Pharmacology Antivirals

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Pharmacology Antivirals
2011-01-26 17:48:37
Pharmacology antivirals

Pharmacology Antivirals
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  1. Acyclovir (general info)
    • Active against: HSV-1, HSV-2, VZV, CMV and EBV
    • Guanine nucleoside analog: (only difference is in deoxyribose moiety, cant get 5'3' synthesis, get chain termination)
    • selective drug: accumulated only in infected cells
    • affects synthesis of viral DNA
    • Oral Bio; 15-20%
    • T1/2: 2-3 hr
    • cleared by glomerular filtration and tubular secretion
    • Used for: genital herpes, herpes proctitis, varicella, zoster, herpes encephalitis severe herpes (IV), herpes labialis(topical)
  2. Acyclovir (Mechanism of action)
    Acyclovir --> monophosphate derivative --> di-triphosphate analogs--> blocks viral DNA polymerase

    • Enzyme 1: viral thymidine kinase
    • Enzyme 2: cellular kinase
    • (mutation in either enzyme can cause resistance to acyclovir)
  3. Acyclovir (side effects)
    • Well tolerated in general
    • Common: pain, swelling, reddness at place of injection
    • Uncommon: stomach pain, diarrhea, renal insufficiency(crystalline nephropathy), headache
    • Rare: coma, seizure, neutropenia, leukopenia, anorexia, fatigue, hepatitis
  4. Valacyclovir
    • Pro drug converted into acyclovir
    • serum conc 3-5 times higher than acyclovir
    • oral bio: 54% about 1/2 in CSF
    • no other advantage over acyclovir, same mechanism, same side effects
  5. Famciclovir
    • Prodrug converted to penciclovir
    • guanosine analog
    • Active against HSV1,2, VZV, EBV, and HBV
    • Actived by viral TK (phosphorylation)
    • Competitive inhibtion of DNA polymerase ONLY, no chain termination
    • Has lower affinity for viral TK than acyclovir but achieves higher intracellular conc
    • T1/2: 7-20 hr
    • Well tolerated
    • headache and gi intolerance uncommon
  6. Penciclovir
    • active metabolite of famciclovir
    • available for topical application against recurring herpes labialis
  7. Ganciclovir (general info)
    • Treats CMV and CMV retinitis
    • Guanosine analog
    • prodrug activated by viral PK phosphotransterase
    • available in oral or IV forms
    • T1/2: 2-4 hr
    • resistance: mutation in drug target (phosphotransferase)
    • Cross resistnace with strains resistant to acyclovir (TK deficiency)
    • excreted by renal system
  8. Ganciclovir (side effects)
    • Common: bone marrow suppression (neutropenia and thrombocytopenica occur in 20-40% and 5-20% respectively)
    • Uncommon: renal insufficiency (crystallization of drug), fever, headache, pain at injection, tremor, tiredness, weakness
    • Rare: skin rash and encephalopathy
  9. Valaganciclovir
    • Ganciclovir prodrug
    • hydrolyzed in intestine and liver
    • 900mg qd
    • plasma protein binding <2%
    • renal ilimination
    • Same ADR and MOA as ganciclovir
  10. Foscarnet
    • Active against HSV, VZV,CMV, EBV, HHV-6, KSHV AND HIV-1.
    • Also used for CMV retinitis (effective as ganciclovir)
    • poor oral bio so IV only
    • CSF is 1/2 of plasma
    • T1/2: 3-7 h but 30% deposit in bond with T1/2 of months
    • Nephrotoxicity (hypo or hyper phosphatemia, hypo magnesemia)
    • N/v, anemia, high LFT
    • CNS toxicity:headache, hallucinations, seizure
  11. Cidofovir
    • cytosine analog
    • active for: CMV retinitis and acyclovir resistant herpes, also HPV, poxvirus, adenovirus, and polyomavirus
    • Cidofovir converts to cidofovir-diPO4
    • Effective against TK strains cuz phosphrylation is independent of viral enzymes
    • bindes to viral DNA polymerase and blocks DNA synthesis
    • T1/2: cidofovir 2-6 h, dipo4 17-65h, cidofovir phosphocholine >87 h
    • Nephrotoxic : give probenecid with it to protect kidney
    • Uveitis, oxular hypotony, neutropenia, acidosis
  12. Lamivudine
    • For Hep B
    • potent NRTI
    • lower dose that when used for HIV
  13. Adefovir
    • For Hep B
    • NRTI
    • failed for HIV
    • nephrotoxic at higher doses
  14. Entecavir
    • For Hep B
    • guanosine nucleoside analog
    • Oral
    • well tolerated
    • side effects: HA, fatigue, dizziness, nausea
  15. Interferon a-2b
    For Hep B
  16. Ribavirin
    • For Hep C
    • guanosine nucleoside analog
    • oral used in combo therapy with IFN-a
    • inhibits capping of viral mRNA but mech unknown
    • teratogenic so contradicted to pregnant and anemic
  17. Interferon a-2A and IFN-a2B
    subq or intramuscular
  18. Zanamivir
    • sialic acid analog
    • prodrug activated by esterases in GI or liver
    • Selective inhibitor of influ A and B virus neuraminidases
    • Prevents release of virus from infected cells (causes viral aggregation at the cell surface)
    • resistance through mutations in neuraminidase and hemagglutinin
    • oral bio: <5%
    • renal excretion: 100%
    • Inhaled or IV
    • T1/2: 2.5-3 hr
    • for treatment and prophylaxis
  19. Osteltamivir
    • Prodrug activated by esterases in gi and liver
    • selective inhibitor of influ A and B virus neuraminidases
    • Mech of Action and resistance same as Zanamivir
    • Oral bio: 80%
    • Effect of meal is negligible
    • renal excretion 95%
    • For treatment and prophylaxis
    • ADR: mild Gi complain, HA
  20. Amantadine and Rimantadine
    • Tricyclic amines
    • target M2 protein with influ A
    • inhibit uncoating of viral RNA
    • oral bio: 90%
    • rimantadine is 4-10x more active than amantadine
    • Amantadine excreted unmetabolized in urine
    • rimantadine undergoes extensive metabolism, reduce dose in renal or hepatic insufficiency
    • Common side effects: GI (no appetite, nausea) and CNS(light headedness and insomnia)
    • Cross resistance with each other
    • decrease the symptoms of flu by 1-2 days, speed recovery and decrease the duration of virus shedding.