013 27
  • 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 AE : Nephrotoxicity, lactic acidosis, hepatomegaly. 10/5/2013 28
  • Adenine nucleoside analogue Convert to Ara-A triphosphate and inhibit DNA polymerase Active against HSV and vaccina virus › Treatment of HSV encephalitis and herpetic keratitis  Poor solubility, given i.v. with big volume of fluids (2.5 L) ⇒ risk of fluid overload 10/5/2013 29
  •  GI  Bone marrow  Hypokalemia  Inappropriate ADH secretion;  Psychosis; painful neuropathy;  Not a drug of choice for anything :  Replaced by Acyclovir because of toxicity and problems in administration. 10/5/2013 30
  • • Active against HSV and VZV • First pyrimidine analogue used as antiviral. • It is iodinated derivative of deoxyuridine. • MOA same as acyclovir 10/5/2013 31
  • • Topical use for treatment of HSV infections of the eyelid, cornea and skin. • Only indication- Herpes simplex kerato-conjunctivitis • High toxicity : • Bone marrow depression • Due to incorporation of idoxuridine into host cell DNA 10/5/2013 32
  • • 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 • Very poor oral bioavalibility so given slow iv. 10/5/2013 34
  • • CMV retinitis and other CMV infections instead of Ganciclovir. • H simplex resistant to Acyclovir • H. simplex in AIDS patients 10/5/2013 35
  • • Nephrotoxicity (25%) most common ADR • Hypocalcaemia (chelates divalent cations) • Others: Hypokalemia, Hypomagnesaemia 10/5/2013 36
  • Inhibit replication of both DNA and RNA viruses Triphosphate inhibits RNA polymerase Anemia due to hemolysis and BM suppression 10/5/2013 37
  • Ribavirin is the drug of choice for: • RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol) Ribavirin is an alternative drug for: • Influenza, Parainfluenza, Measles virus infection in immunocompromised patients 10/5/2013 38
  • • Is a Oligonucleotide • Primarily an anti CMV agent • Binds to mRNA and inhibit synthesis of immediate early proteins needed for replication • Injected intravitreally for : CMV retinitis in patients of AIDS • A/E: Iritis, Vitreitis. 10/5/2013 39
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  • • 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 channell appears to be its one of the target. • Prevent diseases caused by influenza A • Treatment of Parkinson’s disease 10/5/2013 42
  • • GI upset • Headache • Nervousness • Postural hypotension, ankle edema 10/5/2013 43
  • • Inhibit neuraminidase enzyme of influenza • Enzyme essential for release of virus • Examples: zanamivir and oseltamivir • Zanamivir administered via inhalation administered orally • Oseltamivir is converted to O. carboxylate (oral bioavalibility 80%) 10/5/2013 DR RAHUL KUNKULOL 44
  • • Therapeutic Use • Treatment of acute uncomplicated Influenza A (H1N1 virus, swine flu) : Oseltamivir 75mg BD • Prevention : 75mg OD • Adverse effects • N/V, Bronchospasm and abnormal respiratory function 10/5/2013 45
  • • 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 10/5/2013 46
  • 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 The action of these enzymes leads to an inhibition of translation 10/5/2013 47
  • • 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 10/5/2013 48
  • Antivirals Spectrum Acyclovir HSV-1, HSV-2, VZV, Shingles. Ganciclovir CMV Famciclovir Herpes genitalis, shingles Cidofovir CMV Adefovir HBV Idoxuridine, Trifluridine Herpetic keratoconjunctivitis 10/5/2013 49
  • Antivirals Spectrum Foscarnet HSV, CMV in AIDS Ribavirin RSV, Parainfluenza Fomivirsen CMV retinitis in AIDS Amantidine, Rimantidine Influenza A Virus Oseltamivir H1N1 influenza Interferon HBV, HCV 10/5/2013 50
  • Virus Diseases Drug(s) of choice Alternative drugs Inf. 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 10/5/2013 DR RAHUL KUNKULOL 51
  • In normal host No therapy Immunocompromised host, or pregnancy Acyclovir Foscarnet CMV Retinitis Ganciclovir Foscarnet HCV InterferonsHepatitis B Hepatitis C VZV CMV 10/5/2013 DR RAHUL KUNKULOL 52 HBV
  • • Guanosine analogue • Competitively inhibits viral DNA polymerase • Approved by FDA in march 2005 for treatment of chronic hepatitis B • Oral bioavailibility : 95% • AE : Headach, fatigue, NV 10/5/2013 53
  • • Neuramidase inhibitor • Approved in 2009 • For emergency treatment of hospitalised patients of H1N1 infection • Used iv for patients resistant to Oseltamivir, zanamivir…. 10/5/2013 54