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Antiviral Agents

Antiviral Agents. Understanding Viruses. 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. Understanding Viruses.

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Antiviral Agents

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  1. Antiviral Agents

  2. Understanding Viruses 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.

  3. Understanding Viruses Viruses are difficult to kill because they liveinside our cells. • Any drug that kills a virus may also kill our cells.

  4. Viral Infections Competent immune system: • Best response to viral infections • A well-functioning immune system will eliminate or effectively destroy virus replication Immunocompromised patients have frequent viral infections • Cancer patients, especially leukemia or lymphoma • Transplant patients, due to pharmacological therapy • AIDS patients, disease attacks immune system

  5. Antivirals Key characteristics of antiviral drugs: • Able to enter the cells infected with virus. • Interfere with viral nucleic acid synthesis and/or regulation. • Some agents interfere with ability of virus to bind to cells. • Some agents stimulate the body’s immune system.

  6. Antivirals Viruses killed by current antiviral therapy: • cytomegalovirus (CMV) • herpes simplex virus (HSV) • human immunodeficiency virus (HIV) • influenza A (the “flu”) • respiratory syncytial virus (RSV)

  7. Antivirals: Mechanism of Action Inhibit viral replication • Inhibit viral attachment • Prevent genetic copying of virus • Prevent viral protein production

  8. Sites of Drug Action

  9. Sites of Drug Action

  10. Antiviral Agents • Block viral entry into the cell or must work inside the cell • Most agents are pyrimidine or purine nucleoside analogs

  11. Antivirals Synthetic Purine Nucleoside Analogues Two types of nucleosides: Purine nucleosides • guanine • adenosine Pyrimidine nucleosides • thymine • cytosine

  12. Antivirals: Purine Nucleosides Agent Antiviral Activity guanines acyclovir HSV 1 & 2, VZV ganciclovir (DHPG) CMV retinitis and systemic CMV infection ribavirin (RTCD) Influenza types A and B, RSV, LV, HV adenosines didanosine (ddl) HIV vidarabine (Ara-A) HSV, herpes zoster

  13. Antivirals: Pyrimidine Nucleosides Agent Antiviral Activity cytosines lamivudine (3TC) HIV zalcitabine (ddC) HIV thymine idoxuridine (IDU) HSV stavudine (d4T) HIV trifluridine HSV zidovudine (AZT) HIV

  14. Other Antivirals amantadine (Symmetrel) and rimantadine (Flumadine) • influenza A foscarnet (Foscavir) • CMV (retinitis and systemic) Neuraminidase Inhibitors: oseltamivir (Tamiflu) and zanamivir (Relenza) • influenza types A and B

  15. Antivirals: Side Effects acyclovir • Burning when topically applied, nausea, vomiting, diarrhea, headache amantadine and rimantadine • Anticholinergic effects, insomnia, lightheadedness, anorexia, nausea didanosine (ddl) • Pancreatitis, peripheral neuropathies, seizures

  16. Antivirals: Side Effects zidovudine (AZT) • Bone marrow suppression, nausea, headache foscarnet (Foscavir) • Headache, seizures, acute renal failure, nausea, vomiting, diarrhea ganciclovir (Cytovene) • Bone marrow toxicity, nausea, anorexia, vomiting

  17. Antiherpes Agents • Acyclovir- prototype • Valacyclovir • Famciclovir • Penciclovir • Trifluridine • Vidarabine

  18. Mechanism of Action Acyclovir • an acyclic guanosine derivative • Phosphorylated by viral thymidine kinase • Di-and tri-phosphorylated by host cellular enzymes • Inhibits viral DNA synthesis by: • 1) competing with dGTP for viral DNA polymerase • 2) chain termination

  19. Clinical Uses Acyclovir • Oral, IV, and Topical formulations • Cleared by glomerular filtration and tubular secretion • Uses: • Herpes Simplex Virus 1 and 2 (HSV) • Varicella-zoster virus (VZV) • Side Effects: nausea, diarrhea, headache, tremors, and delirium

  20. Valacyclovir • L-valyl ester of acyclovir • Converted to acyclovir when ingested • M.O.A.: same as acyclovir • Uses: • 1) recurrent genital herpes • 2) herpes zoster infections • Side Effects: nausea, diarrhea, and headache

  21. Famciclovir • Prodrug of penciclovir (a guanosine analog) • M.O.A.: same as acyclovir • does not cause chain termination • Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B • Side Effects: nausea, diarrhea, and headache

