antiviral therapy e.mcnamara. challenges virus parasitize host cells target the virus specifically...
TRANSCRIPT
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Antiviral therapy
E.McNamara
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Challenges
• Virus parasitize host cells
• Target the virus specifically
• Latency, quiescent phase
• Is treatment necessary?
• Efficacy of Rx.
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Current agents
• Exploit viral : host replication
• Target viral DNA polymerases
• Accumulate in viral infected cells
• Activated by virus encoded enzymes
• Dose related toxicity
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Acyclovir
• Nucleoside analogue
• Inhibits viral DNA polymerase
• Stops replicating viral DNA chains
• Excreted via renal
• Serum half life 2-3 hrs
• Good tissue distribution
• Activated by HSV-TK to triphosphate form
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Acyclovir toxicities
• CNS,– Confusion, seizures, coma.– Highest risk
• Renal impairment
• Old age
• Prior mental disability
• Potential teratogenicity
• Resistance
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Acyclovir, uses
• In-vitro– HSV
– VZV
– EBV
– CMV
• In-vivo– HSV
– VZV
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Famciclovir
• Nucleotide analogue
• Similar spectrum to acyclovir
• Similar mode of action
• Inactive prodrug of penciclovir
• Activated by viral-TK to penciclovir
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Famciclovir cont.
• Greater bioavailability
• Prolonged intracellular half-life
• TID dosing
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Famciclovir toxicities
• No major S/E
• Potentially teratogenic
• Potential male infertility
• Levels increased by probenecid
• May increase digoxin levels
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Valaciclovir
• Valyl ester of acyclovir
• P.O. metabolised to acyclovir
• Plasma levels equivalent to IV acyclovir
• Sustitute for IV acyclovir
• Bioavailability dependant on GIT and hepatic function
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Valaciclovir
• Toxicities similar to acyclovir
• TTP in immunocompromised on prolonged Rx.
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Penciclovir
• Nucleoside analogue
• Similar activity to acyclovir
• Topical, Herpes labialis.
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Herpes infection Rx.
• Improved PO bioavailability• Different mode of action-resistance• Improved efficacy• Type,
– Primary– Secondary/reactivation– Suppressive Rx.
• Vaccines and immunomodulators
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Herpes Rx.
• HSV– Herpes labialis– Genital herpes– Encephalitis– Immunocompromised
• VZV• H.zoster• EBV
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Gangciclovir
• Competively inhibits viral DNA polymerase
• Incoporates into viral DNA, chain terminator
• Major agent for CMV
• Accumulates in CMV infected cells
• Excreted renally
• Crosses Blood Brain Barrior
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Gangciclovir, toxicity
• Haematologic/bone marrow– Neutropaenia– Thrombocytopaenia– Interacts with cytotoxic drugs
• Renal impairment
• Carcinogenic
• Potentiated by probenecid
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Foscarnet
• Binds viral DNA polymerase and RT.
• Active v Herpes viruses
• Not curative
• Excreted renally
• Variable half-life
• Impairs biochem.– Monitor u/e, creatinine
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Fomivirsen
• Active v CMV
• Inactivates CMV mRNA
• Local, no systemic anti-CMV Rx.
• Substitute for CMV retinitis Rx.
• Intra-vitreal injections
• S/E, intraocular pressure, retinal toxicity
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CMV management
• Disseminated disease– Gangciclovir/Foscarnet/– CMV-Iggs, pneumonitis BMT
• Prophylaxis/preemptive in Tx.– Gangciclovir/acyclovir/valaciclovir
• Retinitis– Formiversin/gangciclovir -local
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Amantadine
• Inhibits Influ-A uncoating on host cell entry• Early Rx. Within 48hrs of symptoms• Prophylaxis of unimmunised high risk• Combined with vaccine until immunity develops• Renal excretion• Rapid resistance• S/E, CNS- dissyness, seizures
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Rimantadine
• Structural analogue of amantadine
• Fewer CNS S/E
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Ribavirin
• Synthetic nucleoside
• Interferes with viral RNA transcription
• Acts on RNA viruses– RSV, HCV– Measles– Lassa fever– Hantaviruses
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Ribavirin uses
• Ribavirin + alpha-interferon for– Chronic HCV– Monitor Hb + WCC
• Aerosol route for RSV, infants
• IV for lassa/hanta
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Ribavirin toxicities
• Potentially teratogenic
• C.I. For 6 months pre-pregnancy
• Anaemia
• Exacerbation of COPD via aerosol
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Interferons
• Natural glycopeptides• Induced by viruses (dsRNA)• Affect
– Antiviral
– Antitumour
– Immunomodulators
• Action, induce cellular enzymes to stop protein synthesis and activate RNA degradation
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Interferons, types
• Alpha-interferon, B-lymphocytes
• Beta-interferon, fibroblasts
• Gamma-interferon, T-lymphocytes
• Recombinant– Interferon alfacon-1– Interferon alfacon-2
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Interferons, uses
• Routes, SC, IM, intralesional
• Chronic HCV
• Condyloma acuminata-intralesional
• Chronic HBV, remission
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Interferons, toxicities
• Flu-like symptoms
• Alopecia
• Exac. Psoriasis
• Depression
• Retinal haemorrhages, rare
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Viral hepatitis
• HAV, – Supportive– Prophylaxis with HAV IGg– Vaccine
• HBV– Interferon-alpha– Lamivudine– Vaccine /HBIG
• HCV– Interferon +ribavirin, Tx.
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New agents
• Oseltramavir – PO
• Zanamivir – topical
– Neuraminidase inhibitors– Active v Influenza A+B
• Sorivudine-VZV+HSV1, 2 step activation
• Cidofovir, resistant HSV and CMV