Exam 4 Stahelin Flashcards
1
Q
Replication cycle of HIV steps
A
- Viral attachment and entry
- Penetration
- Uncoating
- Nucleic acid synthesis
- Integration/Transcription
- Viral protein synthesis
- Packaging and assembly
- Viral release
2
Q
Why is there Resistance to HIV drugs
A
- HIV polymerase HIV prone
- RTs are unable to suppress viral replication
- Large amount of viruses are present
3
Q
HIV drug resistance rate
A
Rate of mutations is inversely related to serum concentration
4
Q
What does a low genetic barrier for a drug mean
A
It is easy for the virus to become resistant
5
Q
What does a high genetic barrier for a drug mean
A
It is hard for a virus to become resistant
6
Q
What drugs block viral attachment and entry
A
- enfuviritde
- docosanol
- maraviroc
- palivizumab
7
Q
What drugs block viral penetration
A
interferon-alfa (HBV, HCV)
8
Q
What drugs block viral uncoating
A
Amantadine, rimantadine (influenza)
9
Q
What drugs block viral nucleic acid synthesis
A
NRTIs (HIV)
NNRTIs (HIV)
Nucleoside/nucleotide analogs (HSV, HBV)
10
Q
What drugs block viral integration (retroviruses) transcription
A
INSTIs (HIV)
11
Q
What drugs block viral protein synthesis
A
PIs (HIV, HCV)
12
Q
What drugs block viral release
A
Neuraminidase inhibitors (influenza)
13
Q
Why do HIV medications have selective toxicity towards the virus
A
Viruses have different proteases and polymerases
14
Q
What drugs blocks chemokine and CD4 receptors
A
Maraviroc
15
Q
What drug blocks attachment and fusion of HIV to host cells
A
Enfuviritide
16
Q
What drugs block reverse transcription
A
NRTIs
Non-NRTIs
17
Q
What drug blocks integrase
A
raltegravir
18
Q
what drugs block viral maturation
A
maturation
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)
20
Q
What drugs are HIV entry and fusion inhibitors
A
Enfuviritide
Maraviroc
21
Q
Enfuviritde MOA
A
binds to HIV gp41 and blocks gp41 conformation change needed for fusion
22
Q
Maraviroc MOA
A
binds to human CCR5 and causes conformational change that blocks GP 120 binding
23
Q
What patients can take maraviroc
A
Patients with HIV strains that utilize CCR5 because it is a selective CCR5 antagonist
24
Q
What is enfurviritide active against
A
Only HIV-1
25
Resistance to enfuvirtide
Mutation within a 10 amino acid motif in gp41
26
Reverse transcriptase activities/types
1. RNA dependent DNA polymerase
2. Ribonuclease H
3. DNA-dependent DNA polymerase
27
What do RTs do
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
28
What do NRTIs interfere with
RNA-dependent DNA polymerase
DNA-dependent DNA polymerase
29
RT DNA polymerase mechanism
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
30
NRTIs mechanism
Nucleoside analogs that lack 3' OH: causing competitive inhibition of reverse transcriptase and is a DNA chain terminator to inhibit elongation
31
What are NRTIs active against
HIV-1 and HIV-2
32
Are NRTIs used in combo or alone
Combo: 2 NRTIs plus NNRTI or PI or integrase inhibitor
33
Preferred NRTI combos
Tenofovir and emtracitabine
| Abacavir and lamivudine
34
Are NRTIs ok to use as is
No
| All must be activated by cellular kinases to triphosphate form (or equivalent)
35
Deoxymethine analogs NRTIs
Azidothymidine
| Stavudine
36
Deoxyadenosine analogs NRTIs
didanosine
| tenofovir
37
deoxycytidine analogs NRTIs
lamivudine
| emtricitabine
38
deoxyguanosine analogs NRTIs
abacavir
39
What is special about the structure of tenofovir
methyl group
| open ring
40
What is special about the structure of emtricitabine
sulfur and fluorine groups
41
Is TDF ok to be used as is
No: prodrug converted to tenofovir
| 2 phosphorylation steps required, but phosphonate cannot be cleaved
42
TDF structure
acyclic nucleoside phosphonate analog of adenosine
43
Advantages of tenofovir
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
44
Problems with TDF
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
45
Advantage of using TAF over TDF
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
46
Why is TAF advantageous for HIV
Better accumulation in lymph nodes
| Higher intracellular concentrations
47
How is TAF converted to TFV
TAF contains phenol and alanine isopropyl ester to make the charge on the phosphonate
Phosphonamidase reaction leads to TFV
48
How are nucleosides and NRTIs must be activated
To their triphosphate forms by cellular kinases
49
