Viruses are obligate intracellular parasites that rely on host cell machinery to replicate. Antiviral drugs work by blocking different stages of the viral replication cycle, either inside or outside infected cells. Common antiviral classes include nucleoside analogs, which interfere with viral DNA/RNA synthesis, and protease/reverse transcriptase inhibitors for HIV. Side effects depend on the specific agent but can include bone marrow suppression, renal toxicity, and gastrointestinal issues.

1. Antiviral Agents www.freelivedoctor.com

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 www.freelivedoctor.com

3. Viruses 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 www.freelivedoctor.com

4. Sites of Drug Action www.freelivedoctor.com

5. Antiviral Agents Block viral entry into the cell or must work inside the cell Most agents are pyrimidine or purine nucleoside analogs www.freelivedoctor.com

6. Sites of Drug Action www.freelivedoctor.com

7. Antiherpes Agents Acyclovir- prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine www.freelivedoctor.com

8. 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 www.freelivedoctor.com

9. Mechanism of Resistance Acyclovir Alteration in viral thymidine kinase Alteration in viral DNA polymerase Cross-resistance with valacyclovir, famciclovir, and ganciclovir www.freelivedoctor.com

10. 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 www.freelivedoctor.com

11. 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 www.freelivedoctor.com

12. 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 www.freelivedoctor.com

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

14. Vidarabine An adenosine analog inhibits viral DNA polymerase incorporated into viral and cellular DNA metabolized to hypoxanthine arabinoside Side Effects : GI intolerance and myelosuppression www.freelivedoctor.com

15. Anti-Cytomegalovirus Agents Gancyclovir Valgancyclovir Cidofovir Foscarnet Fomivirsen www.freelivedoctor.com

16. 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 www.freelivedoctor.com

17. 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 www.freelivedoctor.com

18. Cidofovir Aphosphorylation cytosine analog 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 www.freelivedoctor.com

19. 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 www.freelivedoctor.com

20. Fomivirsen 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 www.freelivedoctor.com

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22. Antiretroviral Agents 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 3)Protease inhibitors www.freelivedoctor.com

23. Reverse Transcriptase Inhibitors Zidovudine (AZT) Didanosine- causes pancreatitis* Lamivudine- causes pancreatitis Zalcitabine- causes peripheral neuropathy * Stavudine- causes peripheral neuropathy* Abacavir www.freelivedoctor.com

24. 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 www.freelivedoctor.com

25. Mechanism of Resistance Zidovudine Due to mutations in the reverse transcriptase gene more frequent after prolong therapy and in persons with HIV www.freelivedoctor.com

26. 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 www.freelivedoctor.com

27. Side Effects Zidovudine Myelosuppression, including anemia and neutropenia GI intolerance, headaches, and insomnia www.freelivedoctor.com

28. 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 www.freelivedoctor.com

29. Nucleotide Inhibitors Tenofovir Adefovir www.freelivedoctor.com

30. 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 www.freelivedoctor.com

31. 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 www.freelivedoctor.com

32. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine Delavirdine Efavirenz www.freelivedoctor.com

33. 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 www.freelivedoctor.com

34. 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 Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) www.freelivedoctor.com

35. Protease Inhibitors Indinavir Ritonavir Saquinavir Nelfinavir Amprenavir www.freelivedoctor.com

36. 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 www.freelivedoctor.com

37. 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 www.freelivedoctor.com

38. Saquinavir A synthetic peptide-like substrate analog inhibits HIV-1 protease prevents cleavage of viral polyproteins www.freelivedoctor.com

39. 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 www.freelivedoctor.com

40. 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 www.freelivedoctor.com

41. 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 www.freelivedoctor.com

42. Anti-Hepatitis Agents Lamivudine - Nucleoside Reverse Transcriptase Inhibitor (NRTI) Adefovir - Nucleotide Inhibitor Interferon Alfa Pegylated Interferon Alfa Ribavirin www.freelivedoctor.com

43. Interferons 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 www.freelivedoctor.com

44. 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 www.freelivedoctor.com

45. 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 www.freelivedoctor.com

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47. Anti-Influenza Agents Amantadine Rimantadine Zanamivir www.freelivedoctor.com

48. 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 www.freelivedoctor.com

49. Zanamivir and Oseltamivir Inhibits the enzyme neuraminidase inhibit the replication of influenza A and Influenza B treats uncomplicated influenza infections administered intranasally www.freelivedoctor.com

50. Antiviral Agents

51. 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.

52. Understanding Viruses Viruses are difficult to kill because they live inside our cells. Any drug that kills a virus may also kill our cells.

53. 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

54. 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.

55. 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)

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

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

58. 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

59. 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

60. 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

61. 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

62. 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

63. Antivirals: Nursing Implications Before beginning therapy, thoroughly assess underlying disease and medical history, including allergies. Assess baseline VS and nutritional status. Assess for contraindications, conditions that may indicate cautious use, and potential drug interactions.

64. Antivirals: Nursing Implications Be sure to teach proper application technique for ointments, aerosol powders, etc. Emphasize hand washing before and after administration of medications to prevent site contamination and spread of infection. Patients should wear a glove or finger cot when applying ointments or solutions to affected areas.

65. Antivirals: Nursing Implications Instruct patients to consult their physician before taking any other medication, including OTC medications. Emphasize the importance of good hygiene. Inform patients that antiviral agents are not cures, but do help to manage symptoms.

66. Antivirals: Nursing Implications Instruct patients on the importance of taking these medications exactly as prescribed and for the full course of treatment. With zidovudine: Inform patients that hair loss MAY occur so that they are prepared for this rare adverse reaction. This medication should be taken on an empty stomach.

67. Antivirals: Nursing Implications Monitor for side effects: effects are varied and specific to each agent

68. Antivirals: Nursing Implications Monitor for therapeutic effects: effects will vary depending on the type of viral infection Effects range from delayed progression of AIDS and ARC to decrease in flu-like symptoms, decreased frequency of herpes-like flare-ups, or crusting over of herpetic lesions.