M-RNA synthesis inhibitors
Inhibitors of viral penetration and uncoating
Amantidine and Rimantidine, Docosanol
Zanamavir , Oseltamavir, Peramavir
Immunomodulators : Interferons, Palivizumab ,
Life cycle of viruses and
steps blocked by medicines
Guanine nucleoside analogue
Effective against HSV-1 and HSV-2,
VZV, CMV, and EBV.
The active metabolite of acyclovir
inhibits herpes virus DNA replication
in two ways.
Acyclovir triphosphate - competitive
Inhibitor deoxyguanosine triphosphate
(dGTP) into the viral DNA.
Acts as a chain terminator -because it lacks the 3 -hydroxy group
necessary for further chain elongation.
Pharmacokinetics :Acyclovir absorption is variable
and incomplete following oral administration.
20% bound to plasma protein
Amniotic fluid, placenta, and breast milk.
Acyclovir is both filtered at the glomeruli and
The plasma half-life of acyclovir is 3 to 4 hours in
patients with normal kidney function and up to 20
hours in patients with renal impairment
Oral acyclovir - HSV-1 and HSV-2 infections, such as
genital herpes, herpes encephalitis, herpes keratitis,
herpes labialis, and neonatal herpes.
long-term suppression of recurrent HSV.
Intravenous acyclovir -herpes simplex encephalitis,
neonatal HSV infection, and mucocutaneous HSV
infection in immunocompromised individuals.
Acyclovir ointment is used in the treatment of
initial genital herpes but is not effective for recurrent
Ophthalmic acyclovir formulations are effective in
the treatment of herpes keratoconjunctivitis.
Acyclovir reduces the extent and duration of VZV
chickenpox treatment and prophylaxis in high- risk
Herpes zoster (shingles),
Does not affect post herpetic neuralgia.
Headache, nausea, and diarrhea.
Skin rash, fatigue, fever, hair loss, and
Reversible renal dysfunction (azotemia) and
neurotoxicity (tremor, seizure, delirium) are
dose- limiting toxicities of intravenous acyclovir.
Adequate hydration and slow drug infusion can
minimize the risk of renal toxicity
Thrombotic thrombocytopenic purpura–
hemolytic uremic syndrome (TTP–HUS)
Safe in Pregnancy
Drug interaction –Probenacid , cyclosporine
Resistance –Mutations resulting in decrease
in thymidine kinase activity.
Altered substrate specificity
Decreased affinity of viral DNA polymerase
- acyclic phosphonate cytosine analogue
- Herpes viruses including CMV, HSV-1, HSV-2, EBV,
and VZV. adenoviruses, papillomaviruses,
polyomaviruses, and poxviruses.
Activation- requires metabolism to a diphosphate.
-competes with deoxycytidine triphosphate (dCTP)
for access to viral DNA polymerase and also acts
as an alternative substrate.
- slows replication
- halts DNA polymerase activity.
low oral bioavailability. T1/2- 2.6 hours,
the diphosphate form -half life of 17 to 65 hours.
A phosphocholine metabolite half-life 87 hours .
is excreted unchanged by the kidney. Glomerular
filtration and probenecid-sensitive tubular
secretion are responsible for cidofovir elimination
-Treatment and prophylaxis of
CMV retinitis in AIDS patients.
-Treatment of acyclovir-resistant (viral thymidine
kinase-deficient) HSV infections,
-Polyomavirus associated progressive multifocal
condylomata acuminata (anogenital warts), and
Probenecid with cidofovir . Probenecid carries its own
adverse effects, including gastrointestinal upset.
Nephrotoxic agents (e.g., aminoglycosides, NSAIDs,
amphotericin B, foscarnet) should not be given
within 7 days of cidofovir administration.
ADR-Hypersensitivity reactions, Anterior uveitis and
Potential human carcinogen- Embryotoxic and
teratogenic effects and to impair fertility .
Nephrotoxicity, Proteinuria, azotemia, glycosuria,
elevated serum creatinine, and
Rarely, Fanconi’s syndrome.
