This document summarizes various antiviral drugs used to treat different viral infections. It discusses the mechanism of action, uses, and side effects of nucleoside analogues like acyclovir, valacyclovir, ganciclovir, cidofovir and ribavirin which inhibit viral DNA or RNA polymerase. It also mentions neuraminidase inhibitors oseltamivir and zanamivir used for influenza, and lamivudine, entecavir, tenofovir for chronic hepatitis B. Interferon-α used with ribavirin for hepatitis C treatment is also summarized.

1. Dr chintan Doshi

2. • Virus – ultramicroscopic infectious parasite
responsible for significant morbidity & mortality
• Structure of virion (intact virus particle):
Genome + capsid + envelop

3. • Obligate parasite
• active only within host cell
• Energy generating, RNA or DNA replicating & protein
synthesis machinery of host cells used for their growth
• Not replicate in host cells but direct them to make new
viral particles
Difficult to find antiviral drug that selectively inhibit or kill
virus without toxic to host

7.  Purine analogues: Acyclovir, Valacyclovir, Ganciclovir,
Valganciclovir, Famciclovir, Penciclovir,
Cidofovir, Vidarabine
 Pyrimidine analogues: Idoxuridine, Trifluridine, Telbivudine
 Non nucleosides: Foscarnet
Fomivirsen
DNA Polymerase Inhibitors
mRNA synthesis inhibitor

8. Acyclovir
• Guanosine analogue
• Converted into active metabolite
↓
inhibit DNA synthesis
& viral replication

9. Acyclovir
Herpes virus specific thymidine kinase
Acyclovir monophosphate
guanidylate kinase (host cell enzyme)
Acyclovir triphosphate
competitively inhibit gets incorporated in viral DNA
herpes virus & stop lengthening of DNA strand
DNA polymerase ↓
terminated DNA inhibit DNA polymerase

10.  Selective toxicity:
• Taken up by infected cells
• In non infected cell – phosphorylation occurs to limited extent
• Inhibit viral DNA polymerase 10-30 times more effectively than
host cell DNA polymerase
Pharmacokinetics:
• Absorption: oral - 20%
• Widely distribution
• Excretion – urine (dose reduction needed in renal impairment )

11. Antiviral spectrum:
• HSV-1 most sensitive
• HSV-2 > VZV = EBV
• CMV not affected
HSV & VZV → resistance
• Mutation - ↓ thymidine kinase activity
• Change in specificity of virus directed enzyme-↓affinity for acyclovir

12. Uses:
1) Genital Herpes simplex: (type 2 virus)
o Primary disease:
• 5% ointment 6 times daily for 10 days
• Late & severe case -
400mg TDS for 10 days
• Symptomatic relief & rapid healing of lesion
• Not prevent recurrence
o Recurrent disease:
• 5mg/kg i.v. over 1 hr, repeat 8 hrly for 10 days
• Suppressive oral therapy – 400 mg BD
• Stop treatment after 1 year
• Continuous treatment - >8 recurrences/year

13. Contd.
2) Mucocutaneous Herpes simplex: (type 1 virus)
• localised to lips & gum
• Acyclovir cream – relief
• Spreading lesion – 10 day oral acyclovir
• Immunocompromised patient – oral or i.v. acyclovir
15 mg/kg/day for 7 days
3) H. simplex encephalitis (type 1 virus):
• 10-20 mg/kg/8 hrly i.v. for ≥10 days(drug of choice)
• Effective only if started early

14. 4) H. simplex keratitis (type 1 virus):
• Equally effective as idoxuridine in superficial dendritic corneal
ulcer
• Blindness prevented
• Ointment applied 5 times daily till 3 days after healing
5) Herpes zoster:
• High dose needed
• 10 mg/kg/8 hrly i.v. for 7 days
• Symptomatic relief & fast healing of lesion
• Post herpetic neuralgia not prevented, but its duration
shortened

