Antiviral Agents

Antiviral Agents
By:Jillian H. Davis
Department of Pharmacology, Howard University

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
* Steps for Viral Replication

Sites of Drug Action
Antiviral Agents
Antiherpes Agents
* Acyclovir- prototype
* Valacyclovir
* Famciclovir
* Penciclovir
* Trifluridine
* Vidarabine
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
* Alteration in viral thymidine kinase
* Alteration in viral DNA polymerase
* Cross-resistance with valacyclovir, famciclovir, and ganciclovir

Clinical Uses Acyclovir
* Oral, IV, and Topical formulations
* Cleared by glomerular filtration and tubular secretion
* Uses:
o Herpes Simplex Virus 1 and 2 (HSV)
o Varicella-zoster virus (VZV)
* Side Effects: nausea, diarrhea, headache, tremors, and delirium

Valacyclovir
* L-valyl ester of acyclovir
* Converted to acyclovir when ingested
* M.O.A.: same as acyclovir
* Uses:
o 1) recurrent genital herpes
o 2) herpes zoster infections
* Side Effects: nausea, diarrhea, and headache

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

Trifluridine
* Trifluridine- fluorinated pyrimidine
o inhibits viral DNA synthesis same as acyclovir
o incorporates into viral and cellular DNA
o Uses: HSV-1 and HSV-2 (topically)
Vidarabine
* An adenosine analog
* inhibits viral DNA polymerase
* incorporated into viral and cellular DNA
* metabolized to hypoxanthine arabinoside
* Side Effects: GI intolerance and myelosuppression

Anti-Cytomegalovirus Agents
* Gancyclovir
* Valgancyclovir
* Cidofovir
* Foscarnet
* Fomivirsen

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

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

Cidofovir
* 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

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

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

Antiretroviral Agents
1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
3)Protease inhibitors

Reverse Transcriptase Inhibitors
* Zidovudine (AZT)
* Didanosine- causes pancreatitis*
* Lamivudine- causes pancreatitis
* Zalcitabine- causes peripheral neuropathy*
* Stavudine- causes peripheral neuropathy*
* Abacavir

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

Mechanism of Resistance Zidovudine
* Due to mutations in the reverse transcriptase gene
* more frequent after prolong therapy and in persons with HIV

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

Side Effects Zidovudine
* Myelosuppression, including anemia and neutropenia
* GI intolerance, headaches, and insomnia

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


Nucleotide Inhibitors
* Tenofovir
* Adefovir

Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
* Nevirapine
* Delavirdine
* Efavirenz
Mechanism of Action NNRTIs
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Protease Inhibitors
Indinavir and Ritonavir
Saquinavir
Nelfinavir and Amprenavir
Fusion Inhibitors
Anti-Hepatitis Agents
Interferons
Ribavirin
Anti-Influenza Agents
Amantadine and Rimantadine
Zanamivir and Oseltamivir
Antifungal Agents
Fungal Infections
Systemic Antifungals
Amphotericin B
Flucytosine
Azoles
Differences in Azoles
Mucocutaneous Antifungals
Topical Antifungals

Antiviral Agents.ppt