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PHRM 865 > Exam 4 Stahelin > Flashcards

Exam 4 Stahelin Flashcards

1
Q

Replication cycle of HIV steps

A
  1. Viral attachment and entry
  2. Penetration
  3. Uncoating
  4. Nucleic acid synthesis
  5. Integration/Transcription
  6. Viral protein synthesis
  7. Packaging and assembly
  8. Viral release
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2
Q

Why is there Resistance to HIV drugs

A
  1. HIV polymerase HIV prone
  2. RTs are unable to suppress viral replication
  3. Large amount of viruses are present
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3
Q

HIV drug resistance rate

A

Rate of mutations is inversely related to serum concentration

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4
Q

What does a low genetic barrier for a drug mean

A

It is easy for the virus to become resistant

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5
Q

What does a high genetic barrier for a drug mean

A

It is hard for a virus to become resistant

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6
Q

What drugs block viral attachment and entry

A
  1. enfuviritde
  2. docosanol
  3. maraviroc
  4. palivizumab
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7
Q

What drugs block viral penetration

A

interferon-alfa (HBV, HCV)

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8
Q

What drugs block viral uncoating

A

Amantadine, rimantadine (influenza)

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9
Q

What drugs block viral nucleic acid synthesis

A

NRTIs (HIV)
NNRTIs (HIV)
Nucleoside/nucleotide analogs (HSV, HBV)

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10
Q

What drugs block viral integration (retroviruses) transcription

A

INSTIs (HIV)

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11
Q

What drugs block viral protein synthesis

A

PIs (HIV, HCV)

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12
Q

What drugs block viral release

A

Neuraminidase inhibitors (influenza)

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13
Q

Why do HIV medications have selective toxicity towards the virus

A

Viruses have different proteases and polymerases

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14
Q

What drugs blocks chemokine and CD4 receptors

A

Maraviroc

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15
Q

What drug blocks attachment and fusion of HIV to host cells

A

Enfuviritide

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16
Q

What drugs block reverse transcription

A

NRTIs

Non-NRTIs

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17
Q

What drug blocks integrase

A

raltegravir

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18
Q

what drugs block viral maturation

A

maturation

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19
Q

How does HIV fuse/enter host cell

A

HIV gp120 binds to CD4 on target cell, which causes conformational changes in gp120 exposes region

Exposed region binds to cytokine receptor (CCR5 or CXCR4 depending on the strain of HIV)

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20
Q

What drugs are HIV entry and fusion inhibitors

A

Enfuviritide

Maraviroc

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21
Q

Enfuviritde MOA

A

binds to HIV gp41 and blocks gp41 conformation change needed for fusion

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22
Q

Maraviroc MOA

A

binds to human CCR5 and causes conformational change that blocks GP 120 binding

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23
Q

What patients can take maraviroc

A

Patients with HIV strains that utilize CCR5 because it is a selective CCR5 antagonist

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24
Q

What is enfurviritide active against

A

Only HIV-1

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25
Q

Resistance to enfuvirtide

A

Mutation within a 10 amino acid motif in gp41

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26
Q

Reverse transcriptase activities/types

A
  1. RNA dependent DNA polymerase
  2. Ribonuclease H
  3. DNA-dependent DNA polymerase
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27
Q

What do RTs do

A
  1. Copies plus-strand RNA to produce minus-strand DNA
  2. Degrades RNA template from RNA-DNA hybrid
  3. Synthesizes plus-strand DNA from minus-strand DNA template
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28
Q

What do NRTIs interfere with

A

RNA-dependent DNA polymerase

DNA-dependent DNA polymerase

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29
Q

RT DNA polymerase mechanism

A

RT catalyzes formation of phosphodiester bond between 3’ OH of last nucleotide added and the 5’ phosphate of the next nucleotide

Pyrophosphate is released –> provides energy needed for reaction

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30
Q

NRTIs mechanism

A

Nucleoside analogs that lack 3’ OH: causing competitive inhibition of reverse transcriptase and is a DNA chain terminator to inhibit elongation