15. 6) Chickenpox:
• Drug of choice - 15 mg/kg/day i.v. for 7 days
• Reduces fever, eruption, fast healing, prevent complications
• In susceptible contacts – oral acyclovir 400 mg QID for 7 days
Side effects:
• Topical: stinging & burning sensation
• Oral: headache, nausea, malaise
• Intravenous: rashes, swelling, emesis, fall in BP (in some pt)
• High dose: reversible neurological manifestation (tremor, lethargy,
disorientation, hallucination, convulsion, coma)
• Dose dependent ↓gfr – normal on discontinuation of drug

16. • Prodrug of acyclovir
• Improved oral bioavaibility
• During passage through intestine & liver – completely converted to
acyclovir by esterase
• More effective than acyclovir for treatment of herpes zoster
 Uses & Dose:
 For genital herpes simplex
 Orolabial herpes
 Herpes zoster
Valacyclovir

17. • Prodrug
• Like acyclovir converted into active metabolite
• Good oral bioavaibility
• Active form persist intra cellular for long time
• Active against H. simplex, H. zoster, HBV
• Herpes zoster -↓duration of post herpetic neuralgia, not incidence
• Dose: 500 mg TDS for 7-10 days
• S/E: headache, nausea, loose motions, itching, rashes, mental confusion
• Active metabolite of famciclovir
• Available for i.v. use
Famciclovir
Penciclovir

18. • Hydroxymethylated analogue of acyclovir
• Action similar to acyclovir
• Poor oral bioavaibility
• Usually administered intravenously – high accumulation
in vitreous humour
 Uses:
• All herpes virus infection
• Most important use – serious & vision threatening retinitis by
CMV
• Intravitreal implant – CMV retinitis in AIDS patient
• Acyclovir resistant HSV infection
• CMV infection in organ transplant & immunocompromised patient
Ganciclovir

19.  Dose: 5 mg/kg BD i.v. for 1-3 weeks
maintenance – 5 mg/kg/day
 Side effects:
• Myelosuppression – bone marrow cells sensitive to drug
• Other: rash, fever, vomiting, neuropsychiatric disturbances
• At injection site – pain , phlebitis
• Animal study – carcinogenic, teratogenic, ↓sperm production

20. • Prodrug of ganciclovir
• Well absorbed from GIT
• 8 times high bioavaibility
• Half life: 2-4 hrs, but inside CMV infected cell >24 hrs
 Uses:
• oral valganciclovir comparable to i.v. ganciclovir
• Treatment & prophylaxis of CMV infection in
immunocompromised patients
Valganciclovir

21. • Adenine nucleoside analogue
• From- streptomyces antibioticus
• Action – inhibit viral DNA synthesis by blocking DNA polymerase
• Only topically used – as ophthalmic ointment
 Uses:
• HSV keratoconjuctivitis & superficial keratitis (not responsive or
hypersensitive to idoxuridine)
 Side effects:
• Lacrimation, irritation, photophobia
 Use with steroid should be avoided – spread HSV infection
- raise intraocular tension
Vidarabine

22. • Analogue of cytidine
 Action:
Cidofovir monophosphate
↓ cellular enzyme
Cidofovir diphosphate
↓
Inhibit DNA polymerase
• Also act as substrate for viral DNA polymerase
• Half life: 2-3 hrs, but persist in host cell
(once weekly i.v. dose)
Cidofovir

23. • Poor oral bioavaibility – give topically or i.v.
• Not metabolized significantly
• Excreted – urine
• i.v. cidofovir administered with probenecid
↓
block tubular secretion & reduces nephrotoxicity
 Uses:
• CMV retinitis & mucocutaneous HSV lesion
• Acyclovir resistant infection

24. Contd.
 Side effects:
• Nephrotoxicity
• Gastric disturbances
• Hypersensitivity reactions
• neutropenia
• Uveitis

25. • 5-iodo-2-deoxyuridine – thymidine analogue
• 1st Pyrimidine antimetabolite –as antiviral agent
Action:
• Compete with thymidine
↓
get incorporated in DNA
↓
faulty DNA formed & break down easily
• Active against DNA viruses
Idoxuridine

