Nelia B. Perez RN, MSNPCU-MJCN

BSN 2014

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

Acyclovir- prototype Valacyclovir Famciclovir Penciclovir Trifluridine Vidarabine

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 Effects: 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 Effects: 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 Effects: 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 Effects: GI intolerance and

myelosuppression

Gancyclovir Valgancyclovir Cidofovir Foscarnet Fomivirsen

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

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

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

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

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

1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

3)Protease inhibitors

Zidovudine (AZT) Didanosine- causes pancreatitis* Lamivudine- causes pancreatitis Zalcitabine- causes peripheral neuropathy*

Stavudine- causes peripheral neuropathy* Abacavir

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

Tenofovir Adefovir

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 effects - nephrotoxicity

Nevirapine Delavirdine Efavirenz

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

Indinavir Ritonavir Saquinavir Nelfinavir Amprenavir

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 Effects: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 Effects: diarrhea and flatulence Amprenavir can cause Stevens-Johnson

syndrome Contraindications:inhibitor/substrate for

CPY3A4

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

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Lamivudine -Nucleoside Reverse Transcriptase Inhibitor (NRTI)

Adefovir -Nucleotide Inhibitor Interferon Alfa Pegylated Interferon Alfa Ribavirin

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

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

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

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Amantadine Rimantadine Zanamivir

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 liveinside 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 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

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 adenosine

Pyrimidine 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, HV

adenosines

didanosine (ddl) HIV

vidarabine (Ara-A) HSV, herpes zoster

Agent Antiviral Activitycytosines

lamivudine (3TC) HIVzalcitabine (ddC) HIV

thymineidoxuridine (IDU) HSVstavudine (d4T) HIVtrifluridine HSVzidovudine (AZT) HIV

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

acyclovir Burning when topically applied, nausea,

vomiting, diarrhea, headache

amantadine and rimantadine Anticholinergic effects, insomnia,

lightheadedness, anorexia, nausea

didanosine (ddl) Pancreatitis, peripheral neuropathies, seizures

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

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.

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