Antivirales Y Antifungicos


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Antivirales Y Antifungicos

  1. 1. Viruses <ul><li>Obligate intracellular parasites </li></ul><ul><li>Consist of a core genome in a protein shell and some are surrounded by a lipoprotein </li></ul><ul><li>lack a cell wall and cell membrane </li></ul><ul><li>do not carry out metabolic processes </li></ul><ul><li>Replication depends on the host cell machinery </li></ul>
  2. 2. Viruses <ul><li>Steps for Viral Replication </li></ul><ul><ul><li>1) adsorption and penetration into cell </li></ul></ul><ul><ul><li>2) uncoating of viral nucleic acid </li></ul></ul><ul><ul><li>3) synthesis of regulatory proteins </li></ul></ul><ul><ul><li>4) synthesis of RNA or DNA </li></ul></ul><ul><ul><li>5) synthesis of structural proteins </li></ul></ul><ul><ul><li>6) assembly of viral particles </li></ul></ul><ul><ul><li>7) release from host cell </li></ul></ul>
  3. 3. Sites of Drug Action
  4. 4. Antiviral Agents <ul><li>Block viral entry into the cell or must work inside the cell </li></ul><ul><li>Most agents are pyrimidine or purine nucleoside analogs </li></ul>
  5. 5. Sites of Drug Action
  6. 6. Antiherpes Agents <ul><li>Acyclovir- prototype </li></ul><ul><li>Valacyclovir </li></ul><ul><li>Ganciclovir </li></ul><ul><li>Famciclovir </li></ul><ul><li>Cidofovir </li></ul><ul><li>Idoxuridine </li></ul><ul><li>Sorivudine </li></ul><ul><li>Trifluridine </li></ul><ul><li>Vidarabine </li></ul><ul><li>Foscarnet </li></ul>
  7. 7. Mechanism of Action Acyclovir <ul><li>an acyclic guanosine derivative </li></ul><ul><li>Phosphorylated by viral thymidine kinase </li></ul><ul><li>Di-and tri-phosphorylated by host cellular enzymes </li></ul><ul><li>Inhibits viral DNA synthesis by: </li></ul><ul><ul><li>1) competing with dGTP for viral DNA polymerase </li></ul></ul><ul><ul><li>2) chain termination </li></ul></ul>
  8. 9. Mechanism of Resistance Acyclovir <ul><li>Alteration in viral thymidine kinase </li></ul><ul><li>Alteration in viral DNA polymerase </li></ul><ul><li>Cross-resistance with valacyclovir, famciclovir, and ganciclovir </li></ul>
  9. 10. Clinical Uses Acyclovir <ul><li>Oral, IV, and Topical formulations </li></ul><ul><li>Cleared by glomerular filtration and tubular secretion </li></ul><ul><li>Uses : </li></ul><ul><ul><li>Herpes Simplex Virus 1 and 2 (HSV) </li></ul></ul><ul><ul><li>Varicella-zoster virus (VZV) </li></ul></ul><ul><li>Side Effects : nausea, diarrhea, headache, tremors, and delirium </li></ul>
  10. 11. Valacyclovir <ul><li>L-valyl ester of acyclovir </li></ul><ul><li>Converted to acyclovir when ingested </li></ul><ul><li>M.O.A. : same as acyclovir </li></ul><ul><li>Uses : </li></ul><ul><ul><li>1) recurrent genital herpes </li></ul></ul><ul><ul><li>2) herpes zoster infections </li></ul></ul><ul><li>Side Effects : nausea, diarrhea, and headache </li></ul>
  11. 12. Famciclovir <ul><li>Prodrug of penciclovir (a guanosine analog) </li></ul><ul><li>M.O.A.: same as acyclovir </li></ul><ul><li>does not cause chain termination </li></ul><ul><li>Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B </li></ul>
  12. 13. Ganciclovir <ul><li>A guanosine analog </li></ul><ul><li>requires triphosphorylation for activation </li></ul><ul><li>monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells </li></ul><ul><li>inhibits DNA polymerase </li></ul><ul><li>does not cause chain termination </li></ul><ul><li>Uses : CMV, HSV, VZV,and EBV </li></ul><ul><li>Side Effect : myelosuppression </li></ul>
  13. 14. Cidofovir <ul><li>A cytosine analog </li></ul><ul><li>phosphorylation not dependent on viral enzymes </li></ul><ul><li>Uses: CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus </li></ul><ul><li>Side Effects: nephrotoxicity (prevented by admin. of probenecid) </li></ul><ul><li>Resistance: mutation in DNA polymerase gene </li></ul>
