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Renal, Hematological, and Cardiovascular Organ Systems > Pharmacology-Anti-HIV Agents > Flashcards

Pharmacology-Anti-HIV Agents Flashcards

1
Q

What are the fusion inhibitors?

A

Enfuviride

Maraviroc

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2
Q

What are the nucleoside reverse transcriptase inhibitors?

A 
zidovudin
Didanosine
Lamivudine
Stavudine
Abacavir
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3
Q

What are the Nucleotide inhibitors?

A

Tenofovir

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4
Q

What are the non-nucleoside reverse transcriptase inhibitors?

A

Nevirapine
Delavirdine
Efvirenz

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5
Q

What are the integrase inhibitors?

A

Raltegravir

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6
Q

What are the protease inhibitors??

A 
Atazanavir 
Saquinavir
Ritonavir
Lopinavir 
Indinavir
Nelfinavir
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7
Q

What are the goals of therapy?

A

Improvement of quality of life
reduction of HIV related morbidity and morality
Restoration and or preservation of immunologic function
Maximal and durable suppression of Viral load

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8
Q

What are the tools to achieve Goals?

A

Selection of ARV regimen
Preservation of future treatment options
Rational sequencing of therapy
Maximizing adherence
Use of resistance testing in selected clinical settings

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9
Q

What are the parts of initiation?

A

attachment
penetration
uncoating

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10
Q

What are the steps in Release?

A

assembly
maturation
exit from cell

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11
Q

What is the mechanism of Enfuviritde adn what type of antiretroviral is it?

A

-increases the effectiveness of HAART in combo chemotherapy
-Binds ot GP41 of hte bviral envelope
-prevents conformational change and impedes the fusion of hte viral and host cell memranes
Fusion inhibitors

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12
Q

What are the resistance mechanisms for Enfuviride?

A

pg41 mutations may develop when drug is given at suboptiaml doses as monotherapy
-No cross resistance with other HIV agents

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13
Q

What are the ADMEs of Enfuvirtide?

A
  • Subcu
  • High protein binding
  • Metabolized by proteolytic hydrolysis (no involvement of cyt P450)
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14
Q

What are the adverse effects of Enfuvirtide?

A
  • injection-site rxns (lrg # of pts. )
  • Hypersensitivity rxnn (occurs rarely <1%)
  • increased risk of bacterial pneumonia (8x more frequently than placebo)
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15
Q

What is Maraviroc, and what is its mechanism of action?

A

Fusion Inhibitor

  • chemokine receptor 5 antagonist
  • binds ot CCR5 co-receptor
  • prevents virus form entering the host cell
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16
Q

What are the ADMEs of Maraviroc?

A

-Oral
-Substrate for both CYP3A4 and P-glycoprotein
T 1/2— 14-18 h
-both feces adn urine

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17
Q

Why would you use Maraviroc?

A
  • txment of CCR5-tropic HI-1 (not CXCR4)
  • in combo for patients failing other antiretroviral drugs
  • Only ~50% of txment experienced pts will be eligible to take
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18
Q

What are the adverse effects of Maraviroc?

A
  • cough, pyrexia, rash, musculoskeletal symptoms, abdominal pain and psotural dizzziness, bladder irritation
  • Phase II studies reported possible liver and cardiac problems (1.3%)
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19
Q

What are the drug interactions of Maraviroc??

A

CYP3A4 inducers or inhibitors

-dosage adjustment needed with efavirenx and lopinavir/ritonavir

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20
Q

What are the combination therapies used for NRTIs?

A

Combirvir (AZT+3TC) (Zidovudine+ Lamivudine)

Trizivir (AZT+3TC+ABC)(Zidovudine+ Lamivudine+ Abacavir)

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21
Q

What is the mechanism of action of the nucleoside reverse transcriptase inhibitors (NRTIs)?

