This document provides an overview of antiviral agents for medical students. It discusses the targets of antiviral drugs, including viral enzymes and virus-specific steps. Several classes of antiviral agents are described, including drugs for influenza, hepatitis, HIV, and herpes viruses. Specific drugs like acyclovir, ganciclovir, and famciclovir are examined in depth, outlining their mechanisms of action, pharmacokinetics, uses, and side effects in treating herpes virus infections. The conclusion emphasizes that antiviral drugs achieve selective toxicity by targeting viral processes and that classification is based on activity against different virus families.

1. Antiviral agents-I
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College
22 July, 2018 (6 Shrawan, 2075), Sunday

2. By the end of the class, MBBS Sem IV
students will be able to:
 Identify the targets of anti-viral agents
 Classify anti-viral agents
 Describe the pharmacology of acyclovir
 Compare the different anti-herpes agents

3. Anti-viral agents: Introduction
 Virus uses host cell metabolic machinery for its
replication
 Selective toxicity difficult to achieve
 Antivirals required for:
 Immunocompromised individuals
 Infection with high morbidity/mortality
 Targets of anti-viral agents:
 Viral enzymes, virus directed enzymes
 Virus specific steps

4. Virus specific steps: Possible Targets
Attachment
and entry
Penetration
Uncoating Nucleic acid
synthesis
Integration
and/or
transcription
Viral Protein
synthesis
Packaging and
assembly
Virus
release
Mammalian cell
1
2
3 4
56
7

5. Virus specific steps: Possible Targets
Target Examples
1 Enfuvirtide, Maraviroc (HIV)
2 Interferon-alpha (HBV, HCV)
3 Amantadine, Rimantadine (Influenza)
4 NRTI, NNRTI (HIV); Nucleoside/
Nucleotide analogues (HSV, HBV)
5 INSTIs (HIV)
6 Protease Inhibitors (HIV)
7 Neuraminidase inhibitor (Influenza)

6. Anti-viral agents: Classification
 Anti-herpes drugs
 Idoxuridine, Trifluridine
 Acyclovir, Valacyclovir
 Ganciclovir, Valganciclovir
 Famciclovir
 Cidofovir
 Foscarnet

7. Anti-viral agents: Classification
 Anti-influenza drugs
 Amantadine, Rimantadine
 Oseltamivir
 Zanamivir

8. Anti-viral agents: Classification
 Anti-Hepatitis drugs/Non-selective antiviral
drugs
 Primarily for Hepatitis B
oLamivudine
oAdefovir dipivoxil
oTenofovir
 Primarily for Hepatitis C
oRibavirin
oInterferon alpha

9. Antiretroviral agents: classification
Class Drugs
Nucleoside reverse
transcriptase
inhibitors (NRTIs)
Zidovudine, Lamivudine,
Didanosine, Stavudine,
Abacavir, Emtricitabine,
Tenofovir
Non-nucleoside RTI
(NNRTIs)
Nevirapine, Efavirenz,
Delavirdine
Protease Inhibitors
(-navir)
Ritonavir, Lopinavir,
Azatanavir, Indinavir,
Nelfinavir, Saquinavir,
Amprenavir

10. Antiretroviral agents: classification
Class Drugs
Entry (fusion)
inhibitors
Enfuvirtide
CCR5 receptor
inhibitor
Maraviroc
Integrase inhibitors Raltegravir

11. Anti-herpes drugs
Idoxuridine, Trifluridine
 Thymidine analogue
 Competes with thymidine
 Gets incorporated into DNA
 Faulty DNA formed, that breaks easily
 Trifluridine: fluorinated nucleoside
 Problems:
 Low virus selectivity
 Rapid development of viral resistance

12. Anti-herpes drugs
Idoxuridine, Trifluridine
 Use:
 Herpes simplex keratitis
(superficial)
 Trifluridine: higher
efficacy
 Side effects:
 Ocular irritation
 Lid oedema

13. Anti-herpes agents
 Acyclovir
 Deoxyguanosine analogue
 Selective toxicity:
oPreferentially taken up by virus infected cells
oHerpes virus specific thymidine kinase
required for its action
oActs by inhibiting viral DNA polymerase
reversibly as well as irreversibly

14. Acyclovir: Mechanism of Action
Acyclovir
Acyclovir
Mono-
phosphate
Acyclovir
Triphosphate
1. Herpes virus specific
thymidine kinase
2.Cellular kinases
1
2
• Inhibits herpes virus DNA
polymerase competitively
• Gets incorporated into viral DNA
• Early termination of lengthening
of viral DNA
• DNA polymerase inhibited
irreversibly

15. Interesting fact….
George Hitchings and Gertrude Elion
Discovered and developed Acyclovir
Nobel Prize in 1988

16.  Active against only herpes group of viruses
 Herpes simplex Virus (HSV)-1
 HSV-2
 Varicella zoster virus (VZV), Ebstein Barr
virus
 Resistance to acyclovir:
 HSV- mutant thymidine kinase (TK)
 VZV- increased substrate specificity of TK
Anti-herpes agents: Acyclovir
IncreasedSensitivity
CMV