What do NRTIs have a higher affinity for
HIV RT than for cellular DNA polymerases
50
What are the two types of NRTI resistances
Discriminatory mutations
| Excision mutations
51
what are discriminatory mutations
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
52
what are excision mutations
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
53
What are NRTIs selective for
HIV RT over human DNA polymerase alpha and beta
54
What do some NRTIs inhibit
human DNA polymerase
55
AE of NRTIs
inhibits human DNA polymerase
Leads to anemia, granulocytopenia, lactic acidosis, lipoatrophy
56
Abacavir black box warning
Hypersensitivity Reaction- highly associated with the HLA-B*5701 allele, recommend testing prior to treatment
57
NNRTIs MOA
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
58
Do NNRTIs need to be phosphorylated
No since they are no incorporated into the DNA chain
59
What do NNRTIs block
RNA and DNA dependent DNA polymerase activities
60
What are the second generation NNRTIs
etravirine
| rilpivirine
61
What is special about second generation NNRTIs
designed to be inherently flexible so it can bind in multiple orientations, which allows to bind to mutants that are resistant to other NNRTIs
62
AE NNRTIs
rash
| drug-drug interactions
63
What are NNRTIs metabolized by
CYP3A
64
What do NNRTIs not bind to
cellular DNA polymerases
65
NNRTIs and NRTIs mutations relationship
Mutations that confer resistance to NNRTIs do not causes resistance to NRTIs
66
What drug is an integrase inhibitor
raltegravir
67
Ralegravir MOA
inhibits insertion of HIV DNA into the human genome by blocking the strand transfer step
68
integrase function
inserts HIV DNA into host cell DNA by 3' processing and strand transfer
69
Ralegravir MOA
chelates metal ions in the integrase and stabilizes the enzyme-DNA complex
70
Integrase inhibitor resistance
caused by primary mutations that reduce INI susceptibility
71
Does Ralegravir have low or high genetic barrier
low
72
Which INI has a higher genetic barrier
dolutegravir
73
Do you use elvitegravir alone or in combo
Combo with cobicistat to boost elvitegravir concentrations by inhibiting metabolism by CYP3A4
74
How does HIV become resistant to INIs
primary mutations that reduce INI susceptibility
secondary mutations further decrease virus susceptibility and/or compensate for the decreased fitness
75
HIV proteases role
cut itself free and the cuts 4 other enzymes free from the long precursor
-peptide bond cleavage via hydrolysis reaction reaction
76
How do protease inhibitors work
they have a replaced amide bond with a non cleavable linkage --> AKA peptidomimetic
Causes change in conformation of the protease to close it
77
PI and CYP3A4 relations
PIs can cause increased levels of other CYP3A4 metabolized drugs
Delavirdine increases indinavir and saquinavir levels
78
Which PI is not an peptidomimetic
tipranavir
79
Which antiviral drug is the most potent inhibitor of CYP450s
ritonavir
80
Ritonavir use
Can be used in sub-therapeutic doses for PI boosting
81
What is PI boosting
Use low doses of ritonavir to inhibit CYP3A4 --> blocking metabolism of other PIs
82
Pros of PI boosting
Increases trough levels of PIs
Reduces emergence of resistant viruses
Improves compliance
83
What drugs are INIs
1. Saquanivir
2. Ritonavir
3. Lopinavir
4. Cobicistat
5. Atazanavir
6. Darunavir
7. Tipranavir
84
Role of cobicistat
inhibit cyp3a4
85
what drugs reduce atazanavir concentrations
efavirenz and tenofovir
86
Darunavir unique features
1. makes extensive hydrogen bonds with protease backbone
| 2. inhibits HIV protease dimerization
87
Mutant HIV protease and PIs
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
88
Which PI is nonpeptidic
tipranavir, which allows use in those resistant to DRV
| Its a CYP3A4 substrate and inducer
89
How do resistance to protease inhibitors occur
Modify contacts between protease and inhibit to bind tightly
90
PI AEs
Hyperlipidemia
Insulin resistance and diabetes
Lipodystrophy
Elevated liver function tests
91
Preferred INSTI based regimens
1. DTG + ABC/3TC if HLA (-)
2. DTG (QD) + tenofovir/ftc
3. EVG/COBI + tenofovir/ftc
4. RAL + tenofovir/ftc
92
Acyclovir MOA
Competitive inhibitor of viral DNA polymerase by competing with dGTP, causing DNA polymerase to become bound to template irreversible
93
is acyclovir a chain terminator?
