Pharm 2- Antivirals

kelseyfmeyer's version from 2015-05-10 01:44


Question Answer
what is the viral enzyme which initiates viral replication in the host cell?neuraminidase
explain RNA virus replication (steps can be drug targets)enzymes within the virion synthesise mRNA--> translation into various enzymes (RNA polymerase) and structural proteins--> assembly of virion--> release by budding or cell lysis
explain replication in retroviruses (steps can be drug targets)virus RNA dependent DNA polymerase makes a DNA copy of viral RNA--> DNA copy is integrated in host DNA (provirus)--> provirus is transcribed into viral RNA and mRNA--> assembly of viral proteins
explain DNA virus replication (steps can be drug targets)transcription into mRNA (polymerase)--> DNA replication--> translation into viral proteins--> release by budding or cell lysis
the drugs used in vetmed that he said in class (based off pic)protease inhibitors, fusion inhibitors, reverse transcriptase inhibitors
Key notes: DRUG TARGETS FOR ANTIVIRAL THERAPY (8)(1) Co-receptor antagonists (chemokine receptor) (2) fusion inhibitors (3) reverse transcriptase inhibitors (4) integrase inhibitors (5) protease inhibitors (6) inhibitors of coat assembly (7) Neuramidase inhibitors (8) Biopharmaceuticals and immunomodulators
how does viral metabolism work?they use the metabolic processes of the host cell itself
different viruses use different...mechanisms of replication/entry into the host cell
most currently available antiviral drugs only work when?when the virus IS REPLICATING
what's diffcult about timing, viruses, and treatment?treatment is often delayed until the infection is well established (there has already bee viremia)
what's better than having to treat a viral infection?vaccinating against it in the first place
vaccinations depend on the _________ immune responseadaptive
what is the role of innate immunity in vaccinations?agonists of innate immune receptors are used as adjuvants in vaccines
what is the huge factor about antivirals we need to account for?cost. they're damn expensive.

against retroviruses

Question Answer
NRTI (stands for? analogues of?)Nucleoside analog Reverse Transcriptase Inhibitor. Analogues of naturally occurring deoxynucleosides
NtRTINucleotide analog Reverse Transcriptase Inhibitors
NNRTINon-nucleoside Reverse Transcriptase Inhibitors
NRRINucleoside Reverse Replicase Inhibitors
NNRRINon-Nucleoside Reverse Replicase Inhibitors
name the long-note reverse transcriptase inhibitorsZidovudine, Lamivudine, Stampidine, Didanosine
Zidovudineinhibits viral reverse transcriptase (RNA dependent DNA polymerase). Because of the affinity to viral enzymes, host toxicity is minimal. bioavailability is relatively high (95%) in cat. Dose dependent and progressive anemia and neutropenia. Shows promise for FeLV and BLV
Lamivudine inhibits viral reverse transcriptase. Better safety profile than zidovudine. Is potent against FIV in-vitro. The pharmacokinetics are similar to those of zidovudine in cats and also the safety profile is comparable.
Stampidine inhibits viral reverse transcriptase. Therapeutic plasma concentrations 3-4 logs higher than its IC50 value can be achieved after oral administration to dogs as well as cats. stampidine was very well-tolerated by dogs and cats at cumulative dose levels. Except for the sporadic occurrence of nausea and vomiting, and elevation of serum ALT levels in some of the cats, not associated with any clinical or laboratory evidence of toxicity.
Didanosine inhibits viral reverse transcriptase. More active in quiescent cells and non-dividing monocytes and macrophages. Didanosine is metabolised in the cell to an active metabolite. Adverse effects include painful peripheral neuropathy and pancreatitis, Animal studies also report gastrointestinal, bone marrow, hepatic and renal dysfunction.
5 mechanisms to fight retroviruses as seen in pic on slide 8(1) inhibitors of viral fusion (2) reverse transcriptase inhibitors (3) protease inhibitors (4) inhibitors of viral integrase (5) chemokine receptor agonists
Nucleoside RTIs (NRTI) do what three things to work? (go in order)phosphorylation by host cell enzymes (triphosphate form)--> competes with host cell triphosphates for proviral DNA synthesis--> incorporation of the triphosphate into the growing viral DNA chain results in chain termination
what are the vet applications of Nucleoside RTIs (NRTI)?FeLV, FIV, Bovine Leukemia Virus: (zidovudine (AZT) and stampidine)
zidovudine pharmacokinetics in cats? (what group is this part of? what route has high bioavail? describe plasma conc. half life? side effects?)NRTIs. high ORAL bioavail (95%). plasma concentrations remained above EC50 for more than 12 hours. t 1/2 is short (1.4 hours). Side effects= hemolysis after iv injection! so go slow, or do oral admin.
lamivudine (when compared to zidovudine) more potent against FIV in vitro (than zido); better safety profile in humans

