Acyclovir (Zovirax)

2-Amino-1,9-dihydro-9-[2-(hydroxyethoxy)methyl]-6H-purin-6-one
Acyclovir, 9-[2-(hydroxyethoxy)methyl]-9H-guanine

1) Antiviral Agent
a) Synthetic purine nucleoside analogue

Antiviral is bioactivated
Target:
o Herpesviruses limited:
Herpes simplex 2
Genital herpes
Skin eruptions
Varicella zoster
Chickenpox (child)
Shingles (adults)

most effective of a series of acyclic nucleosides that possess antiviral activity.

In contrast with true nucleosides that have a ribose or a deoxyribose sugar attached to a
purine or a pyrimidine base, the group attached to the base in acyclovir is similar to an
open chain sugar, albeit lacking in hydroxyl groups.
It is most active (in vitro) against HSV type 1, about two times less against HSV type 2,
and 10 times less potent against varicellazoster virus (VZV).
An advantage is that uninfected human cells are unaffected by the drug.
The ultimate effect of acyclovir
o inhibition of viral DNA synthesis.
o Transport into the cell and monophosphorylation are accomplished by a thymidine
kinase that is encoded by the virus itself.
The affinity of acyclovir for the viral thymidine kinase is about 200 times that of the
corresponding mammalian enzyme. Hence, some selectivity is attained.
Enzymes in the infected cell catalyze the conversion of the monophosphate to acyclovir
triphosphate, which is present in 40 to 100 times greater concentrations in HSV-infected
than uninfected cells.
Acyclovir triphosphate competes for endogenous deoxyguanosine triphosphate (dGTP);
hence, acyclovir triphosphate competitively inhibits viral DNA polymerases.
The triphosphorylated drug is also incorporated into viral DNA, where it acts as a chain
terminator. Because it has no 3-hydroxyl group, no 3,5-phosphodiester bond can form.
This mechanism is essentially a suicide inhibition because the terminated DNA template
containing acyclovir as a ligand binds to, and irreversibly inactivates, DNA polymerase.
 Resistance to acyclovir can occur, most often by deficient thymidine kinase activity in HSV
isolates.
Acyclovir resistance in vesicular stomatitis virus (VSV) isolates is caused by mutations in
VSV thymidine kinase or, less often, by mutations in viral DNA polymerase.

Two dosage forms of acyclovir are available for systemic use: oral and parenteral.
o Oral acyclovir is used in the initial treatment of genital herpes and to control mild
recurrent episodes.
It has been approved for short-term treatment of shingles and chickenpox
caused by VZV.
o Intravenous administration is indicated for initial and recurrent infections in
immunocompromised patients and for the prevention and treatment of severe
episodes.

o The drug is absorbed slowly and incompletely from the GI tract

oral bioavailability is only 15% to 30%.
Nevertheless, acyclovir is distributed to virtually all body compartments.
Less than 30% is bound to protein
Most of the drug is excreted unchanged in the urine, about 10% excreted as
the carboxy metabolite.

o Acyclovir occurs as a chemically stable, white, crystalline solid that is slightly soluble in
water.
o Because of its amphoteric properties (pKa values of 2.27 and 9.25), solubility is increased
by both strong acids and bases.
o The injectable form is the sodium salt, which is supplied as a lyophilized powder,
equivalent to 50 mg/mL of active acyclovir dissolved in sterile water for injection.
o Because the solution is strongly alkaline (pH - 11), it must be administered by slow,
constant intravenous infusion to avoid irritation and thrombophlebitis at the
injection site.

o Adverse reactions are few. Some patients experience occasional GI upset, dizziness,
headache, lethargy, and joint pain.
o An ointment composed of 5% acyclovir in a polyethylene glycol base is available for the
treatment of initial, mild episodes of herpes genitalis
o The ointment is not an effective preventer of recurrent episodes.