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Therapeutics P3 Spring > Exam 4 lecture 4 > Flashcards

Exam 4 lecture 4 Flashcards

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1
Q

What drug blocks attachment and entry of virus into cell

A

Enfuviritide
Maravoric

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2
Q

What drug targets reverse transcription of HIV

A

Nucleoside RT inhibitors
non- nucleoside RT inhibitors

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3
Q

What Anti HIV drug targets Integrase

A

Raltegavir

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4
Q

What drugs target the maturation of HIV drugs

A

Protease inhibitors

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5
Q

What is the use of integrase

A

inserts the HIV DNA into the hosts chromosome

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6
Q

What are the 3 activities of RT

A

RNA dependent DNA polymerase (uses RNA to make DNA)

Ribonuclease H activity (chops up RNA)

DNA depndent DNA polymerase activity (makes complementary strand from synthesized DNA)

  • copies plus strand RNA to produce minus strand DNA
  • Degrades RNA template from RNA-DNA hybrid
  • synthesizes plus strand DNA from minus strand DNA template
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7
Q

What are NRTIs? What are their2 effects?

A

NRTIs are nucleoside analogs that lack the 3’ OH

Two effects
- competitive inhibitor of reverse transcriptase
-DNA chain terminator - inhibit elongation

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8
Q

What do we use NRTIs in combo with

A

2 NRTIs plus NNRTI or PI or integrase inhibitor

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9
Q

what are NRTI combos that work best

A

Tenofovir and emtricitabine

Abacavir and lamivudine

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10
Q

what is a characteristic shared by all NRTIs?

A

all must be activated by cellular kinase to triphosphate form

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11
Q

name NRTIs

A

abacavir
tenofovir
emtricitabine
lamivudine

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12
Q

what enzymes activate NRTIs

A

use cellular enzymes

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13
Q

How is tenofovir different from tenofovir alafenamide

A

Activated by different pathway than previous tenofovir drugs

Increased accumulation in lymphocytes, fewer side effects

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14
Q

What can be a negative about tenofovir alafenamide (TAF)? positive?

A

negative- TAF is associated with higher lipid levels compared to other tenofovir drugs.

Positive- Better accumulation in lymph nodes and higher intracellular concentration (reduced renal damage)

different activation pathway to TAF allows for 10x lower dose compared to other Tenofovir

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15
Q

Tenofovir alafenamide activation

A

It is stable in the plasma, TAF turns into tenofovir diphosphate in HIV cells or infected cells.

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16
Q

What are NRTIs competing with

A

dATP, d CTP, d GTP and dTTP

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17
Q

Do NRTIs have higher affinity to GIV RT or cellular DNA polymerase

A

HIV RT

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18
Q

What must happen to TAF before phosphorylation?

A

TAF must be processed to TFV by cellular enzymes

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19
Q

how many phosphorylations does tenofovir require?

A

2

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20
Q

Why do resistance mutations arise so quickly for HIV

A

-HIV polymerase is error prone
-RT inhibitors unable to suppress viral replication
- large amounts of virus present

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21
Q

What are the two types of resistance mutations seen with resistance to NRTIs

A
  1. discriminatory mutations
    - mutations that selectively impair the ability of reverse transcriptase to incorporate analogues into DNA
  2. Excision mutations
    - ATP molecule mediates the removal of a nuceoside analogue after it has been incorporated
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22
Q

Where do most mutations to NRTIs occur

A

near RT active site

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23
Q

What can mutations against NRTIs do?

A

Help RT to distinguish between normal dNTPs and NRTIs

Promote removal of NRTIs after they have been incorporated into the growing chain

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24
Q

Do NRTIs have high or low barrier of resistance? WHat does that mean?

A

NRTIs have a low barrier of resistance.