A
  • analogs of naturally occuring nucleosides (3’ hydroxyl replaced by an azido, hydrogen or other )
  • competitive inhibitor of viral reverse transcriptase
  • DNA chain terminator
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22
Q

How does do the NRTIs work (2 steps)

A

Triphosphate competes with native nucleotides

incorporation and chain termination

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23
Q

What are the properties of Zidovudine and Stavudine?

A
  • analogs of pyrimidine nucleoside (T)
  • phosphorylated to active triphosphate forms
  • competes with deoxythymidine thriphosphate for incorporation into DNA
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24
Q

What are the properties of Lamivudin adn Emtricitabine?

A
  • Analogous of pyrimiden nucleoside (C)

- compete with deoxycytidine triphosphate for incorportation into viral DNA

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25
Q

What are the properties of Didanosine?

A

Alalog of purine nucleosides (A,G)
-Active 2’ 3’- dideoxyadenosine 5’- triphosphate (ddATP) competes iwth cellular deoxyaadenosine triphosphate for incorporation into viral DNA

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26
Q

What are the properties of Abacavir?

A

analog of purine nucleosides (G)

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27
Q

What are theindications of NRTIs?

A
  • management of HIV infection as components of combination HAART
  • prevent acute infection of susceptible cells
  • little effect on cells already infected by HIB
  • Zidovudine (only NRTI shown to reduce perinatal HIV transmission )
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28
Q

What are the resistance mechanisms for NRTIs?

A

drugs select for differnet mutations of the reverse transcriptase gene at the level of specific codons

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29
Q

What two drugs have AUC changes due to meals and what are they?

A

Zidovudine: v 24 (high fat)
Didanosine: v 50% (acidity)

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30
Q

What is important about the metabolism adn renal excretion of Abacavir?

A

metabolism >80%

renal excretion <5% of parent drug

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31
Q

How is Zidovudine metabolized?

A

glucuronidation

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32
Q

What are the pharmacological propertis of NRTIs?

A
  • good oral absorption
  • poor bindding to plama proteins
  • metabolism does not rely on CYP450 system
  • excteted unchanged in urine except (zidovudine and abacavir)
  • Didanosine is acid labile (~take 1/2 h beofre or 2 h after meals)
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33
Q

How is Abacavir metabolized?

A

by alcohol dehydrogenase

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34
Q

What are the common adverse effects of NRTIs?

A

-GI distress
Lactic acidosis with hepatic steatosis due to mitochondrial toxicity
-higher with stavudine
Lipodystropy (most common with stavudine and zidocudine)

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35
Q

What are the unusual toxicities of Zidovudine?

A

can cause bone marrow suppression

36
Q

What are the unusual toxicites of Dianosine?

A

diarrhea,
peripheral neuopathy
pancreatitis

37
Q

What are the unusual toxicities of stavudine?

A

peripheral neuopathy

pancreatitis

38
Q

What are the unusual toxicities of Abacavir?

A

Hypersensitvity rxn due to genetic predisposition

-HLAB5701 screening , to reduce risk of hypersensitive rxn, if positive do not receive treatment

39
Q

What are the D-D interactions of Zidovudine?

A

avoid concurrent admistration with drugs that are bone marrow suppressive

  • ganciclovir, interferon alpha, dapsone, flucytosine, vincristine, vinblastine
  • avoid use ith stavudine as antagonism results
40
Q

What are the D-D interactions of Didanosine?

A
  • early virologic failure result in combination with lamivudine )or emtricitabine) + tenofovir
  • some drugs can augment the neuropathy and pancreatitis
    • Ethambuto, isoniazid, vincristine, cis-platin
  • stavudine
  • Ganciclovir increases plasma conc 2X
  • methadone decreases plasma levels
  • -dosage adjustment needed
41
Q

What are the D-D interatcions of stavudine?

A

Same as dianosine!!

    • augments the neuopathy and pancreatitis with didanosine, ethambuto, isoniazid, vincristin, cis-platin
  • competition with Zidovudine for activation enzymes
  • –theymidine kinase>thymidylate kinase>nucleoside diphosphate kinase
42
Q

What are the D-D interactions of Laivudine?

