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    Anti viral agents Anti viral agents Presentation Transcript

    • Antiviral Agents www.freelivedoctor.com
    • 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
    • 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
    • Sites of Drug Action www.freelivedoctor.com
    • 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
    • Sites of Drug Action www.freelivedoctor.com
    • Antiherpes Agents
      • Acyclovir- prototype
      • Valacyclovir
      • Famciclovir
      • Penciclovir
      • Trifluridine
      • Vidarabine
      www.freelivedoctor.com
    • 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
    • Mechanism of Resistance Acyclovir
      • Alteration in viral thymidine kinase
      • Alteration in viral DNA polymerase
      • Cross-resistance with valacyclovir, famciclovir, and ganciclovir
      www.freelivedoctor.com
    • 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
    • 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
    • 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
    • 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
    • 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
    • Anti-Cytomegalovirus Agents
      • Gancyclovir
      • Valgancyclovir
      • Cidofovir
      • Foscarnet
      • Fomivirsen
      www.freelivedoctor.com
    • 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
    • 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
    • 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
    • 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
    • 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
    • www.freelivedoctor.com
    • Antiretroviral Agents
      • 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
      • 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
      • 3)Protease inhibitors
      www.freelivedoctor.com
    • Reverse Transcriptase Inhibitors
      • Zidovudine (AZT)
      • Didanosine- causes pancreatitis*
      • Lamivudine- causes pancreatitis
      • Zalcitabine- causes peripheral neuropathy *
      • Stavudine- causes peripheral neuropathy*
      • Abacavir
      www.freelivedoctor.com
    • 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
    • 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
    • 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
    • Side Effects Zidovudine
      • Myelosuppression, including anemia and neutropenia
      • GI intolerance, headaches, and insomnia
      www.freelivedoctor.com
    • 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
    • Nucleotide Inhibitors
      • Tenofovir
      • Adefovir
      www.freelivedoctor.com
    • 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
    • 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
    • Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
      • Nevirapine
      • Delavirdine
      • Efavirenz
      www.freelivedoctor.com
    • 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
      • 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
    • Protease Inhibitors
      • Indinavir
      • Ritonavir
      • Saquinavir
      • Nelfinavir
      • Amprenavir
      www.freelivedoctor.com
    • 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
    • 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
    • Saquinavir
      • A synthetic peptide-like substrate analog
      • inhibits HIV-1 protease
      • prevents cleavage of viral polyproteins
      www.freelivedoctor.com
    • 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
    • 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
    • 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
    • Anti-Hepatitis Agents
      • Lamivudine - Nucleoside Reverse Transcriptase Inhibitor (NRTI)
      • Adefovir - Nucleotide Inhibitor
      • Interferon Alfa
      • Pegylated Interferon Alfa
      • Ribavirin
      www.freelivedoctor.com
    • 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
    • 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
    • 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
    • www.freelivedoctor.com
    • Anti-Influenza Agents
      • Amantadine
      • Rimantadine
      • Zanamivir
      www.freelivedoctor.com
    • 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
    • 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
    • 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
      • Viruses are difficult to kill because they live inside our cells.
      • Any drug that kills a virus may also kill our cells.
    • 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
    • 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.
    • 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)
    • Antivirals: Mechanism of Action
      • Inhibit viral replication
      • Inhibit viral attachment
      • Prevent genetic copying of virus
      • Prevent viral protein production
    • Antivirals Synthetic Purine Nucleoside Analogues
      • Two types of nucleosides:
      • Purine nucleosides
      • guanine
      • adenosine
      • Pyrimidine nucleosides
      • thymine
      • cytosine
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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.
    • 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.
    • 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.
    • 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.
    • Antivirals: Nursing Implications
      • Monitor for side effects:
      • effects are varied and specific to each agent
    • 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.