High risk of mutations

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25
adverse effects of NRTIs
Mitochondrial toxicity - Anemia, granulocytopenia, myopathy, neuropathy and pancreatitis
26
abacavir black box warning? What genes are linked with them?
Abacavir HS rxn, Highly associated with HLA B 5701 in needed before initiating tx
27
Where do NNRTIs bind (Nonnucleoside RT inhibitors)? Competitive or noncompetitive inhibitors?
Directly to site on RT? Do not compete with nucleotides for binding (non competitive)
28
do NNRTIs have to be phosphorylated?
no
29
WHat do NNRTIs block?
block RNA and DNA dependent DNA polymerase activity (blocks polymerization)
30
Name 1st gen NNRTIs? Side effects
Nevirapine Efavirenz Delaviridine CNS side effects Potentially teratogenic
31
Name second gen NNRTIs
Etravirine Rilpivirine
32
Why is there less chance at resistance with second gen NNRTIs
Designed to be inherently flexible. Can bind in multiple orientations
33
adverse effects of NNRTIs
Rash Drug-drug interactions (CYP 450) nevapirine- hepatotoxicity or SJS Efavirenz- teratogenic and neuropsychiatric
34
DO NNRTIs bind to cellular DNA polymerases? How many mutations can confer NNRTI resistance? Do NNRTIs and NRTIs share common resistance mutations?
Do, NNRTIs do not bind to cellular DNA polymerase Resistance to NNRTIs can be acquired through single mutation Mutations that confer resistance to NNRTIs do not cause resistance to NRTIs
35
What do integrase inhibitors (INI) do??
Inhibit insertion of HIV DNA into the human genome
36
Common side effects with INI
N/V/D compatible with other antiretroviral drugs due to favorable interaction profile
37
INI drug drug interactions
SOme interact with CYP450
38
What are the 2 steps to INI
3' processing string transfer- incorporation of HIV strand into host chromosome
39
name integrase inhibitors
Raltegavir Elvitegravir Dolutegravir Bictegravir
40
what is integrase inhibitor resistance caused by
Caused by primary mutations that reduce INI susceptability
41
WHat is special in the way elvitegravir is formulated
Co formulated with cobicistat (COBI) this is because it is metabolized by CYP3A4
42
What is the use of cobicistat
Formulated with elvitegravir to boost its concentrations by inhibiting metabolism by CYP3A4
43
What are things about dolutegavir that we should know (interactions, boosting and barrier for resistance)
No boosting required and no interactions with CYP3A4. Higher barrier for resistance
44
things to know about bictegravir (resistance, drug interactions)
low risk of resistance and few drug interactions. Can not be used with rifampin Raises Scr levels 0.1
45
Which drug can be started without HLA B 5701 testing testing
Bictegravir
46
What type of protease is HIV protease. How is it activated
aspartic acid in active site Dimer- active site formed at interface
47
How do HIV protease inhibitors act
HIV protease inhibitors are transition state mimetics (peptidomimetic) amide bond is replaced by non-cleavable linkages
48
Which drug is the only protease inhibitor that is not a peptidomimetic
Tipranavir
49
what happens when HIV protease inhibitors bind to protease
Protease flaps to closed conformation
50
What is notable about protease inhibitor and interactions
ALL are substrates and some are inhibitors of CYP3A4
51
What are things we can do to boost protease inhibitors (PK enhancement)
Low doses of rotinavir inhibit CYP3A4 blocks metabolism of other PIs
52
How does low doses of ritonavir affect PIs? Advantage vs disadvantage
advantage- increases serum concentrations and blocks metabolism of PIs by inhibiting CYP3A4. disadvantages- Drug-drug interctions with ritonavir and increased risk of hyperlipidemia
53
Name protease inhibitors? most potent of all?
Atazanavir (most potent after darunavir) Darunavir (preferred PI for initial antiretroviral) Tipranavir
54
What two drugs reduce atazanavir levels
Efavirenz and tenofovir
55
What are two unique features of darunavir
makes extensive hydrogen bonds with protease backbone Inhibits HIV protease dimerization
56
