1. Antiviral Agents Dr. Yunita Sari Pane, MS 06 August 2009 1 DEPARTEMEN FARMAKOLOGI & TERAPEUTIK FK USU

2. VIRUSES Obligate intracellular parasites Consist of a core genome in a protein shell and some are surrounded by a lipoprotein lack a cell wall and cell membrane do not carry out metabolic processes Replication depends on the host cell machinery 2

3. Steps for Viral Replication 1) adsorption and penetration into cell 2) uncoating of viral nucleic acid 3) synthesis of regulatory proteins 4) synthesis of RNA or DNA 5) synthesis of structural proteins 6) assembly of viral particles 7) release from host cell VIRUSES 3

4. ANTIVIRAL AGENTS Block viral entry into the cell or must work inside the cell Most agents are pyrimidine or purine nucleoside analogs 4

5. SITES OF DRUG ACTION 5

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7. Sites of Drug Action 7

8. AntiHerpes Agents Acyclovir - prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine 8

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10. 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 AntiHerpes Agents 10

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12. Mechanism of Resistance Acyclovir Alteration in viral thymidine kinase Alteration in viral DNA polymerase Cross-resistance with valacyclovir, famciclovir, and ganciclovir AntiHerpes Agents 12

13. 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 AntiHerpes Agents 13

14. 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 AntiHerpes Agents 14

15. 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 AntiHerpes Agents 15

16. Trifluridine Trifluridine- fluorinated pyrimidine – Inhibits viral DNA synthesis same as acyclovir – Incorporates into viral and cellular DNA – Uses: HSV-1 and HSV-2 (topically) AntiHerpes Agents 16

17. Vidarabine An adenosine analog inhibits viral DNA polymerase incorporated into viral and cellular DNA metabolized to hypoxanthine arabinoside Side Effects: GI intolerance and myelosuppression AntiHerpes Agents 17

18. Anti-Cytomegalovirus Agents Gancyclovir Valgancyclovir Cidofovir Foscarnet Fomivirsen 18

19. 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 Anti-Cytomegalovirus Agents 19

20. 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 Valgancyclovir Anti-Cytomegalovirus Agents 20

21. A cytosine analog phosphorylation not dependent on viral enzymes Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus Side Effects: nephrotoxicity (prevented by admin. of probenecid) Resistance: mutation in DNA polymerase gene Cidofovir Anti-Cytomegalovirus Agents 21

22. 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 Foscarnet Anti-Cytomegalovirus Agents 22

23. An oligonucleotide M.O.A.: binds to mRNA and inhibits protein synthesis and viral replication Uses: CMV retinitis Side effects: iritis and increased intraocular pressure Fomivirsen Anti-Cytomegalovirus Agents 23

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27. AntiRetroviral Agents 1)Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2)Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 3)Protease inhibitors 27

28. o Reverse Transcriptase Inhibitors Zidovudine (AZT) Didanosine- causes pancreatitis* Lamivudine- causes pancreatitis Zalcitabine- causes peripheral neuropathy* Stavudine- causes peripheral neuropathy* Abacavir AntiRetroviral Agents 28

29. 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 AntiRetroviral Agents Reverse Transcriptase Inhibitors 29

30. Due to mutations in the reverse transcriptase gene More frequent after prolong therapy and in persons with hiv AntiRetroviral Agents Mechanism of Resistance Zidovudine (AZT) Reverse Transcriptase Inhibitors 30

31. 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 AntiRetroviral Agents Reverse Transcriptase Inhibitors 31

32. Side Effects Zidovudine Myelosuppression, including anemia and neutropenia GI intolerance, headaches, and insomnia AntiRetroviral Agents Reverse Transcriptase Inhibitors 32

33. o 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 AntiRetroviral Agents 33

34. o Nucleotide Inhibitors Tenofovir Adefovir AntiRetroviral Agents 34

35. 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 AntiRetroviral Agents Nucleotide Inhibitors 35

36. 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 AntiRetroviral Agents Nucleotide Inhibitors 36

37. o Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine Delavirdine Efavirenz AntiRetroviral Agents 37

38. Mechanism of Action NNRTIs 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 AntiRetroviral Agents 38

39. 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 AntiRetroviral Agents o NNRTIs 39

40. 3.Protease Inhibitors Indinavir Ritonavir Saquinavir Nelfinavir Amprenavir AntiRetroviral Agents 40

41. 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 AntiRetroviral Agents o Protease Inhibitors 41

42. Indinavir and Ritonavir M.O.A.: Specific inhibitors of the HIV-1 protease enzyme M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions Side Effects:hyperbilirubinemia Contraindications:inhibitor/substrate for CPY3A4, do not give with antifungal azoles AntiRetroviral Agents Protease Inhibitors 42

43. Saquinavir A synthetic peptide-like substrate analog inhibits HIV-1 protease prevents cleavage of viral polyproteins AntiRetroviral Agents Protease Inhibitors 43

44. Nelfinavir and Amprenavir M.O.A.: Specific inhibitors of the HIV-1 protease enzyme M.O.R.: mediated by expression of multiple and variable protease amino acid substitutions Less cross-resistance with Amprenavir Side Effects: diarrhea and flatulence Amprenavir can cause Stevens-Johnson syndrome Contraindications:inhibitor/substrate for CPY3A4 AntiRetroviral Agents Protease Inhibitors 44

45. Fusion Inhibitors Enfuvirtide (T-20)- binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for fusion of the viral and cellular membranes By blocking fusion (entry into cell), FUZEON prevents HIV from infecting CD4 cells AntiRetroviral Agents Protease Inhibitors 45

46. Nucleoside reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) classes prevent the replication of HIV by working inside CD4 cells after they have been infected with HIV. The drugs in these three classes then target specific steps in the replication process to prevent the creation of new HIV particles. Fusion inhibitors differ from these drugs because they work on the outside of the cell to prevent HIV from fusing with, and infecting the CD4 cells in the first place. from Fuzeon.com 46

47. Anti-Hepatitis Agents Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI) Adefovir -Nucleotide Inhibitor Interferon Alfa Pegylated Interferon Alfa Ribavirin 47

48. Interferon Alfa Endogenous proteins induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA Bind to membrane receptors on cell surface May also inhibit viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release Anti-Hepatitis Agents Interferons 48

49. Interferons Pegylated Interferon Alfa A linear or branced polyethylene gylcol (PEG) moiety is attached to covalently to interferon Increased half-life and steady drug concentrations Less frequent dosing Tx chronic hepatitis C in combination with ribavirin Anti-Hepatitis Agents 49

50. Ribavirin A guanosine analog phosphorylated intracellularly by host enzymes inhibits capping of viral messenger RNA inhibits the viral RNA-dependent RNA polymerase inhibits replication of DNA and RNA viruses Anti-Hepatitis Agents 50

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52. Anti-Influenza Agents Amantadine Rimantadine Zanamivir Oseltamivir 52

53. Amantadine and Rimantadine Cyclic amines Inhibit the uncoating of viral RNA therefore inhibiting replication Resistance due to mutations in the RNA sequence coding for the structural M2 protein Used in the prevention and treatment of influenza A Anti-Influenza Agents 53

54. Zanamivir and Oseltamivir Inhibits the enzyme neuraminidase inhibit the replication of influenza A and Influenza B treats uncomplicated influenza infections administered intranasally Anti-Influenza Agents 54

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