DR.RAHUL
6/15/2014
DR RAHUL KUNKULOL
1
• It contains a single-stranded RNA genome
• Incorporate genome into host cell and hijack
the normal functions of the cell...
6/15/2014DR RAHUL KUNKULOL 3
6/15/2014DR RAHUL KUNKULOL 4
ANTIGEN DESTRUCTION
Innate immunity
6/15/2014 5
• RNA Genome : 9 kilobases long with 9 genes
encoding 15 different proteins
• HIV fuses with host cell and rel...
6/15/2014 6
• Fusion targets of the viral surface envelope
glycoproteins gp120 and other non specified
proteins on the T- ...
• Attachment And Membrane Fusion
• Uncoating
• Reverse Transcription
• Integration
• Transcription Of Viral Genome
• Trans...
6/15/2014 8
• Membrane protein gp120 binds CD4
receptor on lymphocytes and macrophages
• Other non-specified viral membrane
proteins b...
• RNA genome is transcribed by Reverse
Transcriptase into a single stranded viral
DNA
• Reverse Transcriptase acts as DNA
...
6/15/2014 11
• DNA is then transported into the cell
nucleus and is integrated into the host
cell DNA by the viral enzyme ...
6/15/2014 12
6/15/2014 13
• Normal functions of the cell resume except
now instead of transcribing RNA for the
regular proteins of the ...
6/15/2014 14
• Viral enzyme protease cleaves itself
from the viral protein mass
• The Viral Protease then matures the
viri...
6/15/2014 15
6/15/2014 16
6/15/2014 17
• 1985 – Research on anti-viral medication begins
• 1987 – First drug Zidovudine produced (NRTI)
• Early life...
6/15/2014 18
6/15/2014 19
• Thymidine analogue
• Cellular enzyme phosphorylate to the
triphosphate
• Inhibits the action of the viral e...
6/15/2014 20
Adverse effect:
• Granulocytopenia and anemia: 45% in AIDS
but 5% if asymptomatic HIV
• Severe headache, naus...
6/15/2014 21
• Now used only in combination with
ARVs
• NOTE: ↓mortality & opportunistic
infections, gain weight, better q...
6/15/2014 22
• Deoxycytidine analogue
• Inhibits reverse transcriptase and DNA
polymerase in HBV.
• Systemic toxicity is l...
6/15/2014 23
ZALCITABINE
(azt)
DIDANOSINE
( ddI )
STAV
( d4T )
LAMI
( 3TC )
ZALCI
( ddC )
Analog Thymidine Adenosine Thymi...
• No Phosphorylation
required after they
enter the cell.
• Same mechanism of
action as NTRIs
• Nausea and
vomiting are the...
6/15/2014 25
:Rarely used due to a high pill burden
• Mechanism: different with NRTIs
• Used in combination with NRTIs and...
6/15/2014 26
• Inhibitors of the viral enzyme reverse transcriptase
however mechanism of action is different
• This class ...
6/15/2014 27
• More potent against HIV-I but donot
inhibit HIV II.
Adverse effects :
• Hepatotoxicity
• Stevens – Johnson ...
6/15/2014 28
• Drugs :
• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir
• Mechanism: Inhibit precursor molecules
convert ...
6/15/2014 29
• These work by competitive inhibition of the viral
enzyme protease
• These drugs irreversibly bind to the ac...
Absorption Excretion Comments
Saquinavir Poor oral
absorption
Feces
excretion
With ritonavir
Indinavir Good oral
absorptio...
• Newest Class of Drugs
• Drug binds to the glycoprotein gp41 in the
viral envelope inhibiting its fusion with the
CD4+ re...
6/15/2014 33
• HIV INTEGRASE, an enzyme required for
integration of viral DNA into cellular
DNA.
• By blocking integration...
• Multi - drug regimen used for the
treatment of HIV infection is referred as
HAART --
“Highly active anti-retroviral drug...
Currently the recommendation for HIV / AIDS
patient is either
• TWO NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS + ONE PROT...
• Stavudine + Lamivudine + Nevirapine
• Zidovudine + Lamivudine + Nevirapine
• Stavudine + Lamivudine + Efavirenz
• Zidovu...