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31
Q

What are NRTIs active against

A

HIV-1 and HIV-2

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32
Q

Are NRTIs used in combo or alone

A

Combo: 2 NRTIs plus NNRTI or PI or integrase inhibitor

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33
Q

Preferred NRTI combos

A

Tenofovir and emtracitabine

Abacavir and lamivudine

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34
Q

Are NRTIs ok to use as is

A

No

All must be activated by cellular kinases to triphosphate form (or equivalent)

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35
Q

Deoxymethine analogs NRTIs

A

Azidothymidine

Stavudine

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36
Q

Deoxyadenosine analogs NRTIs

A

didanosine

tenofovir

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37
Q

deoxycytidine analogs NRTIs

A

lamivudine

emtricitabine

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38
Q

deoxyguanosine analogs NRTIs

A

abacavir

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39
Q

What is special about the structure of tenofovir

A

methyl group

open ring

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40
Q

What is special about the structure of emtricitabine

A

sulfur and fluorine groups

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41
Q

Is TDF ok to be used as is

A

No: prodrug converted to tenofovir

2 phosphorylation steps required, but phosphonate cannot be cleaved

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42
Q

TDF structure

A

acyclic nucleoside phosphonate analog of adenosine

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43
Q

Advantages of tenofovir

A

Long intracellular half-life
Different resistance profile
Retains some activity against mutant RT
Highly selective for HIV RT over human cellular and mitochondrial DNA polymerases

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44
Q

Problems with TDF

A

Plasma esterases can activate TDF to TFV, which is eliminated by kidney

Causes greater loss of kidney function and a risk of acute renal failure

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45
Q

Advantage of using TAF over TDF

A

Fewer side effects since less TFV gets into the plasma, but associated with higher lipid levels compared to TDF

Different activation pathway of TAF allows for 10-fold lower dose compared to TDF

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46
Q

Why is TAF advantageous for HIV

A

Better accumulation in lymph nodes

Higher intracellular concentrations

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47
Q

How is TAF converted to TFV

A

TAF contains phenol and alanine isopropyl ester to make the charge on the phosphonate

Phosphonamidase reaction leads to TFV

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48
Q

How are nucleosides and NRTIs must be activated

A

To their triphosphate forms by cellular kinases

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49
Q

What do NRTIs have a higher affinity for

A

HIV RT than for cellular DNA polymerases

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50
Q

What are the two types of NRTI resistances

A

Discriminatory mutations

Excision mutations

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51
Q

what are discriminatory mutations

A

mutations that selectively impair the ability of reverse transcriptase to incorporate analogues into DNA

AKA helps the RT to distinguish between normal dNTPs and NRTIs

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52
Q

what are excision mutations

A

ATP molecular mediates the removal (excision) of a nucleoside analogue after it has been incorporated

AKA promote removal of NRTIs after they’ve been incorporated into the growing chain

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53
Q

What are NRTIs selective for

A

HIV RT over human DNA polymerase alpha and beta

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54
Q

What do some NRTIs inhibit

A

human DNA polymerase

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55
Q

AE of NRTIs

A

inhibits human DNA polymerase

Leads to anemia, granulocytopenia, lactic acidosis, lipoatrophy

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56
Q

Abacavir black box warning

A

Hypersensitivity Reaction- highly associated with the HLA-B*5701 allele, recommend testing prior to treatment

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57
Q

NNRTIs MOA

A

bind directly to site on RT at the hydrophobic pocket near catalytic site but do NOT compete with nucleotides for binding- noncompetitive inhibitors so a single mutation in the binding site can promote resistance

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58
Q

Do NNRTIs need to be phosphorylated

A

No since they are no incorporated into the DNA chain

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59
Q

What do NNRTIs block

A

RNA and DNA dependent DNA polymerase activities

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60
Q

What are the second generation NNRTIs

A

etravirine

rilpivirine

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61
Q

What is special about second generation NNRTIs

A

designed to be inherently flexible so it can bind in multiple orientations, which allows to bind to mutants that are resistant to other NNRTIs

