Anti-viral drugs
Viruses have no cell wall and made up of nucleic
acid components
Viruses containing envelope – antigenic in
nature
Viruses are obligate intracellular parasite
They do not have a metabolic machinery of their
own – uses host enzymes/biochemical process
Certain viruses multiply in the cytoplasm but
others do in the nucleus
Most multiplication take place before diagnosis
is made
Virus replication:
1. Attachment of virus to cell surface receptor.
2. Penetration of virus by endocytosis.
3. Uncoating of viral DNA.
4. Transcription.
5. Translation.
6. Replication of viral DNA.
7. Assembly of nucleocapsids,
8. Acquisition of viral envelope by budding from
inner nuclear membrane.
9. Release of assembled virion.
• RNA virus: direct, need virion enzyme (viral
RNA polymerase) to synthesis mRNA or
viral RNA serve as mRNA
• DNA virus: indirect, viral DNA transcribed
to host mRNA by host cell RNA polymerase
• Retro virus: unique, make a copy of DNA
from viral RNA with the help of reverse
transcriptase. DNA get incorporated into host
genome - mRNA - viral proteins
Classification of antiviral drugs
Inhibitors of viral attachment and penetration
e.g. gamma-globulin, arbidol, maraviroc,
pleconaril and enfuvirtide.
Inhibitors of viral translation, transcription
and replication
A. Inhibitors of viral nucleic acid synthesis
1. Inhibitors of DNA virus nucleic acid
a. Nucleoside/Nucleotide analogues
i. Purine analogues
e.g. aciclovir, valaciclovir, ganciclovir,
valganciclovir, penciclovir, famciclovir and
vidarabine.
ii. Pyrimidine analogues
e.g. idoxuridine, trifluridine, sorivudine,
cytarabine and cidofovir.
b. Pyrophosphate analogues e.g. foscamet.
c. Miscellaneous drugs
e.g. docosanol and fomivirsen.
2. Inhibitors of RNA virus nucleic acid
a. Nucleoside/Nucleotide analogues, e.g.
ribavirin and taribavirin.
3.Inhibitors of retrovirus nucleic acid
/Antiretrovirals
a. Reverse transcriptase inhibitors
i. Nucleoside/Nucleotide analogues
e.g. zidovudine, didanosine, zalcitabine,
abacavir, amdoxovir, entacavir and tenofovir.
ii. Non-Nucleosides
e.g. nevirapine, efavirenz, delavirdine, etravirine
and rilpivirine.
B. Protease inhibitors
e.g. saquinavir, ritonavir, indinavir, darunavir,
boceprevir and telaprevir.
C. Integrase inhibitors e.g. raltegravir.
3. Inhibitors of viral assembly
e.g. amantadine, rimantadine and tromantadine.
4. Inhibitors of viral release
a. Neuraminidase inhibitors e.g. zanamivir and
oseltamivir.
5. Immunomodulators
a. Interferons
e.g. interferon-alpha and peginterferon alfa-2a.
b. Interferon inducers
e.g. polyriboinosinic acid-Polyribocytidylic acid
and inosine.
6. Miscellaneous agents.
1. Thiosemicarbazones e.g. methisazone.
2. Antibiotics e.g. rifampicin and actinomycin
D.
3. Others e.g. suramin, levamisole, inosiplex,
ribozymes, antisense oligonucleotides and
dextran sulphate.
Anti-Viral drugs
Many antiviral drugs are Purine or Pyrimidine
analogs.
Many antiviral drugs are Prodrugs. They must be
phosphorylated by viral or cellular enzymes in
order to become active.
Anti-viral agents inhibits active replication so
the viral growth resumes after drug removal.
Current anti-viral agents do not eliminate
non-replicating or latent virus
Effective host immune response remains
essential for the recovery from the viral infection
Clinical efficacy depends on achieving inhibitory
conc. at the site of infection within the infected
cells
Acyclovir & Congeners :
Valacyclovir is a prodrug of Acyclovir with
better bioavailability.
Famciclovir is hydrolyzed to Penciclovir and has
greatest bioavailability.
Penciclovir is used only topically whereas
Famciclovir can be administered orally.
PHARMACOLOGY OF ACYCLOVIR AND
CONGENERS
Acyclovir, Valacyclovir, Ganciclovir,
Famciclovir, Penciclovir all are guanine
nucleoside analogs.
Mechanism of action of Acyclovir and
congeners :
All drugs are phosphorylated by a viral
thymidine-kinase, then metabolized by host cell
kinases to nucleotide analogs.
