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Antivirals
Jason Ryan, MD, MPH
Antiviral Drugs
• Influenza drugs
• Zanamivir, oseltamivir
• Ribavirin
• RSV, Hepatitis C
• Acyclovir AfraTafreeh.com
• Herpes viruses
• CMV Drugs
• Ganciclovir
• Foscarnet
• Cidofovir
• Interferon
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Zanamivir/Oseltamivir
• Used for treatment of influenza
• Inhibit neuraminidase
• Enzyme that cleaves sialic acid from glycoproteins
• Required step in exit from infected cells
• Efficacy only demonstrated 1st 48hrs of illness
DNA/RNA Drugs
General Principles
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Madeleine Price Ball/Wikipedia
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DNA/RNA Drugs
General Principles
Adenosine
Cytidine
Guanosine
Thymidine
Uridine
DNA/RNA Drugs
General Principles
• Many antivirals mimic nucleotides (A, C, G, T)
• Ribavirin, Acyclovir, Ganciclovir, Cidofovir
• Drug used by DNA or RNA polymerase
• Once used, chain terminates (inhibition)
• “Inhibitors” of RNA/DNA polymerase
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• Drugs often need to become tri-phosphorylated
• Viral kinase and/or cellular kinases
• Mutations of viral kinases often lead to resistance
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Ribavirin
• Inhibition of RNA polymerase
• Triphosphorylated by cellular kinase enzymes
• Binds RNA polymerase, prevents binding correct nucleotides
• Result: ↓ in viral replication/production of defective virions
Ribavirin Guanosine
Wikipedia/Public Domain
Ribavirin
• Inhibits IMP dehydrogenase
• Inosine monophosphate dehydrogenase
• Used to synthesize guanine nucleotides Ribavirin
• Inhibited by Ribavirin
• Decreases pool of available guanine nucleotides
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IMP Guanosine Monophosphate
Wikipedia/Public Domain
cacycle /Wikipedia
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Ribavirin
• Two main modern uses
• RSV in children
• Hepatitis C
• Often with interferon
• Key side effect: Hemolytic anemia
• Drug accumulates in RBCs
• Drug phosphorylation → relative ATP deficiency
• Hemolytic anemia in ~10% patients
• Can be severe
• Highly teratogenic
Acyclovir
• Inhibitor of herpes virus DNA polymerase
• Mimics guanosine → terminates chain growth
d-guanosine
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Self/Wikipedia
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Acyclovir
• Phosphorylated by herpes virus thymidine kinase
• Becomes acyclovir monophosphate
• Only occurs in infected cells (targeted effect)
• Monophosphate → triphosphate by cellular enzymes
• Acts as analog to deoxyguanosine triphosphate (dGTP)
• Inhibits viral DNA polymerase
• Resistance:
• ↓ viral thymidine kinase
• Altered viral thymidine kinase
• Altered viral DNA polymerase (↓ binding acyclovir triphos.)
Acyclovir
• Famciclovir: Similar mechanism
• Longer half-life (lower dose can be used)
• Valacyclovir: Pro-drug, converted to acyclovir
• Greater bioavailability (lower dose can be used)
• All 3 drugs generally well tolerated
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• Acyclovir: Nephrotoxicity (IV form)
• Crystalizes in urine
• Given with IV fluids
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Acyclovir
• Effective for HSV-1, HSV-2, and VZV
• Uses
• Genital herpes
• Herpes labials
• Herpes encephalitis
• Herpes zoster
• Sometimes given for “suppressive” therapy
CMV Drugs
• Used to treat CMV infections
• HIV/AIDS
• Transplant patients
• Three key drugs
• Ganciclovir AfraTafreeh.com
• Foscarnet
• Cidofovir
• All interfere with CMV DNA polymerase
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Ganciclovir
• Similar mechanism to acyclovir (analog to guanosine)
• Intracellular conversion by CMV viral kinase
• Becomes ganciclovir 5'-monophosphate
• Monophosphate → triphosphate by cellular enzymes
• Acts as analog to deoxyguanosine triphosphate (dGTP)
• Incorporation terminates chain growth
Ganciclovir
• Major toxicity:
• Bone marrow suppression especially leukopenia
• Inhibits bone marrow DNA polymerase
• Valganciclovir
• Pro-drug AfraTafreeh.com
• Converted to ganciclovir
• Better bioavailability
• Ganciclovir given primarily IV (poor bioavailability)
• Oral valganciclovir preferred for oral dosing
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Foscarnet
• Pyrophosphate analog
• Binds/inhibits viral DNA polymerase
• Blocks cleavage pyrophosphate from triphosphates
• Stops DNA chain elongation
Deoxyadenosine Triphosphate
Foscarnet
Wikipedia/Public Domain
Foscarnet
• Uses:
• CMV when Ganciclovir fails
• Acyclovir-resistant HSV and VZV
• Side effects
• Nephrotoxicity (limiting side effect)
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• Chelates calcium (hypocalcemia)
• Induces renal wasting of magnesium (hypomagnesaemia)
• Seizures (often related to electrolytes)
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Cidofovir
• Nucleotide analog (cytidine)
• Cellular phosphorylation
• No viral kinase required
• Inhibits viral DNA polymerase
• Main use is CMV retinitis
• Main toxicity is renal failure
• Co-administer with saline
• Probenecid (blocks renal tubular secretion of drug)
Wikipedia/Public Domain
Interferons
• Cytokines
• Glycoproteins synthesized by infected cells
• Numerous immunomodulatory effects
• Interferon α
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• Hepatitis B and C
• Kaposi sarcoma (HHV-8)