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62
Q

AE NNRTIs

A

rash

drug-drug interactions

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63
Q

What are NNRTIs metabolized by

A

CYP3A

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64
Q

What do NNRTIs not bind to

A

cellular DNA polymerases

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65
Q

NNRTIs and NRTIs mutations relationship

A

Mutations that confer resistance to NNRTIs do not causes resistance to NRTIs

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66
Q

What drug is an integrase inhibitor

A

raltegravir

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67
Q

Ralegravir MOA

A

inhibits insertion of HIV DNA into the human genome by blocking the strand transfer step

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68
Q

integrase function

A

inserts HIV DNA into host cell DNA by 3’ processing and strand transfer

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69
Q

Ralegravir MOA

A

chelates metal ions in the integrase and stabilizes the enzyme-DNA complex

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70
Q

Integrase inhibitor resistance

A

caused by primary mutations that reduce INI susceptibility

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71
Q

Does Ralegravir have low or high genetic barrier

A

low

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72
Q

Which INI has a higher genetic barrier

A

dolutegravir

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73
Q

Do you use elvitegravir alone or in combo

A

Combo with cobicistat to boost elvitegravir concentrations by inhibiting metabolism by CYP3A4

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74
Q

How does HIV become resistant to INIs

A

primary mutations that reduce INI susceptibility

secondary mutations further decrease virus susceptibility and/or compensate for the decreased fitness

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75
Q

HIV proteases role

A

cut itself free and the cuts 4 other enzymes free from the long precursor

-peptide bond cleavage via hydrolysis reaction reaction

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76
Q

How do protease inhibitors work

A

they have a replaced amide bond with a non cleavable linkage –> AKA peptidomimetic

Causes change in conformation of the protease to close it

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77
Q

PI and CYP3A4 relations

A

PIs can cause increased levels of other CYP3A4 metabolized drugs

Delavirdine increases indinavir and saquinavir levels

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78
Q

Which PI is not an peptidomimetic

A

tipranavir

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79
Q

Which antiviral drug is the most potent inhibitor of CYP450s

A

ritonavir

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80
Q

Ritonavir use

A

Can be used in sub-therapeutic doses for PI boosting

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81
Q

What is PI boosting

A

Use low doses of ritonavir to inhibit CYP3A4 –> blocking metabolism of other PIs

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82
Q

Pros of PI boosting

A

Increases trough levels of PIs
Reduces emergence of resistant viruses
Improves compliance

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83
Q

What drugs are INIs

A
  1. Saquanivir
  2. Ritonavir
  3. Lopinavir
  4. Cobicistat
  5. Atazanavir
  6. Darunavir
  7. Tipranavir
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84
Q

Role of cobicistat

A

inhibit cyp3a4

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85
Q

what drugs reduce atazanavir concentrations

A

efavirenz and tenofovir

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86
Q

Darunavir unique features

A
  1. makes extensive hydrogen bonds with protease backbone

2. inhibits HIV protease dimerization

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87
Q

Mutant HIV protease and PIs

A

DRV hydrogen-bonds with the peptide backbone so it is less affected by changes in amino acid side chains

DRV can inhibit both wildtype and mutants that are resistant to other PIs

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88
Q

Which PI is nonpeptidic

A

tipranavir, which allows use in those resistant to DRV

Its a CYP3A4 substrate and inducer

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89
Q

How do resistance to protease inhibitors occur

A

Modify contacts between protease and inhibit to bind tightly

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90
Q

PI AEs

A

Hyperlipidemia
Insulin resistance and diabetes
Lipodystrophy
Elevated liver function tests

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91
Q

Preferred INSTI based regimens

A
  1. DTG + ABC/3TC if HLA (-)
  2. DTG (QD) + tenofovir/ftc
  3. EVG/COBI + tenofovir/ftc
  4. RAL + tenofovir/ftc
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92
Q

Acyclovir MOA

A

Competitive inhibitor of viral DNA polymerase by competing with dGTP, causing DNA polymerase to become bound to template irreversible

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93
Q

is acyclovir a chain terminator?

