AGENTS TO TREAT HERPES

SIMPLEX VIRUS & VARICELLA-

ZOSTER VIRUS INFECTIONS

Department of Pharmacology
Faculty of Medicine
University of Lampung
SKDI
Classification of
Antiviral Agents
(non-retroviral)
The Major Sites of Antiviral Drug Action
 Anti-HSV and VZV Agents
Foscarnet
Trifluridine
Penciclovir
Famciclovir
Valacyclovir
Acyclovir
 Anti-CMV Agents

Foscarnet
Cidofovir
Ganciclovir
 Acyclovir
Mechanism of action of Acyclovir:
All drugs are phosphorylated by a viral
thymidine-kinase, then metabolized by
host cell kinases to nucleotide analogs.
The analog inhibits viral DNA-polymerase.
Only actively replicating viruses are
inhibited.
M
O
A
 Acycolvir
Acyclovir is thus selectively activated in
cells infected with herpes virus.
Uninfected cells do not phosphorylate
acyclovir.
Acyclovir: PK
Untoward Effects (well-tolerated)
Topical acyclovir: mucosal irritation
Oral: nausea, diarrhea, rash, headache
renal insuff, neurotoxicity
IV: renal insuff, CNS

Therapeutic Uses
- better clinical benefit
- in initial infection than in recurrent
- in HSV than VZV
Resistance
Develop through alteration in either the viral
thymidine kinase or the DNA polymerase.
Reported in immunocompromised hosts.
Cross-resistant to valacyclovir, famciclovir, and
ganciclovir.
Agents such as foscarnet, cidofovir, and trifluridine
do not require activation by viral thymidine kinase
>> have preserved activity against the most
prevalent acyclovir-resistant strains.
PHARMACOLOGY OF ACYCLOVIR AND
CONGENERS
Acyclovir, Valacyclovir, Ganciclovir, Famciclovir,
Penciclovir all are guanine nucleoside analogs.
Acyclovir & Congeners:
Valacyclovir is a prodrug of Acyclovir with
better bioavailability (48%).
Famciclovir is hydrolyzed to Penciclovir and
has greatest bioavailability (70%).
Penciclovir is used only topically whereas
Famciclovir can be administered orally.
 Trifluridine
Trifluridine (trifluorothymidine) is a fluorinated
pyrimidine nucleoside >> inhibits viral DNA synthesis.
It is phosphorylated intracellularly to its active form
by cellular enzymes, then competes with thymidine
triphosphate for incorporation by the viral DNA
polymerase.
Incorporation of trifluridine triphosphate into both
viral and cellular DNA prevents its systemic use.
Ganciclovir
 Ganciclovir
T
Adm
ADR
Resistance
 Valganciclovir
Well-absorbed and rapidly metabolized in the intestinal w
Cidofovir
Cidofovir
 FOSCARNET
A broad in vitro antiviral activity.
Apporoved for CMV retinitis in
immunocompromised hosts and acyclovir-resistant
HSV and HZV inf.
Reversibly inhibiting viral DNA and RNA
polymerases, thereby terminating chain elongation
mutation of polymerase structure, without
requiring activation by phosphorylation.
 FOSCARNET
Poorly absorbed orally and must be injected IV.
Distrib: throughout the body, > 10% enters the bone
matrix
Eliminated: tubular secretion into the urine
ADR: nephrotoxicity, anemia, nausea, and fever.
Hypocalcemia and hypomagnesemia are also seen.
Resistence: due to point mutations in the DNA
polymerase gene