  14. 15. Idoxuridine and Trifluridine <ul><li>Idoxuridine - pyrimidine analog </li></ul><ul><ul><li>1st antiviral agent </li></ul></ul><ul><ul><li>used topically for herpes keratitis </li></ul></ul><ul><li>Trifluridine - fluorinated pyrimidine </li></ul><ul><ul><li>inhibits viral DNA synthesis same as acyclovir </li></ul></ul><ul><ul><li>incorporates into viral and cellular DNA </li></ul></ul><ul><ul><li>Uses : HSV-1 and HSV-2 (topically) </li></ul></ul>
  15. 16. Sorivudine <ul><li>Investigational pyrimidine analog </li></ul><ul><li>competitively inhibits DNA polymerase, however, is not incorporated into viral DNA </li></ul><ul><li>causes bone marrow suppression when administered with 5-FU </li></ul><ul><li>Uses: VZV, HSV-1, and EBV </li></ul>
  16. 17. Vidarabine <ul><li>An adenosine analog </li></ul><ul><li>incorporated into viral and cellular DNA </li></ul><ul><li>metabolized to hypoxanthine arabinoside </li></ul><ul><li>Side Effects: GI intolerance and myelosuppression </li></ul>
  17. 18. Foscarnet <ul><li>An inorganic pyrophosphate </li></ul><ul><li>inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase </li></ul><ul><li>does not have to phosphorylated </li></ul><ul><li>Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV </li></ul><ul><li>Resistance due to point mutations in DNA polymerase gene </li></ul><ul><li>Side Effects: hypo- or hypercalcemia and phosphotemia </li></ul>
  18. 19. Antiretroviral Agents <ul><li>1) Reverse transcriptase inhibitors </li></ul><ul><li>2)Protease inhibitors </li></ul>
  19. 20. Reverse Transcriptase Inhibitors <ul><li>Zidovudine (AZT) </li></ul><ul><li>Didanosine- causes pancreatitis* </li></ul><ul><li>Lamivudine- causes pancreatitis </li></ul><ul><li>Zalcitabine- causes peripheral neuropathy * </li></ul><ul><li>Stavudine- causes peripheral neuropathy* </li></ul>
  20. 21. Mechanism of Action Zidovudine <ul><li>A deoxythymidine analog </li></ul><ul><li>enters the cell via passive diffusion </li></ul><ul><li>must be converted to the triphosphate form by mammalian thymidine kinase </li></ul><ul><li>competitively inhibits deoxythymidine triphosphate for the reverse transcriptase enzyme </li></ul><ul><li>causes chain termination </li></ul>
  21. 22. Mechanism of Resistance Zidovudine <ul><li>Due to mutations in the reverse transciptase gene </li></ul><ul><li>more frequent after prolong therapy and in persons with HIV </li></ul>
  22. 23. Clinical Uses Zidovudine <ul><li>Available in IV and oral formulations </li></ul><ul><li>activity against HIV-1, HIV-2, and human T cell lymphotropic viruses </li></ul><ul><li>mainly used for treatment of HIV, decreases rate of progression and prolongs survival </li></ul><ul><li>prevents mother to newborn transmission of HIV </li></ul>
  23. 24. Side Effects Zidovudine <ul><li>Myelosuppression, including anemia and neutropenia </li></ul><ul><li>seizures may occur in people with advanced AIDS </li></ul>
  24. 25. Protease Inhibitors <ul><li>Indinavir </li></ul><ul><li>Ritonavir </li></ul><ul><li>Saquinavir </li></ul>
  25. 26. Indinavir and Ritonavir <ul><li>M.O.A. : Specific inhibitors of the HIV-1 protease enzyme </li></ul><ul><li>M.O.R. : mediated by expression of multiple and variable protease amino acid substitutions </li></ul><ul><li>Side Effects :hyperbilirubinemia </li></ul><ul><li>Contraindications :inhibitor/substrate for CPY3A4, do not give with antifungal azoles </li></ul>
  26. 27. Saquinavir <ul><li>A synthetic peptide-like substrate analog </li></ul><ul><li>inhibits HIV-1 protease </li></ul><ul><li>prevents cleavage of viral polyproteins </li></ul>
  27. 28. Other Antivirals <ul><li>Amantadine and Rimantadine </li></ul><ul><ul><li>cyclic amines </li></ul></ul><ul><ul><li>inhibit the uncoating of viral RNA therefore inhibiting replication </li></ul></ul><ul><ul><li>resistance due to mutations in the RNA sequence coding for the structural M2 protein </li></ul></ul><ul><ul><li>used in the prevention and treatment of Influenza A </li></ul></ul>
