MBBS Sem IV theory class

1. Antiviral agents-II
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College
24 July, 2018 (8 Shrawan, 2075), Tuesday

2. By the end of the class, MBBS Sem IV
students will be able to:
 Explain the pharmacological basis of treatment
of influenza infection
 Understand the role of drugs in Hepatitis B
virus and Hepatitis C virus infection
 List the categories of anti-retroviral drugs
 Appreciate the salient features of individual
antiretroviral drugs

3. Anti-influenza agents
Amantadine, Rimantadine
 Inhibits influenza virus A
 Resistance wide spread
 Used for both prophylaxis and treatment
 Acts on M2 ion channel
 Early step (uncoating) as well as late step
(viral assembly)
 Resistance: mutation of M2 protein

4. Anti-influenza agents
Amantadine, Rimantadine
 Pharmacokinetics:
 Well absorbed orally
oRimantadine- higher bioavailability
 Excreted unchanged in urine over 2-3 days
oRimantadine metabolised and eliminated
slowly (t½ 30 hrs)

5. Anti-influenza agents
Amantadine, Rimantadine
 Adverse effects:
 Generally well tolerated
 Nausea, anorexia, insomnia, dizziness,
nightmares, lack of mental concentration,
hallucinations
 Ankle edema
 Rimantadine: better tolerated

6. Anti-influenza agents: Oseltamivir
 Prodrug
 Active against Influenza A, Influenza B
 Acts by inhibiting virus neuraminidase enzyme
 Required for release of viruses (last step)
 Resistance: mutation of neuraminidase

7. Anti-influenza agents: Oseltamivir
 Use:
 Prophylaxis: Influenza A, swine flu, bird flu,
influenza B
 Treatment: Influenza A, swine flu, bird flu,
influenza B
 Oseltamivir resistant strains may be sensitive to
zanamivir or vice versa
 Side effects:
 Gastric irritation, skin reaction

8. Anti-influenza agents: Zanamivir
 Similar to oseltamivir
 Poor oral absorption
 Administered by inhalation
 To be used as alternative to oseltamivir
 Side effects:
 Bronchospasm (CONTRAINDICATED IN
ASTHMA PATIENTS)
 Headache, dizziness, nausea, rashes

9. Anti-hepatitis agents: Adefovir
dipivoxil
 Prodrug, Monophosphate analogue of AMP
 Active against HBV, other DNA and RNA viruses
 Use:
 Chronic hepatitis B
 Lamivudine resistant HBV
 HBV with HIV infection

10. Anti-hepatitis agents: Adefovir
dipivoxil
Adefovir
dipivoxil
Adefovir
Adefovir
Diphosphate
1. Esterases (intestine, liver)
2.Cellular kinases (within cells)
1
2
• Inhibits HBV DNA polymerase
• Gets incorporated into viral DNA
• Early termination of viral DNA

11. Anti-hepatitis agents: Adefovir
dipivoxil
 Side effects:
 Well tolerated at dose 10mg/day
 Sore throat, headache, weakness, abdominal
pain, flu syndrome
 Nephrotoxicity
oHigher dose
oPredisposed
 Lactic acidosis
oWith concurrent HAART therapy

12. Anti-hepatitis agents: Tenofovir
 Monophosphate nucleotide related to AMP
 Active against HBV, HIV
 Use:
 Chronic hepatitis B
 Lamivudine resistance hepatitis B
 Well tolerated
 Increase in Sr. Creatinine, Renal toxicity rare

13. Anti-hepatitis agents: Tenofovir
Tenofovir
disoproxil
Tenofovir
Tenofovir
Diphosphate
1. Esterases (intestine, liver)
2.Cellular kinases (within cells)
1
2
• Inhibits HBV DNA polymerase
• Inhibits HIV reverse transcriptase
• Gets incorporated into viral DNA
• Early termination of viral DNA

14. Anti-herpes agents: Ribavirin
 Purine nucleoside analogue
 Active against Influenza A and B, Respiratory
syncytial virus, others
 Acts by:
 Active derivatives generated intracellularly
 Inhibits GTP, viral RNA synthesis
 Accumulates in body, persists after
discontinuation (Long term t½ >10 days)

15. Anti-hepatitis agents: Ribavirin
 Use:
 Hepatitis
oChronic hepatitis C: in combination with
peginterferon
 Severe influenza A/B
 Measles
 Herpes infection
 Respiratory syncytial virus infection

16. Anti-hepatitis agents: Ribavirin
 Side effects:
 Anaemia
 Bone marrow depression
 Haemolysis
 Teratogenic
 Can induce bronchospasm if used by
inhalation

17. Anti-hepatitis agents: Interferon α
 Low molecular weight glycoprotein cytokines
 Broad spectrum antiviral agents
 Host specific
 Human interferon with antiviral activity:
 IFN α, IFN β, IFN γ
 Human IFN produced by recombinant
technology: IFN α2A and IFN α2B
 PegIFN: slower absorption and more
sustained effects seen

18. Anti-hepatitis agents: Interferon α
IFNα
IFN receptor
Inhibition of viral replication:
Penetration
Synthesis of viral mRNA
Assembly and release
Proteins-P Proteins-P
Interferon induced Proteins
Has antiviral activity

19. Anti-hepatitis agents: Interferon α
 Uses:
 Chronic hepatitis B/C
 AIDS related Kaposi’s sarcoma
 Condyloma acuminata
 HSV, VZV, CMV
 Chronic myeloid leukaemia, Follicular
lymphoma, cutaneous T-cell lymphoma,
multiple myeloma

20. Anti-hepatitis agents: Interferon α
 Side effects:
 Flu like symptoms
 Neurotoxicity
 Myelosuppression
 Thyroid dysfunction
 Hypotension, transient arrhythmias, alopecia,
liver dysfunction