-diacetyl ester prodrug of the acyclic guanosine analogue 6-
- HSV-1, HSV-2, VZV, and HBV.
- After oral administration, famciclovir is converted to
penciclovir by first-pass metabolism.
Penciclovir triphosphate acts as a competitive inhibitor of
viral DNA polymerase
Resistance : Mutations in DNA polymerase or thymidine
kinase may result in resistance. Acyclovir-resistant HSV strains
Penciclovir is available as a topical cream
Famciclovir ->converted to penciclovir by hepatic first-
pass metabolism ->Bioavailability 77%.
Penciclovir-t1/2 is 2 to 3 hours; however, the intracellular
half-life of penciclovir triphosphate is 7 to 20 hours in
Eliminated unchanged by the kidney via glomerular
filtration and active tubular secretion.
The plasma half-life is increased in individuals with renal
Shortens the duration of lesion presence and pain
Famciclovir -acute herpes zoster (shingles)
Famciclovir -treatment of HSV
Famciclovir -Recurrent genital herpes.
For HIV-infected individuals- all recurrent
mucocutaneous HSV infections
Headache, nausea, and diarrhea.
Hallucinations and urticaria
Animal studies -Tumorigenic and impair
Dosage adjustment is necessary in individuals with
Famciclovir interact with probenecid -drugs
eliminated by renal tubular secretion.
Increased blood levels of penciclovir or other
Ganciclovir is an acyclic analogue of 2 de-oxyguanosine
Valganciclovir is the L-valyl ester prodrug of ganciclovir.
Activation of ganciclovir --ganciclovir monophosphate
Protein kinase pUL97 in CMV or thymidine kinase in
additional phosphorylations ganciclovir
triphosphate competes with dGTP incorporation
into DNA chain termination
Ganciclovir triphosphate is up to 100-fold more
concentrated in CMV-infected cells than in normal cells .
Resistance : Exposed to the drug for long periods .
-Mutation of the protein kinase gene.
-Mutations in the DNA polymerase .
Pharmacokinetics : - Orally or intravenously
Valganciclovir –orally - rapidly metabolized to
Intravenous -Ganciclovir -vitreous humor
Ganciclovir- eliminated by glomerular filtration and
active tubular secretion.
The T1/2-ganciclovir -3.5 hours (iv)and 4.8 hours (oral)
Oral valganciclovir -4 hours. The intracellular half-life
of ganciclovir triphosphate is over 24 hours.
CMV retinitis in immunocompromised
individuals, including those with AIDS, CMV
infection in organ transplant recipients.
-CMV retinitis in AIDS ,
Ganciclovir -intravitreal implant -CMV retinitis
in AIDS patients.
Resistance : Exposed to the drug for long
-Mutation of the protein kinase gene.
-Mutations in the DNA polymerase .
Neutropenia and anemia (25 to 30% ) and
Thrombocytopenia( 5 to 10%).
sperm production, teratogenesis, and tumor formation.
Severe neutropenia -with zidovudine.
Ganciclovir increases serum levels of didanosine,
whereas probenecid decreases ganciclovir elimination.
Nephrotoxicity (e.g., amphotericin B, cyclosporine,
NSAIDs) are administered in conjunction with ganciclovir
Idoxuridine -is a water-soluble iodinated derivative of deoxyuridine
-Inhibits several DNA viruses including HSV, VZV, vaccinia, and
MOA:The triphosphorylated metabolite of idoxuridine inhibits
both viral and cellular DNA synthesis
Pharmacokinetics: Idoxuridine topical ophthalmic use
Uses : treatment of herpes simplex infections of the eyelid,
conjunctiva, and cornea. soft tissue sarcoma
Adverse Events: local irritation, mild edema, itching, and
photophobia. Corneal clouding and small punctate defects
in the corneal epithelium .
Trifluridine is a fluorinated pyrimidine nucleoside
-HSV-1 and HSV-2, vaccinia, adenoviruses.