A

Yes because it is incorporated into DNA

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94
Q

Acyclovir spectrum of activity

A

Active against HSV-1, HSV-2 and VZV

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95
Q

Resistance to acyclovir

A

Mutations in viral thymidine kinase and viral DNA polymerase

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96
Q

What is valacyclovir

A

L-valyl ester of acyclovir, which is rapidly converted to acyclovir in intestine and liver

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97
Q

Which drug has better efficacy: acyclovir or valacyclovir?

A

valacyclovir

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98
Q

Valacyclovir MOA

A

identical to acyclovir

Competitive inhibitor of viral DNA polymerase by competing with dGTP, causing DNA polymerase to become bound to template irreversible

99
Q

How does acyclovir become active

A

Acyclovir undergoes 3 phosphorylation events to convert to acyclovir TP

100
Q

How is valacyclovir transported

A

By intestinal amino acid transporters

101
Q

Famciclovir and penciclovir relationship

A

Famiciclovir is a prodrug of penciclovir since famciclovir lacks intrinsic antiviral activity

102
Q

How is Famciclovir metabolized

A

famciclovir is converted to penciclovir by first pass metabolism in intestine and liver

103
Q

famciclovir and penciclovir MOA

A

Competitive inhibitor of viral DNA polymerase but does NOT cause immediate chain termination but allows for short chain elongation

104
Q

How does cross resistance occur in famciclovir and penciclovir

A

viral kinase mutants confer cross-resistance to penciclovir and acyclovir

105
Q

Penciclovir vs Acyclovir for HSV

A

penciclovir has a higher affinity for HSV TK than acyclovir

penciclovir triphosphate is more stable than acyclovir triphosphate in HSV infected cells

106
Q

Do HSV polymerases have higher affinity for Penciclovir or Acyclovir

A

Acyclovir-tp, but both drugs have similar antiviral potencies

107
Q

Clinical use of oral famciclovir

A

primary and recurrent genital herpes

acute herpes zoster

108
Q

clinical use of topical penciclovir

A

recurrent herpes labialis

109
Q

ganciclovir MOA

A

Competitive inhibitor of viral DNA polymerase but does NOT cause immediate chain termination but allows for short chain elongation

110
Q

what is ganciclovir active against

A

CMV

111
Q

does ganciclovir have good or poor bioavailability

A

poor

112
Q

ganciclovir toxicity

A

toxicity more severe than acyclovir- can cause myelosuppression

113
Q

ganciclovir resistance

A

due to mutations i CMV kinase or CMV DNA pol

114
Q

how to have better bioavailability for ganciclovir

A

using valganciclovir instead- monovalyl ester

115
Q

valganciclovir metabolism

A

Rapidly hydrolyzed to ganciclovir by esterases in intestine and liver

116
Q

valganciclovir clinical use

A

CMV retinitis in AIDS patients

117
Q

Foscarnet MOA

A

blocks pyrophosphate binding site of the viral DNA polymerase to trap polymerase in closed formation and make DNA is unable to translocate
inhibits cleavage of pyrophosphate from dNTPs

118
Q

Foscarnet and phosphylation relationship

A

Does not require phosphorylation for activity

119
Q

Is foscarnet a chain terminator

A

No

120
Q

Foscarnet clinical use

A

CMV retinitis

121
Q

Foscarnet toxicity

A

renal –> phosphate and calcium issues

122
Q

Foscarnet resistance

A

Mutations in DNA pol or HIV R

Resistant CMV isolates are cross-resistant to ganciclovir

123
Q

Cidofovir MOA

A

Competitive inhibitor and chain terminator: chain termination by CMV pol requires two consecutive incorporation

124
Q

what is cidofovir highly selective for

A

viral DNA pol

125
Q

Cidofovir SOA

A

broad

126
Q

cidofovir AE

A

dose-dependent nephrotoxicity

127
Q

cidofovir clinical use

A

CMV retinitis

128
Q

letermovir clinical use

A

prophylaxis of CMV infection and disease in adult allogenic hematopoietic stem cell transplant patients who have CMV

129
Q

Letermovir MOA

A

inhibits the terminase complex that creates individual genomes for the herpes virus

binds to pUL56
prevents cleavage and packaging
No effect on protein synthesis or DNA replication