21. Anti-retroviral agents: targets of drugs

22. Nucleoside RT inhibitors
 Zidovudine, Stavudine: thymidine analogue
 Competes for thymidine kinase for activation
 Lamivudine: deoxycytidine analogue
 Didanosine: ATP analogue
 Abacavir: guanosine analogue
 Tenofovir: nucleotide analogue

23. Nucleoside RT inhibitors
 Mechanism of action:
 Phosphorylated intracellularly
 Inhibits viral Reverse Transcriptase enzyme
 ds DNA cannot form  viral DNA not
available for incorporation in host cell DNA
 Gets incorporated into proviral DNA and
terminates chain elongation
 Prevents infection of new cell

24. Nucleoside RT inhibitors
 Resistance:
 Point mutation in Reverse Transcriptase
enzyme
 Seen rapidly with lamivudine
 Develops slowly with Abacavir

25. Nucleoside RT inhibitors: Side effects
 Zidovudine:
 Due to partial inhibition of mitochondrial DNA
polymerase gamma
oAnaemia, Neutropenia
 Stavudine:
 Peripheral neuropathy (more severe with
Didanosine)
 Lipodystrophy, lactic acidosis, pancreatitis

26. Nucleoside RT inhibitors: Side effects
 Didanosine:
oHigher toxicity among other NRTIs
 Peripheral neuropathy ( may be irreversible)
 Acute pancreatitis
 Lamivudine:
 Generally well tolerated
 Headache, fatigue, nausea, rashes, anorexia
 Pancreatitis, neuropathy: rare

27. Nucleoside RT inhibitors: Side effects
 Abacavir:
 Hypersensitivity reaction
oStop drug promptly

28. Nucleoside RT inhibitors: Uses
 Zidovudine:
 As a component of HAART
 Post-exposure prophylaxis
 Prevention of Mother to child transmission
 Stavudine: optional first line HAART drugs
 Lamivudine: as an essential component of
HAART

29. Non-nucleoside RT inhibitors
 Nevirapine, Efavirenz
 Directly inhibits HIV Reverse Transcriptase (RT)
 More potent for HIV 1
 Given in combination
 Resistance: point mutation of RT
 Cross resistance seen

30. Non-nucleoside RT inhibitors
 Metabolism:
 Nevirapine: CYP3A4(major), CYP2B6
 Efavirenz: CYP2B6(major), CYP3A4
 Both are enzyme inducers
 Dose escalation in two weeks for nevirapine
 Variable enzyme induction and inhibition

31. Non-nucleoside RT inhibitors: Side
effects
 Nevirapine:
 Rashes
 Potentially hepatotoxic: rise in serum
transaminase
 Efavirenz:
 Rashes, dizziness, Neuropsychiatric
symptoms
 Teratogenic
oContraindication: (to be) pregnant women

32. Protease inhibitors
 Atazanavir, Indinavir, Nelfinavir, Saquinavir,
Ritonavir, Lopinavir
 Acts by:
 Binding to protease enzyme (active site)
 Cleaving function interfered
 Assembly and budding (late step) inhibited
 More effective than Zidovudine
 Both newly and chronically infected cells
affected

33. Protease inhibitors
 Extensively metabolised by CYP3A4
 Nelfinavir- CYP2C19
 Potent inhibitors of CYP3A4
 Ritonavir, Lopinavir
 Large tablet load
 6-18 tablets daily
 Ritonavir at subtherapeutic dose (100mg )
added to decrease tablet load
 Nelfinavir + ritonavir: irrational

34. Protease inhibitors: Side effects
 Most prominent:
 GI intolerance, asthenia, dizziness, limb and
facial tingling, numbness, rashes
 Lipodystrophy (abdominal obesity, buffalo
hump, wasting of limbs and face)
 Dyslipidemia (raised TG and cholesterol):
 Hypolipidaemic drugs
 Insulin resistance (exacerbated diabetes)

35. Protease inhibitors: Side effects
Drug Specific Side effect(s)
Atazanavir Jaundice
Indinavir Nephrolithiasis
Nelfinavir Diarrhoea, flatulence
Ritonavir Drug interactions
Saquinavir Photosensitivity
Lopinavir GI intolerance, dyslipidaemias

36. Entry (fusion) inhibitor
 Enfuvirtide
 Acts by:
 Binds to HIV-1 gp41
 Fusion of viral and cellular membranes
prevented, virus cannot infect the cell
 Given as subcutaneous injection
 Side effects: pain, local nodules/cyst

37. CCR5 receptor inhibitor
 Maraviroc
 Acts by:
 Targets and blocks host cell CCR5 receptors
only
oCXCR4 receptor spared
 Receptors unavailable for attachment of
gp120 of HIV
 Attachment and entry prevented

38. Integrase inhibitor
 Raltegravir, Dolutegravir
 Acts by:
 Inhibiting virus integrase enzyme
 Nicking of host chromosomal DNA and
integration of proviral DNA prevented
 Side effects:
 Myopathy

39. Newer Drugs
Drug Class Drug
NRTI Emtricitabine
NNRTI Delavirdine, Etravirdine,
Rilpivirine
PI Fosamprenavir, Tipranavir,
Darunavir
CXCR4 inhibitor Plerixafor

40. ART Regimen in Nepal

41. ART Regimen in Nepal

42. ART Regimen in Nepal

43. Conclusion
 Amantadine and Rimantadine are specific for
influenza A virus
 Lamivudine and Tenofovir are active against
both HBV and HIV
 PegIFN has better clinical efficacy over IFN
 Three classes of ARV drugs are backbone of
ART
 ARV drugs acting on newer targets are
available

44. Questions???
 Thank you!