Antiretrovirals :Dr Rahul Kunkulol's Power point Presentations
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Antiretrovirals :Dr Rahul Kunkulol's Power point Presentations

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Antiretrovirals :Dr Rahul Kunkulol's Power point Presentations

  1. 1. DR.RAHUL 6/15/2014 DR RAHUL KUNKULOL 1
  2. 2. • It contains a single-stranded RNA genome • Incorporate genome into host cell and hijack the normal functions of the cell to replicate Eventually lead to cell destruction • Target for HIV : • CD4+ Helper T-Cells, Backbone of the immune system 6/15/2014 2
  3. 3. 6/15/2014DR RAHUL KUNKULOL 3
  4. 4. 6/15/2014DR RAHUL KUNKULOL 4 ANTIGEN DESTRUCTION Innate immunity
  5. 5. 6/15/2014 5 • RNA Genome : 9 kilobases long with 9 genes encoding 15 different proteins • HIV fuses with host cell and releases its genome and enzymes into the cell • Envelope contains the following viral enzymes: • Reverse Transcriptase • Integrase • Protease
  6. 6. 6/15/2014 6 • Fusion targets of the viral surface envelope glycoproteins gp120 and other non specified proteins on the T- lymphocytes are : • CD4+ receptor • Chemokine co-receptors • CCR5 • CXCR4
  7. 7. • Attachment And Membrane Fusion • Uncoating • Reverse Transcription • Integration • Transcription Of Viral Genome • Translation Of Proteins • Post Translational Modification • Assembly 6/15/2014 7
  8. 8. 6/15/2014 8
  9. 9. • Membrane protein gp120 binds CD4 receptor on lymphocytes and macrophages • Other non-specified viral membrane proteins bind chemokine co-receptors (major co-receptors are CCR5 and CXCR4) • HIV fuses with host cell and releases its genome and enzymes into the cell 6/15/2014 9
  10. 10. • RNA genome is transcribed by Reverse Transcriptase into a single stranded viral DNA • Reverse Transcriptase acts as DNA Polymerase and transcribes the single stranded DNA into a Double Stranded Viral DNA 6/15/2014 10
  11. 11. 6/15/2014 11 • DNA is then transported into the cell nucleus and is integrated into the host cell DNA by the viral enzyme Integrase.
  12. 12. 6/15/2014 12
  13. 13. 6/15/2014 13 • Normal functions of the cell resume except now instead of transcribing RNA for the regular proteins of the cell it is transcribing viral mRNA • Viral Proteins are produced in one large multi- protein chain from the viral mRNA • Viral Components move toward the cell membrane and bud off into new immature virions
  14. 14. 6/15/2014 14 • Viral enzyme protease cleaves itself from the viral protein mass • The Viral Protease then matures the virion by cutting up the protein mass into the individual viral enzymes • The virion is a mature and infectious virus
  15. 15. 6/15/2014 15
  16. 16. 6/15/2014 16
  17. 17. 6/15/2014 17 • 1985 – Research on anti-viral medication begins • 1987 – First drug Zidovudine produced (NRTI) • Early life extending properties except only temporarily worked as patients became immune • Mid-1990s – Protease Inhibitors and NNRTIs • 1995 – first protease inhibitor Sequinavir FDA approved • Low Bioavailability led to the development of a second protease inhibitor Ritonvir • 1996 first NNRTI, Nevirapine approved by FDA • March 2003 – First Fusion Inhibitor Enfuvirtide approved by FDA
  18. 18. 6/15/2014 18
  19. 19. 6/15/2014 19 • Thymidine analogue • Cellular enzyme phosphorylate to the triphosphate • Inhibits the action of the viral enzyme reverse transcriptase. • Accomplished by incorporation in DNA peptide • Prematurely terminating the transcription process
  20. 20. 6/15/2014 20 Adverse effect: • Granulocytopenia and anemia: 45% in AIDS but 5% if asymptomatic HIV • Severe headache, nausea, insomnia, myalgia • Rare ADR: hepatomegaly, lactic acidosis, encephalopathy
  21. 21. 6/15/2014 21 • Now used only in combination with ARVs • NOTE: ↓mortality & opportunistic infections, gain weight, better quality of life, delays signs and symptoms of AIDS