26. Resistance:
• inactivated by viral deaminase & nucleotidase
Use:
• Low virus selectivity, high local toxicity, resistance
↓
restricted use – superficial dendritic keratitis
• Eye drop act faster than acyclovir ointment, when stromal
involvement of cornea
Side effects:
• Ocular iritation, photophobia, lacrimation, corneal clouding

27. • Trifluoromethyl derivative of idoxuridine
• Action same as idoxuridine
• More potent
• Active against – HSV1, HSV2, CMV
• Virus selectivity low, host cells also affected
• In INDIA approved for – H. simplex keratitis
• S/E: lid edema, ocular irritation
Trifluridine

28. • Simple straight chain phosphonate
Action:
• Not require phosphorylation
• Inhibit viral DNA polymerase & reverse transcriptase by
blocking phosphate binding site on enzyme
P/K:
• Oral absorption low
• Half life: 4-8 hrs
• Not metabolized
• Excretion - urine
Foscarnet

30. • Amantadine
• Rimantadine
• Docosanol
Inhibitors of
viral
penetration &
uncoating
• Oseltamivir
• Zanamivir
• Peramivir
Neuraminidase
inhibitors

31. • Synthetic tricyclic amine
• Effective against influenza A, negligible against influenza B
 Action:
Inhibit uncoating of influenza A virus
↓
prevent replication
inhibit viral M2 protein (ion channel)
↓
prevent H mediated dissociation of ribonucleoprotein
↓
inhibit viral replication
Amantadine

32. Uses:
1) Prophylaxis of influenza A2
• Epidemic or seasonal influenza – generally last 2 months
• Only this period needs prophylaxis
2) Treatment of influenza A2 illness
• Reduction in fever, congestion, cough, quicker recovery
• 5 day treatment
3) Parkinsonism

33.  Dose:
• 100 mg BD & for prophylaxis 100 mg OD
 Side effects:
• Nausea, anorexia, insomnia, dizziness, nightmares, lack
of mental concentration, rarely hallucination
• Ankle edema
 Contraindication:
• Epilepsy & other CNS disease, gastric ulcer, pregnancy

34. • Methyl derivative of amantadine
• More potent, Long acting
• Better tolerated, less side effects
• High oral bioavaibility
• Metabolized by hydroxylation followed by glucuronide
conjugation
• Half life – 25 hrs in young, 33 hrs in elderly
• Excretion – urine
 Dose: 100 mg BD
Rimantadine

35. • New agent
 Broad spectrum activity:
• Influenza A (amantadine sensitive and resistant)
• H5N1 (bird flu)
• H1N1 (swine flu)
• Influenza B
 Prodrug
• Liver – active metabolite oseltamivir carboxylase by esterase
• Oral bioavaibility – 80%
• Half life – 8 hrs
• Excretion - urine
Oseltamivir

36.  Action:
Inhibit influenza virus neuraminidase enzyme
↓
prevent release of progeny virion from infected cell
↓
prevent spread of virus in body
 Dose:
• Therapeutic – 75 mg oral BD for 5 days
• Prophylaxis – 75 mg OD
• For best result drug should be start within 2 days of symptoms
onset
 Side effects:
Nausea, abdominal pain, gastric irritation, headache, weakness,
sadness, diarrhea, cough, insomnia, skin reaction, aggravation of
diabetes

37. • Oral bioavaibility low
• Administered by inhalation as powder
• Half life – 3.5 hrs
• Action, utility, efficacy similar to oseltamivir
• Some strain resistant to oseltamivir remain sensitive
Dose: 10 mg BD for 5 days
: 10 mg OD for prophylaxis
Side effects:
• Bronchospasm, nasal discomfort, headache, dizziness, nausea,
rashes
Zanamivir

38. • Recently approved drug (FEB 2009)
• For emergency treatment of hospitalized patient
with H1N1 influenza infection
• Used in cases resistance to oseltamivir or zanamivir
• Poor oral bioavaibility
• It is the only I.V. option for swine flu
Peramivir

40. → DNA virus
→integrated into host DNA – permanent infection
→ RNA virus
→ NOT integrated into host DNA
→ causes chronic hepatitis
Hepatitis B
Hepatitis C

