Antiviral Agents

Other
Category Drug Name Structure Description Uses
Name
Chemoproph Amantidine - drugs that interfere with penetration of host cells by Symmetrel - Use as a treatment for
ylaxis ( 1- adamantanamine viruses and block early stage replication. Parkinsons disease.
Influenza hydrochloride)
- Inhibit replication of the
Amantadine influenza type A viruses at low
concentrations.

Rimantadine Flumadine
( -methyl-1-
adamantane Rimantadine
methylamine
hydrochloride)
Neuraminida Zanamivir - X-ray crystallography of 2-deoxy-2,3-dehydro-N- - Effective antiviral agent for
se Inhibitors acetylneuraminic acid bound to neuraminidase showed influenza types A and B
the three dimensional structure of the receptor site at
which the sialic acid units on the virus bind. It is identical - For prophylactically treating
to 2-deoxy-2,3-dehydro-N- acetylneuraminic acid except family members of a person who
that it possesses a guanidino group at position 4 instead has developed influenza.
of a hydroxyl group
Oseltamivir - x-ray crystal structures of neuraminidase and the viral Tamiflu - This drug is the first orally
Phosphate receptor site showed clearly that additional binding sites active agent for use against
exist for the C-5 acetamido carbonyl group and the influenza A and B. It is also
arginine residue at position 152 of the receptor site. In indicated for the treatment of
addition, the C-2 carboxyl group of sialic acid binds to Arg acute illness. If administered
118, Arg 292, and Arg 371. Position C-6 is capable of within 2 days after the onset of
undergoing hydrophobic interaction with various amino influenza symptoms, the drug is
acids, including Glu, Ala, Arg, and Ile. effective.
Interferons IFN- - IFN- and IFN- are produced by almost all cells in Intron A, - Antiviral,
response to viral challenge. However, interferon Roferon A immunomodulating, and
( Interferon alfa)
production is not limited to viral stimuli. Various other antiproliferative actions
triggers, including cytokines such as interleukin-1, - IFN- is used clinically in a
interleukin-2, and tumor necrosis factor, will elicit the recombinant.
production of IFNs. Both IFN- - IFN- is a recombinant form
and IFN- are elicited by exposure of a cell to double marketed for the treatment of
IFN- stranded viral RNA. Betaseron multiple sclerosis
( Interferon beta)
Inhibitors of Idoxuridine - The drug is an iodinated analog of thymidine that Stoxil, - - topical treatment of herpes
DNA (5-iodo-2-deoxyuridine) inhibits replication of several DNA viruses in vitro. The Herplex simplex virus (HSV) keratitis.
Polymerase susceptible viruses include the herpesviruses and
poxviruses (vaccinia). - a solution of idoxuridine
- Idoxuridine occurs as a pale yellow, crystalline solid that in dimethyl sulfoxide is available
is soluble in water and alcohol but poorly soluble in most for the treatment of herpes
organic solvents. The compound is a weak acid, with a labialis, genitalis, and zoster
pKa of 8.25. Aqueous solutions are slightly acidic,
yielding a pH of about 6.0.
 Cytarabine - Cytarabine is a pyrimidine nucleoside drug that is - The antiviral use of cytarabine
related to idoxuridine. It blocks the cellular utilization of is in the treatment of herpes
deoxycytidine, hence inhibiting the replication of viral zoster (shingles), herpetic
DNA. Before it becomes active, the drug is converted to keratitis, and viral infections
monophosphates, that resist idoxuridine.
diphosphates, and triphosphates, which block DNA - This agent is primarily used as
polymerase and the C-2 reductase that converts cytidine an anticancer agent for Burkitt
diphosphate into the deoxy derivative. lymphoma and myeloid and
lymphatic leukemias.
