A detailed presentation on Introduction to Virus and Anti-Viral Therapy

1. Presentation By: GAGANDEEP JAISWAL

3. Viruses are the smallest infective agents,
consisting essentially of nucleic acid (either
RNA or DNA) enclosed in a protein coat or
capsid.
Viral particles consist of two to three
parts:
•Genetic material, either DNA or RNA.
•Protein coat (Capsid), which surrounds and
protects the genetic material.
•Envelope of lipid , lipid layer that surround
the protein coat when they are outside cell.
Introduction to Virus

4. Viruses do not have metabolic machinery and
cannot reproduce on their own.
It must attach to and enter a host cell. It then
uses the host cell’s energy to synthesize
protein, DNA, and RNA. Viruses are difficult
to kill because they live inside the cells. Any
drug that kills a virus may also kill cells
A fully assembled infectious virus is known
as “virion” which Often contain crucial virus
specific enzymes and visible by electron
microscopy.
Cont.

5. Some Important Examples of Viruses and the
Diseases They Cause are as Follows:
DNA viruses RNA viruses
Pox viruses (smallpox) Orthomyxo viruses (influenza)
Herpes viruses (chickenpox, herpes
etc)
Paramyxo viruses (measles, mumps)
Adenoviruses (sore throat,
conjunctivitis)
Rubella virus (German measles)
Hepa dna viruses (serum hepatitis) Rhabdo viruses (rabies)
Papilloma viruses (warts) Picorna viruses(colds, meningitis,
poliomyelitis)
Retroviruses (AIDS, T-cell leukemia)
Arena viruses (meningitis, Lassa fever)
Arbo viruses (arthropod-borne
encephalitis, yellow fever)

6. Routes of Virus Transfer
• Skin contact
• Respiratory
• Faecal
• Oral
• Milk
• Transplacental
• Sexual
• Insect vector
• Animal bite

7. Viral Replication

8. Diversity in Viral Genomes

9. Antiviral Therapy
• Through vaccination
• Antiviral drug therapy
• Host immune system stimulation
Ideal Antiviral Agents
• Low toxicity to host
• Greater selectivity
• Should kill latent viruses as well
Drawbacks of Antiviral Drug Therapy
• Antiviral drugs are toxic to host cells
• Some viruses multiply in both cytoplasm as well as nucleus
• Antiviral drugs most effective during rapid multiplications
• Latent virus not affected by antiviral drugs

10. Classification of Antiviral Drugs

11. Anti-
Retroviral
Nucleoside Reverse
Transcriptase Inhibitors(NRTIs)-
Zidovudine(AZT), Didanosine,
Stavudine, Lamivudine, Abacavir,
Emtricitabine, Tenofovir (Nt RTI)
Non-nucleoside Reverse
Transcriptase
Inhibitors(NNRTIs)- Nevirapine,
Efaviranz, Delavirdine
Protease inhibitors-
Ritonavir, Atazanavir, Indinavir,
Nelfinavir, Lopinavir, Saquinavir,
Amprenavir
Entry(fusion)
inhibitor-
Enfuvirtide
CCR5 receptor inhibitor-
Maraviroc
Integrase inhibitor-
Raltegravir

12. Mechanisms of Action of Antiviral Drugs

13. ANTI VIRAL DRUG
THERAPY IN DETAIL

14. Acyclovir (Zovirax)
• Purine (deoxyguanosine) analogue
 Acyclovir
 Acyclovir Monophosphate
 Acyclovir triphosphate
Herpes virus specific thymidine kinase
Cellular kinases
Inhibits herpes virus DNA polymerase
competitively
Gets incorporated into the viral DNA and
stops lengthening of DNA strand, hence
inhibits DNA polymerase irreversibly
Anti-Herpes Virus Drugs

15. Mechanism of Action of Acyclovir

16. 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
Uses of Acyclovir:
Primary Genital Herpes
• 5% ointment locally 6 times a day for 10 days
• 1gm/day in 5 divided doses
Recurrent Genital Herpes
• 5mg/kg IV infused over 1 hr
• Repeated 8 hourly for 10 days

17. Mucocutaneous Herpes Keratoconjuctivitis (Localized To Lips And
Lungs)
• 5% ointment locally 6 times a day for 5days
• 1gm/day in 5 divided doses
Chickenpox
• 15mg/kg/day for 7days
Varicella Zoster
• 15mg/kg/day for 7days
• 10mg/kg/8hr IV for 10 days
Herpes Simplex Encephalitis
• Acyclovir 10mg/kg/8hr IV for 10 days
Cont.

