Page 880 - Basic _ Clinical Pharmacology ( PDFDrive )

866 SECTION VIII Chemotherapeutic Drugs

ACYCLOVIR diffuses readily into most tissues and body fluids. Cerebrospinal
fluid concentrations are 20–50% of serum values.
Acyclovir is an acyclic guanosine derivative with clinical activ- Acyclovir is the only one of the three antiherpes agents that
ity against HSV-1, HSV-2, and VZV, but it is approximately is available for intravenous use in the United States. Intrave-
10 times more potent against HSV-1 and HSV-2 than against nous acyclovir is the treatment of choice for herpes simplex
VZV. In vitro activity against Epstein-Barr virus (EBV), cyto- encephalitis, neonatal HSV infection, and serious HSV or
megalovirus (CMV), and human herpesvirus-6 (HHV-6) is VZV infections (Table 49–1). In neonates with central nervous
present but weaker. system HSV, oral acyclovir suppression for 6 months follow-
Acyclovir requires three phosphorylation steps for activation. ing acute treatment improves neurodevelopmental outcomes.
It is converted first to the monophosphate derivative by the virus- In immunocompromised patients with VZV infection, intrave-
specified thymidine kinase and then to the di- and triphosphate nous acyclovir reduces the incidence of cutaneous and visceral
compounds by host cell enzymes (Figure 49–2). Because it dissemination.
requires the viral kinase for initial phosphorylation, acyclovir is Topical acyclovir cream is substantially less effective than oral
selectively activated—and the active metabolite accumulates— therapy for primary HSV infection. It is of no benefit in treating
only in infected cells. Acyclovir triphosphate inhibits viral DNA recurrent genital herpes.
synthesis by two mechanisms: competition with deoxyGTP for Resistance to acyclovir can develop in HSV or VZV through
the viral DNA polymerase, resulting in binding to the DNA tem- alteration in either the viral thymidine kinase or the DNA poly-
plate as an irreversible complex; and chain termination following merase, and clinically resistant infections have been reported in
incorporation into the viral DNA. immunocompromised hosts. Most clinical isolates are resistant
The bioavailability of oral acyclovir is low (15–20%) and is on the basis of deficient thymidine kinase activity and thus
unaffected by food. Topical formulations produce high concentra- are cross-resistant to valacyclovir, famciclovir, and ganciclovir.
tions in herpetic lesions, but systemic concentrations are undetect- Agents such as foscarnet, cidofovir, and trifluridine do not
able by this route. require activation by viral thymidine kinase and therefore have
Acyclovir is cleared primarily by glomerular filtration and preserved activity against the most prevalent acyclovir-resistant
tubular secretion. The half-life is 2.5–3 hours in patients with nor- strains (Figure 49–2).
mal renal function and 20 hours in patients with anuria. Acyclovir Acyclovir is generally well tolerated, although nausea, diarrhea,
and headache may occur. Intravenous infusion may be associ-
ated with reversible renal toxicity (ie, crystalline nephropathy or
interstitial nephritis) or neurologic effects (eg, tremors, delirium,
Nucleoside seizures). However, these are uncommon with adequate hydration
Blocked by Virus-specified
acyclovir and avoidance of rapid infusion rates. High doses of acyclovir
penciclovir enzymes cause chromosomal damage and testicular atrophy in rats, but
ganciclovir (eg, thymidine
kinase, UL97) there has been no evidence of teratogenicity, reduction in sperm
Monophosphate production, or cytogenetic alterations in peripheral blood lym-
phocytes in patients receiving daily suppression of genital herpes
for more than 10 years. A recent study found no evidence of
Blocked by increased birth defects in infants exposed to acyclovir during the
trifluridine first trimester. In fact, the American College of Obstetricians and
cidofovir Host
kinases Gynecologists recommends suppressive acyclovir therapy begin-
ning at week 36 in pregnant women with active recurrent genital
herpes to reduce the risk of recurrence at delivery and possibly the
Diphosphate need for cesarean section.
Concurrent use of nephrotoxic agents may enhance the
Blocked by
foscarnet potential for nephrotoxicity. Probenecid and cimetidine decrease
acyclovir clearance and increase exposure. Somnolence and leth-
Triphosphate argy may occur in patients receiving concomitant zidovudine
and acyclovir.

Incorporation into Inhibits viral DNA
viral DNA polymerase VALACYCLOVIR

Valacyclovir is the l-valyl ester of acyclovir. It is rapidly converted
Chain
termination to acyclovir after oral administration via first-pass enzymatic
hydrolysis in the liver and intestine, resulting in serum levels
FIGURE 49–2 Mechanism of action of antiherpes agents. that are three to five times greater than those achieved with oral