Antivirals Flashcards
How do antivirals creat specificity if they are targeting the virus or the host cell?
Virus: Target viral-specific enzymes (proteases, mRNA capping proteins, integrases, neuraminadases, ribonucleases, kinases, uncoating)
Host cell: drug activated in ONLY infected cells
What is the theraputic window for antivirals? Definition and numerical value.
Ratio - Toxicity dose for host:Toxicity dose to virus
For antivirals = 100 - 1000 = 100 to 1000 times more toxic to the virus than the host.
What combinations are used for HAART?
Highly Active Anti-Retroviral Therapy: 2 NRTIs + 1 NNRTI OR 1 Protease Inh OR 1 Integrase Inh
How effective are antivirals? WHy is this important?
All viroSTATIC. Means that an intact immune system needed to suppress most viral infections.
What is difficult about treating chronic infections?
viral latency - drugs don’t work; erradication is nearly impossible.
What does viral uncoating in non-enveloped and membrane-containing viruses entail?
Loss of nucleocapsid proteins (non-enveloped), Loss of lipid envelope/membrane in endolysosome. If in endolysosome = pH dependent uncoating (
What is the best available class of antivirals and why?
Inhibition of viral genome replication: Specificity:
1) virus can use its own enzyme for activation
2) viral polymerases are more sensitive to drug harm
Next most widely used: IFN
What is the purpose of a virus carrying a thymidine kinase? How is it used in drug mechanism of action?
Virus - can use for replication in cells not actively dividing and lack phosphorylated nucleic acids.
Used to activate drugs in infected cells only.
For drugs that are activated by viral thymidine kinases, what confers their specificity? What is one added benefit of having the drug phosphorylated by the virus?
Viral thymidine kinases - sloppy/non-specific and phosphorylate the drug. Host thymidine kinases don’t phosphorylate drug (more selective). Viral phosphorylation means you can administer non-phosphorylated = better cell entry.
For inhibiton of viral nucleic acid synthesis, how does chain termination work?
Irriversible binding to the polymerase
What are the targets for antiviral therapy? Which target only has one class of drugs that work for it?
Cell entry & Uncoating, Nucleic acid synthesis & polymerases, mRNA post-transcriptional modifications (ONLY IFN FOR THIS), Proteases, Viral release
What antivirals inhibit cell entry (viruses in general and HIV; 2 for each)?
Amatadine, Rimantadine
HIV: Maraviroc, Enfuvitide
What antivirals Inhibit Nucleic Acid Synthesis (5 gen viruses, 3 HIV)?
Idoxuridine, Ribavirin, Acyclovir, Foscarnet, Cidofovir
HIV: NRTIs (AZT, Lamivudine), NNRTIs, Raltegravir
What drugs inhibit viral release?
Zanamivir, Oseltamivir, Maybe Amatadine (HA maturation inhibition)
What antivirals inhibit proteases (2 gen viruses, 1 class HIV)?
Asuprenavir, Telaprevir - HCV serine protease
HIV: Protease inhibitors - “navir” (e.g. Indinavir)
Which nucleic acid synthesis inhibitors are activated by a viral kinase?
“ovir”, idoxuridine, ribavirin, NRTIs (except AZT)
Which antivirals bind specific proteins OR have a higher affinity for their substrates?
Specificity:
Zanamivir, Oseltamivir - viral N.A.
Asuprenavir/Telapravir - HCV serine protease
“navir” HIV protease inhibitors - HIV aspartyl protease
Raltegravir - HIV integrase
Increased affinity:
Acyclovir - viral thymidine kinase
What drugs are used to treat HSV?
Acyclovir, Idoxuridine
What drugs are used to treat HepC infection?
INF-alpha
Ribavirin
Asuprenavir, Telaprevir
“navirs” - HIV protease inhibitors
Name 3 drugs used or in trial for pre-exposure prophylaxis.
- Nevipine, AZT - Reduce HIV transmission to fetus
- Maraviroc - In testing for HIV prophylaxis in combo w/ emtricitabe, tenofovir
- Oseltamivir, Zanamivir - Influ A high risk populations
What are the mechanisms of actions of interferons?
