Systemic
antiviral agents
Acyclovir is a
synthetic purine nucleoside analogue (similar in chemical structure to
deoxyguanosine) that has a high affinity for HSV-1, HSV-2, and VZV thymidine
kinase, which phosphorylates and activates the drug. Human cellular guanylate
kinase then phosphorylates acyclovir twice, to transform it into acyclovir
triphosphate, which blocks viral DNA synthesis by competitively inhibiting and
inactivating viral DNA polymerase and by becoming irreversibly incorporated
into the viral DNA chain, causing DNA chain termination. Valacyclovir,
penciclovir, and famciclovir have similar mechanisms of action. Cidofovir is an
acyclic nucleoside phosphate analogue of deoxycytosine monophosphate that does
not require viral thymidine kinase to become activated, but otherwise also
has a similar mechanism.
|
SIDE EFFECTS OF SYSTEMIC ANTIVIRAL AGENTS |
|
|
Acyclovir
and valacyclovir |
· Cutaneous:
morbilliform eruption, Stevens–Johnson syndrome, injection site reaction,
urticaria, angioedema · Gastrointestinal:
nausea, vomiting, diarrhea, abdominal pain · Hematologic: aplastic
anemia, leukopenia, thrombocytopenia · Neurologic: headaches,
vertigo, lethargy, confusion, hallucinations, depression, seizures,
encephalopathy, coma (CNS disturbances more likely in elderly patients) · Cardiovascular:
hypertension, tachycardia, anaphylaxis · Other: malaise,
arthralgia, myalgia, dyspnea, dysmenorrhea · Reversible
crystalluria-induced nephropathy with intravenous acyclovir (typically in
patients with pre-existing renal dysfunction or dehydration) · Thrombotic
thrombocytopenic purpura or hemolytic uremic syndrome in immunocompromised
patients with valacyclovir |
|
Famciclovir |
· Pruritus, paresthesia, headache, fatigue, nausea, vomiting, diarrhea, and flatulence |
|
DRUG INTERACTIONS OF SYSTEMIC ANTIVIRAL AGENTS |
|
|
Interacting drug |
Result |
|
Amphotericin |
Increases
serum acyclovir level |
|
Cimetidine |
Decreases
rate of conversion of valacyclovir to acyclovir |
|
Digoxin |
Famciclovir increases digoxin levels |
|
Glyburide
with metformin (Glucovance®) |
Acyclovir
or valacyclovir may cause lactic acidosis in patients with decreased renal
function |
|
Interferon |
May
worsen potential neurotoxicity of acyclovir |
|
Intrathecal
methotrexate |
May
worsen potential neurotoxicity of acyclovir |
|
Nephrotoxic
drugs (i.e. cisplatin) |
Acyclovir
increases risk of nephrotoxicity |
|
Probenecid |
Decreases
rate of conversion of valacyclovir to acyclovir |
|
Theophylline |
Acyclovir
causes decreased metabolism and increased serum levels of theophylline |
|
Zidovudine |
Increases
serum levels of acyclovir and valacyclovir |
Acyclovir
Mechanism of Action
This purine nucleoside analogue has
been the standard treatment for decades. Acyclovir, 9-[(2-hydr-oxyethoxy) methyl]
guanine, was the first orally available drug to be widely used for the
treatment of herpes simplex virus (HSV) and varicella-zoster virus (VZV)
infections. The triphosphate form of the drug is the active form, which has a
potent inhibitory effect on herpes virus-induced DNA polymerases but relatively
little effect on host cell DNA polymerase. Thus it has the ability to inhibit
viral replication without significantly damaging the host cells. The human DNA
polymerase is 30–50 times less sensitive to acyclovir, which is why there are
hardly any undesired effects. As such, it has a tremendous margin of safety when
used to treat herpetic infections. Acyclovir triphosphate causes premature
termination of the nascent viral DNA chain. HSV- and VZV-induced thymidine
kinases result in efficient phosphorylation of acyclovir to acyclovir
monophosphate, the first step in drug metabolism. This step is not accomplished
efficiently by normal cellular kinases, resulting in greater concentrations of
active drug in infected cells.