41. Hepatitis B
• Lamivudine
• Telbivudine
• Entecavir
• Adefovir
• Tenofovir
Hepatitis C
• Ribavirin
• Interferon α

42. • Active against HBV & HIV
• Human DNA polymerase not affected
• Resistance: Point mutation of enzyme
• oral bioavaibility high
 Uses: 1st line drug for chronic hepatitis B
: in combination with other anti-HIV agents
 Dose: hepatitis B – 100mg OD
 S/E: headache, fatigue, rashes, nausea, anorexia, abdominal pain,
pancreatitis & neuropathy rare
Lamivudine
Inhibit HIV reverse transcriptase & HBV DNA Polymerase

43. • Thymidine analogue
 Action: active triphosphate form
↓
Prevent viral replication
 Use: chronic hepatitis B
 S/E: headache, nausea, vomiting
Telbivudine
Inhibit HBV DNA Polymerase

44. • Analogue of adenosine monophosphate
• Active against HBV & HIV
• Low oral absorption – used as disoproxil ester prodrug
• improve bioavaibility & intracellular passage of active form
 Action: hydrolysis of prodrug
↓ cellular kinase
diphosphate form of tenofovir
↓
inhibit HBV DNA polymerase & HIV reverse transcriptase
Tenofovir

45. Use: Chronic hepatitis B, also lamivudine resistant case
 Dose: 300 mg OD
 S/E: nausea, flatulence, abdominal discomfort,
loose motion, headache, rarely renal toxicity

46. • Synthetic analogue of guanosine
 Broad spectrum activity:
• Influenza A & B
• Respiratory syncytial virus
• Many other DNA & RNA viruses
 Action: monophosphate derivative triphosphate derivative
↓ ↓
inhibit viral GTP synthesis inhibit viral RNA polymerase
• Oral absorption – 50%
• Accumulate in body on daily dosing, persist months after
discontinuation
• Long half life - >10 days
Ribavirin

47. Uses:
• Most common use – chronic hepatitis C
• 1st line treatment for hepatitis C – oral ribavirin with
injected peginterferon(6-12 months)
• Severe influenza A/B & measles
• Herpes virus infection
• Nebulized ribavirin – respiratory syncytial virus bronchiolitis
• Dose: 200 mg QID
 S/E: anaemia, bone marrow depression, haemolysis,
CNS & GI symptom, bronchospasm

48. • Production of cytokine called interferon is important defense
against viral infection
• antiproliferative & immunoregulatory effects
 Action:
• bind with Interferon receptors
↓
on activation phosphorylate cellular proteins
↓
migrate into nucleus
↓
induce transcription of ‘ interferon induced protein’
↓
exert antiviral effects
Interferon α

49.  3 types of human interferon: (α, β, )
 Only IFNα2A & IFNα2B – by recombinant technology
- clinically used
• Both are low MW protein & administered by s.c. or i.m.
 Degraded in liver & kidney
 Remain detectable in plasma for 24 hrs
• Cellular effects long lasting - Interferon induced protein persist
 Complex with polyethylene glycol (peginterferon)
• Absorbed more slowly
• Exert more sustained effects
• Permitting weekly administration
• Improving clinical efficacy

50. Uses:
1) Chronic hepatitis B
2) Chronic hepatitis C
3) AIDS related kaposi’s sarcoma
• treat kaposi’s sarcoma not AIDS
• ↑toxicity of zidovudine
4) H. simplex, H. zoster & CMV infection:
• Inferior to acyclovir/ganciclovir
• Used as second line drug
5) CML, follicular lymphoma, cutaneous T cell lymphoma

51. Contd.
Side effects:
• Flu like symptoms – fatigue, aches, pains, malaise, fever,
dizziness, anorexia, nausea, taste & visual disturbances
• Neurotoxicity – numbness, neuropathy, altered behaviour,
mental depression, tremor, rarely convulsion
• Myelosuppression
• Thyroid dysfunction, liver dysfunction
• Hypotension, transient arrhythmia, alopecia