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SBL - Exam 2 > HIV Pharmacology > Flashcards

HIV Pharmacology Flashcards

1
Q

what is the life cycle of HIV (8 steps)?

A
  1. entry
  2. fusion and uncoating
  3. reverse transcription
  4. integration
  5. transcription
  6. translation
  7. virion assembly
  8. budding and maturation
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2
Q

MOA of miraviroc

A

binds specifically to CCR5 to prevent viral entry into the host cell

  • miraviroc is not efficatious in viruses with a tropism for CCR5 and CXCR4 or just CXCR4
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3
Q

what surface receptors are usually seen in advanced HIV?

A

CXCR4

  • this means miraviroc may not be useful in patients with advanced HIV (it only binds CCR5)
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4
Q

what are the pharmacokinetics of miraviroc?

A
  • oral administration
  • CYP450 metabolism
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5
Q

mechanisms of resistance to miraviroc

A
  1. mutations in the V3 loop of gp120
  2. emergence of CXCR4-tropic virus
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6
Q

what stage of the life cycle does miraviroc act on?

A

fusion

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7
Q

MOA of enfuvirtide

A

binds gp41, preventing the conformational changes needed for fusion of the viral envelope with the host cell membrane

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8
Q

what are the pharmacokinetics of enfuvirtide?

A
  • subcutaneous injection
  • metabolized by proteolytic hydrolysis, without involvement of CYP450
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9
Q

mechanisms of resistance of enfuvirtide

A
  • mutations in gp41 to prevent enfuvirtide binding
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10
Q

adverse effects of enfuvirtide

A
  • local injection site reactions
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11
Q

can NRTIs eradicate virus from cells that are already infected?

A

no, once the cells are infected the virus’ genetic material is integrated into the host cell DNA

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12
Q

what is the mechanism of action of nucleoside/tide reverse transcriptase inhibitors (NRTIs)?

A

competitive inhibition of HIV reverse transcriptase

  • the NRTI is incorporated into the growing DNA, leading to premature chain termination
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13
Q

mechanisms of resistance to NRTIs

A
  • point mutations in HIV reverse transcriptase
  • impaired kinase activity to prevent phosphorylation and subsequent activation (only for nucleosides)
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14
Q

abacavir

A

guanosine nucleoside RT inhibitor

  • drug combinations inculde
    • abacavir + lamivudine
    • abacavir + zidovudine
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15
Q

pharmacokinetics of abacavir

A

metabolized by alcohol dehydrogenase

  • serum levels of abacavir can be increased with concurrent ingestion of EtOH
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16
Q

adverse effects of abacavir

A

hypersensitivity (consitutional sx, respiratory sx, skin rash)

  • do not reintroduce abacavir if hypersensitivity occurs; may cause death
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17
Q

didanosine

A

adenosine nucleoside RT inhibitor

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18
Q

adverse effects of didanosine

A
  • dose-dependent pancreatitis
    • contraindicated in alcoholism and hypertrigyceridemia
  • retinal changes
    • mandated periodic retinal exams
  • lactic acidosis and hepatic steatosis when combined with stavudine
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19
Q

lamivudine

A

cytosine nucleoside RT inhibitor

  • active against HIV and HBV
    • discontinuation could exacertbate HBV symptoms
  • should not be used in conjuction with emtricitabine; since they are related, they select for the same point mutation in HIV reverse transcriptase
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20
Q

emtricitabine

A

cytosine nucleoside RT inhibitor

fluorinated analog of lamivudine

  • active against HIV and HBV
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21
Q

pharmacokinetics of emtricitabine

A

has a long intracellular half-life that allows for once daily dosing

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22
Q

adverse effects of emtricitabine

A
  • constitutional sx
  • hyperpigmentation of the palms and soles
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23
Q

stavudine

A

thymidine nucleoside RT inhibitor

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24
Q

adverse effects of stavudine

A
  • dose-dependent peripheral neuropathy
  • dyslipidemia
  • lactic acidosis and hepatic steatosis when combined with didanosine
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25
Q

zidovudine

A

deoxythymidine nucleoside RT inhibitor

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26
Q

adverse effects of zidovudine

A
  • macrocytic anemia
  • neutropenia
  • constitutional symptoms
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27
Q

tenofovir

A

adenosine nucleoTide RT inhibitor

  • active against HIV and HBV
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28
Q

what drugs enhance absorption of tenofovir?

A

disoproxil and alafenamide

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29
Q

MOA of non-nucleoside reverse transcriptase inhibitors (NNRTIs)?