against herpes viruses

Question Answer
Acyclovir (and its analogues and pro-drugs) Belongs to what group? what virus does it focus on?viral DNA polymerase inhibitors (DPI). it is a ANTI-HERPESVIRUS DRUG
how is acyclovir able to work in only infected cells? explain how it worksconverted to monophosphate (MP) by viral thymidine kinase (only works in infected cells!). Then host cell kinases convert MP to triphosphate= active form that inhibits viral DNA polymerase
what does acyclovir inhibit, which is what makes it fight the herp?inhibits viral DNA polymerase
compare efficacy of acyclovir to the host's enzymes30xs more effective
veterinary applications of acyclovir?EHV-1 (equine herpes virus 1), FHV (feline herpes virus), CHV (canine herpes virus)
which prodrug of acyclovir is TOXIC for CATS?valacyclovir
pharmacodynamic studies for acyclovir were done on who? what did they determine it was efficacious against?Horses and cats, and they found it was effective against FHV and EHV (feline/equine herpes virus)
what is the prodrug of acyclovir?valacyclovir
you can't just give acyclovir, you gotta do what? why?give the prodrug valacyclovir, because acyclovir doesnt always have good oral bioavail
what is the oral bioavailability of acyclovir (sp diffs)it is variable: dogs > 80% - humans 10-30% - horses < 5% (valacyclovir oral bioavail is 26% tho!)
what is the half life of acyclovir? (sp diffs)t 1/2 in horses is between 5 and 9 hours; dogs 2.3 hours, and cats 2.5 hours
horses and acyclovir-> age differences with tx differences, and with what disease?usually in horses you need to tx equine herpes virus with valacyclovir (the prodrug). in equine neonatal herpesvirus infections, you are able to tx with acyclovir, because their tight jxns in their GI arent totally closed so more acyclovir gets in
which member of the acyclovir family is used for topical admin in cats?penciclovir
what does he say about famciclovir?efficacy of famciclovir is questionable: clinical studies are needed
ribavirin is effective against what?herpes AND influenza A/B, and others.
ribavirin works how?( a polymerase inhibitor, but it's unique in that it inhibits RNA and DNA)--inhibits replication of a wide variety of viruses (DNA and RNA), with mult sites of actions (long notes say: The drug is activated by viral phosphorylation and subsequently inhibits the formation of mRNA and replication of the viral genome. The actions involve specific inhibition of virus associated enzymes, inhibition of capping of viral mRNA and inhibition of viral polypeptide synthesis.)
ribavirin application in veterinary medicine (incld sp diffs)in vitro work looks promising, toxic in cats, not used in vivo in cows and dogs
key note: Antiviral therapy for herpesvirus infections--> Pyrimidine nucleosides (do what? what are the 3 main drugs in this category, and the subtypes of the one?)inhibition of viral DNA polymerase. (1) idoxuridine (2) trifluridine (3) Sorivudine (phosphorylation by viral enzymes: thymidine and thymidylate kinases)
Key note: Antiviral therapy for herpesvirus infections--> Purine nucleosides (do what? what are the 5 drugs in this category?)inhibit viral DNA polymerase. (1) Vidarabine (2) Acyclovir - Valacyclovir (pro-drug): small spectrum (3) Penciclovir - Famciclovir (pro-drug): small spectrum (4)Ganciclovir: small spectrum (5) Ribavirin

recombinant interferon stuff (interferons made for any sort of viral infection!)

Question Answer
the recombinant interferons are different types of _________ interferonomega
what are the three properities recombinant interferons have?antiviral, immune modulating, and anticancer properties
how do interferons act as antivirals (how does it work?)anti-viral by promoting the synthesis of enzymes that interfere with viral replication (protein synthesis and degradation of viral RNA)
how is it that a little interferon goes a long way?cell-cell interaction converts antiviral effects without additional interferon (you can transfer/share the enzymes without transferring the interferon b/c there is cell-cell contact!)
interferons in CATS treat which diseases? (3)FeLV, FIP, FIV
interferons in DOGS treat what disease? (1)CPV-2 (parvovirus)
interferons in BOVINE treat which diseases? (2)vaccinia (bovine smallpox), IBR (infectious bovine rhinotracheitis)
interferons in EQUINE treat which diseases? (2)EHV-1 (equine herpes virus), inflammatory airway dz

against influenza viruses (A or A/B)