Trifluridine - a fluorinated pyrimidine nucleoside that demonstrates Viroptic -treatment of primary
(5-trifluoromethyl-29- in vitro inhibitory activity against HSV-1 and HSV-2, CMV, keratoconjunctivitis and
deoxyuridine) vaccinia, and some adenoviruses.33 Trifluridine recurrent epithelial keratitis
possesses a trifluoromethyl group instead of an iodine caused by HSV types 1 and 2.
atom at the 5- position of the pyrimidine ring. -Topical trifluridine shows some
efficacy in patients with
acyclovir-resistant HSV
cutaneous infections.
Vidaribine - Vidarabine inhibits viral DNA synthesis. Enzymes within Vira-A - active against herpesviruses,
(9--D- the cell phosphorylate vidarabine to the triphosphate, poxviruses, rhabdoviruses,
arabinofuranosyladenin which competes with deoxyadenosine triphosphate for hepadnavirus, and some RNA
e) viral DNA polymerase. Vidarabine triphosphate is also tumor viruses.
incorporated into cellular and viral DNA, where it acts as - an alternative to idoxuridine for
a chain terminator. The triphosphate form of vidarabine the treatment of
also inhibits a set of enzymes that are involved in HSV keratitis and HSV
methylation of uridine to thymidine: ribonucleoside encephalitis
reductase, RNA polyadenylase, and S-
adenosylhomocysteine hydrolase.
- Vidarabine occurs as a white, crystalline monohydrate
that is soluble in water to the extent of 0.45 mg/mL at
25C.
Adefovir Dipivoxil - The dipivoxil moieties are hydrolyzed by ubiquitous - an orally active prodrug that is
esterases to yield adefovir, which is phosphorylated by indicated for the
adenylate kinase to yield adefovir diphosphate. This treatment of the chronic form of
compound is inhibitory at HBV DNA polymerase. In hepatitis B.
addition, adefovir undergoes incorporation into viral DNA
and causes chain termination. Adefovir is poorly
absorbed by the oral route, but the dipivoxil ester groups
cause the bioavailability to increase to approximately
60%.
Acyclovir - The most effective of a series of acyclic nucleosides that Zovirax - most active (in vitro) against
(9-[2- possess antiviral activity. In contrast with true HSV type 1, about 2 times less
(hydroxyethoxy)methyl] nucleosides that have a ribose or a deoxyribose sugar against HSV type 2, and 10
-9H-guanine) attached to a purine or a pyrimidine base, the group times less potent against
attached to the base in acyclovir is similar to an open varicellazoster virus (VZV).
chain sugar, albeit lacking in hydroxyl groups. - short-term treatment of
- The ultimate effect of acyclovir is the inhibition of viral shingles and chickenpox caused
DNA synthesis. Transport into the cell and by VZV.
monophosphorylation are accomplished by a thymidine
kinase that is encoded
by the virus itself.35 The affinity of acyclovir for the viral
thymidine kinase is about 200 times that of the
corresponding mammalian enzyme.
-Acyclovir occurs as a chemically stable, white, crystalline
solid that is slightly soluble in water. Because of its
 amphoteric properties (pKa values of 2.27 and 9.25),
solubility is increased by both strong acids and bases.
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. 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.
Valacyclovir - is the hydrochloride salt of the L-valyl ester of acyclovir. Valtrex - treatment for herpes
Hydrochloride The compound is a water-soluble crystalline solid, and it zoster (shingles) in
is a prodrug intended to increase the bioavailability of immunocompromised patients.
acyclovir by increasing lipophilicity. Valacyclovir is
hydrolyzed rapidly and almost completely to acyclovir
following oral administration. Enzymatic hydrolysis of the
prodrug is believed to occur during enterohepatic cycling.