Yes because it is incorporated into DNA
94
Acyclovir spectrum of activity
Active against HSV-1, HSV-2 and VZV
95
Resistance to acyclovir
Mutations in viral thymidine kinase and viral DNA polymerase
96
What is valacyclovir
L-valyl ester of acyclovir, which is rapidly converted to acyclovir in intestine and liver
97
Which drug has better efficacy: acyclovir or valacyclovir?
valacyclovir
98
Valacyclovir MOA
identical to acyclovir
Competitive inhibitor of viral DNA polymerase by competing with dGTP, causing DNA polymerase to become bound to template irreversible
99
How does acyclovir become active
Acyclovir undergoes 3 phosphorylation events to convert to acyclovir TP
100
How is valacyclovir transported
By intestinal amino acid transporters
101
Famciclovir and penciclovir relationship
Famiciclovir is a prodrug of penciclovir since famciclovir lacks intrinsic antiviral activity
102
How is Famciclovir metabolized
famciclovir is converted to penciclovir by first pass metabolism in intestine and liver
103
famciclovir and penciclovir MOA
Competitive inhibitor of viral DNA polymerase but does NOT cause immediate chain termination but allows for short chain elongation
104
How does cross resistance occur in famciclovir and penciclovir
viral kinase mutants confer cross-resistance to penciclovir and acyclovir
105
Penciclovir vs Acyclovir for HSV
penciclovir has a higher affinity for HSV TK than acyclovir
penciclovir triphosphate is more stable than acyclovir triphosphate in HSV infected cells
106
Do HSV polymerases have higher affinity for Penciclovir or Acyclovir
Acyclovir-tp, but both drugs have similar antiviral potencies
107
Clinical use of oral famciclovir
primary and recurrent genital herpes
| acute herpes zoster
108
clinical use of topical penciclovir
recurrent herpes labialis
109
ganciclovir MOA
Competitive inhibitor of viral DNA polymerase but does NOT cause immediate chain termination but allows for short chain elongation
110
what is ganciclovir active against
CMV
111
does ganciclovir have good or poor bioavailability
poor
112
ganciclovir toxicity
toxicity more severe than acyclovir- can cause myelosuppression
113
ganciclovir resistance
due to mutations i CMV kinase or CMV DNA pol
114
how to have better bioavailability for ganciclovir
using valganciclovir instead- monovalyl ester
115
valganciclovir metabolism
Rapidly hydrolyzed to ganciclovir by esterases in intestine and liver
116
valganciclovir clinical use
CMV retinitis in AIDS patients
117
Foscarnet MOA
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
Foscarnet and phosphylation relationship
Does not require phosphorylation for activity
119
Is foscarnet a chain terminator
No
120
Foscarnet clinical use
CMV retinitis
121
Foscarnet toxicity
renal --> phosphate and calcium issues
122
Foscarnet resistance
Mutations in DNA pol or HIV R
| Resistant CMV isolates are cross-resistant to ganciclovir
123
Cidofovir MOA
Competitive inhibitor and chain terminator: chain termination by CMV pol requires two consecutive incorporation
124
what is cidofovir highly selective for
viral DNA pol
125
Cidofovir SOA
broad
126
cidofovir AE
dose-dependent nephrotoxicity
127
cidofovir clinical use
CMV retinitis
128
letermovir clinical use
prophylaxis of CMV infection and disease in adult allogenic hematopoietic stem cell transplant patients who have CMV
129
Letermovir MOA
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
Amatadine MOA
inhibits influenza penetration into host cells by blocking uncoating and targeting the M2 protein of influenza A
131
what do neuraminidases do
for influenza
| cleaves glycolytic bonds between terminal sialic acids and adjacent sugars to facilitate virus dissemination
132
what is the main neraminidase inhibitor
oseltamivir
133
Is tamiflu a prodrug
Yes- converted to active form by liver esterases
134
Tamiflu MOA
inhibits NA
135
Tamiflu resistance
resistance is associated with mutations in the active site of neuraminidase
136
what drugs are neuraminidase inhibitors
oseltamivir
zanamivir
peramivir
baloxavir
137
Zanamivir administration
oral inhaler
138
Zanamavir MOA
same as tamiflu
139
zanamavir toxicity
bronchospasms- not recommended in pts with asthma and COPD
140
peramivir MOA
transition state analog of sialic acid
141
which is viral cap-snatching in influenza
influenza steals the mRNA cap from host cell mRNAs and uses it to make its own viral mRNAs