A

binds HIV reverse transcriptase at a site distant from the active site

  • binding leads to reduced activity
  • non-competitive inhibitor
30
Q

mechanisms of resistance to NNRTIs

A
  • point mutations in HIV reverse transcriptase that alter NNRTI binding
  • there is no cross resistance between NNRTIs and NRTIs since they bind such different sites
31
Q

pharmacokinetics of NNRTIs

A

metabolized by CYP450 system

32
Q

delavirdine

A

first generation NNRTI

33
Q

adverse effects of delavirdine

A
  • skin rash
  • constitutional symptoms
  • increased aminotransferase levels
34
Q

efavirenz

A

first generation NNRTI

35
Q

pharmacokinetics of efavirenz

A

can only be given once daily d/t increased t1/2

36
Q

adverse effects of efavirenz

A
  • CNS symptoms - dizziness, drowsiness, insomnia, nightmares, HA
  • skin rash
37
Q

nevirapine

A

first generation NNRTI

  • used in preventing transmission of HIV from mother to child
    • single dose to mother at onset of labor, and a dose to the baby within 3 days after birth
38
Q

adverse effects of nevirapine

A
  • rash (can be dose-limiting)
  • liver toxicity
39
Q

etravirine

A

second generation NNRTI

  • increased potency, increased t1/2, and less adverse effects
  • has a higher genetic barrier to resistance; designed to overcome resistance to first generation NNRTIs
40
Q

pharmacokinetics of etravirine

A

metabolized by CYP450 system

  • induces CYP3A4
  • inhibits CYP2C9 and CYP2C19
41
Q

rilpivirine

A

second generation NNRTI

  • increased potency, increased t1/2, and less adverse effects
  • coformulated with emtricitabine + tenofovir; allows for once daily oral administration
42
Q

adverse effects of rilpivirine

A
  • rash, depression, HA, insomnia, increased serum aminotransferases
  • high doses associated with QT prolongation
43
Q

what stage of the HIV life cycle do integrase strand transfer inhibitors (INSTIs) work at?

A

integration

44
Q

MOA of integrase strand transfer inhibitors (INSTIs)

A

bind HIV integrase to inhibit strand transfer and ligation of reverse-transcribed HIV DNA into the chromosomes of the host cell

45
Q

dolutegravir

A

integrase strand transfer inhibitor (INSTI)

  • used for treatment of naïve patients in combination with:
    • tenofovir + emtricitabine
    • abacavir + lamivudine
46
Q

elvitegravir

A

integrase strand transfer inhibitor (INSTI)

  • only available as a combination pill
    • elvitegravir + cobicistat + emtricitabine + tenofovir
  • requires boosting with cobicistat
47
Q

raltegravir

A

integrase strand transfer inhibitor (INSTI)

  • preferred treatment for treatment naïve patients
48
Q

what stage of the HIV life cycle do protease inhibitors work on?

A

budding and maturatino

49
Q

MOA of protease inhibitors

A

competitively inhibit HIV aspartyl protease to prevent maturation of final structural proteins that make up the mature virion core

  • prevents production of gag and pol polypeptides
50
Q

adverese effects of protease inhibitors

A
  • GI intolerance (can be dose-limiting)
  • lipodystrophy
    • ​metabolic - hyperglycemia + hyperlipidemia
    • morphologic - lipoatrophy + fat depositino
  • redistribution and accumulation of body fat
    • central obesity, buffalo hump, facial wasting, breast enlargment, cushingoid appearance
51
Q

pharmacokinetics of protease inhibitors

A
  • metabolized by CYP450 system
    • ritonavir has the strongest inhibitory effect on CYP3A4
    • saquinavir has the weakest
52
Q

atazanavir

A

protease inhibitor

  • once daily dosing
53
Q

adverse effects of atazanavir

A
  • diarrhea and nausea
  • skin rash
  • not associated with dyslipidemia or hyperglycemia (unlike most protease inhibitors)
54
Q

pharmacokinetics of atazanavir

A

inhibits CYP3A4, CYP2C9, UGT1A1

55
Q

darunavir

A

protease inhibitor

  • must be boosted with ritonavir or cobicistat
56
Q

adverse effects of darunavir

A

sulfa drug

57
Q

fosamprenavir

A

protease inhibitor

58
Q

adverse effects of fosamprenavir

A

sulfa drug

  • personal parasthesias
  • depression
59
Q

indinavir

A

protease inhibitor

60
Q

adverse effects of indinavir

A

unconjugated hyperbilirubinemia and nephrolithiasis

  • consuming 1.5L of water each day helps prevent kidney stones
61
Q

pharmacokinetics of indinavir

A

boosting with ritonavir allows for twice daily dosing

  • this carries increased risk for kidney stones–drink lots of water!
62
Q

lopinavir

A

protease inhibitor

  • available only in combination with low-dose ritonavir
63
Q

nelfinavir

A

protease inhibitor

64
Q

ritonavir

A

protease inhibitor

65
Q

pharmacokinetics of ritonavir

A
  • at standard dosing for protease inhibitors, it has a high rate of GI side effects
  • very potent CYP450 inhibitor; used primarily as a booster
  • lower doses are used for inhibition of CYP3A4
66
Q

saquinavir

A

protease inhibitor

  • formulated for once daily dosing with ritonavir
67
Q

tipranavir

A

protease inhibitor

  • indicated in patients resistant to other protease inhibitors
  • combined with ritonavir
68
Q

adverse effects of tipranavir

A

sulfa drug

69
Q

what is highly active antiretroviral therapy (HAART)?

A

combinations of 3-4 drugs used to treat HIV and prevent resistance by inhibiting various steps of the life cycle

70
Q

what drug combinations are used in HAART?

A

2 NRTIs plus either:

  • 1 protease inhibitor (sometimes 2 for boosting)
  • 1 NNRTI
  • 1 INSTI

SBL - Exam 2 (5 decks)

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