Antiviral drugs

1. Antiviral Drugs ( Non retroviral
drugs)
-Dr. Rahul Kumar Bhati

2. 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.

3. Contd..
• viruses multiply in nucleus and cytoplasm.
• usually diagnosis is made late as symptoms
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.

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

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

6. Mechanism of action
• Anti-viral drugs 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

7. 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.

8. 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.

9. Mechanism of Action of 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

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

11. Anti-viral 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

12. 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- ribavirin

13. 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.

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

15. 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

16. Cidofovir
It is approved for the treatment of CMV retinitis in
immunocompromised patients (ganciclovir failure)
• It is a nucleotide analogue 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.

17. Vidarabine
• Vidarabine is a nucleoside (adenosine) analogue
• The drug is converted to its triphosphate
analogue 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.

18. 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

19. Foscarnet
• an inorganic pyrophosphate analogue 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.

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

21. 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.

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

23. 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.

24. 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 48 hrs.

25. 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, skin reactions

26. 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.

27. 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 do not integrate so can be
eradicated.
• Interferons and ribavirin are non specific antiviral
agents.

28. Ribavirin
• Ribavirin is a guanosine analogue.
• 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.

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

30. 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

31. Contd..
• 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

32. 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

33. 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.

34. 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

35. Therapeutic uses of 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

36. 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.

37. 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

38. 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.

39. 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

40. 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.

41. 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)

42. Important points
• Sofusbuvir- prodrug, chain terminator, against
all (1-6) genotypes,resistance do not 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.

43. Contd..
• Dactalasvir- can be given in patients with
concomitant 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.

44. 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

45. Thank You