130
Q

Amatadine MOA

A

inhibits influenza penetration into host cells by blocking uncoating and targeting the M2 protein of influenza A

131
Q

what do neuraminidases do

A

for influenza

cleaves glycolytic bonds between terminal sialic acids and adjacent sugars to facilitate virus dissemination

132
Q

what is the main neraminidase inhibitor

A

oseltamivir

133
Q

Is tamiflu a prodrug

A

Yes- converted to active form by liver esterases

134
Q

Tamiflu MOA

A

inhibits NA

135
Q

Tamiflu resistance

A

resistance is associated with mutations in the active site of neuraminidase

136
Q

what drugs are neuraminidase inhibitors

A

oseltamivir
zanamivir
peramivir
baloxavir

137
Q

Zanamivir administration

A

oral inhaler

138
Q

Zanamavir MOA

A

same as tamiflu

139
Q

zanamavir toxicity

A

bronchospasms- not recommended in pts with asthma and COPD

140
Q

peramivir MOA

A

transition state analog of sialic acid

141
Q

which is viral cap-snatching in influenza

A

influenza steals the mRNA cap from host cell mRNAs and uses it to make its own viral mRNAs

142
Q

baloxavir marboxil MOA

A

binds to PB2 subunit of the RNA polymerase of virus and inhibits the influenza cap-dependent endonuclease so that viral mRNAs can no longer be produced

143
Q

Nonspecific defenses against HCV

A

interferons induce synthesis of cellular proteins

144
Q

How do interferons work against HCV

A

ribonuclease degrades viral DNA

Protein kinase phosphorylates and inactivates EIF-2 (a translation initiation factor)

145
Q

What is interferon alpha usually in combo with

A

ribavirin to treat HCV

146
Q

Ribavirin SOA

A
  • influenza A and B
  • hep a,b, and c
  • gentical herpes
  • herpes zoster
  • measles
  • hantavirus
  • lassa fever virus
147
Q

ribavirin MOA

A

not definitely known

  • Inhibit IMPDH to reduce GTP levels
  • Direct inhibition of viral RNA polymerase
  • Incorporation into viral RNA leading to error catastrophe
148
Q

What drugs are HCV NS3 p1-p3 substrate analog protease inhibitors

A
  • simeprevir

- paritaprevir

149
Q

What drugs are HCVNS3 p2-p4 substrate analog protease inhibitors

A
  • grazoprevir
  • voxilaprevir
  • glecaprevir
150
Q

Second gen HCV PIs resistance

A
  • mutations in NS3 active site
  • low genetic barrier of resistance
  • similar but not identical pattern of mutations for linear and macrolytic inhibitors
151
Q

What drugs are HCV nucleoside RNA polymerase inhibitors

A
  • Sofosbuvir (prodrug)
152
Q

Sofosbuvir MOA

A

incorporated in viral RNA chain to causes chain termination

153
Q

Sofosbuvir resistance

A

Single mutation in active site S288T

154
Q

What drugs are HCV non nucleoside RNA polymerase inhibitors

A

Dasabuvir

155
Q

Dasabuvir MOA

A

binds to palm I site of HCV RNA polymerase to prevent conformations changes and blocks nucleotide incorporation into viral RNA

156
Q

Dasabuvir resistance

A

genetic barrier

157
Q

What drugs are HCV NS5A inhibitors

A 
Ombitasvir
Ledipsavir
Daclatasvir
Velpatasvir
Pibrentasvir
158
Q

HCV NS5A inhibitors MOA

A

inhibits both viral RNA replication and assembly or release of infectious viral particles

159
Q

black box warning for HCV direct acting antivirals

A

HBV reactivation has occurred in patients co-infected with HCV while undergoing treatment for DAAs for HCV infection used without interferon

160
Q

Anti-retrovirals for HBV

A

tenofovir and lamivudine

161
Q

resistance to HVC NS5A first gen inhibitors

A

low genetic barrier
varies between genotypes
single mutations confer high resistance
similar resistance pattern

