what is the best protection against viruses?
vaccines, because developing viral selective drugs is very hard
what is the usual combination for HAART?
- Two nucleoside reverse transcriptase inhibitors
- one NNRT or a protease inhibitor
- HAART does not eradicate HIV but it keeps it viral load down
how do interferons work?
those work by modulating the immune response
they bind to specific gangloside receptors which causes the production of enzymes that inhibit the translation of viral mRNA into viral proteins
what is Palivizumab?
this is given as prophyalxis to children who are at high risk of contracting RSV. This is an Ig which prevents the entry of the virus into the cell
what is enfuvritide?
this prevents entry of HIV-1 into cells, it is an analogue of gp41 which is essential to viral entry into the cell
given to patients who do not respond to normal HAART
What is the mechanism of action of amanatidine? and what is it used for?
used for:
- prophylaxis and treatment of influenza A
- it blocks the M2 channel which will allows proton influx, which is necessary for the viral uncoating
what is the mechanism of action for Zanamivir or Oseltmavir?
those are used as prophylaxis and treatment for influenza A and B
- both those are sialic acid analogues
- so they inhibit neuromindase action
- prevent budding of the virus from host cells
what is the mechanism of action of acycloivr?
acyclovir is given as a pro-drug, it becomes mono-phosphorylated by viral thymidine kinase. then double phosphorylated by cellular kinases. this inhibits DNA polymerase of the virus and inhibits its viral replication
acyclovir as an acyloguanosine trisphosphate
give two reasons why acyclovir has selective toxicity
because only infected cells have thymidine kinase with a high affinity to mono-phospharylate the drug
also the triple phosphorylated drug has a higher affinity for viral DNA polymerase than cellular DNA polymerase
when is acyclovir used?
to treat HSV and VZV
high dosages can be used for shingles
when is ganciclovir used? and why?
in extreme causes of CMV (e.g. CMV retinitis) given I.V
given because CMV does not have thymidine kinase. the drug itself can cause neutropenia
how does Zidovudine work?
AZT; a thymidine analogue (N3 instead of OH)
- triple phosphorylated by cellular kinases
- but the phosphorylate drug has a much higher affinity for the reverse transcriptase than cellular DNA polymerase
- this drug is a nucleoside analogue
- the drug does not have OH at its 3’end so cannot form the phosphodiesterase bonds required for chain elongation
what is so special about the resistance of the NRTI
they do not have cross resistance. and using more than one type suppresses resistance
give the four stages of the viral response to AZT
1: this is a rapid decrease in viral plasma load (days)
2. (weeks) a rapid increase of viral plasma load, independent of resistance
3. months - slow increase in viral load probably due to resistance
4. this is rebound of virus load to baseline line because of withdrawal of treatment
what is nevarapine?
this is a NNRTI - which acts by denaturing RT
What is saquinavir and Indinavir?
those are protease inhibitors and they prevent the formation of mature viral particles
what is ribavarin?
this is a guanosine analogue
used in treatment of RSV
inhibits viral RNA polymerase
also inhibits GTP dependant enzymes which affects viral mRNA capping
What is saquinavir and Indinavir, ritonavir, idinavir
those are protease inhibitors and they prevent the formation of mature viral particles
this is because proteases are required for splicing viral proteins which are polycistronic
what is ribavarin?
this is a guanosine analogue
used in treatment of RSV
inhibits viral RNA polymerase
also inhibits GTP dependant enzymes which affects viral mRNA capping
what is the treatment for Hep B virus?
