This document discusses antiviral drugs used to treat various viral infections. It begins by explaining the characteristics of viruses and stages of viral replication. It then categorizes and describes antiviral drugs for herpes, influenza, hepatitis B and C viruses. The drugs discussed include acyclovir, ganciclovir, amantadine, ribavirin, interferons, entecavir, tenofovir and newer oral antivirals for hepatitis C. The mechanisms of action, spectra, pharmacokinetics and therapeutic uses of these drugs are summarized. Adverse effects and importance of drug resistance are also mentioned.

1. Antiviral Drugs
( Non retroviral drugs)
by
Dr. Alka Bansal
Associate Professor,
Department of Pharmacology,
SMS Medical College, Jaipur

2. 11/18/12 Dr.T.V.Rao MD 2

3. Viruses are special pathogens because they-
- are obligate intracellular parasites.
- cannot replicate on its own.
- use the host cell’s machinery to synthesize
their protein, DNA, and RNA.
- virus containing envelope is antigenic in nature.
- difficult to kill because they live inside the cells.

4. Contd..
- viruses multiply in nucleus and cytoplasm.
- usually diagnosis is made late as symptomms
appear late.
- antiviral drugs do not kill, only inhibit
multiplication so relapse common after stopping
treatment.
- current antiviral drugs do not affect non-
replicating and latent infections.

5. Non –retro viruses controlled by
current antiviral therapy
• Herpes viruses
• Cytomegalovirus (CMV)
• Hepatitis viruses
• Influenza viruses (the “flu”)
• Respiratory syncytial virus (RSV)

6. Stages of viral replication
• Cell entry – attachment
- penetration
• Uncoating
• Transcription of viral genome
• Translation
• Assembly of virion components
• Release

7. Mechanism of action
viruses selectively enter the cells infected with virus.
- 1-interfere/inhibit early events like ability of virus to bind to
cells and uncoating
2-interfere/ inhibit viral nucleic acid synthesis and/or
regulation
3- inhibit viral protein synthesis.
 Best responses to antiviral drugs are in patients
with competent immune systems

8. 11/18/12 8Dr.T.V.Rao MD

9. Antiviral drugs- classification
A)-Anti herpes (DNA virus) drugs- acyclovir,
valacyclovir, famciclovir, ganciclovir, valganciclovir,
idoxuridine, trifluridine,cidofovir, foscarnet
B)-Anti influenza (RNA)virus drugs-amantadine,
rimantadine, oseltamivir, zanamivir, peramivir
C)-Anti-hepatitis (BOTH)virus drugs-
HBV-lamivudine, entecavir, adefovir dipivoxil, tenofovir,
telbivudine
HCV- ribavirin etc.

10. Anti-Viral drugs
Pharmacology of acyclovir and congeners-
• All are guanosine nucleoside analogues.
• Valacyclovir is prodrug of acyclovir
• Famciclovir is prodrug of penciclovir.
• Penciclovir is used only topically whereas Famciclovir can
be administered orally.

11. Mechanism of Action of Acyclovir
11/18/12 Dr.T.V.Rao MD 20

12. M/A - Acyclovir
• Acyclovir is phosphorylated by a viral
thymidine- kinase, then metabolized by host
cell kinases to nucleotide analogues.
• The analogue inhibits viral DNA- polymerase.
• Acyclovir is thus selectively activated in cells
infected with herpes virus.
• Uninfected cells do not phosphorylate
acyclovir

13. Contd..
-Resistance is due to altered viral thymidine
kinase, DNA polymerase.
-Cross resistance with famciclovir, valacyclovir,
ganciclovir

14. 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

15. Virus and Drug treatment
HSV- idoxuridine, acyclovir,
valacyclovir,famciclovir, penciclovir
CMV- ganciclovir, valganciclovir, cidofovir,
foscarnet
Influenza- amantadine, rimantadine,
oseltamivir, zanamvir, peramivir
HBV – entecavir, tenofovir, lamivudine,
adefovir, telbivudine
HCV-

16. Acyclovir
Pharmacokinetics of Acyclovir :
• Oral bioavailability ~ 20-30%
• Distribution in all body tissues including CNS
• Renal excretion: > 80%
• Half life: 2-5 hours
• Administration: Topical, Oral , IV depending on
severity and recurrences.

17. Adverse effects of Acyclovir/
Ganciclovir
• Nausea, vomiting and diarrhea
• Nephrotoxicity - crystalluria, haematuria,
renal insufficiency
• Myelosuppression – Neutropenia and
thrombocytopenia – Ganciclovir

18. Therapeutic uses
Acyclovir is the drug of choice for
HSV Genital , mucocutaneous infections
HSV encephalitis, keratitis
Herpes zoster, chicken pox
HSV infections in immunocompromised persons.
Ganciclovir is the drug of choice for:
CMV retinitis in immunocompromised patient
Prevention of CMV disease in transplant patients

19. Cidofovir-
It is approved for the treatment of CMV retinitis in
immunocompromised patients( ganciclovir failure)
• It is a nucleotide analog of cytosine – no
phosphorylation required.
• It inhibits viral DNA synthesis
• Available for IV, Intravitreal inj, topical on anogenital
warts.
• weekly given.
• Nephrotoxicity is a major disadvantage.
• Given with pre and post dose oral probeneacid which
inhibits its tubular secretion increasing availability and
decreases nephrotoxicity.