Pharmacokinetics
While acyclovir is available in oral,
intravenous, and topical formulations, the oral bioavailability is only in the
range of 15%–30%, while the topical form even less. Excretion is almost entirely
renal, with approximately 62% of renally excreted drug being unmetabolized.
Because of this reliance on renal excretion, the dose must be reduced for
patients with a creatinine clearance of less than 50 mL/min. Acyclovir is water
soluble and achieves good levels in a variety of body fluids, including the
contents of vesicles, cerebrospinal fluid (1:2 ratio from serum concentration),
and vaginal secretions. Acyclovir has been marketed as a 5% cream. The effectiveness of such external
applications is, however, low, as they need to be applied in the early phase
and at intervals of about 2 h in order to sufficiently inhibit the virus.
Commonly Used
Dosing Regimens for Acyclovir
|
Condition |
Dosage |
Route |
Duration |
|
Primary
HSV infection, immunocompetent host |
400 mg
tid |
Oral |
7–10
days |
|
Recurrent
genital HSV infection, immunocompetent host |
400 mg
tid or 800 mg
tid |
Oral Oral |
5 days 2 days |
|
Recurrent
oral labial HSV infection, immunocompetent host |
400 mg
5×/day or 5% cream
6×/day |
Oral Topical |
5 days 7 days |
|
Mucocutaneous
HSV infection, immunocompromised host |
5 mg/kg
q8h or 400 mg
5×/day |
IV Oral |
7 days 14–21
days |
|
Perinatal
HSV infection |
10–20
mg/kg q8h |
IV |
10–21
days |
|
Chronic
suppression of HSV infection |
400 mg bid or 800 mg
qd |
Oral |
Up to 1
year |
|
HSV-1
Encephalitis |
10
mg/kg q8h |
IV |
14–21
days |
|
Varicella:
adolescent >40 kg /adult |
800 mg
4×/day |
Oral |
5 days |
|
Varicella:
pneumonia or third trimester pregnancy |
800 mg
5×/day or 10
mg/kg q8h |
Oral IV |
5 days 5 days |
|
Herpes
zoster: normal host or not severe disease in immunocompromised host |
800 mg
5×/day |
Oral |
7–10
days |
|
Herpes
zoster: severe disease or immunocompromised host |
10–12
mg/kg q8h |
IV |
7–14
days |
HSV = herpes simplex virus.
Acyclovir
is indicated in variety of infections, including that of primary HSV-1/ HSV-2
as well as VZV. It has been
suggested that suppression of genital HSV recurrences may reduce the risk of
acquisition of HIV.
Acyclovir given in late pregnancy to women with recurrent genital herpes has been
shown to decrease the frequency of genital lesions as well as subclinical viral
shedding. This can result in a decrease in the number of Caesarean sections
performed. Unfortunately, breakthrough lesions
and viral shedding can still occur and recent evidence suggests that standard
oral dosing of acyclovir in late pregnancy often results in insufficient levels to prevent viral
shedding on delivery. As a result, acyclovir treatment is still recommended to
neonates of mothers with recent genital HSV infection
Despite its high efficacy,
resistance to acyclovir remains an issue with herpes infections. Data from
corneal HSV-1 isolates suggests that infections commonly represent mixtures of acyclovir-sensitive and resistant viruses
with different thymidine kinase gene sequences. The acyclovir-resistant
HSV-1 can establish latency and reactivate intermittently to cause
acyclovir-refractory disease.
Initiation of Therapy
Treatment for mucocutaneous HSV
disease should begin as early as possible. For recurrent disease, treatment may
be in the form of continuous suppression or episodic treatment beginning during
the prodromal period. Treatment for varicella is most effective if it can be
started within 24 hours of onset of vesicles. In immunocompetent patients,
treatment for zoster has proven benefit if started within 72 hours of onset of
the eruption.
Dosing Regimens
Treatment regimens with acyclovir vary depending on
the indication and route of administration. An IV dose of 5mg per kg every 8
hours or oral dose of 400 mg 3 times daily is generally recommended and more
successful for patient compliance than 200 mg 5 times daily. Chronic
suppression requires an oral dose of 400 mg 2 times daily for up to 12 months. In
immunosuppressed and newborn babies, IV treatment should be considered.
