11-2-a-Antivirals non-HIV.txt

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11-2-a-Antivirals non-HIV.txt
2010-11-02 20:22:33

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  1. 11-2-a-Antivirals non-HIV
  2. Agents for Influenza A
    Adamantanes: Amantidine and Rimantidine
  3. Amantadine and Rimantidine MoA, MoR, antiviral activity
    • MoA: Inhibits early stage of viral replication presumably by uncoating of the viral genome in the lysosome
    • MoR: Occurs easily in the lab through unclear mechanisms
    • Antiviral activity: Influenza A ONLY!
  4. Amantadine and Rimantidine Adverse reactions
    • Anticholinergic: dry mouth, papillary dilatation, toxic psychosis
    • Side effects are common especially with increased age and decreased renal function
    • CNS Toxicity: !
    • GI disturbance
    • Dehydration increases drug levels. Drug-Drug interaction with the diuretic triamterene and HCTZ
    • Rimantidine has longer half-life and less side effects: .
  5. Amantadine and Rimantidine: Clinical use
    • Prevention and treatment of sensitive strains of Influenza A
    • NOT effective against influenza B
    • Rapid selection of resistant virus during treatment (excretion of resistant virus)
    • Recommendation to NOT use for both treatment and prophylaxis in the same household
  6. Neuraminidase Inhibitors: MoA, MoR, Antiviral activity
    • MoA: Inhibition of neuraminidase activity decreases release of virus from infected cells, increases formation of viral aggregates and decreases viral spread
    • MoR: mutation in the pocket of neuraminidase site – can become resistant to Oseltamivir
    • Antiviral activity: active against BOTH Influenza A and B in the absence of resistance
  7. Neuraminidase inhibitors: use
    • Oseltamivir – ORAL; Zanamivir – inhalation
    • Therapy of Influenza A or B of less than 48 hours duration
    • Decrease duration of influenza approximately 24 hours on average
    • Approval for prophylaxis with both zanamivir and oseltamivir; won’t secrete drug-resistant viruses!
  8. Neuraminidase Inhibitors: Adverse effects
    • Children: w high doses – psychosis, neurologic toxicity
    • Adults: tracheal irritation
  9. Can get Oseltamivir Resistance
    Oseltamivir resistsnt, zanamivir-sensitive
  10. Ribavarin: MoA, MoR, Antiviral activity
    • MoA: Not fully defined, interferes with initiation and elongation of capped mRNA primer fragments
    • MoR: none to date
    • Antiviral activity: wide range of DNA and RNA viruses in lab
    • Clinically useful for RSV and Hep C: .
  11. Ribavarin Adverse Reactions
    • Aerosolized form: bronchospasm and reversible pulmonary deterioration
    • Systemic form: can cause bone marrow toxicity, hemolysis and anemia!
  12. Ribavarin clinical use
    • Use carefully risk vs. benefit…
    • RSV bronchiolitis in children: . (respiratory syncithial virus)
    • Combination therapy for hepatitis C with interferon: .
    • Lassa fever, hantavirus, and other viral hemorrhagic fevers…
  13. Acyclovir MoA, MoR, Antiviral activity
    • MoA: Acyclovir uptake and intracellular phosphorylation are facilitated by HSV-induced thymidine kinase. Acyclovir triphosphate is present in 40-100 fold higher concentrations in HSV infected cells. The triphosphate form inhibits DNA polymerase and is incorporated into viral DNA and FUNCTIONS AS A CHAIN TERMINATOR
    • MoR: can occur through altered expression of deficiency of thymidine kinase (lack not a very severe disease) or through altered sensitivity of the DNA polymerase to triphosphate acyclovir.
    • Antiviral activity: Herpes simplex types I and II, Varicella-Zoster virus, animal herpesviruses (including Herpes B simian virus – monkeys)
  14. Acyclovir: Excretion and Adverse effects
    • Renal excretion – major pathway
    • Oral, IV, ointment
    • Adverse effects: Generally well-tolerated
    • Reversivle renal dysfunction in ~5% of patients treated with high doses for HSV encephalitis – secondary to tubular precipitation of acyclovir: .
    • Peripheral neuropathy
    • Less than 1 % have CNS dysfunction
  15. Acyclovir: Clinical Use
    • Primary and recurrent genital herpes: .
    • Herpes simplex encephalitis!:
  16. Acyclovir ointment use
    Modest utility in the treatment of primary genital HSV disease – only useful in primary!
  17. Acyclovir oral
    • Documented effective in primary HSV disease
    • Use during primary episode does NOT alter the likelihood of recurrence.
    • Only modest effect in treatment of recurrent disease
  18. Valacyclovir
    • Esteryfied acyclovir for oral administration
    • Hydrolyzed to acyclovir
    • Longer half-life and better oral absorption: .
    • Documented efficacy in discordant sexual partners. Well-done study
  19. Penciclovir
    • Topical formulation of famciclovir
    • May have activity in herpes labialis but the effect is clinically small but statistically significant
  20. Agents for CMV
    • Ganciclovir
    • Cidofovir
    • Foscarnet
  21. Ganciclovir MoA, MoR, Antiviral activity
    • MoA: Inhibitor of viral DNA synthesis; CHAIN TERMINATION is the eventual mechanism of action
    • MoR: altered or deficiency of thymidine kinase or altered sensitiviry of DNA polymerase to triphosphate ganciclovir; rare clinically
    • Antiviral activity: cytomegalovirus; still retains potent HSV activity
    • BUT: poor oral bioavailability with <5% absorbed – NEW, Valganciclovir ester – has much better absorption – can now be oral
  22. Ganciclovir Adverse Reactions
    • Leukopenia!!!: major adverse reaction
    • Thrombocytopenia also a major problem
    • Drug-drug interactions
    • CNS toxicity, headache, psychosis, seizures, and behavioral changes
  23. Ganciclovir Clinical Use
    • CMV retinitis: – useful in decreasing the progression of the disease but can’t cure it, AIDS patients generally require life-long therapy
    • Oral therapy limited prophylaxis – NOW VALGANCICLOVIR HIGHLY EFFECTIVE ORALLY
  24. Cidofovir MoA, MoR, Antiviral activity
    • MoA: Inhibitor of viral DNA synthesis
    • MoR: unclear
    • Antiviral activity: CMV and HSV, Other viruses – maybe JC virus, small pox??
  25. Cidofovir adverse reations
    • Nephrotoxicity: major toxicity – renal excretion the major pathway, ½ life of 33 hours! “rat poison”
    • Co-Administration of probenicid reduces renal toxicity along with hydration.
    • Probenicid competes with cidofovir for tubular uptake and blocks some of the renal tubular accumulation of the drug.
  26. Cidofovir Clinical use
    CMV retinitis: very useful, but limited use because of renal toxicity
  27. Foscarnet MoA, Antiviral activity
    • MoA: Inhibits DNA polymerase of most herpes group viruses, including CMV. The drug also inhibits the reverse transcriptase of HIV!
    • Antiviral activity: CMV, and some HIV
  28. Foscarnet Adverse reactions
    • Impaired renal function, generally reversible: most common dose-limiting side effect
    • Anemia seen in 20-50% of patients
    • Thrombocytopenia and leucopenia have been reported
  29. Anivirals against CMV
    • Foscarnet
    • Cidofovir
    • Ganciclovir