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Pharm 2 - Antivirals

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rilohoji's version from 2016-11-20 17:53

Intro

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 w/in the virion synthesize mRNA → translation into various enzymes (RNA polymerase) & 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 & 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 & 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, & Tx?Tx is often delayed until the infxn is well established (there has already been viremia)
What's better than having to Tx a viral infxn?Vaccinating against it in the 1st 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.
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Against Retroviruses

Question Answer
NRTI (stands for? Analogues of?)Nucleoside analog Reverse Transcriptase Inhibitor. Analogues of naturally occurring deoxynucleosides (RNA antiviral)
NtRTINucleotide analog Reverse Transcriptase Inhibitors (RNA antiviral)
NNRTINon-nucleoside Reverse Transcriptase Inhibitors (RNA antiviral)
NRRINucleoside Reverse Replicase Inhibitors (DNA antiviral)
NNRRINon-Nucleoside Reverse Replicase Inhibitors (DNA antiviral)
Name the long-note reverse transcriptase inhibitorsZidovudine, Lamivudine, Stampidine, Didanosine (NRTI) (did nerty Zido stamps lamps for 5 FeLVers (flavors)??)
ZidovudineInhibits viral reverse transcriptase (RNA dependent DNA polymerase). Bc of the affinity to viral enzymes, host toxicity is minimal. Bioavailability is relatively high (95%) in cat. Dose dependent & progressive anemia & neutropenia. Shows promise for FeLV & BLV
LamivudineInhibits viral reverse transcriptase. Better safety profile than Zidovudine. Is potent against FIV in-vitro. The pharmacokinetics are similar to those of Zidovudine in cats & also the safety profile is comparable.
StampidineInhibits 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 & cats at cumulative dose levels. Except for the sporadic occurrence of nausea & vomiting, & elevation of serum ALT levels in some of the cats, not associated w/ any clinical or laboratory evidence of toxicity.
DidanosineInhibits viral reverse transcriptase. More active in quiescent cells & non-dividing monocytes & macrophages. Didanosine is metabolized in the cell to an active metabolite. Adverse effects incld painful peripheral neuropathy & pancreatitis, Animal studies also report gastrointestinal, bone marrow, hepatic & renal dysfxn.
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 3 things to work? (Go in order)Phosphorylation by host cell enzymes (triphosphate form) → competes w/ 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) & Stampidine)
Zidovudine pharmacokinetics in cats? (What group is this part of? What route has high bioavail? Describe plasma conc. half-life? SFx?)NRTIs. High ORAL bioavail (95%). Plasma concentrations remained above EC50 for more than 12 hours. t 1/2 is short (1.4 hours). SFx = hemolysis after IV injxn! 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
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Against Herpes viruses

Question Answer
Acyclovir (& its analogues & pro-drugs) Belongs to what group? What virus does it focus on?Viral DNA polymerase inhibitors (DPI). It is an ANTI-HERPESVIRUS DRUG
How is Acyclovir able to work in only infected cells? Explain how it works****TQIt is converted 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 & cats, & they found it was effective against FHV & 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, bc Acyclovir doesnt always have good oral bioavail
What is the oral bioavailability of Acyclovir (sp diffs)It is variable: Dogs > 80% - humans 10-30% - adult horses < 5% - neonatal foals 26% (Valacyclovir oral bioavail is 26% in adult horses)
What is the half-life of Acyclovir? (sp diffs)T 1/2 in horses is btwn 5 & 9 hours; dogs 2.3 hours, & cats 2.5 hours
Horses & Acyclovir → age differences w/ Tx differences, & w/ what Dz?Usually in horses you need to Tx equine Herpes virus w/ Valacyclovir (the prodrug). In equine neonatal Herpesvirus infxns, you are able to Tx w/ Acyclovir, bc their tight jxns in their GI arent totally closed so more Acyclovir gets in (no gut closure yet)
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 & influenza A/B, & others.
Ribavirin works how?(A polymerase inhibitor, but it's unique in that it inhibits RNA & DNA) - inhibits replication of a wide variety of viruses (DNA & RNA), w/ multi sites of actions (long notes say: The drug is activated by viral phosphorylation & subsequently inhibits the formation of mRNA & replication of the viral genome. The actions involve specific inhibition of virus associated enzymes, inhibition of capping of viral mRNA & 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 & dogs
Key note: Antiviral therapy for Herpesvirus infxns → Pyrimidine nucleosides (do what? What are the 3 main drugs in this category & the subtypes of the 1?)Inhibition of viral DNA polymerase. (1) Idoxuridine
(2) Trifluridine
(3) Sorivudine (phosphorylation by viral enzymes: Thymidine & thymidylate kinases)(I'd tri pyrim sorority thys) (I'd try prime sorority thighs)
Key note: Antiviral therapy for Herpesvirus infxns → 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 (Gan's pure-ace rib grilling video penetrated the web)
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Recombinant interferon stuff (interferons made for any sort of viral infxn!)