Ganciclovir -It is an analog of acyclovir, with an additional - This structural modification,

(9-[(1,3-dihydroxy-2- hydroxymethyl group on the acyclic side chain. while maintaining the activity
propoxy) Ganciclovir is phosphorylated inside the cell by a virally against HSV and VSV possessed
methyl]guanine) encoded protein kinase to the monophosphate.37 Host by acyclovir, greatly enhances
or DHPG) cell enzymes catalyze the formation of the triphosphate, the activity against CMV
which reaches more than 10-fold higher concentrations in infection.
infected cells than in uninfected cells. This selectivity is
caused by the entry and -Toxicity limits its therapeutic
monophosphorylation step. Further phosphorylation with usefulness to the treatment
cellular enzymes occurs, and the triphosphate that is and suppression of sight-
formed selectively inhibits viral DNA polymerase. threatening CMV retinitis in
Ganciclovir immunocompromised
triphosphate is also incorporated into viral DNA causing patients and to the prevention of
strand breakage and cessation of elongation. life threatening
CMV infections in at-risk
transplant patients
Famciclovir - Famciclovir is a diacetyl prodrug of penciclovir.
Peniciclovir is an acyclic guanine nucleoside analog. The
structure is similar to that of acyclovir, except in
penciclovir, a side chain oxygen has been replaced by a
carbon atom and an extra hydroxymethyl group is
present. Inhibitory concentrations for HSV and VSV are
typically within twice that of acyclovir. Penciclovir also
inhibits the growth of hepatitis B virus.
- Penciclovir inhibits viral DNA synthesis. In HSV- or VSV-
infected cells, penciclovir is first phosphorylated by viral
thymidine kinase41 and then further elaborated to the
Penciclovir triphosphate by host cell kinases. Penciclovir - Topical treatment of recurrent
(9-[4-hydroxy-3- triphosphate is a competitive inhibitor of viral DNA Denvir herpes labialis (cold sores) in
hydroxymethylbut-1-yl] polymerase. The pharmacokinetic parameters of adults.
guanine) penciclovir are quite different from those of acyclovir. It is effective against HSV-1 and
HSV-2.
 Cidofovir -Cidofovir is an acyclonucleotide analog that possesses - Cidofovir possesses a high
[ (S)-3-hydroxy-2- broad-spectrum activity against several DNA viruses. therapeutic index against CMV
phosphonomethoxyprop Unlike other nucleotide analogs that are activated to and has been approved for
yl cytosine ] nucleoside phosphates, Cidofovir is a phosphonic acid treating CMV retinitis in patients
derivative. with AIDS
The phosphonic acid is not hydrolyzed by phosphatases
in vivo but is phosphorylated by cellular kinases to yield a
diphosphate. The diphosphate acts as an antimetabolite
to deoxycytosine
triphosphate (dCTP). Cidofovir diphosphate is a
competitive inhibitor of viral DNA43 polymerase and can
be incorporated into the growing viral DNA strand,
causing DNA chain termination.
Foscarnet Sodium -Foscarnet is a reversible, Foscavir - Second-line drug for the
noncompetitive inhibitor at the pyrophosphatebinding treatment of retinitis caused by
site of the viral DNA polymerase and RT. The CMV in patients with AIDS.
ultimate effect is inhibition of the cleavage of
pyrophosphate from deoxynucleotide triphosphates and a -Hypocalcemia,
cessation of the incorporation of nucleoside hypomagnesemia,
triphosphates into DNA hypokalemia, and
(with the concomitant release of pyrophosphate).45 hypophosphatemia and
Because hyperphosphatemia