18. Adverse Effects
• Stinging and burning sensation
• Nausea, Vomiting, Diarrhea, Headache, Malaise
• Vomiting, Rash, Sweating, Hypotension
• Renal dysfunction, Neurotoxicity
• Myelosuppression – Neutropenia and thrombocytopenia – Ganciclovir
Congeners of Acyclovir
• 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.

19. 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
Therapeutic Uses :
Ganciclovir is the drug of choice for:
• CMV retinitis in immunocompromised patient
• Prevention of CMV disease in transplant patients

20. Mechanism of Resistance to Acyclovir
• Impaired production of thymidine kinase.
• Altered thymidine kinase substrate specificity (phosphorylation of
thymidine but not of acyclovir).
• Altered viral DNA polymerase by point mutations and base insertion or
deletions in corresponding genes.

21. Acts against respiratory viral infections Influenza –
• Amantadine / Rimantadine
• Oseltamivir / Zanamavir (Neuraminidase inhibitors)
Acts against RSV bronchiolitis –
• Ribavirin
Amantadine (Amantrel)
Influenza B is not affected as antiviral activity is strain specific.
• Prevention & Treatment of influenza A
• Inhibition of viral uncoating by inhibiting the viral membrane protein
M2(matrix protein) of Influenza A virus . Due to interruption of function of
the M2 protein, the drugs inhibit the acid (H+)-mediated dissociation of the
ribonucleoprotein (RNP) complex early in the process of replication.
• Amantadine also has anti- parkinsonian effect.
Anti-Influenza Virus Drugs

22. Pharmacokinetics of Amantadine
• Oral bioavailability ~ 50-90%
• Amantadine cross extensively BBB whereas Rimantadine does not cross
extensively
• Administration: Oral.
Adverse Effects
• GI intolerance
• CNS side effects
• Anticholinergic effects
• Teratogenic
Uses
 Prophylaxis of influenza A2
 Treatment of influenza A2
 Dose 100mg BD
Contraindications
 Epilepsy and other CNS disease, gastric ulcer, pregnancy.

23. Rimantadine (Flumadine)
Methyl derivative of Amantadine.
Interfere with virus uncoating by inhibiting release of specific protein also
its more effective than Amantadine.
More potent, Long acting.
Less side effects and less neurotoxic, High GIT intolerance.
Dose 100mg BD.
Cont.

24. Oseltamivir (Tamiflu)
Sialic acid analogue with braod spectrum activity covering infleunza A,
H5N1(bird flu), H1N1(swine flu) strains and influenza B.
First orally active neuraminidase (NA) inhibitor. A prodrug compound.
Hydrolysis of the ester takes place in the body to give the active carboxylic
acid derivative of Oseltamivir.
As a structural analogue of a key intermediate in sialic acid/NA chemistry,
oseltamivir serves as a competitive inhibitor of viral NA by binding strongly
to the active site of NA. This interaction ultimately prevents the release of
new viral particles from the host cell.
Dose-75 mg oral BD for 5 days.
Cont.

25. Zanamivir (Relenza)
Effective for both influenza A and B.
• Poor bioavailability and poor plasma portion binding
• Use oral inhalation.
No conformational change required to allow binding while oseltamivir
requires change in active sites for binding. Hence, does not tightly bind than
zanamivir leads to differences in development of resistance.
Contraindicated in asthmatics, can induce bronchospasm.
Cont.

26. Adefovir dipivoxil
•Adenosine analogue
•Nucleotide inhibitor
•Mechanism of action: It is phosphorylated to adefovir diphosphate
incorporated into viral DNA termination of further DNA synthesis
prevents viral replication.
•Both decreased viral load and improved liver function.
•Indicated in chronic hepatitis B, also in Lamivudine resistant cases and in
concurrent HIV infection.
Anti-Hepatitis Virus/ Nonselective Antiviral
Drugs

27. Its plasma t½ is 7 hours; intracellular t½ of the diphosphate is upto 18
hours.
Adverse effects:
• Sore throat, headache, weakness, abdominal pain and flu syndrome
• Nephrotoxicity ( higher doses and in those with preexisting renal
insufficiency )
• Lactic acidosis ( patients receiving anti-HIV drugs ).
Dose-10mg/day
Cont.

