Anti-HIV Drugs Flashcards
1
Q
Viral Entry Sequence of Events
A
- CD4 changes cause GP120 changes
- GP120 binds coreceptor CCR5 or CXCR4
- GP120 releases GP41 and becomes open
- Virus and enter cell
2
Q
Fostemsavir
A
- for multi-drug resistant HIV who fail other treatment protocols
- fostemsavir -> temsavir
- temsavir binds gp120 PREVENTING conformational changes in GP120 necessary to bind CD4
- – locks GP120 in place; can’t release
- pill taken 2x a day
- taken with other anti-HIV drugs
3
Q
Fostemsavir is a prodrug which is metabolized to
A
temsavir
4
Q
Fostemsavir is cleared by
A
CYP3A4
- be aware of co-administration with CYP3A4 inducers
5
Q
Ibalizmab
A
- for multi-drug resistant HIV who fail other treatment protocols
- CD4 receptor distorts when bound by gp120– this creates an epitope of CD4 that is recognized by the antibody
- the drug-bound CD4-GP120 complex cannot dock with either co-receptor (CXCR4 or CCR5) = viral entry is blocked
- ** only binds when CD4 is bound to viral protein; DOESNT EFFECT NORMAL CD4 ACTIVITY! ***
- IV infusion every 14 days
- taken with other anti-viral drugs
6
Q
Conversion of RNA genome to a DNA copy by Reverse Transcriptase
A
- RT and all other polymerases that create DNA strands must work off a free 3’ hydroxyl end
- tRNA serves as 3/ hydroxyl primer
- RNA is degraded as first DNA strand is synthesized
- Final bit of RNA is left to serve as primer for second DNA strand synthesis
- double stranded HIV DNA genome is integrated into host genome
7
Q
Reverse Transcriptase
A
- contains both the RT and RNAase activities
- crystal structure that resembles a hand
8
Q
Where does building occur on nucleosides
A
3’OH
- if no 3’OH can’t continue chain elongation
9
Q
NRTIs
Nucleoside Reverse Transcriptase Inhibitors
A
- prodrugs: lack phosphates necessary for DNA synthesis
- enter cell and then are converted to triphosphates by host enzymes
- – phosphorylation traps drug inside cell
10
Q
Emtricitabine (FTC)
A
- fluorinated analog of lamivudine
- long t1/2
- no clinically significant drug-drug p450 interations
- pill 1x a day
11
Q
Tenofovir Disoproxil (TDF)
A
- synthetic adenosine analog with a P
- – presence of first P overcomes rate limiting phosphorylation step within cells
- nucloTIDE RT inhibitor
- protective groups stripped in plasma before transport into cells
12
Q
Tenofovir Disoproxil (TDF) Acts
A
- competes with dATP for binding HIV RT and then CHAIN TERMINATES
- interacts little with P450s; few drug-drug interactions
13
Q
Systemic use of Tenofovir Desoproxil
A
- can cause nephrotoxicity
- can decrease bone mineral density
14
Q
Tenofovir Disoproxil (TDF) Resistance
A
- develops slowly
- drug retains activity even with resistance to other NRTIs
15
Q
Tenofovir Alafenamide (TAF)
A
- ** protecting groups stay on until inside cells = can give less drug because faster entry into cells ***
- less bone and kidney toxicity than tenofovir disoproxil, but higher lipid levels
16
Q
NRTIs
Mechanistic Details
A
- Acts as suicide substrates by poisoning RT chain elongation
- Drugs bind the active site of the HIV RT
- Selectivity because drugs do not bind well to nuclear DNA polymerases
- Drugs prevent acute infection by have little effect on infected cells
17
Q
NRTIs
Pharmacodynamics
A
- taken orally and generally well absorbed from GI
- NRTIs are prodrugs that must be triphosphorylated by cytoplasmic enzymes
- T1/2 is usually extended by transport into cell and subsequent phosphorylation
18
Q
NRTIs
Adverse Reactions
A
- can poison mitochondrial polymerases, which can lead to potentially fatal lactic acidosis
- each NRTI also has intrinsic side effects
19
Q
NRTIs
Resistance
A
- ## due to mutations in RT active site, EACH NRTI HAS UNIQUE PROFILE OF RESISTANCE MUTATIONS
20
Q
Which NRTI develops resistance more rapidly
A
Lamivudine
21
Q
non-NRTI
A
doravirine
22
Q
Doravirine
A
“STRATEGIC FLEXIBILITY”
- designed to retain high binding affinity with only minimal contacts = drug works in mutated binding pockets
23
Q
Doravirine
general advantages over older NNRTIs
A
- once daily dosing
- minimal side effects
- effective at lower concentrations than other NNRTIs
- different resistance profile
24
Q
Doravirine
drug-drug interactions
A
eliminated by CYP3A4
25
non-NRTIs
| Mechanistic Details
