Pharmacology Lecture 36

Front 1

Human immunodeficiency viruses are ________ which are a family of mammalian retroviruses evolved to establish chronic, persistent infection with gradual onset of symptoms

Back 1

lentiviruses

Front 2

Unlike herpesviruses, replication of HIV is _______ following infection so there is no true viral latency following infection

Back 2

constant

Front 3

Humans and _______ are the only known hosts of HIV

Back 3

chimps

Front 4

Most of AIDS epidemic involves which family of HIV

Back 4

HIV-1

Front 5

HAART stands for
*multi drug regimen

Back 5

highly active antiretroviral therapy

Front 6

Five classes of antiretroviral Rx based upon their MOA

Back 6

1. nucleoside and nucleotide RT inhibitors (NTRIs)
2. Non-nucleoside RT inhibitors (NNRITs)
3. Protease inhibitors
4. Entry inhibitors
5. Integrase inhibitors

Front 7

Goal of modern Rx for treatment of HIV infection

Back 7

suppress replication of HIV and restore the number of CD4+ cells to the patient

Front 8

REVERSE TRANSCRIPTASE, converts viral RNA into proviral DNA which is incorporated into host cell chromosome

Back 8

NRTIs
Nucleoside/nucleotide reverse transcriptase inhibitors

Front 9

This class of HIV Rx acts by competitive inhibition of HIV-1 reverse transcriptase
*also HIV-2

Back 9

NRTIs

Front 10

This class of HIV Rx prevent infection of susceptible cells but have NO EFFECT on INFECTED cells

Back 10

NRTIs

Front 11

MOA of this class of HIV Rx:

Enter cell→ require phosphoryation to triphosphate analog →block viral replication by
1) competitively inhibiting incorporation of native nucleotides and
2) by terminating elongation of nascent proviral DNA as they lack a 3’-hydroxyl group.

Back 11

NRTIs

Front 12

Typical resistance mutations of this HIV Rx class include mutations in M184V, L74V, D67N and M41L

Back 12

NRTIs

Front 13

Abacavir, Didanosine, Tenofovir, Zidovudine, Stavudine and Lamivudine are all considered to be in this class of HIV Rxs

Back 13

NRTIs

Front 14

This class of HIV Rxs include adverse events that may be associated with MITOCHONDRIAL TOXICITY which leads to the inhibition of mitochondrial DNA polymerase γ

Back 14

NRTIs

Front 15

This class of HIV Rxs are highly selective competitive inhibitors of HIV-1 reverse transcriptase but LACK activity against HIV-2

Back 15

NNRTIs

Front 16

MOA for this class of HIV Rxs:
Bind DIRECTLY to HIV-1 reverse transcriptase at the site adjacent to the active site which induces CONFORMATIONAL CHANGE resulting in allosteric enzyme inhibition

Back 16

NNRTIs

Front 17

Do NNRTIs require phosphorylation to be active, like NRTIs?

Back 17

NO

Front 18

Do NNRTIs compete with nucleoside triphosphates, like NRTIs?

Back 18

NO

Front 19

A major advantage to this class of HIV Rx is the lack of effect on host blood forming elements and lack of cross resistance with other class

Back 19

NNRTIs

Front 20

Mutations in K103N and Y181C confer resistance across the entire class of which HIV Rxs

Back 20

NNRTIs

Front 21

Do NNRTIs have cross reactivity with NRTIs?

Back 21

NO

Front 22

Resistance to this class of HIV Rxs occurs rapidly with mono therapy and can be due to a single mutation

Back 22

NNRTIs

Front 23

Adverse effects of this class of HIV Rxs include a high incidence of SKIN RASH and varying levels of GI intolerance

Back 23

NNRTIs

Front 24

NNRTIs are metabolized by ______ causing numerous DDIs

Back 24

CYP450s

Front 25

All NNRTIs are substrates for CYP3A4 and can act as _______, _________ or _______

Back 25

inducers (nevirapine), inhibitors (delavirdine) or mixed inducers/inhibitors (efavirenz, etravirine)

Front 26

During the later stages of HIV growth cycle, the ____ and ___-___ genes are translated into polyproteins causing immature budding particles

Back 26

gag and gag-pol genes

Front 27

Virus ASPARATYLl protease cleaves precursor molecules leading to the final structural proteins of the mature virion core... associated with which class of HIV Rxs

Back 27

protease inhibitors

Front 28

This class of HIV Rxs are peptide-like compounds that competitively inhibit the enzyme and prevent the post-translational cleavage of Gag and Pol polyproteins (which prevents the processing of viral proteins into functional form and leads to the production of immature, non-infectious viral particles)

Back 28

protease inhibitors

Front 29

Gag, Gag-pol and Asparatyl protease are all involved in what HIV Rx MOA

Back 29

protease inhibitors

Front 30

This class of HIV Rxs are active against both HIV-1 and HIV-2

Back 30

protease inhibitors

Front 31

MOA for this class of HIV Rx:
Competitively inhibit the viral ASPARATYL protease enzyme that cleaves the precursor molecules which lead to mature virions BY PREVENTING the post-translational cleavage (by viral asparatyl protease) of Gag and Pol polyproteins, stopping the production of mature virions

