15 Antiviral agents Flashcards
why is it harder to develop selectively toxic antiviral drugs compared to antibiotics
viruses are intracellular parasites and rely on many of the host cells mechanism and machinery for replication, so most drugs target replication and damage the host cell too
however, when it was discovered that viruses carry their own enzymes, this became a target for selective antiviral treatment
what was the first successful antiviral drug to be developed without damaging host cell
aciclovir
aciclovir is an analogue of
deoxyguanosine
how does aciclovir work (main thing it does)
incorporated into a growing DNA chain, acts as a DNA chain terminator
highly effective but only works against viruses which are able to phosphorylate it, herpes family, only HSV and VZV
mechanism of action in aciclovir (steps)
aciclovir is inactive, it has to be triphosphorylated
the key to selectivity is that an enzyme derived from virus phosphorylates aciclovir first (thymidine kinase), host cells cannot phosphorylate it, so nontoxic to normal cells
2nd and 3rd phosphate groups are added by cellular enzymes to produce aciclovir triphosphate
then competes with deoxyguanosine triphosphate for incorporation into a growing DNA chain and terminates it
give 3 ways aciclovir is selectively toxic
1 only activated in virally active cells
2 becomes concentrated in virally active cells (when cell has virus which can phosphorylate, as aciclovir gains a phosphate group, the intracellular concentration of free aciclovir will drop, more will diffuse into cell)
3 final molecule will bind better and inhibit viral DNA polymerase better than cellular DNA polymerase
describe 3 ways aciclovir resistance occurs
1 if virus doesn’t have thymidine kinase pre-treatment, but without this enzyme they’re non-pathogenic
2 mutations in thymidine kinase genes during therapy so can’t phosphorylate, but also non-pathogenic
3 mutations in DNA polymerase so the final molecule can’t bind to it and act as a chain terminator, clinical problem
what is valaciclovir formed of
ester of valine and aciclovir
benefits of valaciclovir compared to aciclovir
better orally absorbed and available in blood stream, easier in terms of dosage regimes
describe penciclovir, what is it administered as and is it better than aciclovir
also an analogue of deoxyguanosine, works in same way as aciclovir but not a chain terminator, although still an inhibitor with a higher affinity for viral DNA polymerase than cellular
administered as famciclovir (esterified)
aciclovir and penciclovir are equal in clinical trials
describe the presence of genital herpes in men
recurs as clusters of vesicular lesions on an erythematous base, usually on penis shaft or glans
aciclovir in genital herpes- prophylaxis
frequent, severe, atypical genital HSV= continuous aciclovir therapy to suppress recurrences
start on high dose and drop down to minimal dose so they remain disease free
usually leads to reversion to pre-therapy state, long-term therapy
what’s a dendritic ulcer and complications involved
shallow ulcer on cornea, complication of herpes
usually resolves without leaving much damage, but problem is when the virus goes latent in the nerves which supply the cornea
each time it recurs= more potent inflammatory response
can lead to complete opacity of cornea, commonest infection cause of blindness in UK
would give aciclovir but most damage is by host’s immune response, so would give steroids, should be managed by ophthalmologist
describe complication of herpes in the brain
infection of the brain= encephalitis
replication of herpes in brain substance
aciclovir can be life saving, ASAP for survival and survival without brain damage, use IV if suspicious before confirmed diagnosis to minimise brain damage
3 complications with HSV
dendritic ulcer in eye
encephalitis in brain
eczema herpeticum- complication in patients with eczema, spread across non-intact skin, can gain access to peripheral blood stream and organs (have supplies of aciclovir at home if have eczema and herpes in case of recurrence)