Question Answer
The recombinant interferons are different types of _________ interferonOmega
What are the 3 properties recombinant interferons have?Antiviral, immune modulating, & anticancer properties
How do interferons act as antivirals (how does it work?)Anti-viral by promoting the synthesis of enzymes that interfere w/ viral replication (protein synthesis & degradation of viral RNA)
How is it that a little interferon goes a long way?Cell-cell interaction converts antiviral effects w/o additional interferon (you can xfer/share the enzymes w/o xferring the interferon bc there is cell-cell contact!)
Interferons in CATS Tx which Dzs? (3)FeLV, FIP, FIV
Interferons in DOGS Tx what Dz? (1)CPV-2 (parvovirus)
Interferons in BOVINE Tx which Dzs? (2)Vaccinia (Bovine smallpox), IBR (infectious Bovine rhinotracheitis)
Interferons in EQUINE Tx which Dzs? (2)EHV-1 (Equine Herpes virus), inflammatory airway dz
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Against influenza viruses (A or A/B)

Question Answer
M2-ion channel inhibitors (inhibitors of coat disassembly) → explain exactly what is meant by this (what is the virus doing, how does this work?)Virus comes over to cell, & 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 & then they are released to go & 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 hemagglutinin attaches to host Neuraminic acid
What are the 2 M2-ion channel inhibitors drugs?Amantadine & 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 Rimantadine)
Which drug is useful for equine influenza?****TQRimantadine (rim is also safer than Amantadine)
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 Amantadine? Why? Specifics/species?For Tx of PAIN! It is an NMDA antagonist (like ketamine). Czs relief of pain symptoms, can be combined w/ NSAIDs, & is well tolerated in dogs
What are the Neuramidase/Sialidase inhibitors? (2)Zanamivir & Oseltamivir
What are the applications of Zanamivir & Oseltamivir?No info on use in animals avail. It was made to Tx "Mexican/swine flu"
Ribavirin is effective against what?Herpes & influenza A/B, & others
Ribavirin works how?Inhibits replication of a wide variety of viruses (DNA & RNA), w/ multi sites of actions (long notes say: The drug is activated by viral phosphorylation & subsequently inhibits the formation of mRNA & replication of the viral genome. The actions involve specific inhibition of virus associated enzymes, inhibition of capping of viral mRNA & 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 & dogs
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By type (the red 1s are the 1s 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, BLV
Viral DNA polymerase inhibitors (DPI) - what drugs are in this category? Indications?Acyclovir/Valacyclovir
Idoxuridine
Ribavirin
Trifluridine
Foscarnet
Indications = Herpes virus infxns, (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 & 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)
Interferons in CATS Tx what Dz? FeLV, FIP, FIV
Interferons in DOGS Tx what Dz? CPV-2 (parvovirus)
Interferons in BOVINE Tx which Dzs? Vaccinia (Bovine smallpox), IBR (infectious Bovine rhinotracheitis)
Interferons in EQUINE Tx which Dzs? EHV-1 (Equine Herpes virus), inflammatory airway dz
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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 & 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 multi 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 & DNA)
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