Antiretrovirals

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Antiretrovirals

  1. 1. DR.RAHUL 10/5/2013 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 10/5/2013 3
  3. 3. 10/5/2013DR RAHUL KUNKULOL 4 ANTIGEN DESTRUCTION Innate immunity
  4. 4. • Attachment And Membrane Fusion • Uncoating • Reverse Transcription • Integration • Transcription Of Viral Genome • Translation Of Proteins • Post Translational Modification • Assembly 10/5/2013 5
  5. 5. 10/5/2013 6
  6. 6. 10/5/2013 7 • Fusion targets of the viral surface envelope glycoproteins gp120 and other non specified proteins on the surface of the T- lymphocyte : • CD4+ receptor • Chemokine co-receptors • CCR5 • CXCR4
  7. 7. 10/5/2013DR RAHUL KUNKULOL 8
  8. 8. • 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 10/5/2013 9
  9. 9. • 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 10/5/2013 10
  10. 10. 10/5/2013 11 • DNA is then transported into the cell nucleus and is integrated into the host cell DNA by the viral enzyme integrase.
  11. 11. 10/5/2013 12
  12. 12. 10/5/2013 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
  13. 13. 10/5/2013 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
  14. 14. Nucleoside reverse transcriptase inhibitors NRTI Nucleotide reverse transcriptase inhibitors NtRTI Non-nucleoside reverse transcriptase inhibitors NNRTI Protease inhibitor PI Fusion inhibitor HIV Integrase inhibitor 10/5/2013 15
  15. 15. 10/5/2013 16 • 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
  16. 16. 10/5/2013 17
  17. 17. 10/5/2013 18 • 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
  18. 18. 10/5/2013 19 Adverse effect: • Granulocytopenia and anemia: 45% in AIDS but 5% if asymptomatic HIV • Severe headache, nausea, insomnia, myalgia • Rare ADR: hepatomegaly, lactic acidosis, encephalopathy
  19. 19. 10/5/2013 20 • Now used only in combination with ARVs • NOTE: ↓mortality & opportunistic infections, gain weight, better quality of life, delays signs and symptoms of AIDS
  20. 20. 10/5/2013 21 • 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
  21. 21. 10/5/2013 22 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
  22. 22. • No Phosphorylation required after they enter the cell. • Same mechanism of action as NTRIs • Nausea and vomiting are the disadvantages 10/5/2013DR RAHUL KUNKULOL 23 Tenofovir Disproxil Fumarate
  23. 23. 10/5/2013 24 :Rarely used due to a high pill burden • Mechanism: different with NRTIs • Used in combination with NRTIs and PI • Toxicity: rash
  24. 24. 10/5/2013 25 • 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.
  25. 25. 10/5/2013 26 • More potent against HIV-I but donot inhibit HIV II. Adverse effects : • Hepatotoxicity • Stevens – Johnson syndrome • It is an inducer of Cyto P 450
  26. 26. 10/5/2013 27 • Drugs : • Saquinavir • Ritonavir • Indinavir • Nelfinavir • Mechanism: Inhibit precursor molecules convert to mature virions during HIV replication
  27. 27. 10/5/2013 28 • 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
  28. 28. Oral Absorption Excretion Comments Saquinavir Poor Feces With ritonavir Indinavir Good Feces Hepatitis : jaundice Renal stones Ritonavir Good Feces Liver toxicity Increase plasma conc. of other PI Nelfinavir Good Feces Diarrhea
  29. 29. • 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
  30. 30. 10/5/2013 32 • 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.
  31. 31. • Multi - drug regimen used for the treatment of HIV infection is referred as HAART -- “Highly active anti-retroviral drugs”.
  32. 32. 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
  33. 33. • Stavudine + Lamivudine + Nevirapine • Zidovudine + Lamivudine + Nevirapine • Stavudine + Lamivudine + Efavirenz • Zidovudine + Lamivudine + Efavirenz • PI –based regimens :- (Disadvantages) High pill burden Significant interactions with other drugs RESERVED FOR SECOND LINE THERAPY

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