A

-trimethoprim-sulfamethoxazole increases plasma concentration

43
Q

What are the D-D interactions of Abacavir?

A

Ethanol significantly increases plasma levels

44
Q

What are the indications of NRTIs?

A

treatmetn of HIV as a part of combo therapy

45
Q

What are the MoA of MRTIs?

A

inhibit viral reverse transcriptasze

46
Q

What are the resistance mechanisms against NRTIs?

A

mutations in reverse transcriptiase gene

47
Q

What are ADMEs for NRTIs?

A
  • Well absorbed by the GI tract; good oral biovalibilty

- excreted unchanged by kidney ep AZT and ABC

48
Q

What are the adverse effects of NRTIs?

A

all cause GI distress

-lactic acidosis with hepatic steatosis due to mitochondrial toxicity

49
Q

What are the D-D interactions of NRTIs?

A

cam be sever due to synergistic effects on myelosuppression and peripheral neuropathy

50
Q

What is a Nucleotide reverse Transcriptase inhibitor ?

A

Renofovir disoproxil fumarate (DF)

51
Q

What are the properties of Tenofovir?

A
  • first nucleotide reverse transcriptasze inhibitor
  • apporved for use in combo with other anti-HIV agents
  • requires only tow intracellular phosphorylation steps for activation
  • more rapid and complete conversion to active triphosphate
52
Q

What is the MoA for Tenofovir?

A

inhibits viral revese transcriptase?

53
Q

What are the mechanisms of resistance for Tenofovir?

A

-thymidine analogue mutations
(corss resistance with preexisitng AZT associated mutations)
-not effected by lamivudine-abacavir associated mutations

54
Q

How is tenofovir administered?

A

1x a day
increased bioavilibility taken with a meal
spearte dosing form didanosine by 1-2 hrs

55
Q

What is the metabolism of tenofovir?

A

not substrate for P405

no adverse D-D interactions with other p450 substrate drugs

56
Q

What are the adverse effects of Tenofovir?

A
  • most commonly (>3%) inclinical trials- nausea, diarrhea, asthenia, headache, vomiting, flatulence, abdoinal pain, and anorexia
  • increased liver enzymes
57
Q

What is improtant about tenofovir and emtricitabine?

A
  • Truvada
  • better than Abacavir-Lamivudine for initial HIV therapy
  • truvada better at extending time to virologic failure an fist adverse event
  • truvada effective as antiretrovial chemophrphylasxis before exposure
58
Q

What are the indications of Non nucleoside reverse transcriptase inhibitors (NNRTIs)?

A
  • Hiv-I inffections

- do not have signigicant activity against HIV-2

59
Q

What are the mechanism of action for NNRTIs?

A
  • bind directly to a hydrophobic pocket of the RT protein
  • induce confrontational change in active site and block enzyme activity
  • do not require intraccellular phophorylation for activity
60
Q

What are the mechanism of resitance for NNRTIs?

A

-each drug selects of differnt muations of the RT gene at the level of specific codons

61
Q

What are the properties of NNRTIs?

A
  • excellent oral absoprtion
  • highly bound to plasma proteins
  • metabolized by the CYP450 systems (siginication d-d interations)
  • excreted therouh the urine as glucuronide conjugates
62
Q

What is unique about Dlavirdin with CYP3A4?

A

it is an inhibiotr

-increase PIs, rifabutin, clathromycin, methadone, and ethinyl estradiol plasma levels

63
Q

What is unique about Efavirenz adn Neviraphine with CYP3A4?

A

inducer

-reduces PIs, rifabutin, clathromycin, methadone, and ethinyl estradiol plasma levels

64
Q

What are the common toxicites of NNRTIs?

A

-maculopapular rashes in the trunk and extremities

65
Q

What are the unique toxicites of Nevirapine?

A
  • fever, fatigue, headache, comnolence, nausea,

- hepatotoxicity (elevated liver enxymes); may be sever and life-threatening

66
Q

What are the unique toxicites of Efavirenz?