20. Vidarabine
• Vidarabine is a nucleoside (adenosine) analogue
• The drug is converted to its triphosphate analog
which inhibits viral DNA- polymerase.
• Antiviral spectrum of Vidarabine:
HSV-1, HSV-2 and VZV.
• Oral bioavailability ~ 2%
• Administration: Ophthalmic ointment
• Its use is limited to HSV keratoconjunctivitis in
immunocompromised patient only.
• Anemia and SIADH are adverse effects.

21. Trifluridine
• Trifluridine is a Pyrimidine nucleoside
analogue - inhibits viral DNA synthesis.
• Antiviral spectrum :
• HSV-1, HSV-2 and VZV.
• Use is limited to Topical - Ocular HSV
Keratitis

22. Foscarnet
• an inorganic pyrophosphate analog
unrelated to any nucleic acid
precursor.
• It directly inhibits viral DNA and RNA-polymerase and
viral inverse transcriptase(it does not require
phosphorylation for antiviral activity)
• HSV-1, HSV-2, VZV, CMV and HIV.
• Oral bioavailability ~ 10-20% so given I.V.
Distributed to all tissues including CNS
Adverse effects Hypocalcemia and hypomagnesemia (due
to chelation of the drug with divalent cations) are
common,neurotoxic ,nephrotoxic, renal diabetes,
anaemia.

23. Contd..
Therapeutic uses of Foscarnet
• It is an alternative drug for
• HSV infections (acyclovir resistant
/ immunocompromised patient )
• CMV retinitis (ganciclovir resistant
/ immunocompromised patient

24. Anti-influenza virus
-Infuenza virus is a RNA virus which causes
respiratory infections
-Segmented genome and core proteins
define its type A, B, C.
-A produces pandemics ,epidemics and B
produces sporadic infections
-H5N1 ( bird flu) and H1N1 (swine flu) are
prevalent now.

25. Anti-influenza drugs
-Amantadine / Rimantadine ( prevent
uncoating by inhibiting M2 proteins)
- Oseltamivir / Zanamavir/Peramivir( viral
neuraminidase inhibitors)
RSV bronchiolitis–Ribavirin

26. Amantadine and Rimantadine
(methyl derivative)
- Tricyclic amine unrelated to any nucleic acid precursor
• Prevention & Treatment of influenza A (not B)
• Inhibition of viral uncoating by inhibiting the viral membrane protein M2
• Oral bioavailability ~ 50-90%
• Amantadine cross extensively BBB whereas Rimantadine does not cross
extensively
• Dose P-100mgOD; T/t 100mg BD for 5 days
• Not preferred now
• Amantadine has anti-parkinsonian effects also.

27. Neuraminidase inhibitors :
- Prevent the release of new virions and
their spread from cell to cell.
-Broad spectrum so against type A and B
both.
- Oseltamivir requires activation to
oselamivir carboxylate by liver esterases so
may not be effective in infants.
-More useful if given in initial 48hrs.

28. Contd..
• Do not interfere with immune response to
influenza A vaccine.
• Can be used for both prophylaxis and
acute treatment.
• Dose : P-75mg OD; T/t-75mgBD
• A/E- nausea ,weakness, abdominal
pain, diarrhoea, cough, sadness , skin
reactions

29. Contd…
• Zanamavir is given intranasally, useful in oseltamivir
resistant cases also.
• Dose :P- 10mg through inhaler, rotacap OD, T/t- 10mg
BD for 5-7 days
• Risk of bronchospasm with zanamavir.
• Laninamivir -long acting inhaled neuraminidase
inhibitor against oseltamivir resistant virus.
• Peramivir- drug given i.v., single dose 600 mg
treatment.

30. Hepatic viral infections
Hepatic Viral infections:
AIM : HBV- suppression of replication
HCV-eradication
HBV is DNA virus which integrates into host Dna like HIV virus and can
cause permanent, latent infection.
HCV is RNA virus which donot integrate so can be eradicated.
• Interferons and ribavirin are non specific antiviral agents.

31. 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
• Distribution in all body tissues, except CNS
• Administration : Oral, IV, Inhalational in RSV.
• Anemia and jaundice are adverse effects
• Not advised in pregnancy.

32. Contd..
Therapeutic uses Ribavirin
Drug of choice for:
• RSV bronchiolitis and pneumonia in
hospitalized children (given by aerosol)
• Lassa fever
An alternativedrug for:
• Influenza, parainfluenza, measles virus
infection in immunocompromised patients

33. Interferons
- are natural proteins produced by the cells of
the host 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

34. Contd..
• α and βinterferons 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

35. Mechanism of action of Interferons
-act by JAK –STAT pathway to increase antiviral proteins,
and promote formation of natural killer cells.
-Act at multiple steps like viral penetration, synthesis of
viral RNA/ DNA, viral assembly and release.
Used in chronic HBV and with ribavirin in acute HCV.
• Induction of:?????
1) a protein kinase which inhibits protein
synthesis
2) an oligo-adenylate synthase which leads to
degradation of viral mRNA
3) a phosphodiesterase which inhibit t-RNA
The action of these enzymes leads to an inhibition
of translation

36. Anti-viral drugs
Antiviral spectrum :
Interferon α
• Includes HBV, HCV
and HPV.
• Anti-proliferative
actions may inhibit
the growth of certain
cancers - like Kaposi
sarcoma and hairy
cell leukemia.