28. •Cytokines produced by host cells in response to viral infections and other
inducers
•Three types of human IFNs (α, β and γ) are known to have antiviral activity
Mechanism of action:
Induction of host cell enzymes that inhibit viral RNA translation
degradation of viral mRNA and tRNA
Interferon receptors are JAK-STAT tyrosine protein kinase receptors
which on activation phosphorylate cellular proteins .
These then migrate to the nucleus and induce transcription of ‘interferon-
induced- proteins’ which exert antiviral effects.
Interferon α

29. Uses of Interferon α
 Chronic hepatitis B-IFNα2A
 Chronic hepatitis C-IFNα2B
 AIDS-related Kaposi’s sarcoma
 Condyloma acuminata
 H. simplex, H. zoster and CMV
Pharmacokinetics
 Not active orally; administered subcutaneously, or intravenously
 High cellular uptake and metabolism by the liver and kidney, less plasma
level
 Negligible renal elimination occurs.

30. Adverse Effects of IFN
 Flu-like symptoms: fatigue, aches and pains, malaise, fever, dizziness,
anorexia, nausea, taste and visual disturbances develop few hours after each
injection, but become milder later
 Neurotoxicity: numbness, neuropathy, altered behaviour, mental
depression, tremor, sleepiness, rarely convulsions
 Myelo suppression: dose dependent neutropenia, thrombocytopenia
 Thyroid dysfunction (hypo as well as hyper)
 Hypotension, transient arrhythmias, alopecia and liver dysfunction.
Drug Interaction:
• It interferes with hepatic drug metabolism
• Toxic accumulations of theophylline
• It may also potentiate the myelosuppression caused by other bone marrow
depressing agents ( Zidovudine )

31. • Aim of anti-HIV therapy is to cause maximal suppression of viral
replication for the maximal period of time that is possible.
• ARV drugs are always used in combination of at least 3 drugs and
regimens have to be changed over time due to development of resistance.
• Life long therapy is required.
The established targets for anti-HIV attack are:
1. HIV Reverse Transcriptase
2. HIV Protease
3. Fusion of viral envelope with plasma membrane of CD4 cells through
which RNA enters the cell.
4. Chemokine Co-Receptor (CCR5) on the host cells which provide
anchorage for surface proteins of virus
5. HIV Integrase
Anti-Retrovirus Drugs

33. Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)
Zidovudine:
•It is a thymidine analogue (azido- thymidine/ AZT), the prototype NRTI.
•After phosphorylation in the host cell - Zidovudine triphosphate selectively
inhibits viral reverse transcriptase in preference to cellular DNA polymerase
Single-stranded viral RNA
Double-stranded proviral DNA
Virus directed reverse transcriptase
(inhibited by Zidovudine triphosphate)

34. Pharmacokinetics:
Rapid oral absorption, but bioavailability is ~65%
It is quickly cleared by hepatic glucuronidation (t1⁄2 1 hr); 15–20% of the
unchanged drug along with the metabolite is excreted in urine
Plasma protein binding is 30% and CSF level is ~50% of that in plasma
It crosses placenta and is found in milk.
Adverse effects:
Anaemia and neutropenia
Nausea, anorexia, abdominal pain, headache, insomnia and myalgia are
common at the start of therapy, but diminish later
Myopathy, pigmentation of nails, lactic acidosis, hepatomegaly,
convulsions and encephalopathy are infrequent.

35. Uses
 Zidovudine is used in HIV infected patients only in combination with at
least 2 other ARV drugs
 It is one of the two optional NRTIs used by NACO for its first line triple
drug ARV regimen
 AZT also reduces neurological manifestations of AIDS and new Kaposi’s
lesions do not appear
 AZT, along with two other ARV drugs is the standard choice for post-
exposure prophylaxis of HIV, as well as for mother to offspring
transmission.