Question Answer
M2-ion channel inhibitors (inhibitors of coat dissambly)--> explain exactly what is meant by this (what is the virus doing, how does this work?)virus comes over to cell, and has to get in. Binds to receptors on cell memb. to get let it. the membrane surrounds them (endocytosis!) but once they're inside the cell, they need to get OUT of the vesicle, so they use their viral M2 ion channel to let H+ ions in to break down the membrane and then they are released to go and infect the cell
what is the viral protein that attaches to (which) host cell receptor to trigger endocytosis of the virus to get it in the cell?viral hemaglutinin attaches to host neuraminic acid
what are the two M2-ion channel inhibitors drugs?amantadine and rimantadine
which of the M2-ion channel inhibitors is TOXIC?amantadine
which admin is not reliable for these types of drugs? which is better if you had to choose?oral admin not reliable. (oral bioavailability differences: much better for rimantidine)
which drug is useful for equine influenza?rimantidine (rim is also safer than amantidine)
why is china mentioned in this section?he mentions that use in poultry in china might be the reason there are resistant strains
aside from tx of influenza viruses, what is the additional indication for amantidine? why? specifics/species?for tx of PAIN! it is an NMDA antagonist (like ketamine). causes relif of pain symptoms, can be combined with NSAIDs, and is well tolerated in dogs
what are the neuramidase/sialidase inhibitors? (2)zanamivir and oseltamivir
what are the applications of zanamivir and oseltamivir?no info on use in animals avail. it was made to tx "mexican/swine flu"
ribavirin is effective against what?herpes AND influenza A/B, and others.
ribavirin works how?inhibits replication of a wide variety of viruses (DNA and RNA), with mult sites of actions (long notes say: The drug is activated by viral phosphorylation and subsequently inhibits the formation of mRNA and replication of the viral genome. The actions involve specific inhibition of virus associated enzymes, inhibition of capping of viral mRNA and inhibition of viral polypeptide synthesis.)
ribavirin application in veterinary medicine (incld sp diffs)in vitro work looks promising, toxic in cats, not used in vivo in cows and dogs

By type (the red ones are the ones he said we need to know)

Question Answer
nucleoside reverse transcriptase inhibitors (NRTI)- what drugs are in this category? Indications?zidovudine, stampidine, lamivudine. Indications= HIV, FIV, FeLV
viral DNA polymerase inhibitors (DPI)- what drugs are in this category? Indications?acyclovir, idoxuridine, ribavirin, trifluridine, foscarnet. Indications= herpes virus infections, (foscarnet FeLV)
inhibitors of coat disassembly (M2-ion channel inhibitors)- what drugs are in this category? Indications?amantadine, rimantadine. Indications= Influenza A or A/B
neuramidase inhibitors- what drugs? Indications? zanamivir, oseltamivir. Indications= Influenza A or A/B
biopharmaceuticals and immunomodulators- what drugs are in this category? Indications?(recombinant) interferon. Indications= IBR (Infectious Bovine Rhinotracheitis), FeLV/FIV, CPV-2 (canine parvovirus type 2), EHV-1 (equine herpes virus 1)

by drug (what group does it belong to)

Question Answer
zidovudinenucleoside reverse transcriptase inhibitors (NRTI)
stampidinenucleoside reverse transcriptase inhibitors (NRTI)
lamivudinenucleoside reverse transcriptase inhibitors (NRTI)
amantadineinhibitors of coat disassembly (M2-ion channel inhibitors)
rimantadineinhibitors of coat disassembly (M2-ion channel inhibitors)
zanamivirneuramidase inhibitors
oseltamivirneuramidase inhibitors
(recombinant) interferonsbiopharmaceuticals and immunomodulators
acyclovirDPI's= (viral) DNA polymerase inhibitors (purine nucleosides)
valacyclovirDPI's= (viral) DNA polymerase inhibitors (purine nucleosides)
penciclovirDPI's= (viral) DNA polymerase inhibitors (purine nucleosides)
famciclovirDPI's= (viral) DNA polymerase inhibitors (prodrug of penciclovir)(purine nucleosides)
ribavirinviral DNA polymerase inhibitors (chart had it in this category, it has mult actions tho)
idoxuridineviral DNA polymerase inhibitors (pyrimidine nucleosides)
trifluridineviral DNA polymerase inhibitors (pyrimidine nucleosides)
foscarnetviral DNA polymerase inhibitors (specific for FeLV, is what i think the table says)
sorivudineviral DNA polymerase inhibitors (pyrimidine nucleosides)
thymidine/thymidalate kinasesviral DNA polymerase inhibitors (pyrimidine nucleosides) which are phosphorylated from sorivudine by viral enzymes
Vidarabineinhibit viral DNA polymerase (purine nucleosides)
Ganciclovirinhibit viral DNA polymerase (purine nucleosides)
Ribavirininhibit viral DNA polymerase (purine nucleosides) ( a polymerase inhibitor, but it's unique in that it inhibits RNA and DNA)

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