- non-NRTIs bind adjacent to RT active site, preventing conformational changes that are required for TR activity
- does not require cellular activation (phosphorylation)
26
non-NRTIs
| Pharmacodynamics
- diffuses into cells
27
non-NRTIs
| Resitance
- resistance develops rapidly
| - NNRTIs always prescribed in combination with other drugs
28
non-NRTIs
| Metabolism
- NNRTIs interactive with P450 CYP3A4 and either inhibit or induce P450 activity
- adjunct dose of other drugs in metabolic pathway
29
Fostemsavir
Viral Entry Inhibitors
| Virus Targeting
30
Ibalizumab
Viral Entry Inhibitors
| Human Targeting
31
Emtricitabine
Reverse Transcriptase Inhibitors
| Nucleoside
32
Tenofovir Desoproxil
Reverse Transcriptase Inhibitors
| Nucleoside
33
Tenofovir Alafenamide
Reverse Transcriptase Inhibitors
| Nucleoside
34
Doravirine
Reverse Transcriptase Inhibitors
| Non- Nucleoside
35
Bictegravir
Viral Integrase Inhibitors
36
Darunavir
Protease Inhibitors
37
Active site of HIV integrase bound by DNA
| Drug Bound
- drug binds Mg2+ and displaces terminal nucleotide from active site
38
Bictegravir
- once a day combo pill
- -- also contains tenofovir alafenamide and emtricitabine (2 reverse transcriptase inhibitors, 1 integrase inhibitor)
- drug binds Mg2+ and displaces terminal nucleotide from active site
- recommended for treatment-naive patients, as well as an alternative for patients who are effectively treated by other regimes
- little resistance seen so far
- few drug-drug interactions
- -- is a CYP3A4 substrate
39
HIV Protease Dimer Bound by Drug
- each subunit of the protease dimer contributes an aspartic acid to form the catalytic site
- human aspartic acid proteases function as monomers and thus evade viral protease inhibitors
- HIV protease cleaves polyproteins into separate enzymes (RT, protease, integrase) and structural proteins
- the protease recognizes the common shape of cutting sites, not the sequence
40
Aspartyl Acid Proteases
| Proteolysis and Inhibition
- all are transition state analogs with a hydroxyl group and a F mimic
- stabilize transition state = relaxes and breaks
- all bind reversible
- -- EARLIER INHIBITORS FILLED THE ENTIRE ACTIVE SITE POCKET
- no cross reaction with human proteases
41
Darunavir
- touch fewer but most important active site features
- resist mutation issues
- binds with higher affinity than old PIs
- mimics substrate shape = smaller
42
Darunavir Adverse Effects
- typical of other PIs
43
Darunavir
| Pharmacodynamics
- highly bound by plasma proteins
- inhibitor and substrate of CYP3A
- orally 2x daily
44
Singles tablet treatment of HIV
| Symutza
- daunavir
- cobicistate
- emtricitabine
- tenofovir alafenamide
45
Protease Inhibitors
| Efficacy
- when combined with NRTIs, HIV drops below detectable limit in most cases
- failures due to poor patient compliance
46
Protease Inhibitors
| Resistance
- due to mutations in HIV protease
47
Protease Inhibitors
| Pharmacodynamics
- administered orally but most have low systemic bioavailability
- metabolized by P450 and CYP3A4 in liver and in intestinal epithelial cells
- substrates for mutlidrug efflux pumps, which limits intracellular concentration
- high binding to plasma proteins
48
Protease Inhibitors
| Drug Interactions
- many due to interactions with P450/CYP3A4
49
Protease Inhibitors
| Adverse Effects
- changes in body fat distribution
- -- "lipodystrophy syndrome" or "pseudo-cushings syndrome"
- hyperlipidemia from interference of PIs with normal lipid metabolism
- worsening glycemic controls in patients w/ pre-existing diabetes, and cases of new onset diabetes
50
Why Multidrug Therapy
- treat drug that fights current virus & drugs that cover possible mutations
- RTs have no editing function and thus are error prone
- single and double mutations occur at alarming rates
- proper therapy requires multiple drugs
- compliance is huge
51
When coformulating drugs seek the following parameters
- few overlapping toxicities
- no overlapping resistance profiles
- comparable pharmacokinetic parameters
52
Pre-exposure Prophylaxis
- Truvada
| - non-infected individuals within populations at high risk
53
Post-Exposure Prophylaxis
- take 3 anti-HIV drugs within 72 hours of exposure for 28 days
(raltegravir + emtricitabine/tenofovir)