MOA: Activation of trifluridine 5
monophosphate inhibits the conversion of
deoxyuridine monophosphate (dUMP) to
deoxythymidine monophosphate (dTMP) by
Resistance alterations in thymidylate synthetase
Pharmacokinetics :- topical instillation of trifluridine into
the eyes. Its half-life is approximately 12 minutes.
Trifluridine (topical ophthalmic solution)- primary
keratoconjunctivitis, recurrent keratitis due to HSV-1 or
Unresponsive or intolerant to topical idoxuridine or
Adverse effects:Transient burning or stinging and
-Superficial punctate keratopathy, epithelial keratopathy,
hypersensitivity, stromal edema, irritation, keratitis
sicca, hyperemia, and increased intraocular pressure.
Foscarnet is an inorganic pyrophosphate analogue
HSV-1, HSV-2, VZV, CMV, EBV, HBV, and HIV.
Noncompetitive inhibitor of viral DNA polymerase
and reverse transcriptase
Resistance -mutation of viral DNA polymerase.
Pharmacokinetics : IV -14 to 17% bound to plasma
-accumulates in bone bimodal initial half-life of 4
to 8 hours and prolonged terminal elimination half-life
of 45 to 130 hours.
- eliminated as unchanged drug glomerular
filtration and active tubular secretion.
CMV retinitis in AIDS patients.
refractory retinitis, Kaposi’s sarcoma
Acyclovir- resistant mucocutaneous HSV infections in
Acyclovir-resistantVZV and nonretinitis forms of CMV
Nephrotoxicity -second week of induction therapy
Serum creatinine levels may be elevated in up to 33 to 50%
Dehydration, previous renal impairment, and concurrent
administration of other nephrotoxic drugs increase the
risk of renal toxicity.
-synthetic guanosine analogue
-Influenza A and B, parainfluenza, RSV, HCV, HIV-1, and
various herpesviruses, arena viruses, and paramyxo viruses.
-inhibits the synthesis of viral mRNA
ribavirin monophosphate, diphosphate, and
Ribavirin monophosphate-- inhibits the guanosine
triphosphate (GTP) synthesis Ribavirin triphosphate
inhibits the 5 capping of viral mRNA with GTP increasing
the mutation rate of RNA viruses nonviable progeny virions
Resistance has not been documented in clinical isolates.
Pharmacokinetics : Aerosol respiratory tract secretions
approximately 100 times
Oral absorption is rapid, and first-pass metabolism is
Ribavirin’s oral bioavailability is 64% -high-fat meal.
Steady-state levels are reached after 4 weeks.
Ribavirin triazole carboxylic acid metabolite urine
The plasma half-life -9.5 hours
The drug accumulates in erythrocytes, with a half-life of 40
Severe bronchiolitis or pneumonia due to RSV infection.
Oral ribavirin in combination with interferon- α
Intravenous ribavirin -Hantaan virus infection, Crimean or
Congo virus hemorrhagic fever, Lassa fever, and severe
Local adverse effects.
Pulmonary function -chronic obstructive lung disease or
Headache, conjunctivitis, rash, and rarely, bronchospasm.
Oral and intravenous- hemolytic anemia
With interferon-α - fatigue, nausea, insomnia,
depression, and anemia, fatal or nonfatal
Ribavirin is mutagenic, teratogenic, and embryotoxic
C/I- pregnant women ,Effective forms of
contraception during ribavirin treatment .
Sickle cell anemia and other
hemoglobinopathies,coronary disease ,severe renal
D/I-In vitro, ribavirin inhibits the phosphorylation
reactions zidovudine and stavudine
First antisense oligonucleotide immediate early
region 2 (IE2) of CMV mRNA.
By binding to IE2 mRNA, fomivirsen prevents its
translation to protein and thereby blocks viral
replication. Because this mechanism of action is
different from that of other antiviral agents, cross-
resistance with other drugs used to treat CMV is
Pharmacokinetics: Fomivirsen is injected directly
into the vitreous humor of the eye.-->retina and iris
over 3 to 5 days and is cleared from the vitreous
humor within 7 to 10 days.
