Clinical use of antiviral drugs Flashcards
What are the difficulties in developing a safe anti-viral?
- Viruses use cellular receptors to get inside cells
- Genetic integration - no way to reverse it
- Latency is common - then no real target while dormant
- High mutation rate
- Must replicate inside cells and take over host’s biochemistry
How do we use antivirals?
- treatment of acute infection
- Post-exposure prophylaxis and preventing infection
- Post-exposure prophylaxis and allowing infection
- Pre-exposure prophylaxis
- Prophylaxis for reactivated infection (e.g. in transplant after immunosuppression)
What drugs can we use for herpes?
- Aciclovir/valaciclovir (IV/oral/topical) - HSV and VSV
- Gangciclovir/ valgangciclovir (IV/oral) - CMV
- Foscarnet (IV/topical)
- Cidofovir (IV)
What is the mechanism of action of aciclovir?
- Aciclovir is very closely related to guanosine
- Our body take ACV into the cell, then gets phosphorylated by a HSV derived thymidine kinase
- Our own TK can then phosphorylate it twice
- When guanosine is being incorporated into the growing DNA, ACV takes its place, inhibitng the DNA synthesis
- This means that the virus cannot replicate and so dies
What is aciclovir used for?
• Herpes simplex – Treatment of encephalitis – Treatment of genital infection – suppressive therapy for recurrent genital herpes • Varicella zoster virus – Treatment of chickenpox – Treatment of shingles – Prophylaxis of chickenpox • CMV – Prophylaxis only
What is ganciclovir used for?
• CMV
• Goes into latent phase and can come back
– Treatment of reactivated infection in organ transplant recipients
– Treatment of congenital infection in newborn
– Prophylaxis in organ transplant recipients (if donor had latent CMV)
• Mismatch
What is the difference between valaciclovir/ valaganciclovir and their normal versions?
- By adding valine ester on it, it is more bioavailable
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How can Herpes viruses become resistant to antivirals?
- Two main mechanisms = thymidine kinase mutants and DNA polymerase mutants
- If occurs in TK, drugs not needing phosphorylation are still effective (foscarnet and cidofovir)
- If occurs in DNA polymerase, all drugs are rendered less effective
What drugs can we use for influenza?
- Amantidine - inhibits virus uncoating by blocking the influenza encoded M2 protein when inside cells, and assembly of HA (now rarely used)
- Zanamivir and Oseltamivir - inhibits release from infected cells via inhibition of NA
How effective are NA inhibitors?
- Marginal overall benefit
- Treatment needs to be commenced early
- Very useful in post-exposure prophylaxis or in the flu season
- Resistance is rare, but more likely in immunocompromised patients
How does resitance to antivirals occur in influenza?
- Resistance sometimes only requires a single amino acid change - seen recently with swine flu (H1N1) and Tamiflu (oseltamivir)
- Point mutation (H275Y; tyrosine replacing histidine)
- Seen in immunocompromised patients; shed virus for weeks/months
- Likely to be selected for among quasispcies on Rx
- Transmissible and virulent
- Remains sensitive to zanamivir; probably because of low levels of exposure
How do we treat HepB?
- For a long time we used IFN to treat pts with chronic infections, however can have some bad side effects
- Specific anti-virals - Lamivudine, tenofovir, entecavir, adefovir
How do we treat HepC?
- HCV is curable in some
- Response influenced by viral genotype and host genotype
- Treat with pegylated IFN and ribavirin
- However starting to produce specific antivirals and IFN-free treatments
How does the HIV virus infect us?
- gp120 binds to the CD4 receptor and CCR5 co-receptor, followed by penetration and uncoating
- The RNA is then reverse transcribed into a DNA provirus, which is integrated into the cell genome
- Makes mRNA for new proteins and genomic RNA to produce new strains
- Followed by synthesis and maturation of virus progeny
What are anti-retrovirals?
The drugs do not kill or cure the virus. However, when taken in combination they can prevent the growth of the virus. When the virus is slowed down, so is HIV disease.