36. Interactions:
 Paracetamol increases AZT toxicity, probably by competing for
glucuronidation
 Azole antifungals also inhibit AZT metabolism
 Other nephrotoxic and myelosuppressive drugs and Probenecid enhance
toxicity
 Stavudine and Zidovudine exhibit mutual antagonism by competing for
the same activation pathway.

37. Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
Nevirapine (NVP), Efavirenz (EFV) & Delavirdine
Enzyme inducers, and cause autoinduction of their own metabolism
Nevirapine is started at a lower dose (200 mg/day); the dose is doubled
after 2 weeks when its blood levels go down
Rifampin induces NVP metabolism and makes it ineffective, but has little
effect on EFV levels
Either NVP or EFV is included in the first line triple drug regimen used by
NACO

38. Nevirapine
Rashes are the commonest adverse effect, followed by nausea and
headache
Occasionally skin reactions are severe
NVP is potentially hepatotoxic
Efavirenz
 Side effects are headache, rashes, dizziness, insomnia and a variety of
neuropsychiatric symptoms
Contraindicated in pregnancy and in women likely to get pregnant, since
it is teratogenic
Because of its longer plasma t1⁄2, occasional missed doses of EFV are less
damaging
Cont.

39. Retroviral protease inhibitors (PIs)
 Acts at a late step in HIV replication, i.e. Maturation of the new virus
particles when the RNA genome acquires the core proteins and enzymes
 Bind to the active site of protease molecule, interfere with its cleaving
function, and are more effective viral inhibitors than AZT
 Because they act at a late step of viral cycle, they are effective in both
newly as well as chronically infected cells
 Nelfinavir, Lopinavir and Ritonavir induce their own metabolism
 Patient acceptability and compliance are often low
 Most prominent adverse effects of PIs are gastrointestinal intolerance,
headache, dizziness, limb and facial tingling, numbness and rashes

40. Lipodystrophy, dyslipidaemia and insulin resistance are of particular
concern
 Diabetes may be exacerbated
 Indinavir crystalises in urine and increases risk of urinary calculi
Atazanavir (ATV)
It is administered with light meal which improves absorption, while acid
suppressant drugs decrease its absorption
Bioavailability and efficacy of ATV is improved by combining with RTV
Dyslipidaemia and other metabolic complications are minimal with ATV
Jaundice occurs in some patients without liver damage due to inhibition
of hepatic glucuronyl transferase
Cont.

41. Entry (fusion) Inhibitor
Enfuvirtide
HIV derived synthetic peptide
Binds to HIV 1 envelope transmembrane glycoprotein (gp41) involved in
fusion of viral and cellular membranes
Entry of virus into host cell is blocked
Not active against HIV 2
Pharmacokinetics: administered s.c twice daily, used as add on drug in
earlier regimens
Adverse reactions: local nodule/ cyst at injection site

42. CCR5 receptor inhibitor
Maraviroc
Targets the host cell chemokine -CCR5 receptor and blocks it
Attachment and entry of virus is inhibited
Has no effect on CXCR4 receptor tropic HIV strains
Adverse reactions: impaired immune surveillance
Increased risk of infection/malignancy

43. Integrase Inhibitor
Raltegravir
Inhibits the viral enzyme integrase
HIV Integrase nicks the host chromosomal DNA and integrates the
proviral DNA with it
Active against both HIV 1 and 2 and causes improved CD4 cell count
Uses: As a component of initial triple drug regimen along with 2NRTIs
Adverse effect: Myopathy
HIV treatment principles and guidelines

44. Anti-Retroviral Combinations
Recommended by National AIDS control Organization
Preferred regimen:
1) Lamivudine + Zidovudine + Nevirapine
Alternative regimens:
1) Lamivudine + Zidovudine + Efavirenz
2) Lamivudine + Stavudine + Efavirenz
3) Lamivudine + Stavudine + Nevirapine
Other regimens:
1) Lamivudine + Tenofovir + Nevirapine
2) Lamivudine + Tenofovir + Efavirenz
3) Lamivudine + Zidovudine + Tenofovir

45. References
Goodman & Gilman “The Pharmacological Basis of Therapeutics” 12th
edition
Tripathi K.D. “Essentials of Medical Pharmacology” 7th edition 2013
Dr. TV Rao MD “Antiviral Drugs Basics” published in Health &
Medicine on Nov 17 2012