Back 31

protease inhibitors

Front 32

Resistance to this class of HIV Rxs is common with mono therapy and occurs as an accumulation of stepwise mutations in the protease gene

Back 32

protease inhibitors

Front 33

Adverse effects of this class of HIV Rxs include a syndrome of redistribution and accumulation of BODY FAT (central obesity, lipodistrophy, "BUFFALO HUMP", cushings-like symptoms usually associated)

Back 33

protease inhibitors

Front 34

This class of HIV Rxs has an adverse effect of possible association with bone loss and increased bleeding in hemophiliacs

Back 34

protease inhibitors

Front 35

Are DDIs a significant problem in protease inhibitors? Why or why not?

Back 35

Yes they are a significant problem, because they are extensively metabolized by CYP3A4

Front 36

1. Binding of the viral envelope glycoprotein complex gp160 (gp 120 + gp 41) to it’s receptor, CD4.
2. Binding induces conformational change in gp120→access to chemokine co-receptors, CCR5 or CXCR4.
3. Co-receptor binding induces further conformational changes in gp120→allows exposure of gp41 → fusion of viral envelope w/host cell membrane → entry of viral core into the cellular cytoplasm.
This is the process of what

Back 36

viral attachment to the host cell

Front 37

This HIV Rx entry inhibitor is a 36 amino acid peptide that binds to GP41 and inhibits its function-->inhibits conformational changes

Back 37

ENFUvirtide
(ENtry/FUsion inhibitor)

Front 38

This HIV Rx entry inhibitor is a CCR5 ANTAGONIST that blocks binding of GP120 to CCR5 which prevents fusion events required for viral entry

Back 38

Maraviroc

Front 39

Resistance to this HIV Rx entry inhibitor can occur as result of mutation in GP41 CODONS, however LACKS cross-resistance with other antiretroviral Rx

Back 39

Enfuviritide

Front 40

Resistance to this HIV Rx entry inhibitor is associated with 1+ mutations in the V3 LOOP of GP120 and there is NO CROSS RESISTANCE with other HIV Rx

Back 40

Maraviroc

Front 41

Adverse effects with this HIV entry inhibitor are injection site rxns, hypersensitivity rxns (rate) and increased risk of pneumonia

Back 41

Enfuviritide

Front 42

Adverse effects with this HIV entry inhibitor are cough, muscle and joint pain, and sleep disturbances

Back 42

Maraviroc

Front 43

This is a viral enzyme involved in final integration of viral DNA into host cell DNA
*VITAL STEP in retroviral replication, blocking it can stop further spread of HIV-1 and 2

Back 43

Integrase viral enzyme

Front 44

This drug, an HIV Rx integrase inhibitor, binds to and inhibits viral integrase

Back 44

Raltegravir

Front 45

Resistance to this integrase inhibitor occurs with mono therapy or a single point mutation at codons 148 or 155

Back 45

Raltegravir

Front 46

Adverse effects of this integrase inhibitor include GI upset and headache

Back 46

Raltegravir

Front 47

This integrase inhibitor is metabolized via UGT1A1-mediated glucuronidation so it does NOT interact with CYP450 enzymes... leading to DDIs with drugs that are strong inducers or inhibitors of UGT1A1

Back 47

Raltegravir

Front 48

Raltegravir, an integrase inhibitor, is metabolized by what

Back 48

UGT1A1-mediated glucuronidation

Front 49

These may bind integrase inhibitors and alter activity... antacids should be used with caution

Back 49

polyvalent cations like Magnesium and Calcium

Front 50

This step of viral replication is blocked by:
enfuviridie (HIV), maraviroc (HIV), docosanol (HSV), and palivizumab (RSV)

Back 50

viral attachment and entry/fusion

Front 51

This step of viral replication is blocked by:
interferon-alfa (HBV, HCV)

Back 51

penetration

Front 52

This step of viral replication is blocked by:
amantadine and rimantadine (influenza)

Back 52

uncoating

Front 53

This step of viral replication is blocked by:
NRTIs (HIV), NNRTIs (HIV), acyclovir (HSV), foscarnet (CMV-HSV) and entecavir (HBV)

Back 53

nucleic acid synthesis

Front 54

This step of viral replication is blocked by:
protease inhibitors (HIV)

Back 54

late protein synthesis and processing

Front 55

This step of viral replication is blocked by:
neuraminidase inhibitors-zanamivir and oseltamivir (influenza)

Back 55

packaging and assembly

Front 56

This step of viral replication is blocked by:
NRTIs (HIV), NNRTIs (HIV), acyclovir (HSV), foscarnet (CMV-HSV) and entecavir (HBV)

Back 56

nucleic acid synthesis

Front 57

This step of viral replication is blocked by:
protease inhibitors (HIV)

Back 57

late protein synthesis and processing

Front 58

This step of viral replication is blocked by:
neuraminidase inhibitors-zanamivir and oseltamivir (influenza)

Back 58

packaging and assembly