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
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
Block viral entry into the cell or must work inside the cell Most agents are pyrimidine or purine nucleoside analogs
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
Alteration in viral thymidine kinase Alteration in viral DNA polymerase Cross-resistance with valacyclovir, famciclovir, and ganciclovir
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 Ef fects: nausea, diarrhea, headache, tremors, and delirium
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 Ef fects: nausea, diarrhea, and headache
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 Ef fects: nausea, diarrhea, and headache
Trifluridine- fluorinated pyrimidine inhibits viral DNA synthesis same as acyclovir incorporates into viral and cellular DNA Uses: HSV-1 and HSV-2 (topically)
An adenosine analog inhibits viral DNA polymerase incorporated into viral and cellular DNA metabolized to hypoxanthine arabinoside Side Ef fects: GI intolerance and myelosuppression
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 Ef fect: myelosuppression
Monovalyl ester prodrug of gancyclovir Metabolized by intestinal and hepatic esterases when administered orally M.O.A.: same as gancyclovir Uses: CMV* Side Ef fect: myelosuppression
Aphosphorylation cytosine analog not dependent on viral enzymes Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus Side Ef fects: nephrotoxicity (prevented by admin. of probenecid) Resistance: mutation in DNA polymerase gene
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 Ef fects: hypo- or hypercalcemia and phosphotemia
An oligonucleotide M.O.A.: binds to mRNA and inhibits protein synthesis and viral replication Uses: CMV retinitis Side ef fects: iritis and increased intraocular pressure
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
Due to mutations in the reverse transcriptase gene more frequent after prolong therapy and in persons with HIV
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
Myelosuppression, including anemia and neutropenia GI intolerance, headaches, and insomnia
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
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
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 ef fects - nephrotoxicity
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
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
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
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 Ef fects:hyperbilirubinemia Contraindications:inhibitor/substrate for CPY3A4, do not give with antifungal azoles
A synthetic peptide-like substrate analog inhibits HIV-1 protease prevents cleavage of viral polyproteins
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 Ef fects: diarrhea and flatulence Amprenavir can cause Stevens-Johnson syndrome Contraindications:inhibitor/substrate for CPY3A4
Enfuvir tide (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
Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI) Adefovir -Nucleotide Inhibitor Inter feron Alfa Pegylated Inter feron Alfa Ribavirin
Inter feron 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
Pegylated inter feron 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
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
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
Inhibits the enzyme neuraminidase inhibit the replication of influenza A and Influenza B treats uncomplicated influenza infections administered intranasally
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.
Viruses are difficult to kill because they live inside our cells. Any drug that kills a virus may also kill our cells.
Competent immune system: Best response to viral infections A well-functioning immune system will eliminate or effectively destroy virus replicationImmunocompromised patients have frequent viral infections Cancer patients, especially leukemia or lymphoma Transplant patients, due to pharmacological therapy AIDS patients, disease attacks immune system
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.
Viruses killed by current antiviral therapy: cytomegalovirus (CMV) herpes simplex virus (HSV) human immunodeficiency virus (HIV) influenza A (the “flu”) respiratory syncytial virus (RSV)
Inhibit viral replication Inhibit viral attachment Prevent genetic copying of virus Prevent viral protein production
Two types of nucleosides:Purine nucleosides guanine adenosinePyrimidine nucleosides thymine cytosine
Agent Antiviral Activityguanines acyclovir HSV 1 & 2, VZV ganciclovir (DHPG) CMV retinitis and systemic CMV infection ribavirin (RTCD) Influenza types A and B, RSV, LV, HVadenosines didanosine (ddl) HIV vidarabine (Ara-A) HSV, herpes zoster
Agent Antiviral Activitycytosines lamivudine (3TC) HIV zalcitabine (ddC) HIVthymine idoxuridine (IDU) HSV stavudine (d4T) HIV trifluridine HSV zidovudine (AZT) HIV
amantadine (Symmetrel) and rimantadine (Flumadine) influenza Afoscarnet (Foscavir) CMV (retinitis and systemic)Neuraminidase Inhibitors: oseltamivir (Tamiflu) and zanamivir (Relenza) influenza types A and B
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.
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.
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.
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.
Monitor for side effects: effects are varied and specific to each agent
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.