  22. 22. 6/15/2014 22 • Deoxycytidine analogue • Inhibits reverse transcriptase and DNA polymerase in HBV. • Systemic toxicity is low, and is well tolerated. • Resistance rapid • Used in combination with other ARVs • Chronic hepatitis B
  23. 23. 6/15/2014 23 ZALCITABINE (azt) DIDANOSINE ( ddI ) STAV ( d4T ) LAMI ( 3TC ) ZALCI ( ddC ) Analog Thymidine Adenosine Thymidine Cytidine Cytidine Notes Avoid BM suppressive drugs Avoid neuropathy drugs Avoid neuropathy drugs Active against HBV also. Avoid neuropathy drugs and antacids. Adverse effects Anemia Neutropenia Pancreatitis Neuropathy Sensory Neuropathy Headache Pancreatitis Neuropathy
  24. 24. • No Phosphorylation required after they enter the cell. • Same mechanism of action as NTRIs • Nausea and vomiting are the disadvantages 6/15/2014DR RAHUL KUNKULOL 24
  25. 25. 6/15/2014 25 :Rarely used due to a high pill burden • Mechanism: different with NRTIs • Used in combination with NRTIs and PI • Toxicity: rash
  26. 26. 6/15/2014 26 • Inhibitors of the viral enzyme reverse transcriptase however mechanism of action is different • This class of drugs works by noncompetitive inhibition • Binds to the viral enzyme at a place other than the active site • Changes the conformation of the active site • Decreasing the enzyme’s affinity for nucleoside binding.
  27. 27. 6/15/2014 27 • More potent against HIV-I but donot inhibit HIV II. Adverse effects : • Hepatotoxicity • Stevens – Johnson syndrome • It is an inducer of Cyto P 450
  28. 28. 6/15/2014 28 • Drugs : • Saquinavir • Ritonavir • Indinavir • Nelfinavir • Mechanism: Inhibit precursor molecules convert to mature virions during HIV replication
  29. 29. 6/15/2014 29 • These work by competitive inhibition of the viral enzyme protease • These drugs irreversibly bind to the active site of protease preventing it from completing the maturation of the virion • Protease inhibitors prevent immature virions from becoming mature, infectious Viruses Ritonvir More successful because it inhibits Cytochrome P450 3A4 which breaks down Protease Inhibitors Sequinavir Low Bioavailability
  30. 30. Absorption Excretion Comments Saquinavir Poor oral absorption Feces excretion With ritonavir Indinavir Good oral absorption Feces excretion Hepatitis / renal stones / jaundice Ritonavir Good absorption Feces excretion Liver toxicity / increase plasma conc. of other PI Nelfinavir Good absorption Feces excretion Diarrhea
  31. 31. • Newest Class of Drugs • Drug binds to the glycoprotein gp41 in the viral envelope inhibiting its fusion with the CD4+ receptor on the host cell • Usually used as a last line option • Only available as an injection and its high cost : More than $25000 per year
  32. 32. 6/15/2014 33 • HIV INTEGRASE, an enzyme required for integration of viral DNA into cellular DNA. • By blocking integration, an integrase inhibitor would prevent HIV from infecting "new" cells, but would not have any effect on cells with established infection.
  33. 33. • Multi - drug regimen used for the treatment of HIV infection is referred as HAART -- “Highly active anti-retroviral drugs”.
  34. 34. Currently the recommendation for HIV / AIDS patient is either • TWO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS + ONE PROTEASE INHIBITORS • TWO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS + NON-NUCLEOSIDE RT INHIBITORS • 3 NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS
  35. 35. • Stavudine + Lamivudine + Nevirapine • Zidovudine + Lamivudine + Nevirapine • Stavudine + Lamivudine + Efavirenz • Zidovudine + Lamivudine + Efaviren • PI –based regimens :- (Disadvantages) High pill burden Significant interactions with other drugs RESERVED FOR SECOND LINE THERAPY

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