Download - Antiviral therapy
Antiviral therapy
E.McNamara
Challenges
• Virus parasitize host cells
• Target the virus specifically
• Latency, quiescent phase
• Is treatment necessary?
• Efficacy of Rx.
Current agents
• Exploit viral : host replication
• Target viral DNA polymerases
• Accumulate in viral infected cells
• Activated by virus encoded enzymes
• Dose related toxicity
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
Acyclovir toxicities
• CNS,– Confusion, seizures, coma.– Highest risk
• Renal impairment
• Old age
• Prior mental disability
• Potential teratogenicity
• Resistance
Acyclovir, uses
• In-vitro– HSV
– VZV
– EBV
– CMV
• In-vivo– HSV
– VZV
Famciclovir
• Nucleotide analogue
• Similar spectrum to acyclovir
• Similar mode of action
• Inactive prodrug of penciclovir
• Activated by viral-TK to penciclovir
Famciclovir cont.
• Greater bioavailability
• Prolonged intracellular half-life
• TID dosing
Famciclovir toxicities
• No major S/E
• Potentially teratogenic
• Potential male infertility
• Levels increased by probenecid
• May increase digoxin levels
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
Valaciclovir
• Toxicities similar to acyclovir
• TTP in immunocompromised on prolonged Rx.
Penciclovir
• Nucleoside analogue
• Similar activity to acyclovir
• Topical, Herpes labialis.
Herpes infection Rx.
• Improved PO bioavailability• Different mode of action-resistance• Improved efficacy• Type,
– Primary– Secondary/reactivation– Suppressive Rx.
• Vaccines and immunomodulators
Herpes Rx.
• HSV– Herpes labialis– Genital herpes– Encephalitis– Immunocompromised
• VZV• H.zoster• EBV
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
Gangciclovir, toxicity
• Haematologic/bone marrow– Neutropaenia– Thrombocytopaenia– Interacts with cytotoxic drugs
• Renal impairment
• Carcinogenic
• Potentiated by probenecid
Foscarnet
• Binds viral DNA polymerase and RT.
• Active v Herpes viruses
• Not curative
• Excreted renally
• Variable half-life
• Impairs biochem.– Monitor u/e, creatinine
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
CMV management
• Disseminated disease– Gangciclovir/Foscarnet/– CMV-Iggs, pneumonitis BMT
• Prophylaxis/preemptive in Tx.– Gangciclovir/acyclovir/valaciclovir
• Retinitis– Formiversin/gangciclovir -local
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
Rimantadine
• Structural analogue of amantadine
• Fewer CNS S/E
Ribavirin
• Synthetic nucleoside
• Interferes with viral RNA transcription
• Acts on RNA viruses– RSV, HCV– Measles– Lassa fever– Hantaviruses
Ribavirin uses
• Ribavirin + alpha-interferon for– Chronic HCV– Monitor Hb + WCC
• Aerosol route for RSV, infants
• IV for lassa/hanta
Ribavirin toxicities
• Potentially teratogenic
• C.I. For 6 months pre-pregnancy
• Anaemia
• Exacerbation of COPD via aerosol
Interferons
• Natural glycopeptides• Induced by viruses (dsRNA)• Affect
– Antiviral
– Antitumour
– Immunomodulators
• Action, induce cellular enzymes to stop protein synthesis and activate RNA degradation
Interferons, types
• Alpha-interferon, B-lymphocytes
• Beta-interferon, fibroblasts
• Gamma-interferon, T-lymphocytes
• Recombinant– Interferon alfacon-1– Interferon alfacon-2
Interferons, uses
• Routes, SC, IM, intralesional
• Chronic HCV
• Condyloma acuminata-intralesional
• Chronic HBV, remission
Interferons, toxicities
• Flu-like symptoms
• Alopecia
• Exac. Psoriasis
• Depression
• Retinal haemorrhages, rare
Viral hepatitis
• HAV, – Supportive– Prophylaxis with HAV IGg– Vaccine
• HBV– Interferon-alpha– Lamivudine– Vaccine /HBIG
• HCV– Interferon +ribavirin, Tx.
New agents
• Oseltramavir – PO
• Zanamivir – topical
– Neuraminidase inhibitors– Active v Influenza A+B
• Sorivudine-VZV+HSV1, 2 step activation
• Cidofovir, resistant HSV and CMV