Fomivirsen exhibits minimal systemic absorption
and is degraded locally by cellular exonucleases.
Fomivirsen -CMV retinitis in patients with AIDS.
Adverse effects: Iritis, (25%) -topical
- Vitreitis IOT
C/I- with cidofovir
Amantadine is a synthetic tricyclic amine, and
rimantadine is its α -methyl derivative. Both drugs
inhibit the replication of the three antigenic
subtypes of influenza A (H1N1, H2N2 and H3N2) ,
less activity against influenza B.
Mechanism Of Action
- involves inhibition of the viral M2 protein, (H
channel) Blockade acid-mediated dissociation
of the ribonucleoprotein complex -inhibited
The pH changes M2 inhibition alter the
hemagglutinin inhibit viral assembly.
-Viral resistance -30% ,-failure of drug prophylaxis
-Mutation in the transmembr- M2 protein
Pharmacokinetics : Amantadine -2 to 5 hours.
T1/2- 17 hours -29 hours in the elderly.
Eliminated unchanged by glomerular filtration and
tubular secretion. Rimantadine -5 to 7 hours.
Its elimination half-life averages 25- 32 hours in the
elderly. -25% -unchanged drug ,75%- hydroxylated or
Uses :-influenza A strains
Adverse effects:- Nausea, anorexia, dizziness, and insomnia
Dose-related effects - amantadine than rimantadine.
-Depression, impaired coordination, confusion, anxiety,
Cardiac arrhythmias, delirium, hallucinations
long-term treatment may cause peripheral edema, Abrupt
withdrawal -neuroleptic malignant syndrome.
-Seizures or worsen preexisting seizure disorders.
Amantadine is teratogenic and Rimantadine - embryotoxic.
Pregnancy and lactation.
Drug interactions:- Anticholinergic drugs,
sulfamethoxazole, quinine, and quinidine
increase plasma amantadine levels.
Cimetidine decreases rimantadine clearance,
and aspirin and acetaminophen decrease
rimantadine plasma levels.
Docosanol is a long-chain saturated alcohol
HSV. CMV, influenza virus, and respiratory syncytial
-Blocks the entry of the virion
Docosanol cream -herpes labialis.
Adverse effects -Skin irritation occurs infrequently.
Oseltamivir phosphate is the ethyl ester prodrug of
- competitive antagonist of influenza A and B
Neuraminidase -then destroys these hemagglutinin
receptors cleavage of hemagglutinin receptors is
required for the release of progeny virus from the host
Spread of infection by allowing viral particles to
penetrate the neuraminic acid–rich respiratory mucus
and by preventing the clumping of virus that results from
the binding of hemagglutinins to neuraminic acid residues
on neighboring viral particles –inhibited
Resistant strains –mutations- neuraminidase
P/KOrally -80%- 2.5 to 5 hours.
Plasma t1/2 -7 to 9 hours.
Elimination -active tubular secretion and glomerular
Uses :Oseltamivir - uncomplicated acute influenza in
patients aged 1 year and older. --Prophylaxis of influenza in
individuals aged 13 and older.
Post- exposure prophylaxis
-Nausea and vomiting, Bronchitis, insomnia, and vertigo
-Chronic cardiac or respiratory disease renal insufficiency;
-Probenecid decreases the elimination of oseltamivir,
No interference with antibody production in response to
the influenza vaccine.
Zanamivir is a neuraminidase inhibitor with activity
against influenza A and B strains. - reversible
competitive antagonist of viral neuraminidase.
- inhibits the release of progeny virus,
Resistant variants with hemagglutinin and/or
Pharmacokinetics : bioavailability < 5% oral.
breath-actuated inhaler device- 12 to 17%, -1.5
Eliminated -by the kidneys t1/2.5 to 5 hours.
Uses :- Uncomplicated acute influenza A and B virus
Effective prophylaxis against influenza.
-Bronchospasm and impaired lung function -
underlying pulmonary disease.