17. Anti-herpes agents: Acyclovir
 Pharmacokinetics:
 Oral bioavailability: 10-30%
o Decreases with increasing dose
oValacyclovir: 55-70%
 Low percutaneous absorption
 Widely distributed
 Eliminated unmetabolized by glomerular
filtration and tubular secretion
 Elimination t½ 2.5 hrs

18. Anti-herpes agents: Acyclovir
 Uses:
 Herpes simplex infections:
oGenital (Primary, Recurrent)
oMucocutaneous
oEncephalitis
oKeratitis
 Varicella zoster infections:
oHerpes zoster
oChickenpox

19. Anti-herpes agents
Acyclovir Formulations:
Valaciclovir Formulations:

20. Anti-herpes agents: Acyclovir
 Adverse effects:
 Dose dependent decrease in GFR
 Reversible neurological manifestation (lethargy,
disorientation, hallucinations, convulsions,
coma) at higher doses
 Topical: Stinging and burning sensation after
each application
 Oral: Headache, nausea, malaise
 Intravenous: Rashes, sweating, fall in BP

21. Anti-herpes agents: Ganciclovir
 Analogue of acyclovir
 Active against:
 H. simplex, H. zoster, EBV
 Cytomegalovirus (CMV, most sensitive)
oHigher concentration
oEliminated slowly ( >24 hours)

22. Anti-herpes agents: Ganciclovir
 Mechanism of action: Similar to acyclovir
 Mechanism of resistance:
 Mutation of viral phosphokinase and/or viral
DNA polymerase
 Pharmacokinetics:
 Oral bioavailability <10%
oValganciclovir higher oral bioavailability
 Excreted in urine
 Plasma half life 2-4 hrs

23. Anti-herpes agents: Ganciclovir
Side effects:
 Bone marrow toxicity
 Precursor cells quite sensitive to ganciclovir
 Rash, fever, vomiting, neuropsychiatric
disturbances
Uses:
 Prophylaxis and treatment of severe CMV
infections in immunocompromised
 CMV retinitis in AIDS patients

24. Anti-herpes agents: Famciclovir
 Guanine nucloeside
 Prodrug of penciclovir
 Good oral bioavailability
 Prolonged intracellular t½ of the active
triphosphate metabolite
 Penciclovir available in some countries for
intravenous use

25. Anti-herpes agents: Famciclovir
 Mechanism of action:
 Requires viral TK for activation
 Inhibits viral DNA polymerase
 Inhibits:
 Acyclovir sensitive H. simplex, H. zoster
oAs alternative
oReduces duration of illness
 Hepatitis B virus
oChronic hepatitis B

26. Anti-herpes agents: Famciclovir
 Side effects:
 Headache, mental
confusion
 Nausea, loose
motions
 Itching, rashes

27. Anti-herpes agents: Cidofovir
 Monophosphate nucleotide analogue of
cytidine
 Inhibits:
 HSV, CMV, pox and adenoviruses
 Acyclovir resistant HSV
 Ganciclovir resistant CMV

28. Anti-herpes agents: Cidofovir
 Mechanism of Action:
 Does not require viral phosphokinase
 Converted into diphosphate by cellular kinase
oRemains intracellularly for long time
oActs as alternative substrate for viral DNA
polymerase
oInhibits viral DNA polymerase
 Mechanism of resistance: mutation of DNA
polymerase (CMV)

29. Anti-herpes agents: Cidofovir
Pharmacokinetics:
 Given as intravenous infusion
 Along with pre and post dose oral
probenecid: decreases tubular secretion of
cidofovir
oAvailable to enter cells for longer duration
oReduces nephrotoxicity

30. Anti-herpes agents: Cidofovir
 Uses:
 CMV retinitis (who have failed on ganciclovir
therapy)
 Acyclovir resistant mucocutaneous HSV
infection in immunocompromised
 Anogenital warts: topical
 Side effects:
 Dose related kidney damage
 Neutropenia, uveitis, hypersensitivity reaction

31. Anti-herpes agents: Foscarnet
 Unrelated to any nucleic acid
 Inhibits viral DNA polymerase and reverse
transcriptase
 Resistance to foscarnet- minimal
 Acts on:
 H. simplex (acyclovir sensitive / resistance)
 CMV (ganciclovir sensitive / resistant)
 HIV

32. Anti-herpes agents: Foscarnet
 Pharmacokinetics:
 Poorly absorbed orally
 Not metabolised
 t½ 4-8 hrs
 Uses:
 CMV retinitis/ infections in AIDS patients
 Acyclovir resistance cases in AIDS patients

33. Anti-herpes agents: Foscarnet
 Side effects:
 Renal diabetes like condition
 Acute renal failure
 Anaemia, phlebitis, tremor, convulsions
 Due to hypocalcaemia:
oNumbness and tingling sensation
oMuscle cramps
oIrritability, seizures

34. Conclusion
 Selective toxicity for antiviral agents is achieved
by targeting viral enzymes and virus specific
steps
 Anti-viral agents are broadly classified into four
groups depending upon their activity on viruses
 Idoxuridine and trifluridine are used only
topically
 Variation in the sensitivity of anti-herpes agents
to herpes family viruses is well recognised

35. Questions??
 Thank you..