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Pharmacology Test 3 > Anti-HIV Drugs > Flashcards

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
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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
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3
Q

Fostemsavir is a prodrug which is metabolized to

A

temsavir

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4
Q

Fostemsavir is cleared by

A

CYP3A4

- be aware of co-administration with CYP3A4 inducers

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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
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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
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7
Q

Reverse Transcriptase

A
  • contains both the RT and RNAase activities

- crystal structure that resembles a hand

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8
Q

Where does building occur on nucleosides

A

3’OH

- if no 3’OH can’t continue chain elongation

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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
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10
Q

Emtricitabine (FTC)

A
  • fluorinated analog of lamivudine
  • long t1/2
  • no clinically significant drug-drug p450 interations
  • pill 1x a day
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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
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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
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13
Q

Systemic use of Tenofovir Desoproxil

A
  • can cause nephrotoxicity

- can decrease bone mineral density

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14
Q 
Tenofovir Disoproxil (TDF)
Resistance
A
  • develops slowly

- drug retains activity even with resistance to other NRTIs

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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
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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
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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
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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
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19
Q

NRTIs

Resistance

A
  • ## due to mutations in RT active site, EACH NRTI HAS UNIQUE PROFILE OF RESISTANCE MUTATIONS
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20
Q

Which NRTI develops resistance more rapidly

A

Lamivudine

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21
Q

non-NRTI

A

doravirine

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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
Q

non-NRTIs

Mechanistic Details

A
  • non-NRTIs bind adjacent to RT active site, preventing conformational changes that are required for TR activity
  • does not require cellular activation (phosphorylation)
26
Q

non-NRTIs

Pharmacodynamics

A
  • diffuses into cells
27
Q

non-NRTIs

Resitance

A
  • resistance develops rapidly

- NNRTIs always prescribed in combination with other drugs

28
Q

non-NRTIs

Metabolism

A
  • NNRTIs interactive with P450 CYP3A4 and either inhibit or induce P450 activity
  • adjunct dose of other drugs in metabolic pathway
29
Q

Fostemsavir

A

Viral Entry Inhibitors

Virus Targeting

30
Q

Ibalizumab

A

Viral Entry Inhibitors

Human Targeting

31
Q

Emtricitabine

A

Reverse Transcriptase Inhibitors

Nucleoside

32
Q

Tenofovir Desoproxil

A

Reverse Transcriptase Inhibitors

Nucleoside

33
Q

Tenofovir Alafenamide

A

Reverse Transcriptase Inhibitors

Nucleoside

34
Q

Doravirine

A

Reverse Transcriptase Inhibitors

Non- Nucleoside

35
Q

Bictegravir

A

Viral Integrase Inhibitors

36
Q

Darunavir

A

Protease Inhibitors

37
Q

Active site of HIV integrase bound by DNA

Drug Bound

A
  • drug binds Mg2+ and displaces terminal nucleotide from active site
38
Q

Bictegravir

A
  • 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
Q

HIV Protease Dimer Bound by Drug

A
  • 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
Q

Aspartyl Acid Proteases

Proteolysis and Inhibition

A
  • 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
Q

Darunavir

A
  • touch fewer but most important active site features
  • resist mutation issues
  • binds with higher affinity than old PIs
  • mimics substrate shape = smaller
42
Q

Darunavir Adverse Effects

A
  • typical of other PIs
43
Q

Darunavir

Pharmacodynamics

A
  • highly bound by plasma proteins
  • inhibitor and substrate of CYP3A
  • orally 2x daily
44
Q

Singles tablet treatment of HIV

Symutza

A
  • daunavir
  • cobicistate
  • emtricitabine
  • tenofovir alafenamide
45
Q

Protease Inhibitors

Efficacy

A
  • when combined with NRTIs, HIV drops below detectable limit in most cases
  • failures due to poor patient compliance
46
Q

Protease Inhibitors

Resistance

A
  • due to mutations in HIV protease
47
Q

Protease Inhibitors

Pharmacodynamics

A
  • 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
Q

Protease Inhibitors

Drug Interactions

A
  • many due to interactions with P450/CYP3A4
49
Q

Protease Inhibitors

Adverse Effects

A
  • 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
Q

Why Multidrug Therapy

A
  • 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
Q

When coformulating drugs seek the following parameters

A
  • few overlapping toxicities
  • no overlapping resistance profiles
  • comparable pharmacokinetic parameters
52
Q

Pre-exposure Prophylaxis

A
  • Truvada

- non-infected individuals within populations at high risk

53
Q

Post-Exposure Prophylaxis

A
  • take 3 anti-HIV drugs within 72 hours of exposure for 28 days
    (raltegravir + emtricitabine/tenofovir)

Pharmacology Test 3 (9 decks)

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