the inhibition is noncompetitive with respect to are observed in patients treated
nucleoside triphosphate binding, foscarnet can act with foscarnet.
synergistically with
nucleoside triphosphate antimetabolites (e.g., zidovudine
and didanosine triphosphates) in the inhibition of viral
DNA
synthesis. Foscarnet does not require bioactivation by
viral or cellular enzymes and, hence, can be effective
against resistant viral strains that are deficient in virally
encoded nucleoside kinases.
Reverse Zidovudine - This nucleoside was synthesized in 1978 by Lin and - Antiviral activity against HIV-1,
Transcriptas (3-azido-3- Prusoff47 as an intermediate in the preparation of amino HIV-2, HTLV-1.
e Inhibitors deoxythymidine or AZT) acid analogs of thymidine. A screening program directed - Recommended for the
toward the identification of agents potentially effective management of adult
for the treatment of patients with AIDS led to the patients with symptomatic HIV
discovery of its unique antiviral properties 7 years infection (AIDS or ARC)
later.48 The next year, the clinical effectiveness of AZT in who have a history of confirmed
patients with AIDS and AIDS-related complex (ARC) was Pneumocystis carinii pneumonia
demonstrated. or an absolute CD4_ (T4 or TH
cell) lymphocyte count below
200/mm3 before therapy. The
hematological toxicity of the
drug precludes its use in
asymptomatic patients.
Didanosine - A synthetic purine nucleoside analog that is Videx, ddI - Didanosine is recommended
[2,3-dideoxyinosine bioactivated to 2,3 -dideoxy-ATP (ddATP) by host cellular for the treatment of patients
(ddI)] enzymes. The metabolite, ddATP, accumulates with advanced HIV infection who
intracellularly, where it inhibits RT and is incorporated have received prolonged
into viral DNA to cause chain termination in HIV infected treatment with AZT but have
cells. The potency of didanosine is 10- to 100-fold less become intolerant to, or
than that of AZT with respect to antiviral activity and experienced
cytotoxicity, but the drug causes less myelosuppression immunosuppression from, the
 than AZT causes drug.
- AZT and ddI act synergistically
to inhibit HIV replication in vitro,
and
ddI is effective against some
AZT-resistant strains of HIV.
Zalcitabine - It is an analog of cytosine that demonstrates activity - Treatment for HIV infection in
( 2,3-dideoxycytidine or against HIV-1 and HIV-2, including strains resistant to adults with advanced disease
ddCyd ) AZT. The potency (in peripheral blood mononuclear cells) who are intolerant to AZT or who
is similar to that of AZT, but the drug is more active in have disease progression while
populations of monocytes and macrophages as well as in receiving AZT. ddC is combined
resting cells. with AZT for the treatment of
advanced HIV infection.
Stavudine - It is an unsaturated pyrimidine nucleoside that is related D4T, Zerit - Treatment for adults with
(2,3-didehydro-2- to thymidine. The drug inhibits the replication of HIV by a advanced
deoxythymidine) mechanism similar to that of its close congener, AZT.60 HIV infection who are intolerant
Stavudine is bioactivated by cellular enzymes to a of other approved therapies
triphosphate. The triphosphate competitively inhibits the or who have experienced clinical
incorporation of thymidine triphosphate (TTP) into or immunological deterioration
retroviral DNA by RT. Stavudine also causes termination while receiving these therapies.
of viral DNA elongation through its incorporation into
DNA.

