DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1598
Herpes
simplex
Cytoplasm
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Cell
membrane
HO O
O
Acyclovir
Herpes thymidine
kinase
P O
O
Acyclovir
monophosphate
P P O
O
Acyclovir
diphosphate
P
Nucleus
P P O
O
Acyclovir
triphosphate
O –
H 2 C
O
P
O
H 2 C
OH
O
O
O
O P
O
P O –
O– O –
O
P O
O –
O
Herpes DNA
polymerase
O
CH 2
O
O P O –
O
CH 2
O
O P O –
O
CH 2
O
O P O –
O
Figure 58–3. Mechanism of Action of Acyclovir in Cells Infected by Herpes Simplex Virus. A herpes simplex virion is shown attaching to
a susceptible host cell, fusing its envelope with the cell membrane, and releasing naked capsids that deliver viral DNA into the nucleus,
where it initiates synthesis of viral DNA. Acyclovir molecules entering the cell are converted to acyclovir monophosphate by virusinduced
thymidine kinase. Host-cell enzymes add two more phosphates to form acyclovir triphosphate, which is transported into the
nucleus. After the herpes DNA polymerase cleaves pyrophosphate from acyclovir triphosphate (indicated by the red arrow in the
inset), viral DNA polymerase inserts acyclovir monophosphate rather than 2′-deoxyguanosine monophosphate into the viral DNA
(indicated by black arrows in the inset). Further elongation of the chain is impossible because acyclovir monophosphate lacks the 3′
hydroxyl group necessary for the insertion of an additional nucleotide, and the exonuclease associated with the viral DNA polymerase
cannot remove the acyclovir moiety. In contrast, ganciclovir and penciclovir have a 3′ hydroxyl group; therefore, further synthesis of
viral DNA is possible in the presence of these drugs. Foscarnet acts at the pyrophosphate-binding site of viral DNA polymerase and
prevents cleavage of the pyrophosphate from nucleoside triphosphates, thus stalling further primer template extension. The red bands
between the viral DNA strands in the inset indicate hydrogen bonding of the base pairs. (Adapted with permission from Balfour HH.
Antiviral drugs. N Engl J Med, 1999, 340:1255–1268. Copyright © 1999. Massachusetts Medical Society. All rights reserved.)
secretion is the principal route of elimination. Less than 15% is
excreted as 9-carboxymethoxymethylguanine or minor metabolites.
The pharmacokinetics of oral acyclovir and valacyclovir
appear to be similar in pregnant and nonpregnant women
(Kimberlin et al., 1998).
Untoward Effects. Acyclovir generally is well tolerated. Topical acyclovir
in a polyethylene glycol base may cause mucosal irritation
and transient burning when applied to genital lesions.
Oral acyclovir has been associated infrequently with nausea,
diarrhea, rash, or headache and very rarely with renal insufficiency
or neurotoxicity. Valacyclovir also may be associated with
headache, nausea, diarrhea, nephrotoxicity, and central nervous system
(CNS) symptoms. High doses of valacyclovir have been associated
with confusion and hallucinations, nephrotoxicity, and
uncommonly, severe thrombocytopenic syndromes, sometimes
fatal, in immunocompromised patients. Acyclovir has been associated
with neutropenia in neonates. Chronic acyclovir suppression of
genital herpes has been used safely for up to 10 years. No excess
frequency of congenital abnormalities has been recognized in
infants born to women exposed to acyclovir during pregnancy
(Ratanajamit et al., 2003).