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PHRM 865: Theraputics V > Lecture 20: Antivirals I > Flashcards

Lecture 20: Antivirals I Flashcards

1
Q

What are some viruses sounded by?

Which are enveloped and non-enveloped

A
  • LIPIDS
  • Enveloped: HIV, Flu, Herps, SARS-CoV-2, Filo
  • Non-Enveloped: Picorn, Adeno
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2
Q

What is the generic virus life cycle?

A
  • Viral attectment and entry –> Uncoating –> Synthesis –> transcription –> Assembly –> Release

Each step is blocked by different drug cless

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3
Q

What are the two important parts of a HIV structure?

A
  • gp120: Docking
  • gp41
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4
Q

What are some of the drug class for the Antivirals?

A
  • Entry & Fusion Inhibitors
  • Nucleoside Reverse Transcriptase Inhibitors
  • Non-nucleoside Reverse transcriptase Inhibitors
  • Integrase Inhibitors
  • Protease Inhibitors
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5
Q

What is the Mechanism of action for the HIV entry fusion inhibitors?

Maraviroc? Enfuvirtide?

A
  • Maraviroc: Binds to HUMAN CCR5 and blocks gp120 binding
  • Enfuvirtide: Binds to HIV gp41 and block gp41 changes
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6
Q

What is the HIV Entry Inhibitor?>

A
  • Maraviroc: Will bind to CCR5 preventing gp120 binding [ONLY used in patients with CCR5]
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7
Q

What are some of the potential problems with using Maraviroc?

A
  • Mutants that bind to CXCR4
  • HIV binds to CCR5
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8
Q

What is the HIV Fusion Inhibitor?

A
  • Enfuvirtide [NO FUSION!]
  • ONLY active against HIV-1
  • Blocks the conformation changes = prevntion into the cell
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9
Q

What is some of the resistance toward Enfuviritide?

A
  • Mutantion within the gp41
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10
Q

What are the 3 activities for reverse Transcriptase Inhibitors?

A
  • RNA dependent DNA polymerase [makes DNA from RNA]
  • Ribonyclease H [Chops up RNA]
  • DNA-dependent DNA polymerase [Copies DNA from template]

NRTIs will block the 1st and 3rd one

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11
Q

What is the Mechanism of Action for the Nucleoside RT Inhibitors [NRTIs]?

A
  • Lack 3’ OH = inhibitor of reverse transcriptase & DNA chain terminator [inhibits elongation]

Active toward HIV-1 & -2

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12
Q

What are the NRTIs that are used?

A
  • Zidovudine [T]
  • Stavudine [T]
  • Abacavir [G]
  • Didanosine [A]
  • Tenofovir [A]
  • Zalcitabine [C]
  • Lamivudine [C]
  • Emtricitabine [C]
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13
Q

What are some of the important stuctural things to note about the NRTIs?

A
  • Azidothymidine: N=N=N; stops synthesis
  • Stavudine: = ; stops synthesis
  • Tenofovir: - ; binds enzyme & stops synthesis
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14
Q

What is the one things that must happen to the NRTIs?

A
  • MUST be phosphorlyated
  • Thymidine Kinase = 1 P
  • Thymidylate Kinase = 2 P
  • NDP Kinase = 3 P
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15
Q

What is important to know about Tenofovir?

A
  • Tenofovir Disoproxilfumarate = Prodrug
  • Only needs 2 phos; wierd carboxyl group protects it

The phos CANNOT be cleaved by cellular esterases

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16
Q

What are some of the advantages of Tenofivr?

A
  • LONG half life [slows down any mutations that occurs]\
  • Highly selective for HIV RT over human & mito
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17
Q

What are some of the problems for Tenofovir disoproxilfumarate [TDF]?

A
  • Plamasa Esterases: TDF –> TFV
  • TFV is eliminated in the Kidney
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18
Q

What is Tenofovir Alafenamide [TAF]?

A
  • Alternative Tenofovir Prodrug; activated differently
  • Lower conc., less side effects,. higher lipid levels
  • Maybe better targeting [better in lymph & higher intra conc]
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19
Q

What are some of the things that TAF might be better at then TDF?

A
  • Targeting HIV; better accumlation in lymph & higher intracellular conc
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20
Q

What is the way that TAF is converted into TFV?

A
  • TAF contains Phenol and alaine isopropyl ester to masks the chrage on the phosphonates
  • Increase delivery and decrease toxicitiy
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21
Q

What are some of the important things to note with summarizing NRTI Activation?

A
  • MUST be activited to their triphos form by cellular Kinases
  • Different kinases add the 2 & 3 phos
  • Different nucleodies require different kinases
  • NRTIs compete with dATP, dCTP, dGTP, and dTTP
  • Some are inhibited by DNA Po;ymerase
  • Tenofovir requires 2 phos steps
22
Q

What are some of the ways that their is resistance to anti-HIV drugs?

A
  • HIV polymerase is error prone
  • RT Inhibitors unable to suppress by >90%
  • Large amounts of virus
  • decreased drug lebel = increased resistance
24
Q

What are the two specific ways that there is resistance towards NRTIs?

A
  • Discriminartory Mutations: selectively impair the ability of reverse transcriptase into DNA
  • Excision Mutation: ATP removal of analogue; selected by AZT & d4T
25
Q

When talking about the resistance to NRTIs, what are some of the main Key Points?

A
  • Mutations are near the active site
  • Helps distingusih between normal dNTPs or NTRIs & Promote Removal of NRTIs
26
Q

What are some of the adverse effects of the NRTIs?