Tenofovir Disoproxil - Tenofovir disoproxil is a prodrug analogously with - Treatment for HIV infections in
abacavir. adult patients.
Plasma and tissue esterases cleave the phosphate
protecting groups, releasing the active drug. The
bioavailability
of tenofovir is about 35% when administered with
food.
Lamivudine - is a synthetic nucleoside analog that differs from 2,3- - It is interesting that the
(_)-2_,3_-dideoxy-3_- dideoxycytidine (ddC) by the substitution of a unnatural stereoisomer (_)-(S)-
thiacytidine, (_)-_-L- sulfur atom in place of a methylene group at the 3_- ddC exhibits greater antiviral
(2R,5S)-1,3- position of the ribose ring. In early clinical trials, activity against HIV than the
oxathiolanylcytosine, lamivudine exhibited highly promising antiretroviral natural enantiomer (_)-(S)-ddC
3TC, or (_)-(S)-ddC. activity against HIV
and low toxicity in the dosages studied

Emtricitabine - An orally active NRTI whose pharmacokinetics are

favorable for once-daily administration.

Miscellaneou Ribavirin - The broad antiviral spectrum of ribavirin, however, -Ribavirin inhibits the replication
s Nucleoside (1--D-ribofuranosyl- suggests multiple modes of action. The nucleoside is of a very wide variety of
Antimetaboli 1,2,4-thiazole-3- bioactivated by viral and host cellular kinases to give the RNA and DNA viruses,68
tes carboxamide) monophosphate (RMP) and the triphosphate (RTP). RMP including orthomyxoviruses,
inhibits inosine monophosphate (IMP) dehydrogenase, paramyxoviruses, arenaviruses,
thereby preventing the conversion of IMP to xanthine bunyaviruses, herpesviruses,
monophosphate (XMP). adenoviruses, poxvirus,
 XMP is required for guanosine triphosphate (GTP) vaccinia, influenza virus
synthesis. RTP inhibits viral RNA polymerases. It also (types A and B), parainfluenza
prevents the end capping of viral mRNA by inhibiting virus, and rhinovirus
guanyl-N_- methyltransferase. - Unlabeled uses of ribavirin
-Ribavirin occurs as a white, crystalline, polymorphic solid include aerosol treatment of
that is soluble in water and chemically stable. influenza types A and B and oral
treatment of hepatitis, genital
herpes, and Lassa fever.
Nucleoside Nevirapine -It is more than 90% absorbed by the oral route and is Viramune -
Reverse widely distributed throughout the body. It distributes well
Transcriptas into breast milk and crosses the placenta.
e Inhibitors Transplacental conc. are about 50% those of serum. The
drug is extensively transformed by cytochrome P450
(CYP) to inactive hydroxylated metabolite
Delavirdine - The oral absorption of delavirdine is rapid, and peak - must be used with at least two
plasma concentrations develop in 1 hour. Extensive additional antiretroviral agents
metabolism occurs in the liver by CYP isozyme 3A to treat HIV-1 infections.
(CYP3A) or possibly CYP2D6. Bioavailability is 85%. Unlike
nevirapine, which is 48% protein bound, delavirdine is
more than 98% protein bound. The half-life is 2 to 11
hours, and elimination is 44% in feces, 51% in urine, and
less than 5% unchanged in urine. Delavirdine induces its
own metabolism.
HIV Protease Saquinavir - It is well tolerated following oral administration. Invirase, -Saquinavir lowers p24
Inhibitors Absorption of saquinavir is poor but is increased with a Fortovase antigen levels in HIV-infected
fatty meal. The drug does not distribute into the CSF, and patients, elevates CD4_
it is approximately 98% bound to plasma proteins. counts, and exerts a synergistic
Saquinavir is extensively metabolized by the firstpass antiviral effect when combined
effect. Bioavailability is 4% from a hard capsule and 12% with RT inhibitors such as AZT
to 15% from a soft capsule. and ddC
Indinavir - When administered with a high-fat diet, indinavir Crixivan
achieves a maximum serum concentration of
77% of the administered dose. The drug is 60% bound in
the plasma. It is extensively metabolized by CYP3A4, and
seven metabolites have been identified. Oral
bioavailability is good, with a tmax of 0.8 _ 0.3 hour. The
half-life of elimination is 1.8 hour, and the elimination
products are detectable in feces and urine. Indinavir also
causes dyslipidemia.
- Have similar properties and cautionary statements. All - These agents must always be
cause dyslipidemia, and they have a host of drug used with at least two other
Ritonavir, interactions, mainly because they inhibit CYP3A4. Norvir antiretroviral
agents. Used properly, the PIs
are an important
part of HIV therapy.

Amprenavir, Agenerase
 Viracept

Nelfinavir

Lopinavir - Lopinavir is used in excess over ritonavir. Ritonavir at - Protease inhibitor that has
amounts given has no antiretroviral activity, Ritonavir been approved for use in
inhibits lopinavirs metabolism by CYP3A4, causing a combination with ritonavir for
higher level of lopinavir in the system. patients with HIV who have not
responded to other treatment
modalities
Atazanavir - The drug is always used in combination with RT - an antiretroviral agent that has
inhibitors. been approved
by the FDA for use in
combination with other anti-RT
agents for the treatment of HIV
infections.

Fosamprenavir - Like the other PIs, this compound - used in combination with other
is a prodrug that produces the active drug upon HIV drugs in adult patients
hydrolysis. In this case, the active drug is amprenavir, a
peptidomimetic transition state inhibitor.

Tipranavir - Tipranavir is unique among the PIs because it is not a

peptidomimetic
compound. It does appear to bind to the active site of
HIV-1 protease the same as the peptidomimetics do.
The benefit of this agent is that, because it is a different
chemical structure, cross-resistance does not develop to
the same extent as seen with the peptidomimetics. The
drug is administered with a booster dose of ritonavir. This
protocol inhibits CYP3A4, causing the levels of tipranavir
to increase.