37. Anti-viral drugs
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

38. Therapeutic uses Interferons
• Chronic hepatitis B and C (complete
disappearance is seen in 30%).
•HZV infection in cancer patients (to
prevent the dissemination of the infection)
•CMV 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

39. Adverse effects of Interferons
• Acute flu-like syndrome (fever,
headache)
• Bone marrow suppression
(granulocytopenia, thrombocytopenia)
• Neurotoxicity (confusion, seizures)
• Cardiotoxicity – arrhythmia, hypotension
• Impairment of fertility
• Thyroid dysfunction, alopecia, hepatic
dysfunction.

40. Specific Anti- hepatitis drugs for HBV
• -DOC for treating chronic HBV is Entecavir
• Entecavir-guanosine analogue-viral DNA
polymerase inhibitor, for lamivudine resistant HBV
strains and chronic HBV.
• PK- taken empty stomach T1/2- 128-148 hrs.
• Dose :0.5 mgOD, for lamivudine resistant: 1mg
OD,A/E- lactic acidosis.
• Tenofovir- another first line drug for chronic
hepatitis, few GIT related adverse effects, 300mg
OD, given as disoproxil prodrug

41. CONTD..
• Lamivudine- cytosine analogue for chronic HBV, HIV.
• High resistance(upto70%), 100mg OD.
• A/E less .NO any hepatic, hematological,pancreatic,
neurological toxicity.
• Lamivudine resistant cases respond well to adefovir, tenofovir.
• Adefovir- antimetabolite, slow acting , least active so not first
line
• A/E-nephrotoxicity, lactic acidosis, hepatomegaly and steatosis,
flu like syndrome.
• Telbivudine-more resistance, myalgia, cough, git, 600mg OD.

42. Anti-hepatitis drugs- HCV
-For acute and chronic HCV DOC is
pegylated IFNα with ribavirin.
-Ribavirin-wide spectrum, orally, chronic
HCV
A/E- dose dependent hemolytic
anaemia

43. New drugs for HCV
-Target specific non structural viral proteins which play
important role in viral replication
All are given orally and in combination with ribavirin+
PegIFN α or amongst themselves.
Show drug drug interactions with CYP3A4 and Pgp
inducers and inhibitors.
Duration of therapy- 12-24 weeks.

44. Classification of anti HCV drugs
1- Protease inhibitors(NS3A/4)- Teloprevir,
boceprevir, simeprevir, grazoprevir, paritaprevir,
glecaprevir, volixaprevir.( functional RNA is not
formed and no replication).
2-RNA polymerase NS5A inhibitors- Elbasvir,
orbitasvir, dactalasvir,ledipasvir, velpatasvir(
affect replication and assembly;not given with
PPI/ H2 blockers)
3- NS5B polymerase inhibitors- sofusbuvir,
dasabuvir( chain terminator)

45. Important points
Sofusbuvir- prodrug, chain terminator, against
all (1-6) genotypes,resistance donot develop
easily, used in decompensated liver disease also,
taken with fatty meal.400mg OD.
A/e- - abdominal pain, fatigue, joint pain,
anaemia.
Simepravir-blocks cleavage of HCV polyprotein
complex so functional RNA is not formed and no
replication.
Against genotype 1,4.

46. Contd..
Dactalasvir- can be given in patients with
concommitant HIV and advanced liver
disease, all genotypes.
Ledipasvir-FDC (LDV/SOF)OD, genotypes
1,4,5,6, used in HIV coinfection.
Velpatasvir- FDC(VEL/SOF) OD, all
genotypes.

47. Summary
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

48. Virus Diseases
Drug( s) of
choice
Alternative
drugs
FLU
Influenza Oseltamivir,
zanamivir
amantadine
Rimantadine
RSV
Pneumonia,
bronchiolitis
Ribavirin
(aerosol)
HSV Genital herpes Acyclovir Foscarnet
Keratitis
Conjunctivitis Trifluridine
Idoxuridine
Vidarabine
Encephalitis Acyclovir
Neonatal HSV
infection Acyclovir Vidarabine
Herpes infections in
immuno-
compromised host.
Acyclovir Foscarnet
1 51

49. VZV In normal host No therapy
In immunocompro-
mised host, or during
pregnancy
Acyclovir Foscarnet
CMV Retinitis Ganciclovir Foscarnet
HIV AIDS
HIV antibody positive
with CD4 count <
500/mm3
Zidovudine ±
protease
inhibitors
Didanosine,
Stavudine
HBV
HCV
Hepatitis B, C Interferon