Clinical Use of Antiviral Drugs Flashcards
Explain the possible targets for antiviral drugs
Drugs that block or modify host receptor so the virus can’t bind
Inhibit transport of virus, prevent uncoating of viral genome in host cell
Inhibit expression of viral gene/translation
Block viral RNA and DNA strand synthesis
Inhibit full assembly of virus during maturation
Inhibit release of mature virus
What are the difficulties in developing a safe anti viral agent?
Antiviral needs to be intracellular
Viruses use host receptors for entry, but blocking these receptors block important host functions
RNA viruses = high mutation rate (quasispecies), so develop fast resistance
Latency common (e.g. Herpes viruses), thus difficult to target
Describe the treatment for influenza
Oseltamivir and zanamivir: inhibits neuraminidase which inhibits virus release from infected cells
Oseltamivir –oral
Zanamivir- inhaled or IV, resistance less likely
Amantadine: blocks influenza encoded M2 protein and haemagglutinin assembly- inhibits virus uncoating. Rarely used
Describe the effectiveness of Anti influenza drugs, when should they be used, when is resistance more likley?
Treatment must start early BUT, only 25% patients can see their GP within 36hrs of symptom onset
Should be used for “at risk” groups, useful in post-exposure prophylaxis or in the flu season
Resistance rare, more likely in immunocompromised.
Describe influenza resistance to antivirals- what kind of mutations cause it, who is resistance seen in? Are there any drugs which influenza remains sensitive to?
Resistance sometimes is a single amino acid change - eg swine flu (H1N1), Tamiflu (oseltamivir)
Point mutation (H275Y; tyrosine replacing histidine)
Seen in immunocompromised patients
Remains sensitive to zanamivir; probs bc of low exposure levels
Herpes viruses include…
Herpes simplex (HSV): cold sores, genital ulcers (HSV-1 and HSV-2)
Varicella zoster (VZV): chickenpox and shingles
Cytomegalovirus (CMV)
Epstein-Barr (EBV): glandular fever/infectious mononucleosis
All cause acute infection w subsequent latency and possible re-activation
How do you treat herpes viruses?
Draw a diagram to describe the mode of action of aciclovir
Aciclovir triphosphate has 30x the affinity for HSV DNA polymerase compared w cellular DNA polymerase
Aciclovir triphosphate= highly polar- difficult to leave/enter cells (but aciclovir is easily taken into cells pre phosphorylation)
Outcompetes guanosine when dNA is being elongated
So when DNA polymerase is inserting a guanosine into the growing chain, acyclovir can replace guanosine
Acyclovir is incorporated into the DNA
Results in chain termination
When is Ganciclovir used?
Used to treat CMV
Treats congenital CMV infection
Treats reactivated infection in transplant recipients + immunocomp patients
Prophylaxis in organ transplant recipients
Sometimes used to treat HHV-6 infection
Gancciclovir is used to treat CMV
Give the mechanism of action of Ganciclovir
Synthetic analogue of guanosine
Phosphorylated by CMV TKinase (UL97), then more phosphorylation by cellular enzymes
Inhibits polymerase (called UL54 in CMV)
Overall this causes inhibition of viral DNA synthesis – chain termination
What is the difference between Valaciclovir and valganciclovir?
Basically the same as acyclovir and ganciclovir but has an attached val group and can be given orally
Describe other anti herpes viral agents
When would you use them, when would you NOT use them etc
Foscarnet: for CMV infection in immunocomp e.g. pneumonia in transplants. May be used in ganciclovir resistance/toxicity
Has renal toxicity= not used for renal transplant patients w CMV reactivation unless ganciclovir resistance
Cidofovir= for CMV; but MUCH MORE nephrotoxic
Describe the mechanism of action of Foscarnet and cidofovir, and how resistance can arise
Mutations in ? can lead to…
Foscarnet and cidofovir inhibit DNA (NOT HBV) polymerase and thus viral DNA synthesis
Cidofovir- chain terminator
Foscarnet inhibits the pyrophosphate binding site
Mutations in viral thymidine kinase gene can lead to decreased phosphorylation of cidofovir–>drug becomes less effective–>resistance.
Mutations in DNA polymerase gene can impair the ability of the enzyme to be inhibited by drugs like foscarnet
Outline the risk of chronic infection from hepB and age
Drugs to treat Hep B do not cure it, but they can be used prophylactically and reduce cancer/cirrhosis risk
Describe these drugs used to treat Hep B virus
Note- tenofovir is an NRTI
Lamivudine: triphosphate form competes w cytosine triphosphate in developing vDNA strand–> chain termination
Tenofovir: adenosine analogue. Entecavir: guanosine analogue
Phosphorylated & inhibits HBV polymerase-> chain termination
Adefovir: phosphorylated to adefovir diphosphate–> inhibits HBV polymerase–> chain termination
What is the main way in which we treat HIV?
Combination therapy reduces risk of resistance
Adherence to treatment is ESSENTIAL
Use up to 5 drugs may be combined in one pill
Once a day tablets best
What is the difference between NRTI and NNRTIs?
Give examples of NRTIs and NNRTIs
NRTIs act as chain terminators, while NNRTIs bind allosterically to the reverse transcriptase enzyme to inhibit viral replication.
(NRTIs): emtricitabine, tenofovir, used in HIV PreP
(NNRTIs): Efavirenz, Rilpirivine: (no action against HIV-2)
Describe other anti retrovirals apart from NRTIs and NNRTIs
Protease inhibitors: inhibit polyprotein cleavage. Atazanivir (usually “boosted” with ritonavir)
Integrase inhibitors: inhibits proviral DNA formation. Dolutegravir, elvitegravir (“boosted” with cobicistat)
CCR5 inhibitors: maraviroc (blocks cell surface receptor)
Capsid inhibitors: Lenacapavir (stops viral capsid uncoating)
Describe why there are high levels of HIV resistance and how we can test for resistance
Selection pressure and high mutation frequency in HIV (and HCV)
Most RNA viruses have no proof reading capacity, so mutations are not fixed
Can test for resistance by cell culture (plaque assay), but slow process, or molecular methods in anti-viral sensitivity testing
When is someone given PEP? What about PrEP?
Pre-exposure prophylaxis (PrEP):
Truvada = emtricitabine and tenofovir
For those at risk of HIV from sexual exposure
Can lead to increase rates of other STDs
Which viral infections are currently untreatable?
Rabies
Dengue
Common cold (many viruses)
