Inhibition of Intracellular Synthesis by

Analogs of Viral Nucleic Acids

Ribavirin, Acyclovir, Valacyclovir, Ganciclovir,
Valganciclovir, Famciclovir, Penciclovir,
Foscarnet, Adefovir Dipivoxil, Entecavir, and
Telbivudine
Many antivirals end in -ovir.
Mechanism of action
Ribavirin and the other drugs interfere with intracellular viral
replication processes. Most of these drugs are guanosine
analogs (acyclovir, valacyclovir, ganciclovir, valganciclovir,
famciclovir, penciclovir, and entecavir). Adefovir dipivoxil
and telbivudine are analogs of adenosine monophosphate
and thymidine, respectively. Adefovir dipivoxil is phosphorylated
to its active metabolite, adefovir diphosphate, and
telbivudine is phosphorylated to its triphosphate form, both
of which inhibit hepatitis B virus (HBV) DNA polymerase
(reverse transcriptase). The exact mechanism of ribavirin
is not known, but it may act as an analog of guanosine or
xanthosine. These drugs are first phosphorylated by a viral
thymidine kinase and subsequently phosphorylated by the
host cell before drug incorporation into viral nucleic acids.
When the phosphorylated drugs are encountered by viral
polymerases, the drugs are recognized as foreign and viral
polymerase action is halted.
Unlike other antivirals in this class, foscarnet, although
still an inhibitor of viral DNA polymerases, does not need
to be activated (or phosphorylated) for its activity. Foscarnet
binds directly to viral DNA polymerases and inhibits their
activity.
Pharmacokinetics
Valacyclovir, valganciclovir, and famciclovir are simply prodrugs
of acyclovir, ganciclovir, and penciclovir, respectively,
with superior bioavailability over the parent compounds.
These antivirals are excreted renally, so dosage adjustments
are necessary at low glomerular filtration rates.
Clinical use
Ribavirin is approved as an aerosol for treating respiratory
syncytial virus, a leading cause of pneumonia in infants; however,
the aerosolized drug has cumbersome requirements
(e.g., endotracheal intubation) because sometimes patients,
especially infants, suddenly get worse with inhalation. In addition,
strict isolation is necessary to prevent drug exposure to
pregnant visitors and caregivers.