The analog inhibits viral DNA-polymerase
Only actively replicating viruses are inhibited
Acyclovir is thus selectively activated in cells
infected with herpes virus.
Uninfected cells do not phosphorylate acyclovir.
Antiviral spectrum :
Acyclovir: HSV-1, HSV-2, VZV, Shingles.
Ganciclovir / Cidofovir : CMV
Famciclovir : Herpes genitalis and shingles
Foscarnet : HSV, VZV, CMV, HIV
Penciclovir : Herpes labialis
Trifluridine : Herpetic keratoconjunctivitis
Pharmacokinetics of Acyclovir :
Oral bioavailability ~ 20-30%
Distribution in all body tissues including CNS
Renal excretion: > 80%
Half lives: 2-5 hours
Administration: Topical, Oral , IV PHARMACOLOGY OF FOSCARNET
Adverse effects of Acyclovir / Ganciclovir Foscarnet is an inorganic pyrophosphate analog
Nausea, vomiting and diarrhea It directly inhibits viral DNA and RNA
Nephrotoxicity - crystalluria, haematuria, renal -polymerase and viral inverse transcriptase (it
insufficiency does not require phosphorylation for antiviral
Myelosuppression – Neutropenia and activity)
thrombocytopenia – Ganciclovir Foscarnet
Therapeutic uses : HSV-1, HSV-2, VZV, CMV and HIV.
Acyclovir is the drug of choice for: Oral bioavailability ~ 10-20%
HSV Genital infections Distribution to all tissues including CNS
HSV encephalitis Administration: IV
HSV infections in immunocompromised patient Adverse effects of Foscarnet
Ganciclovir is the drug of choice for: Hypocalcemia and hypomagnesemia (due to
CMV retinitis in immunocompromised patient chelation of the drug with divalent cations) are
Prevention of CMV disease in transplant patients common.
Anti-viral drugs Neurotoxicity (headache, hallucinations,
Cidofovir : seizures)
It is approved for the treatment of CMV retinitis Nephrotoxicity (acute tubular nephrosis,
in immunocompromised patients interstitial nephritis)
It is a nucleotide analog of cytosine – no Therapeutic uses of Foscarnet
phosphorylation required. It is an alternative drug for
It inhibits viral DNA synthesis HSV infections (acyclovir resistant /
Available for IV, Intravitreal inj, topical immunocompromised patient )
Nephrotoxicity is a major disadvantage. CMV retinitis (ganciclovir resistant /
PHARMACOLOGY OF VIDARABINE immunocompromised patient )
Idoxuridine, Vidarabine - nucleoside analogs.
(adenosine)
Antiviral spectrum: Zidovudine- Anti Retroviral drug
HSV-1, HSV-2 and VZV. Reverse-transcriptase inhibitor - used for the
Its use is limited to HSV keratitis only treatment of HIV/AIDS infection
Vidarabine (azidothymidine, AZT) is a thymidine analog.
The drug is converted to its triphosphate analog Inhibition of RNA-dependent DNA polymerase
which inhibits viral DNA-polymerase. (reverse transcriptase). Effective for acute
Oral bioavailability ~ 2% infections but are relatively ineffective for
Administration: Ophthalmic ointment chronically infected cells. Effective against
Used in HSV keratoconjunctivitis in feline leukemia virus if administered early.
immunocompromised patient. Granulocytopenia and anemia are the major
Used with Acyclovir or in Acyclovir resistant adverse effects
patients
Anemia and SIADH are adverse effects. Respiratory viral infections
PHARMACOLOGY OF TRIFLURIDINE Influenza –
Trifluridine is a Pyrimidine nucleoside analogs - Amantadine / Rimantadine
inhibits viral DNA synthesis. Oseltamivir / Zanamavir (Neuraminidase
Antiviral spectrum Trifluridine : inhibitors)
HSV-1, HSV-2 and VZV. RSV bronchiolitis –
Use is limited to Topical - Ocular HSV Keratitis Ribavirin
Amantadine and Rimantadine : Influenza
Prevention & Treatment of influenza A
Inhibition of viral uncoating by inhibiting the
viral membrane protein M2
Influenza A virus
Amantadine has anti-parkinsonian effects.
Pharmacokinetics of Amantadine
Oral bioavailability ~ 50-90%
Amantadine cross extensively BBB whereas
Rimantadine does not cross extensively .
Administration: Oral
Neuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir
Influenza contains an enzyme neuraminidase
which is essential for the replication of the virus.