- Allergic reactions, including angioedema,
C/I -Severe or decompensated chronic obstructive lung
disease or asthma
-serious adverse pulmonary reactions. Moderate
Severe renal insufficiency
Other antiviral drugs
Immunoglobin ->( γ-globulin, immunoglobulin [Ig] G)
-primarily of IgG and contains trace amounts of IgA
inhibit viral penetration of host cells, opsonize viral
particles, activate complement, and stimulate cell-
Pharmacokinetics: γ-Globulin im/iv - viral disorders.
Protection lasts for 2 to 3 weeks after a single
injection, although for prolonged infections,
injections can be repeated every 2 to 3 weeks.
Uses :- CMV, HBV, rabies, RSV , and VZV
- heterogeneous human immune globulin solution- measles,
varicella, or rubella infection
- adjunctive form of therapy with other therapeutic
Adverse effects : Hypersensitivity reactions
-Anaphylactoid reaction, urticaria, angioedema, fever, and
injection site reactions.
- flushing, dizziness, blood pressure changes, palpitations,
abdominal cramps, and dyspnea; Aseptic meningitis
Interference- live virus vaccines (e.g., measles mumps,
-Potent antiviral, immunoregulatory, and
Interferon-α (type I, leukocyte) and
Interferon - β (type I, fibroblast)
Interferon- γ (type II, immune) -natural killer (NK)
cells and T lymphocytes
inhibition of viral penetration, uncoating, mRNA
synthesis, translation, and/or virion assembly and
Initiate the JAK-STAT signal transduction
pathway 2 -5 –oligo adenylate synthetase (2 -5
OAS)- initiates the activation of a cellular
ribonuclease that cleaves single-stranded RNAs,
Protein kinase phosphorylates and inactivates an
elongation factor (eIF-2)
Interferons inflammatory cytokines, biological
oxidants immune response.
Natural interferons ,recombinant interferons
,Monomethoxy polyethylene glycol (PEG; pegylated
Subcutaneously, intramuscularly, intravenously, or
intralesionally (e.g., into genital warts).
-peak plasma levels within 4 to 8 hours within 16
to 36 hours.
Pegylated interferons 15 to 44 hours 48 to 72
Eliminated cellular uptake and catabolism in the
kidney and liver
Interferon- α -2a chronic hepatitis C, hairy cell
leukemia, AIDS- related Kaposi’s sarcoma, and
chronic phase Philadelphia chromosome–positive
chronic myelogenous leukemia.
Interferon-α -2b Hairy cell leukemia, malignant
melanoma, follicular lymphoma, condylomata
acuminata, AIDS-related Kaposi’s sarcoma, and
chronic hepatitis B and C.
Interferon-α -2b and RibavirinChronic hepatitis C.
Interferon- α -n3 condylomata acuminata by
Interferon alfacon-1 5 times Interferon α -
2a or -2b.
Interferon alfacon-1 and peg interferon- α -
2b chronic hepatitis C.
Interferon β -1a and interferon β -1b
Interferon -1b chronic granulomatous
disease , malignant osteopetrosis.
Flu like symptoms fever, chills, weakness,
fatigue, myalgia, and arthralgia, (50% )of
patients CNS complaints headache,
dizziness, impaired memory and concentration,
agitation, insomnia, and anxiety occur with
Depression interferon-α and interferon- β .
Myelosuppression dose limiting
Gastrointestinal symptoms nausea, vomiting,
Elevation of hepatic enzymes
Injection site reaction alopecia, fertility, cause
Palivizumab is a humanized monoclonal antibody F
protein on the surface of RSV.
It contains 95% human and 5% murine antibody
inhibits its ability to fuse with host cell membranes.
Pharmacokinetics : prophylactically IM/monthly—RSV
season. T1/2- 20 days.
Uses : Serious LRTI due to RSV.
bronchopulmonary dysplasia or chronic lung disease
Premature infants (less than 32 weeks gestation)
Adverse effects : Mild erythema and pain
Anaphylactoid reactions –protein.