  22. Trifluridine • Trifluridine- fluorinated pyrimidine • inhibits viral DNA synthesis same as acyclovir • incorporates into viral and cellular DNA • Uses: HSV-1 and HSV-2 (topically)

  23. Vidarabine • An adenosine analog • inhibits viral DNA polymerase • incorporated into viral and cellular DNA • metabolized to hypoxanthine arabinoside • Side Effects: GI intolerance and myelosuppression

  24. Anti-Cytomegalovirus Agents • Gancyclovir • Valgancyclovir • Cidofovir • Foscarnet • Fomivirsen

  25. Ganciclovir • An acyclic guanosine analog • requires triphosphorylation for activation • monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells • M.O.A.: same as acyclovir • Uses: CMV*, HSV, VZV,and EBV • Side Effect: myelosuppression

  26. HIV

  27. HIV

  28. Valgancyclovir • Monovalyl ester prodrug of gancyclovir • Metabolized by intestinal and hepatic esterases when administered orally • M.O.A.: same as gancyclovir • Uses: CMV* • Side Effect: myelosuppression

  29. Foscarnet • An inorganic pyrophosphate • inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase • does not have to be phosphorylated • Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV • Resistance due to mutations in DNA polymerase gene • Side Effects:hypo- or hypercalcemia and phosphotemia

  30. HIV AIDS- treatment

  31. Antiretroviral Agents 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 3)Protease inhibitors

  32. Reverse Transcriptase Inhibitors • Zidovudine (AZT) • Didanosine- causes pancreatitis* • Lamivudine- causes pancreatitis • Zalcitabine- causes peripheral neuropathy* • Stavudine- causes peripheral neuropathy* • Abacavir

  33. Mechanism of Action Zidovudine (AZT) • A deoxythymidine analog • enters the cell via passive diffusion • must be converted to the triphosphate form by mammalian thymidine kinase • competitively inhibits deoxythymidine triphosphate for the reverse transcriptase enzyme • causes chain termination

  34. Mechanism of Resistance Zidovudine • Due to mutations in the reverse transcriptase gene • more frequent after prolong therapy and in persons with HIV

  35. Clinical Uses Zidovudine • Available in IV and oral formulations • activity against HIV-1, HIV-2, and human T cell lymphotropic viruses • mainly used for treatment of HIV, decreases rate of progression and prolongs survival • prevents mother to newborn transmission of HIV

  36. Side Effects Zidovudine • Myelosuppression, including anemia and neutropenia • GI intolerance, headaches, and insomnia

  37. Other NRTIs • Didanosine- synthetic deoxy-adenosine analog; causes pancreatitis* • Lamivudine- cytosine analog • Zalcitabine- cytosine analog; causes peripheral neuropathy* • Stavudine- thymidine analog;causes peripheral neuropathy* • Abacavir- guanosine analog; more effective than the other agents; fatal hypersensitivity reactions can occur

  38. Nucleotide Inhibitors • Tenofovir • Adefovir

  39. Tenofovir • An acyclic nucleoside phosphonate analog of adenosine • M.O.A.- competively inhibits HIV reverse transcriptase and causes chain termination after incorporation into DNA • Uses – in combination with other antiretrovirals for HIV-1 suppression

  40. Adefovir • An analog of adenosine monophosphate • Phosphorylated by cellular kinases • M.O.A. - Competitively inhibits HBV DNA polymerase and results in chain termination after incorporation into viral DNA • Uses - Hepatitis B • Side effects - nephrotoxicity

  41. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Nevirapine • Delavirdine • Efavirenz

  42. Mechanism of ActionNNRTIs • Bind to site on viral reverse transcriptase, different from NRTIs • results in blockade of RNA and DNA dependent DNA polymerase activity • do not compete with nucleoside triphosphates • do not require phosphorylation • these drugs can not be given alone • substrates and inhibitors of CYP3A4

  43. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) • Nevirapine- prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery • Delavirdine- teratogenic, therefore can not be given during pregnancy • Efavirenz- teratogenic, therefore can not be given during pregnancy

  44. Protease Inhibitors • Indinavir • Ritonavir • Saquinavir • Nelfinavir • Amprenavir

  45. Protease Inhibitors • The protease enzyme cleaves precursor molecules to produce mature, infectious virions • these agents inhibit protease and prevent the spread of infection • These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia

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