A
  • Mitochondrial Toxicitiy: anemia, granulocytopeniam myopathy, lactic acidosis
  • Abacavir Hypersenstivity Reations: BLACK BOX –> Malaise, Dizziness, Headache, GI

Abacavir associated with HLA-B*5701

27
Q

What are some of the recommended combination fo NRTIs?

A
  • Tenofovir & Emtracitabine [or lamivudine]: QD, less mutation
  • Abacavir & lamivudiae [or emtracitabine]: If HLA-B*5701
28
Q

When should Antiretoviral medications NOT be offered>

NOT RECOMMENDED

A
  • Monoterapy
  • Dual NRTIs Therapy
  • 3-NRTIs Regimen [maybe abacavir/lamivudine/zidovudine & lamivudine/zidovudine + tenofobir]
29
Q

How do the Nonnucleoside RT inhibitors [NNRTIs] act?

A
  • They Bind to Hydrophobic Pocket, near but distinct from NRTIs
  • NNRTIs do NOT compete wiht nucleotides [noncompetitive]
  • Block RNA- and DNA-dependent DNA polymerase
30
Q

What is the Mechanism of Action for the NNRTIs?

A
  • Will bind NEAR the active site of RT; blocking polymerization
  • Single mutation in binding can promote resistance
31
Q

What are the first generation NNRTIs?

A
  • Nevirapine & Efavirenz
  • Half-life = 40-55h; CNS side effecst, Teratogenic
32
Q

What are the second generation NNRTIs?

A
  • Etravirine & Rilpivirine
  • Diaryl-pyrimidine based; binds in multiple orientations [helps against resistance]
33
Q

What are some of the adverse effects of NNRTIs?

A
  • Rash, Drug Interations
  • Nevirapine: Hepatotoxicity, SJS
  • Efavirenz: Neuropsychiatric, Teratogenic [Preg D]
34
Q

What is the way that the NNRTIs are metabolized?

A
  • ALL by CYP3A
  • Interactions with Rifampin [inducer] = reduced levels & inhibitors = increased levels

Efavirenz, Nevirapine, Etravirine = Inducers
Efavirenz, Delavirdine = Inhibitors 3A4
Etravirine = Inhibitors 2C9 & 2C19

35
Q

What are some of the important things to note about the NNRTIs/

A
  • DO NOT require activiation, compete with dNTP or go into DNA
  • single mutation = resistance
  • NO cross-resistance with NRTIs
36
Q

What are some of the important things to know about the Integrase Inhibitors [INI]?

MOA? AE? Dosage Form? Interaction?

A
  • Inhibits insertion of HIV DNA into the human genome
  • Most commonly causes: Diarrhea, nausea, fatigue, headache, itching
  • Orally Active
  • DOES NOT interact with CYP450
37
Q

What is the main function of Integrase?

A
  • Will inhibit the strand transfer step; stopping HIV from going into cellular DNA
38
Q

What are the Integrase Inhibitors that are used?

A
  • Reltegravir, Elvitegravir, Dolutegravir
39
Q

What are some of the causes for resistance within the Integrase Inhibitores?

A
  • Reduce INI susceptibility
  • Low Genetic Barriers [Dolutegravir higher]
  • Cross Resistance [Dolutegravir less affected]
40
Q

What are some of the important things to note about Elvitegravir?

A
  • Metabolised by 3A4
  • Given with Cobicistat [cobi NOT active against HIV & boosts elvitegravir]
41
Q

What are some of the important things to note about Dolutegravir?

A
  • Long Plasma Half Life = 14h [QD]
  • NO boosting
  • NO 3A4 interations
  • HIGH barrier for resistance
42
Q

What is the mechanism of action for the HIV Protease?

A
  • Peptides bond cleavage is a hydroysis reaction
  • Makes carboxyic acid and amine
43
Q

What is the Mechanism of action for the HIV Protease Inhibitors?

A
  • Amide Bond is replaced by non-cleavable linkage
  • Inhibitor will cause conformaiton change [CLOSED]
44
Q

What is the Metabolism of the Protease Inhibitors?

A
  • ALL are substarates and some are Inhibitors of 3A4
  • Drug interactions; increase levels of other 3A4’s
45
Q

What is important to know about Saquanivir?

A
  • FIRST protease inhibitor
  • Hydroxyethylamine keeps it trapped
  • LOW bioavailabilty
46
Q

What is important to know abuot Ritonavir?

A
  • HIGHER bioavailability
  • MOST POTENT PI inhibitor of 3A4
  • Currently initial treatment
47
Q

What is important to know about Atazanavir?

A
  • QD
  • MOST POTENT protease prior to darunavir
  • Efavirenz & tenofovir reduce ATV conc.
48
Q

What is important to know about Darunavir?

A
  • Preferred PI for Initial antiretroviral combo
  • Extensive Hydrogen bonds
  • Inhibits HIV protease dimerization

BLOCK activity in multiple spots

49
Q

What are some of the initial treatment [preferred regimens] for HAART

INSTI Based

A
  • DTG + ABC/3TC [ONLY if HLA-B 5701 is neg]
  • DTG [QD] + Tenofovir/FTC
  • EVG/COBI + Tenofovir/FTC
  • RAL + Tenofovir/FTC
50
Q

What are some of the initial treatment [Alternative] for HAART?

NNRTI

A
  • Boosted DRV or ATV _ TDF/FTC or ABC/3TC [if HLA-B 5701 is neg]
  • EFV + Tenofovir/FTC
  • RPV + Tenofovir/FTC

PHRM 865: Theraputics V (42 decks)

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