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Anti viral 1


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Anti viral 1

  1. 1. Antiviral Agents <ul><li>Restricted spectrum </li></ul><ul><li>No standardized in-vitro susceptibility tests </li></ul><ul><li>Most inhibit replication. Cure depends on host immune system to eradicate. If patients are immunocompromized, may have recurrences. </li></ul><ul><li>Many need to be activated by viral and cellular enzymes before exerting antiviral effect. Activity of enzymes and concentration of substrates will influence the efficacy. </li></ul>
  2. 2. Classification <ul><li>Purine and Pyrimidine Analogues (Herpes, CMV, HIV, Resp. Syncitial) </li></ul><ul><li>Non-nucleoside inhibitors of reverse transcriptase (HIV) </li></ul><ul><li>Direct inhibitor of DNA polymerase and RT – Foscarnet </li></ul><ul><li>Protease Inhibitors (HIV) </li></ul><ul><li>Interferon-alpha (Hep. B&C, Herpes) </li></ul><ul><li>Others: Amantadine, Rimantadine (Influenza) </li></ul>
  3. 3. Nucleoside Analogues General Mechanism of Action <ul><li>Taken up by cells </li></ul><ul><li>Converted by viral and cellualr enzymes to the triphosphate form </li></ul><ul><li>The triphosphate form inhibits: </li></ul><ul><ul><li>DNA polymerase </li></ul></ul><ul><ul><li>Reverse transcriptase </li></ul></ul><ul><ul><li>RNA polymerase </li></ul></ul><ul><li>Or it may get incorporated into growing DNA leading to abnormal proteins or breakage. </li></ul>
  4. 4. Acyclovir and Valacyclovir (prodrug, better availability) <ul><li>A Guanine analogue with antiviral for Herpes group only </li></ul>Acyclovir AcycloGMP AcycloGTP Thymidine kinase Cellular kinases Viral 200x affinity of mammalian <ul><li>Inhibits viral DNA polymerase selectively </li></ul><ul><li>Incorporated into DNA and terminates synthesis </li></ul>Resistance: 1. ↓ activity of thymidine kinase 2. altered DNA polymerase Toxicity: 1. Encephalopathy 2. Renal Insuficiency Use: 1. H. simplez I and II 2. H. zoster and Varicella, not good for CMV
  5. 5. Ganciclovir <ul><li>Mechanism like Acyclovir </li></ul><ul><li>Active against all Herpes viruses including CMV </li></ul><ul><li>Low oral bioavailability given I.V. </li></ul><ul><li>Most common adverse effect: bone marrow suppression (leukopenia 40%, thrombocytopenia (20%) and CNS effects (headache, behavioral, psychosis, coma, ocnvulsions). </li></ul><ul><li>1/3 of patients have to stop because of adverse effects </li></ul><ul><li>Drug of choice for CMV infections: retinitis, pneumonia, colitis… </li></ul>
  6. 6. Guanine Acyclovir Ganciclovir
  7. 7. Other Nucleoside Analogues <ul><li>Vidarabine </li></ul><ul><li>Poor solubility, give i.v. with big volume of fluids (2.5 L) ⇒ risk of fluid overload </li></ul><ul><li>Toxicity: GI; Bone marrow; Hypokalemia; inappropriate ADH secretion; (psychosis; painful neuropathy; </li></ul><ul><li>Not a drug of choice for anything. Replaced by Acyclovir because of toxicity and problems in administration . </li></ul><ul><li>Idoxuridine and Trifluridine </li></ul><ul><li>Topical agents for Herpes keratitis </li></ul><ul><li>Trifluridine also for CMV and others </li></ul><ul><li>Trifluridine better for H. simplex II keratoconjuctivitis </li></ul><ul><li>Ribavirin </li></ul><ul><li>Aerosol: inhibits replication of Influenza A & B and RCV </li></ul><ul><li>Triphosphate inhibits RNA polymerase </li></ul><ul><li>Anemia due to hemolysis and BM suppression </li></ul>
  8. 8. Foscarnet <ul><li>An inorganic pyrophosphate analog </li></ul><ul><li>Active against Herpes (I, II, Varicella , CMV), inlcuding those resistant to Acyclovir and Ganciclovir. </li></ul><ul><li>Direct inhibition of DNA polymerase and RT </li></ul><ul><li>Nephrotoxicity (25%) most common ADR </li></ul><ul><li>Hypocalcemia (chelates divalent cations) </li></ul><ul><li>Others: hypokalemia, hypomagnesemia </li></ul><ul><li>Use: CMV retinitis and other CMV infections instead of ganciclovir. H simplex resistant to Acyclovir. HIV. </li></ul>
  9. 9. Anti-retroviral Agents <ul><li>Zidovudine (AZT) </li></ul><ul><li>Cellular enzyme phosphorylate to the triphosphate form which inhibits RT and causes chain termination </li></ul><ul><li>Adverse effect: </li></ul><ul><ul><li>Granulocytopenia and anemia: 45% in AIDS but 5% if asymptomatic HIV </li></ul></ul><ul><ul><li>Severe headache, nausea, insomnia, myalgias </li></ul></ul><ul><li>↓ mortality & opportunistic infections, gain weight, better quality of life, delays signs and symptoms of AIDS </li></ul>
  10. 10. Other Retroviral RT Inhibitors <ul><li>Other nucleoside analogs: didanosine, stavudine, zalcitabine : same as AZT but can cause peripheral neuropathy and pancreatitis. Can be used with AZT for enhanced effect and less toxicity. </li></ul><ul><li>Non-nucleoside RT inhibitors: e.g. neviparine. Noncompetitive binding to RT and direct inhibition at a site different from AZT and others. May be active against AZT-resistant strains. Can be used in combination. Main adverse effect is rash (75). </li></ul>
  11. 11. Protease Inhibitors <ul><li>Produce non-infectious particles or virions </li></ul><ul><li>Reduces the number of new rounds of infection in susceptible cells </li></ul><ul><li>To be effective must be prolonged, profound and constant. </li></ul><ul><li>Pharmacokinetics important to maintain constant concentrations within the effective range. </li></ul><ul><li>Metabqolic adverse effects (DM, hyperglycemia) and GI (diarrhea, pain vomiting). </li></ul>
  12. 12. Panel C shows the translational products of the HIV gag–pol gene and the sites at which the gene product is cleaved by the virus-encoded protease. p17 denotes capsid protein, p24 matrix protein, and p7 nucleocapsid; p2, p1, and p6 are small proteins with unknown functions. The arrows denote cleavage events catalyzed by the HIV-specific protease. Protease Inhibitors Protease action
  13. 13. Fig. 3. HIV-1 virion forms. (a) Particles assembling and budding at the cell membrane. (b) An immature virus particle. (c) Mature forms of HIV-1.
  14. 14. Other Drugs <ul><li>Amantadine </li></ul><ul><li>Prevents uncoating (?) &/or assembly </li></ul><ul><li>CNS Toxicity due to dopaminergic action </li></ul><ul><li>Prophylaxis of Influenza A during epidemics. </li></ul><ul><li>If used within 48 hours may help cure Influenza infection </li></ul><ul><li>Rimantadine: analog with less CNS toxicity </li></ul><ul><li>Interferons </li></ul><ul><li>Antiviral, anticancer and immunomodulating </li></ul><ul><li>Several sites of action in viral cycle but mainly inhibit translation of viral proteins </li></ul><ul><li>Toxicity: flu-like syndrome, BM suppression; CNS </li></ul><ul><li>Hepatitis B and C </li></ul>