Monitoring of Therapy
The dose should be adjusted for
patients with a creatinine clearance level of less than 50 mL/min, but drug
level assays are not routinely performed.
Side effects and Precautions
Renal (5% incidence of adverse
reactions)
·
Crystallization in renal tubules leading to
obstructive nephropathy
·
Interstitial nephritis
Central nervous system (1%
incidence)
·
Lethargy
·
Tremors
·
Confusion
·
Seizures
Miscellaneous
·
Phlebitis with intravenous administration
·
Rash
·
Recall dermatitis
·
Fixed drug eruption
·
Elevated liver function tests
·
Neutropenia
Acyclovir is generally very well tolerated. Renal impairment is uncommon (5% incidence). The major risk for impairment is renal tubular crystallization with rapid intravenous administration. The infusion duration should be at least 1 h. Caution must be exercised with high doses and in the setting of dehydration. Interstitial nephritis has also been reported. Central nervous system toxicity is uncommon, but may manifest as lethargy, tremors, or seizures. Patients with these side effects commonly have underlying diseases involving the central nervous system. Thrombophlebitis is a known complication of infusion, and appears to be related to the high pH of the reconstituted solution (pH 11).
It should be warned that acyclovir crosses the
human placenta and is excreted in breast milk. However, it has determined safe
for use in pregnancy (pregnancy category B). During pregnancy, primary infections or
recurrences can be treated despite the lack of official approval; no
significant risks for the fetus have been documented. Particularly in the first
14 weeks of pregnancy, the indication for administration must be carefully
weighed. The drug
is also safe for administration during active breast-feeding, so long as the
nursing mother does not have active lesions near or on the breast.
Valacyclovir
Mechanism of Action and
Pharmacokinetics
Valacyclovir, the l-valine ester of acyclovir, was developed to provide
increased oral bioavailability of the active drug acyclovir. Valacyclovir is readily absorbed from the
gastrointestinal tract and almost entirely converted to acyclovir by intestinal
and hepatic esterases, so that it can reach an average blood concentration as
high as that of intravenously (IV) administered acyclovir, and thus also
represents a per oral alternative in cases of immunosuppression.
The mechanism of action and spectrum of
activity of valacyclovir are identical to those of acyclovir, though improved
from its predecessor. Valacyclovir has an oral bioavailability of 55%. Following
a 1-g oral dose of valacyclovir, peak plasma concentrations of acyclovir in the
range of 5.7 μg/mL are achieved in 1.75 hours, and area-under-the-curve (AUC)
concentrations are similar to those achieved with 5 mg/kg of acyclovir given
intravenously. Excretion is primarily renal, with 89% metabolized to acyclovir. Like acyclovir, the dose must be adjusted for
those with underlying renal impairment.
Dosing Regimens for
Valacyclovir
|
Condition |
Dosage |
Route |
Duration |
|
Primary
HSV infection, immunocompetent host |
1,000
mg bid |
Oral |
10 days |
|
Recurrent
genital HSV infection, immunocompetent host |
500 mg
bid |
Oral |
3 days |
|
Recurrent
oral labial HSV infection, immunocompetent host |
2,000
mg bid |
Oral |
1 day |
|
Oral
labial HSV infection, immunocompromised host |
500 mg
bid |
Oral |
5–10
days |
|
Chronic
suppression of HSV infection |
1,000
mg qd |
Oral |
Undefined/indefinite |
|
Varicella:
adolescent/adult |
1,000
mg tid |
Oral |
5 days |
|
Herpes
zoster: normal host or not severe disease in immunocompromised host |
1,000
mg tid |
Oral |
7 days |
HSV = herpes simplex virus.
Initiation of Therapy
As with acyclovir, valacyclovir therapy should be initiated at
the earliest symptom of an HSV or VZV infection as soon as possible after the
onset of an HSV or VZV infection.
Side effects and Precautions
Most adverse effects are those
that also occur with acyclovir, including a potential for acute
renal failure as well as CNS effects of hallucinations, seizures and
encephalopathy. Additionally, the drug
has also been reported to produce both immediate hypersensitivity and a
symmetrical drug-related intertriginous and flexural exanthem. Severe and even
fatal cases of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS)
have been reported in patients with acquired immunodeficiency syndrome (AIDS)
and transplant recipients receiving high dosages of 8 g/day of valacyclovir.