  28. 29. Interferons <ul><li>Endogenous proteins </li></ul><ul><li>induce host cell enzymes that inhibit viral RNA translation and cause degradation of viral mRNA and tRNA </li></ul><ul><li>3 classes: IFN-  , IFN-  and IFN-  </li></ul>
  29. 30. Ribavirin <ul><li>A guanosine analog </li></ul><ul><li>phosphorylated intracellularly by host enzymes </li></ul><ul><li>inhibits capping of viral messenger RNA </li></ul><ul><li>inhibits the viral RNA-dependent RNA polymerase </li></ul><ul><li>inhibits replication of DNA and RNA viruses </li></ul>
  30. 31. Antifungal Agents
  31. 32. Fungal Infections <ul><li>Develop due to a loss of mechanical barriers (i.e. burns,major surgery) or immunodeficiency (chemotherapy,organ transplant, AIDS) </li></ul><ul><li>fungal infections may be superficial or systemic </li></ul><ul><li>Fungi possess different ribosomes, cell wall components, and discrete nuclear membrane </li></ul>
  32. 33. Systemic Antifungals <ul><li>Amphotericin B </li></ul><ul><li>Flucytosine </li></ul><ul><li>Azoles </li></ul><ul><ul><li>Ketoconazole </li></ul></ul><ul><ul><li>Itraconazole </li></ul></ul><ul><ul><li>Fluconazole </li></ul></ul>
  33. 34. Amphotericin B <ul><li>An amphoteric polyene macrolide </li></ul><ul><li>Broad spectrum of activity </li></ul><ul><li>Binds to ergosterol and alters the permeability of the cell by forming pores in the membrane leading to cell death </li></ul><ul><li>Resistance occurs when ergosterol binding is impaired </li></ul>
  34. 35. Amphotericin B <ul><li>2 categories of toxicity </li></ul><ul><ul><li>Infusion-related: fever, chills, muscle spasm, and hypotension </li></ul></ul><ul><ul><li>Slower toxicity: renal damage </li></ul></ul>
  35. 36. Flucytosine <ul><li>A pyrimidine analog </li></ul><ul><li>related to fluorouracil (5-FU) </li></ul><ul><li>spectrum of activity narrower than amphotericin B </li></ul><ul><li>used in combination with amphotericin B </li></ul>
  36. 37. Flucytosine <ul><li>Enters the cell via a cytosine-specific permease </li></ul><ul><li>converted to 5-FU via cytosine deaminase </li></ul><ul><li>5-FU is converted to 5-FdUMP which inhibits thymidylate synthase  inhibiting DNA synthesis </li></ul><ul><li>metabolized to 5-FUTP which is incorporated into fungal RNA, inhibiting nucleic acid and protein synthesis </li></ul>
  37. 38. Flucytosine <ul><li>Decreased levels of any of the enzymes can lead to resistance </li></ul><ul><li>toxic effects may be related to the formation of 5-FU including, anemia, leukopenia, and thrombocytopenia </li></ul><ul><li>hepatic dysfunction may occur </li></ul>
  38. 39. Azoles <ul><li>Prototype- Ketaconazole </li></ul><ul><li>interact with C-14  -demethylase (P450 enzyme) to block the demethylation of lanosterol to ergosterol, thereby disrupting membrane function and increasing permeability </li></ul><ul><li>Ketaconazole has additive effect with flucytosine and antagonizes amphotericin B </li></ul>
  39. 40. Differences in Azoles <ul><li>Refer to Katzung table 48-1 </li></ul>
  40. 41. Mucocutaneous Antifungals <ul><li>Griseofulvin </li></ul><ul><ul><li>enters fungal cells by an energy-dependent process </li></ul></ul><ul><ul><li>interacts with the microtubules within the fungus to disrupt the mitotic spindle and inhibit mitosis </li></ul></ul><ul><ul><li>resistance due to lack of energy-dependent uptake system </li></ul></ul><ul><ul><li>toxicities include allergic syndrome and hepatitis </li></ul></ul>
  41. 42. Topical Antifungals <ul><li>Nystatin </li></ul><ul><ul><li>polyene macrolide </li></ul></ul><ul><ul><li>M.O.A. same as amphotericin B </li></ul></ul><ul><ul><li>due to toxicity it is only used topically </li></ul></ul>
  42. 43. Antiviral Agents
  43. 44. Antiherpes Agents <ul><li>Prototype- Acyclovir </li></ul><ul><li>M.O.A. - Chemistry and Antiviral Activity . Acyclovir (9-[(2-hydroxy-ethoxy)methyl]-9H-guanine) is an acyclic guanine nucleoside analog that lacks a 3  -hydroxyl on the side chain </li></ul><ul><li>ADD STRUCTURES******* </li></ul>