142
baloxavir marboxil MOA
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
Nonspecific defenses against HCV
interferons induce synthesis of cellular proteins
144
How do interferons work against HCV
ribonuclease degrades viral DNA
| Protein kinase phosphorylates and inactivates EIF-2 (a translation initiation factor)
145
What is interferon alpha usually in combo with
ribavirin to treat HCV
146
Ribavirin SOA
- influenza A and B
- hep a,b, and c
- gentical herpes
- herpes zoster
- measles
- hantavirus
- lassa fever virus
147
ribavirin MOA
not definitely known
- Inhibit IMPDH to reduce GTP levels
- Direct inhibition of viral RNA polymerase
- Incorporation into viral RNA leading to error catastrophe
148
What drugs are HCV NS3 p1-p3 substrate analog protease inhibitors
- simeprevir
| - paritaprevir
149
What drugs are HCVNS3 p2-p4 substrate analog protease inhibitors
- grazoprevir
- voxilaprevir
- glecaprevir
150
Second gen HCV PIs resistance
- mutations in NS3 active site
- low genetic barrier of resistance
- similar but not identical pattern of mutations for linear and macrolytic inhibitors
151
What drugs are HCV nucleoside RNA polymerase inhibitors
- Sofosbuvir (prodrug)
152
Sofosbuvir MOA
incorporated in viral RNA chain to causes chain termination
153
Sofosbuvir resistance
Single mutation in active site S288T
154
What drugs are HCV non nucleoside RNA polymerase inhibitors
Dasabuvir
155
Dasabuvir MOA
binds to palm I site of HCV RNA polymerase to prevent conformations changes and blocks nucleotide incorporation into viral RNA
156
Dasabuvir resistance
genetic barrier
157
What drugs are HCV NS5A inhibitors
```
Ombitasvir
Ledipsavir
Daclatasvir
Velpatasvir
Pibrentasvir
```
158
HCV NS5A inhibitors MOA
inhibits both viral RNA replication and assembly or release of infectious viral particles
159
black box warning for HCV direct acting antivirals
HBV reactivation has occurred in patients co-infected with HCV while undergoing treatment for DAAs for HCV infection used without interferon
160
Anti-retrovirals for HBV
tenofovir and lamivudine
161
resistance to HVC NS5A first gen inhibitors
low genetic barrier
varies between genotypes
single mutations confer high resistance
similar resistance pattern
162
resistance to HVC NS5A second gen inhibitors
higher genetic barrier to resistance among NS5a inhibitors
| retain activity against common resistance associated substituations
163
remdisivir MOA
prodrug that is bio-transformed to a ribonucleotide analog that can inhibit viral RNA polymerase
164
nirmatrelvir MOA
peptidomimetic inhibits active site cysteine residue in 3CLpro
Can no longer make active nonstructural proteins from the polyprotein
165
What drugs are used against COVID
- remdisivir
| - noematrelvir
166
What is dermatophytosis and what causes it
Classic skin and hair infections that involve 3 genera of mold that grow on keratin on living host --> epidermophyton, trichophyton, and microsporum
167
what is onychomycosis
refers to non-dermatophyte nail infections or any fungal nail infection caused by any fungus
168
what part of the cell wall is specific to fungals
beta glucan
169
what antifungal drug is a polyene
amphotericin B
170
is amphotericin B fungicidal or fungistatic
fungicidal
171
aphotericin B MOA
binds and pulls ergosterol out of fungal cell membrane to create leaking of membrane
172
amphotericin B PK
poorly absorbed from GI tract
173
amphotericin B AE
RENAL DAMAGE:
reduced renal perfusion: reversible
renal tubular injury: irreversible >4 g
174
which antifungal does amphotericin not cover
Candida lusitaniae
175
5-FC SOA
1. Candidas
| 2. Cryptococcus neoformans
176
which antifungals do FLU not cover
1. candida krusei
2. aspergillus
3. mucorales
4. fusarium
5. scedosporium
177
what antifungal does ITR not cover
mucorales
178
POS and ISA SOA
everything
179
CAS SOA
Candidas and aspergillus
180
MICA SOA
Candidas and aspergillus
181
ANI SOA
candidas and aspergillus
182
What drug is not active against candida krusei
FLU
183
what drug is not active against candida lusitaniae
AMB
184
What drugs are not active against aspergilus
5FC and FLU
185
What drugs are not active against cryptococcus
CAS
MICA
ANI
186
What drugs are active against mucorales
AMB
POS
ISA
187
What drugs are active against fusarium
```
AMB
ITR
VOR
POS
ISA
```
188
what drugs are active against scedosporium
```
AMB
ITR
VOR
POS
ISA
```
189