TTP/HUS has not been reported in patients taking conventional dosages
(up to 3 g/day) of valacyclovir.
Valacyclovir has been shown to
precipitate in renal tubules and should be used with caution in those with
renal impairment. It’s most severe
effects have been observed in elderly and immunocompromised patients, for which
it is recommended to give the lowest dose possible. Given its metabolism to
acyclovir, which can be detected in breast milk, breast-feeding mothers should
be aware that their nursing infants may receive small, though clinically
insignificant, amount of acyclovir.
Famciclovir and Penciclovir
Mechanism of Action
Famciclovir is also a
purine nucleoside analogue that is metabolized to penciclovir in the
gastrointestinal tract and liver. Penciclovir is then phosphorylated to penciclovir
triphosphate. The initial phosphorylation of penciclovir to penciclovir
monophosphate is efficiently carried out by HSV- or VZV-induced thymidine
kinases in a manner similar to that of the initial phosphorylation of acyclovir. Phosphorylation to diphosphate
and triphosphate forms of penciclovir then occurs via cellular kinases.
Penciclovir triphosphate competitively inhibits viral DNA polymerases and
inhibits extension of the nascent viral DNA chain in a manner similar to
acyclovir; however, because of the presence of the hydroxyl group on the
acyclic side chain of penciclovir, more DNA chain extension may occur.
Pharmacokinetics
Famciclovir is marketed as an oral
formulation, which is converted to penciclovir by deacetylation and oxidation
in the liver and intestine. The bioavailability of oral famciclovir is 77%,
with a peak plasma concentration of 3.3 μg/mL reached 1 hour after oral
administration of 500 mg of famciclovir. The plasma half-life of penciclovir is
2 hours, and 60%–70% of the drug is excreted unchanged in the urine. This
occurs via both glomerular filtration and tubular secretion. As with acyclovir, the dose of penciclovir should
be reduced in patients with advanced renal dysfunction. Compared with the
intracellular half-life of acyclovir triphosphate, that of penciclovir
triphosphate is markedly prolonged in both HSV-infected cells (10–20 hours) and
VZV-infected cells, allowing the drug to be administered two to three times
daily. Penciclovir is available as a 1% ointment for the treatment of recurrent
oral HSV. At least in some vehicles, topical penetration of penetration of
penciclovir is superior to that of acyclovir. Macroemulsion and nanoparticle
formulations are being evaluated and this could be a promising vehicle for
topical delivery of pencyclovir.
Dosing Regimens for
Famciclovir and Penciclovir
|
Condition |
Dosage |
Route |
Duration |
|
Primary
HSV infection, immunocompetent host |
250 mg
tid |
Oral |
10 days |
|
Recurrent
genital HSV infection, immunocompetent host |
125 mg
bid or 1,000
mg bid |
Oral Oral |
5 days 1 day |
|
Recurrent
oral labial HSV infection, immunocompetent host |
1500 mg
or 1% penciclovir cream q2h |
Oral Topical |
1 dose 5 days
or until lesions healed |
|
Oral
labial HSV infection, immunocompromised host |
500 mg
bid |
Oral |
7 days |
|
Chronic
suppression of HSV infection |
250 mg
bid |
Oral |
Up to 1
year |
|
Varicella:
adolescent/adult |
500 mg
tid |
Oral |
5days |
|
Herpes
zoster: normal host or not severe disease in immunocompromised host |
500 mg
tid |
Oral |
7 days |
HSV = herpes simplex virus.
Side effects and Precautions
Like acyclovir and valacyclovir, famciclovir is generally well tolerated. The
dose should be reduced for patients with a creatinine clearance less than 60
mL/min. The drug has been used safely along with hydration in patients with
prior renal toxicity related to acyclovir. Leukocytoclastic vasculitis has been
reported with the drug. Famciclovir should not be used during pregnancy.
Common side effects: Headache, Nausea,
Diarrhea and Dizziness