Induce an antiviral state in the adjacent cell:
- Iinhibit RNA post-translational modifications (processing, capping, adenylation, splicint)
- Inhibit translation
- Enhance MHC I expression on infected cells.
What drugs are used in CMV treatment?
Gancyclovir (first line), Acyclovir, Foscarnet, Cidofovir
Name 5 drugs used to treat influenza. What are the advantages to each?
Zanamivir (aerosol), Oseltamivir (oral) - Influ A & B, M2 inh and uncoating inhibition
Amantidine, Rimantadine - Influ A only; Riman better than Amant in renal failure; not used frequently
Gamma globulins
When should antivirals for influenza be taken?
W/ in 48 hours of the illness presentation.
What is Ribavirin used for?
Broad spectrum, esp RSV, chronic HepC, HIV, influenza, hemorrhavic fevers.
Name the mechanisms of action of the following: Idoxuridine Ribavirin Acyclovir Valacyclovir Famciclovir Gancyclovir Valganciclovir Foscarnet Cidofovir
Idoxuridine - Pyrimidine analog, chain termination
Rivavirin - Guanosine analog, IMP DH/guanosine synthesis inhibition; inhibit mRNA pol; inhibit mRNA capping
Acyclovir (Valacyclovir, Famcyclovir) - Guanosine analog, chain termination
Gancyclovir (Valganciclovir) - Guanosine analog, chain termination
Foscarnet - DNA pol and RT inhibitor
Cidofovir - DNA pol inhibitor
Why is gancyclovir first line for CMV?
It can be activated by the host kinase, and CMV can lack a viral thymidine kinase.
What is used as an alternative to the orthomyxovirus vaccine in the elderly?
Amantadine
What are the mechanisms of the following? Asuprenavir Telaprevir Zanamivir Oseltamivir
Asuprenavir, Telaprevir - Inhibit HCV serine protease
Zanamivir, Oseltamivir - Bind NA and prevent viron release.
What are the actions of alpha, beta, and gamma interferons?
alpha and beta - secreted by viral infected cells, induce antiviral state in adjacent cell, enhance MHC expression
gamma - T cells secrete; enhances cell mediated immunity
What is lamivudine often used in combo with and for?
HIV - AZT
HBV - adofovir
combination helps prevent resistance
Which antiviral can only be used topically and why?
Idoxuridine - to toxic for systemic use: Leukopenia, Hepatotoxicity, GI upset
What antivirals are contraindicated in pregnancy?
Ribavirin, Gancyclovir
What are some pros and cons of Acyclovir use?
Pro: Very selective for viral thymidine kinase, widly distributed (to the CNS), all forms of administration possible
CONS: Tissue irritation w/ extravasation, Nephrotoxicity, GI upset
Why might you use the precursors to acyclovir and gancyclovir, valacyclovir and valganciclovir?
Better oral bioavailability
What are the toxicities of gancyclovir?
Leukopenia, thrombocytopenia, mutagen, tetratogen, nephrotoxicity
What antivirals are nephrotoxic?
Acyclovir
Gancyclovir
Foscarnet
Cidofovir (coadminister w/ probenecid & saline)
What is the treatment for severe influenza?
Zanamivir or oseltamivir w/ in 48 hours. Decreases illness duration and reduces risk of complications.
For a pateint who is <1 year old, what would you use to treat severe influenza infection?
Zanamivir
What antiviral is contraindicated in patients with respiratory disease?
Oseltamivir
What are the toxicities associated with Interferons?
Neutropenia, myopathy, neurotoxicity
What are the toxicities associated with the following HIV drugs?
Protease inhibitors
NRTIs
Protease inhibitors: Hyperglycemia, GI intolerance, lipodystrophy (increased TG and LDL)
NRTIs: Bone marrow suppression, peripheral neuropathy
What might you use G-CSF and EPO to treat?
Bone marrow suppression caused by HIV NRTIs
What anti-HIV medications:
1) inhibit CYP 450
2) Use/compete for the glucuronyl transferase pathway
why is this important?
1) Ritonavir (protease inhibitor) - CYP450 inhibitor
2) AZT - severe reactions w/ asprin, tylanol, others that use glucuronidation in liver.