what drugs are active against blastomyces
```
AMB
FLU
ITR
VOR
POS
ISA
```
190
what drugs are active against coccidioides
```
AMB
FLU
ITR
VOR
POS
ISA
```
191
what drugs are active against histoplasma
```
AMB
FLU
ITR
VOR
POS
ISA
```
192
antifungals that causes hepatic toxicity
azoles
AMB
5-FC
Echinocandins
193
antifungals that cause renal toxicity
AMB
| IV voriconazole
194
antifungals that cause CNS toxicity
voriconazole
195
antifungals that cause photopsia toxicity
voriconazole
196
antifungals that cause GI toxicity
itraconazole
posaconazole
5-FC
197
antifungals that cause cardiac toxicity
itra --> myopathy
azoles --> qtc
198
antifungals that cause infusion reactions
Amphotericin B
| Echinocandins
199
antifungals that cause bone marrow suppression
5-FC
| Amphotericin B
200
what drug is an allyamine
terbinafine
201
terbinafine MOA
inhibits squalene epoxidase by binding to it; leading to pore formation and toxicity
202
is terbinafine static or cidal
Cidal: death results from accumulation of squalene, not loss of ergosterol
203
Azoles MOA
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
are azole metabolites actice or inactive
inactive
205
What happened when going from clotrimazole to miconalzole
increasing the distance of azole group from asymmetric carbon increases spectrum of activity, less metabolism in CYP 450
206
Ketoconazole and CYP3A relationship
reduced CYP3A relationship
207
difference between itraconazole and ketoconazole
improved specificity for fungal P450 enzyme
208
special structure difference in fluconazole
2nd triazole ring
| f in place of CL on benzene ring
209
special structure difference in voriconazole
Added methyl group- improved binding to fungal 14 alpha demethylase and increase spectrum
210
does voriconazole or posaconazole have greater SOA and why
posaconazole because it has a furan ring and the F replaces Cl
211
Which azole is a prodrug
Isavuconazole: water soluble thus reduced nephrotoxicity
212
Ketoconazole and CYP450
Ketoconazole is potent inhibitor of 3A4:
increases bioavailability of cyclosporin
Inducers (rifampin) reduce keotconazole levels
213
itraconazole metabolism
extensively metabolized by CYP3A4 in liver
214
fluconazole metabolism
8-% excreted by kidney unchanged
215
voriconazole metabolism
metabolized extensively in liver by CYP2C19>3A4>2C9
216
posaconazole metabolism
glucuronidation
217
can fluconazole be used for fungal meningitis and why
Yes --> has high solubility, bioavailability so it can penetrate CSF
218
which azole is teratogenic
voriconazole
219
what drugs are echinocandins
Caspofungin
micafungin
andulafungin
220
what are echinocandins
synthetically modified fungal compounds that are lipopeptides
221
echinocandins MOA
inhibit syntheis of glucan cell wall synthase
222
do echinocandins have selectivity
yes because mammalian cells lack glucan cell wall
223
are echinocandins static or cidal
cidal
224
what is echinocandins not metabolized by
liver CYPs
225
flucytosine MOA
inhibits thymidylate synthase to deprive fungal cell of precursors for DNA synthesis
interferes with protein synthesis
226
flucytosine specificity
mammalian cells are unable to convert flucytosine to active metabolite
227
what is flucytosine synergistic with
amphotericin B
228
flucytosine PK
oral
removed by kidney --> toxicity
narrow therapeutic window
229
flucytosine AE
intestinal flora can metabolize 5-FU (anticancer drug) to cause inhibition of endogenous DNA synthesis
230
which antifungal disrupts fungal microtubles
griseofulvin
231
is griseofulvin static or cidal
cidal
232
griseofulvin ROA
given orally to become incorporated in keratin precursor cells
233
which antifungals reach CSF
Voriconazole
| Fluconazole
234
tavaborole MOA
inhibits leucyl transfer RNA synthetase to inhibit protein synthesis
235
what is essential for tavaborole
boron
236
tavaborole clinical use
topical treatment of onychomycosis
237
candida krusei intrinsic resistance
***fluconazole
| reduced susceptibility to flucytosine and AMB
238
candida glabrata intrinsic resistance
multiazole
| echinocandin
239
aspergillus intrinsic resistance
amb
240
Azoles resistance mechanisms
Target site alteration
Efflux pumps
Target enzyme upregulation
Bypass pathways
241
Polyenes resistance mechanisms
reduced ergosterol content
242
echinocandins resistance mechanisms
target site mutations
243
flucytosine resistance mechainsms
cytosine deaminase or UPRT