162
Q

resistance to HVC NS5A second gen inhibitors

A

higher genetic barrier to resistance among NS5a inhibitors

retain activity against common resistance associated substituations

163
Q

remdisivir MOA

A

prodrug that is bio-transformed to a ribonucleotide analog that can inhibit viral RNA polymerase

164
Q

nirmatrelvir MOA

A

peptidomimetic inhibits active site cysteine residue in 3CLpro

Can no longer make active nonstructural proteins from the polyprotein

165
Q

What drugs are used against COVID

A
  • remdisivir

- noematrelvir

166
Q

What is dermatophytosis and what causes it

A

Classic skin and hair infections that involve 3 genera of mold that grow on keratin on living host –> epidermophyton, trichophyton, and microsporum

167
Q

what is onychomycosis

A

refers to non-dermatophyte nail infections or any fungal nail infection caused by any fungus

168
Q

what part of the cell wall is specific to fungals

A

beta glucan

169
Q

what antifungal drug is a polyene

A

amphotericin B

170
Q

is amphotericin B fungicidal or fungistatic

A

fungicidal

171
Q

aphotericin B MOA

A

binds and pulls ergosterol out of fungal cell membrane to create leaking of membrane

172
Q

amphotericin B PK

A

poorly absorbed from GI tract

173
Q

amphotericin B AE

A

RENAL DAMAGE:
reduced renal perfusion: reversible
renal tubular injury: irreversible >4 g

174
Q

which antifungal does amphotericin not cover

A

Candida lusitaniae

175
Q

5-FC SOA

A
  1. Candidas

2. Cryptococcus neoformans

176
Q

which antifungals do FLU not cover

A
  1. candida krusei
  2. aspergillus
  3. mucorales
  4. fusarium
  5. scedosporium
177
Q

what antifungal does ITR not cover

A

mucorales

178
Q

POS and ISA SOA

A

everything

179
Q

CAS SOA

A

Candidas and aspergillus

180
Q

MICA SOA

A

Candidas and aspergillus

181
Q

ANI SOA

A

candidas and aspergillus

182
Q

What drug is not active against candida krusei

A

FLU

183
Q

what drug is not active against candida lusitaniae

A

AMB

184
Q

What drugs are not active against aspergilus

A

5FC and FLU

185
Q

What drugs are not active against cryptococcus

A

CAS
MICA
ANI

186
Q

What drugs are active against mucorales

A

AMB
POS
ISA

187
Q

What drugs are active against fusarium

A 
AMB
ITR
VOR
POS
ISA
188
Q

what drugs are active against scedosporium

A 
AMB
ITR
VOR
POS
ISA
189
Q

what drugs are active against blastomyces

A 
AMB
FLU
ITR
VOR
POS
ISA
190
Q

what drugs are active against coccidioides

A 
AMB
FLU
ITR
VOR
POS
ISA
191
Q

what drugs are active against histoplasma

A 
AMB
FLU
ITR
VOR
POS
ISA
192
Q

antifungals that causes hepatic toxicity

A

azoles
AMB
5-FC
Echinocandins

193
Q

antifungals that cause renal toxicity

A

AMB

IV voriconazole

194
Q

antifungals that cause CNS toxicity

A

voriconazole

195
Q

antifungals that cause photopsia toxicity

A

voriconazole

196
Q

antifungals that cause GI toxicity

A

itraconazole
posaconazole
5-FC

197
Q

antifungals that cause cardiac toxicity

A

itra –> myopathy

azoles –> qtc

198
Q

antifungals that cause infusion reactions

A

Amphotericin B

Echinocandins

199
Q

antifungals that cause bone marrow suppression

A

5-FC

Amphotericin B

200
Q

what drug is an allyamine

A

terbinafine

201
Q

terbinafine MOA

A

inhibits squalene epoxidase by binding to it; leading to pore formation and toxicity

202
Q

is terbinafine static or cidal

A

Cidal: death results from accumulation of squalene, not loss of ergosterol

203
Q

Azoles MOA

A

inhibition of 14 alpha-demethylase by binding to the iron on cyt p450

inhibit the binding and activation of molecular oxygen by ctyochrome P450 to inhibit the conversion of lanosterol to ergosterol