Treatment of Hepatitis B:
• The virus requires reverse transcriptase
• Usually use Lamivudine (a nucleoside reverse transcriptase inhibitor)
o But resistance quickly arises
o To phosphonate analogues are used: dAMP (Adefovir)
o dGMP: entecavir
o those are nucleotide analogues that inhibit viral DNA polymerase
what’s the difference between bacteriostatic and bactericidal agents?
bacteriostatic prevent bacterial proliferation, whereas the bactericidal agents actually kill the bacteria
how is resistance in bacteria developed?
there is two ways:
selection:
- where the antibiotic will eliminate the sensitive bacteria and the resistant bacteria remain
transferred resistance:
- a gene coding for resistance is passed from one bacteria to another
- the gene for resistance can be within the plasmid which is easily passed between organisms via conjugation
what enzyme do sulphonamides work?
they inhibit dihydropetroate synthetase, which is required for folate synthesis
what enzyme does trimethoprim inhibit?
this inhibit dihydrofolate reductase, which is required for folate synthesis
what are the sulphonamides and trimethoprim used for?
they’re used for UTIs
what enzyme does the quinolone inhibit?
inhibits DNA gyrase (topoisomerase II) which is required to seal the nicks of DNA strands in the process of DNA supercoiling
why are the quinolones specific?
because humans have no DNA gyrase
giva an example of a quiolone
ciproflaxcin - which is a broad spectrum antibiotic
what is the mechanism of action of Metronidazole, and why is it selectively toxic?
metronidazole penetrates into organism and becomes reduced by ferridoxin (which is only found in the bacterial electron chain, and not found in the human electron transport chain)
this reduced metabolites are toxic and bind to DNA inducing mutations and reduce replication
what is the active product of penicillin
the beta lactam group, without this beta lactam the drug will not work, the beta lactam work because they mimic the D-alanyl D-alanine of the peptide chains of the bacterial walls
what is flucloxacillin used for?
used in infections with staphylococci which produce Beta lactmase -
this is still effective because it has a steric group which prevents the access of the lactmase enzyme to the beta-lactam group
give an example of a narrow spectrum penicillin
benzylpenicillin
give example of broad spectrum penicillin?
amoxicilin and ampicillin
- those are actually active against gram negative bacteria
give example of broad spectrum penicillin?
amoxicilin and ampicillin
- those are actually active against gram negative bacteria, therefore can be used in the treatment of E.coli, H.influenzae and salmonella
what is co-amoxicillin?
this is clavulanic acid (which inactivates the beta lactamase) and amoxicillin. this is used when the infection is penicillin resistant
what is the major side -effects with amino glycosides?
oto-toxicity (by damaging the 7th cranial nerve)
damage to the kidney
can impair neuromuscular transmission - so not recommended for patients with MG
what is the mechanism of action for the amino glycosides?
they bind to the 30s sub-unit and inhibit binding of aminoacyl -RNA
they also cause misreading of MRNA forming non-functional proteins
what are the side effects of the macrolides?
they’re generally quite safe drugs, but they inhibit p450 enzymes, so they can cause warfarin accumulation
give examples of a macrolide
erythromycin and clarithromycin
when are cephalosporins used>
they’re usually used for meningitis, pneumonia and septicaemia
what are the main side-effects of tetracyclines
binds to calcium in growing teeth and bone (therefore, cause teeth discolouration in the young)
diarrhoea and nausea
nephrotoxicity
what is the mechanism of action of the tetracyclines?
they bind to the 30-s subunit preventing the binding of aminoacyl tRNA
what is the mechanism of action of chloramphenicol?
inhibits peptidyl transferase activity of 50s ribosomal subunit (and this inhibits peptide chain elongation)
what is the side effect of chloramphenicol?
bone marrow depression, Grey baby syndrome and diarrhoea
when is chloramphenicol used?
usually used to treat bacterial conjunctivitis
what is zidovudine used for?
HIV
What is nevarapine used for?
HIV - this is a non-nucleoside inhibitor
what is indinavir and squanivir used for?
HIV
protease inhibitors
what is acyclovir used for?
HSV, VZV, immunocomprosided patient (encephalitis, mucocutaneous infections and genital herpes and varicella
what is ganciclovir used for?
this is used for cytomegalovrius retinitis - because acylcovir is inactive against it
what can vidarabine be used for?
HSV, VZV, (same as acyclovir but stronger side-effects)
idoxurdine
HSV, corneal infections