A

NEUROPSYCHIATRIC (headache, dizziness, abnormal dreams, psychosis, sucidal ideation)

  • teratogenic in nonhuman primates
  • FDA pregnacy Category D
67
Q

What are the mechanism of actions for Integrase inhibitors?

A

inhibits HIV-1 integrase enxyme

-needed for insterion of viral DNA into host genome

68
Q

What are the ADMEs for the integrase inhibitors?

A
  • oral
  • glucuronidation in liver
  • T1/2 — 9h
  • feves and urine
69
Q

What are the indication of Raltegravir?

A

-use in combination therapy for treatment-experienced adults with HIV-1 strains restraint to mltiple antiretroviral agents

70
Q

What are the adverse effects of Raltegravir?

A

Diarrhea
nausea
headache
fever

71
Q

What are the in drug-drug interaction of raltegravir?

A
  • not inducer, inhibitor or substrate of CYP3A4
  • metabolized by UDP glucoruronsylatransferase (UFT)
  • rifampin induces UGT
  • PI atazanavir inhibits UGT
72
Q

What are the indications of Protease inhibitors?

A

treatmetn of HIV as part of combination therapy
most effective ART availble
-Effective in both acutely adn chroic HIV-1 infected cells
-Effective in monocytes and macrophages (not affected by RT inhibitors)
-early stages of HIV-1 replication cycle no affected

73
Q

What is the MoA of protease inhibitors?

A
  • selective, competivie inhibitors of HIV proteases
  • Bind reversibly to protease active site
  • prevent cleavage of polyprotein and block viral maturation
74
Q

What is the resistance to Protease Inhibitors?

A

-EAch drug selects for differnt mutations in protease gene at level of specific codons

75
Q

What is the ADMEs of protease inhibitors?

A
  • oral absorption varies
  • bind extensively to plasma proteins
  • metabolized by cyp450 (concurrent use of potent P450 inducer -rifampin- leads to decresaed PI concetration
  • renal excreation is minimal (no adjustments needed for renal dysfunctions
76
Q

what are protease inhibitors effects on CYP3A4?

A

INHIBITORS!!!

  • ritonavir used ot increase plasma of other PIs (inhibits GI p450, during absorption and hepatic p450 for metabolism)
  • toxic adverse effects related to drug accumulation due to PI-=mediated inhibition of hepatic P450 system
77
Q

What are the drug interactions with PIs?

A

carbamazepines lower indiavir AUC potentially other PIs (adjust dose)

  • Ketoconazole upregulates PIs AUC (adjust does)
  • sildenafil AUC augmented by PIs
  • methadone AUC reduced by rionavir and lopinavir
  • oral contraceptive AUC reduced by PIs
78
Q

What are common Adverse effects of PIs?

A
  • Hyperlipiemia
  • insulin resistance and diabetes
  • lipodystrophy – fat wastingm buffalo hump, crix-belly,- extremity wasting with venous prominence- facial thinning- breat enlargement
  • elevated liver function tests
  • possible increased bleeding risk in hemophailiacs
  • D-Dinteractions
79
Q

Ritonavir AEs?

A
  • hepatotoxicity at high doses

- used at low doses to boost level of other PIs

80
Q

Undinavir AEs?

A
  • Alopecia, kidney stones, and renal insufficiency

- pts should drink water

81
Q

Atazanavir AEs?

A

-hyperbilirubinemia due to inhibiton of UDP glycuronsyltranferase (reversible)

82
Q

Tipranavir AEs?

A

induces PP-glycoprotein transporter

83
Q

What is the selectivity of NRTIs?

A

once phosphorylated by cellular kinases have grater affinity for viral reverse transcriptase than for cellular DNA polymerases

84
Q

What is the selectivity of NNRTIs?

A
  • dont undergo phosphorylation

- have grater affinity for viral reverse transcripatse

85
Q

What is the selectivity for PIs?

A

-greater affinity for HIV aspartyl protease than for human protease

Renal, Hematological, and Cardiovascular Organ Systems (9 decks)

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