204
Q

are azole metabolites actice or inactive

A

inactive

205
Q

What happened when going from clotrimazole to miconalzole

A

increasing the distance of azole group from asymmetric carbon increases spectrum of activity, less metabolism in CYP 450

206
Q

Ketoconazole and CYP3A relationship

A

reduced CYP3A relationship

207
Q

difference between itraconazole and ketoconazole

A

improved specificity for fungal P450 enzyme

208
Q

special structure difference in fluconazole

A

2nd triazole ring

f in place of CL on benzene ring

209
Q

special structure difference in voriconazole

A

Added methyl group- improved binding to fungal 14 alpha demethylase and increase spectrum

210
Q

does voriconazole or posaconazole have greater SOA and why

A

posaconazole because it has a furan ring and the F replaces Cl

211
Q

Which azole is a prodrug

A

Isavuconazole: water soluble thus reduced nephrotoxicity

212
Q

Ketoconazole and CYP450

A

Ketoconazole is potent inhibitor of 3A4:

increases bioavailability of cyclosporin
Inducers (rifampin) reduce keotconazole levels

213
Q

itraconazole metabolism

A

extensively metabolized by CYP3A4 in liver

214
Q

fluconazole metabolism

A

8-% excreted by kidney unchanged

215
Q

voriconazole metabolism

A

metabolized extensively in liver by CYP2C19>3A4>2C9

216
Q

posaconazole metabolism

A

glucuronidation

217
Q

can fluconazole be used for fungal meningitis and why

A

Yes –> has high solubility, bioavailability so it can penetrate CSF

218
Q

which azole is teratogenic

A

voriconazole

219
Q

what drugs are echinocandins

A

Caspofungin
micafungin
andulafungin

220
Q

what are echinocandins

A

synthetically modified fungal compounds that are lipopeptides

221
Q

echinocandins MOA

A

inhibit syntheis of glucan cell wall synthase

222
Q

do echinocandins have selectivity

A

yes because mammalian cells lack glucan cell wall

223
Q

are echinocandins static or cidal

A

cidal

224
Q

what is echinocandins not metabolized by

A

liver CYPs

225
Q

flucytosine MOA

A

inhibits thymidylate synthase to deprive fungal cell of precursors for DNA synthesis
interferes with protein synthesis

226
Q

flucytosine specificity

A

mammalian cells are unable to convert flucytosine to active metabolite

227
Q

what is flucytosine synergistic with

A

amphotericin B

228
Q

flucytosine PK

A

oral
removed by kidney –> toxicity

narrow therapeutic window

229
Q

flucytosine AE

A

intestinal flora can metabolize 5-FU (anticancer drug) to cause inhibition of endogenous DNA synthesis

230
Q

which antifungal disrupts fungal microtubles

A

griseofulvin

231
Q

is griseofulvin static or cidal

A

cidal

232
Q

griseofulvin ROA

A

given orally to become incorporated in keratin precursor cells

233
Q

which antifungals reach CSF

A

Voriconazole

Fluconazole

234
Q

tavaborole MOA

A

inhibits leucyl transfer RNA synthetase to inhibit protein synthesis

235
Q

what is essential for tavaborole

A

boron

236
Q

tavaborole clinical use

A

topical treatment of onychomycosis

237
Q

candida krusei intrinsic resistance

A

***fluconazole

reduced susceptibility to flucytosine and AMB

238
Q

candida glabrata intrinsic resistance

A

multiazole

echinocandin

239
Q

aspergillus intrinsic resistance

A

amb

240
Q

Azoles resistance mechanisms

A

Target site alteration
Efflux pumps
Target enzyme upregulation
Bypass pathways

241
Q

Polyenes resistance mechanisms

A

reduced ergosterol content

242
Q

echinocandins resistance mechanisms

A

target site mutations

243
Q

flucytosine resistance mechainsms

A

cytosine deaminase or UPRT

PHRM 865 (59 decks)

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