Neuraminidase inhibitors prevent the release
of new virions and their spread from cell to cell.
Neuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir
These are effective against both types of
influenza A and B.
Do not interfere with immune response to
influenza A vaccine.
Can be used for both prophylaxis and acute
treatment.
Neuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir
Oseltamivir is orally administered.
Zanamavir is given intranasal.
Risk of bronchospasm with zanamavir
PHARMACOLOGY OF RIBAVIRIN
Ribavirin is a guanosine analog.
Inhibition of RNA polymerase
Antiviral spectrum : DNA and RNA viruses are
susceptible, including influenza, parainfluenza
viruses, RSV, Lassa virus
Anti-viral drugs
Ribavirin : RSV( Respiratory syncytial virus).
Distribution in all body tissues, except CNS
Administration : Oral, IV, Inhalational in RSV
Anemia and jaundice are adverse effects
Not advised in pregnancy.
Therapeutic uses Ribavirin
Ribavirin is the drug of choice for:
RSV bronchiolitis and pneumonia in hospitalized
children (given by aerosol)
Lassa fever
Ribavirin is an alternative drug for:
Influenza, parainfluenza, measles virus infection
in immunocompromised patients
Hepatic Viral infections :
Interferons
Lamivudine – cytosine analog – HBV
Entecavir – guanosine analog – HBV –
lamivudine resistance strains
Ribavirin – Hepatitis C (with interferons)
Interferons
Interferons (IFNs) are natural proteins produced
by the cells of the immune systems in response
to challenges by foreign agents such as viruses,
bacteria, parasites and tumor cells.
Antiviral, immune modulating and
anti-proliferative actions
Three classes of interferons – α , β, γ
Interferons
α and β interferons are produced by all the cells
in response to viral infections
γ interferons are produced only by T
lymphocyte and NK cells in response to
cytokines – immune regulating effects
γ has less anti-viral activity compared to α and
β interferons
Mechanism of action of Interferons :
Induction of the following enzymes:
a protein kinase which inhibits protein synthesis
an oligo-adenylate synthase which leads to
degradation of viral mRNA
a phosphodiesterase which inhibit t-RNA
The action of these enzymes leads to an
inhibition of translation
Antiviral spectrum : Interferon α
Includes HBV (hepatitis B Virus), HCV and
HPV (Human Papilloma virus).
Anti-proliferative actions may inhibit the growth
of certain cancers - like Kaposi sarcoma and
hairy cell leukemia. Cat- Feline leukemia virus.
Pharmacokinetics : Interferons
Oral bioavailability: < 1%
Administered Intralesionally, S.C, and I.V
Distribution in all body tissues, except CNS and
eye.
Half lives: 1-4 hours
Adverse effects of Interferons Narrow spectrum.
Acute flu-like syndrome (fever, headache) Drugs target specific enzymes – Polymerase
Bone marrow suppression (granulocytopenia, transcriptase involved in viral nucleic acid
thrombocytopenia) synthesis.
Neurotoxicity (confusion, seizures) Hence development of resistance is easier ( point
Cardiotoxicity - arrhythmia mutation – substitution of single important
Impairment of fertility nucleic acid )
Therapeutic uses Interferons Inhibits only actively replicating virus, unable to
Chronic hepatitis B and C (complete eliminate non replicating/latent viral infection
disappearance is seen in 30%). Mostly static, hence success depends on hosts
HZV infection in cancer patients (to prevent the immune response
dissemination of the infection)
CMV (cytomegalo virus) infections in renal
transplant patients
Condylomata acuminata (given by intralesional
injection). Complete clearance is seen ~ 50%.
Hairy cell leukemia (in combination with
zidovudine)
AIDS related Kaposi’s sarcoma.
Immunization
Passive immunization by im, iv or sc injection
with Immunoglobulin can prevent entry of virus
into cells
The proteolytic effect lasts for several weeks but
may not be completed. This is useful to control
CD, Rabies, TVT and Gastroenteritis in swine,
Infectious hepatitis, Measles, Poliomyelitis,
Chicken pox.

Immunization
If hyper immune serum is not available pooled
sera from the recovered or vaccinated animals
may be used.
To avoid anaphylactic shock only one injection
should be given.
Gamma globulins (concentrated antibodies)
extracted from normal blood may also be useful
in preventing viral infections in animals.

Reasons for failure of antiviral therapy

Drugs that target viral process must penetrate the

host cell
Toxicity - narrow therapeutic index
Lack of broad spectrum antiviral drugs
Lack of in vitro susceptibility testing procedures