What is important to note about darunavir
Peptide backbones of wildtype and mutant HIV protease have similar structures so darunavir can inhibit both wildtype and mutants
57
What is special about tipranavir
Retains activity against protease in highly treated patients including resistant to DRV Nonpeptidic PI
58
tipranavir drug ia
CYP3A4
59
Describe the resistance to protease inhibitors
Highest genetic barrier of antiretrovirals
60
what two drugs retain activity against most PI resistant mutant proteases
darunavir and tipranavir
61
adverse effects of PI
hyperlipidemia drug dfrug i/a (cyp3A4)
62
Name two long acting injectable therapies for HIV
Cabotegavir (INI) and rilpivirine (NNRTI)
63
Where are HSV1 common? Where are HSV2 common?
HSV 1 is common in oral mucosa HSV 2 is common in genital mucosa
64
describe HSV1 and HSV2
HSV 1- cold sore, transferred viral oral secretions. first episodes can systemic side effects (fever, body aches etc) Re occurance can start with tingling or burning sensation where sore will form prodrome) HSV 2- genital/anus transferred via infected secretions. Prodrome is there for this one as well.
65
which HSV mostly causes HSV encephalitis
HSV 1
66
Name drugs that are used for HSV
Acyclovir Valacyclovir famciclovir
67
MOA of acyclovir? elimination?
Prodrug actively converted to acyclovir triphosphate. Acyclovir TP competitively inhibits viral DNA polymerase to inhibit viral replication. Also incorporated into viral DNA to cuase premature chain termination renally eliminated
68
adverse effects of acyclovir
N/V/D nephro (important)
69
Dose for acyclovir for HSV encephalitis
10 mg/kg IV q8hr for 14-21 days (adjusted body weight)
70
MOA of valacyclovir
Prodrug of acyclovir. (Same MOA, adverse effects and spectrum)
71
MOA of famciclovir
Prodrug of penciclovir, converted to active form via triphosphorylation. Linear kinetics
72
What is the drug of choice for variclla zoster
Acyclovir or valacyclovir
73
Drug of choice for cytomegalovirus (CMV)
ganciclovir
74
MOA of ganciclovir
The drug is a pro drug trned into the active form by thymidine kinase
75
Describe how resistance can develop in ganciclovir
Resistance can develop via a UL97 gene mutation, leading to viral kinase deficiency
76
Ganciclovir adverse effects
Bone marrow suppression (reversible)
77
How to treat CMV retinitis, esophagitis, colitis, pneumonitis and prevention of CMV in bone marrow
Ganciclovir
78
Describe valganciclovir? Toxicity and MOA? Elimination?
Pro drug of ganciclovir, more bioavailable Adverse effects same as ganciclovir (hematologic toxicity) Counsel to take with food
79
use of valganciclovir
CMV retinitis and prevention of CMV disease in transplant patients at high risk
80
letermovir MOA
inhibits the pUL56 subunit of CMV, prevents cleavage ofDNA, resulting in inhibition of CMV replication and prevention of CMV infection
81
letermovir use
Prophylaxis of CMV infection in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT)
82
What are some letermovir drug interactions
CYP 3A4 substrate (A LOT of interactions) Azole, statin, warfarin
83
Foscarnet MOA
Does not require phosphorylation (is not a pro drug) and it directly inhibits viral DNA polymerase
84
Use of foscarnet
last line against drug resistant HSV, VZV and CMV
85
Foscarnet adverse effects
Nephrotoxicity
86
Name neuraminidase inhibitors used in influenza (flu)
Zanamivir (dry powder inhallation) Oseltamivir Peramivir (IV)
87
Oseltamivir MOA, excretion and adverse effects
Prodrug Renally dose adjusted N/V/D
88
Who do we give oseltamivir to
symptomatic for no more than 2 days. (same with zanamivir) Prophylaxis of influenza inpts >1
89
zanamivir adverse effects
Brochospasms
90
use of baloxavir marboxil
Used for flu in 12 and older, not used if symptomatic for more than 48 hrs
91
Drug of choice in CMV
ganciclovir and vanganciclovir
92
Drug of choice in VZV
Acyclovir and valacyclovir
93
Drug of choice in HSV 1/2
acyclovir/valacyclovir
94
WHat drug is used for flu B
Zanamivir

Therapeutics P3 Spring (33 decks)

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