Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

Year 4 - Toxicology > Lecture 8 - Antivirals > Flashcards

Lecture 8 - Antivirals Flashcards

1
Q

Describe the targets for therapy in bacteria vs. viruses

A

Bacteria are complex and have many targets for therapy

Viruses are simple and few targets. May viruses have a “latent” stage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Do any natural antivirals exist?

A

nope

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is toxicity of most antivirals linked to?

A

their therapeutic mechanism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Acute toxicity of antivirals is very ___

A

low

*reports of 5-20g overdose of azidothymidine (AZT) with only mild and transitory effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Toxic effects of antivirals may not be easily ______

A

reversible

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Acute toxicity is rare but _____ toxicity is common

A

chronic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

___ treatment is by far the most common cause of toxicity by antivirals

A

HIV

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Nucleoside analogs mimic the structure of what?

A

normal nucleosides

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How do nucleoside analogs become active?

A

must be phosphorylated by cellular or viral enzymes to nuceloTIDES in order to become active

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Nucleoside analogs compete with normal nucleosides for what?

A

the viral polymerase or reverse transcriptase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

How do nucleoside analogs prevent viral replication?

A

they are incorporated into the viral DNA and then stop DNA replication

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

_____ for the viral polymerase is crucial

A

Selectivity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Give some examples of nucleoside analogs

A
  • deoxycytidine (dC)
  • zalcitabine (ddC)
  • lamivudine (-3TC)
  • (+3TC)
  • zidovudine (AZT)
  • carbovir (active form of abacavir)
  • stavudine (D4T)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Which is toxic?

-3TC) or (+3TC

A

+3TC

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Describe how activation of antivirals is good for efficacy but bad for toxicity

A

The analog will get phosphorylated once it’s in the cell. There are no transport mechanisms that will get it out of the cell once it’s phosphorylated.

If the analog is not phosphorylated, it is useless as an antiviral.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Why doesn’t Cidofovir need to be phosphorylated?

A

Bc it doesn’t have an oxygen ring?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Toxic and therapeutic effects are due to analog ______

A

triphosphate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are some toxic effects of pol gamma?

A
  • peripheral neuropathy
  • liver damage
  • myopathy
  • lactic acidosis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

What are some toxic effects of pol alpha/delta?

A

bone marrow suppression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are some toxic effects of pol beta?

A
  • mutagenesis
  • teratogenesis (embryo or fetal malformations)
  • bone marrow suppression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What phosphorylates nucleosides and nucleoside analogs?

A

thymidine kinase (TK-1)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Wha tis thymidine kinase 2 (TK2)?

A

the TK iso-enzyme found in the mitochondria

*in non-dividing cells with many mitochondria this is the most abundant species of TK (ex. neural cells, liver cells, muscle cells)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Bc phopsphorylation happens in the mitochondria - lots of ______ toxicity

A

mitochondrial

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

List 4 things that can hep from mitochondrial toxicity

A
  • Hepatotoxicity
  • Peripheral neuropathy
  • Central neuropathy (rare)
  • Myopathies (rare)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Mitochondrial toxicity: Describe hepatotoxicity pathogenesis
loss of mitochondrial function in liver cell causes reduced aerobic metabolism and liver cell damage
26
Mitochondrial toxicity: Describe hepatotoxicity signs and symptoms
- Hepatitis (high enzymes) - Fatty liver and alteration of lipid metabolism - Lactic acidosis - Death
27
Mitochondrial toxicity: Describe peripheral neuropathy pathogenesis
shortage of energy for transmission of action potential along myelinated axons
28
Mitochondrial toxicity: Describe peripheral neuropathy signs and symptoms
- Dysestesia (tingling, burning sensation) starting in the feet - Loss of sensation and reflexes - Spontaneous pain
29
Mitochondrial toxicity: | Describe central neuropathy
causes central deafness
30
Mitochondrial toxicity: Describe pathogenesis of Myopathies
loss of mitochondrial in muscles causes loss of contraction strength, and disruption of muscle architecture
31
Mitochondrial toxicity: Describe signs and symptoms of myopathies
- weakness and fatigue | - cardiomyopathy (loss of contractility, enlargement of the heart)
32
How is bone marrow suppression believed to be caused?
by inhibition of DNA polymerases in bone marrow precursor cells
33
What will AZT cause?
mostly the erythroid series affected - leads to anemia
34
What will ganciclovir cause?
anemia, myelosuppression, thrombocytopenia
35
List some other adverse effects of nucleoside analogs
- skin rash (frequent) - serious hypersensitivity of immunological origin (abacavir) - pancreatitis - mainly with ddC, ddI (mechanism is unknown) - tubular renal toxicity (cidofovir, tenofovir)
36
List some NNRTIs (non-nucleoside reverse transcriptase inhibitors)
- nevirapine - efavirenz - delavirdine
37
Describe the binding of NNRTIs
- bind the reverse transcriptase or polymerase at sites other than the nucleotide-triphosphate binding sites - binding results in distortion of the polymerase, which becomes unable to catalyze DNA elongation
38
NNRTIs are classic ___-________ inhibitors
non-competitive
39
HIV that is resistant to NRTI are NOT resistant to _____
NNRTIs
40
Describe the toxicity of NNRTIs
- usually mild - total adverse events frequent (5-20%) - rash and hypersensitivity most common and troublesome event - dyslipidemia
41
What are other events that can happen that are not "class" specific?
- teratogenic in monkeys - psychiatric symptoms - dizziness and other mild CNS symptoms - hepatic problems (connected with the P450 metabolism and interaction with other drugs) - Delavirdine decreases P450 activity
42
Protease inhibitors: | give an example
Saquinavir
43
Protease inhibitors themselves are not very toxic, but they must be taken for life in combination with other ____ meds
toxic
44
Why must protease inhibitors be taking in combination?
when given as monotherpay, they rapidly cause onset of resistant viruses
45
List 2 things that PIs can cause
1) Redistribution of fat - "buffalo hump", peripheral wasting, lipodystrophy 2) Dyslipidemia - increase in serum lipids - increase risk of heart disease - high cholesterol - high triglycerides
46
Protease inhibitors increase the risk of MI by ___% per year of treatment
16
47
The risk of PI causing MI is similar to the risk of a _____ or a _____
smoker or a diabetic
48
Who is anti-retroviral therapy recommended for?
for treatment-naive HIV-infected patients *this is always a combo of 3 drugs
49
Describe some problems with HIV therapy
-it's very effective, HIV viral load is undetectable in over 90% of patients, CD4+ count is > 500/mL and AIDS is rarely observed BUT -chronic inflammation remains and immune system is never completely normal -aging people with HIV show increased age-related problems and co-morbidities
50
Describe some kidney problems in those with HIV
AKI - 10% prevalence - 52% systemic infections - 32% caused by drugs (antibiotics, indinavir or tenofovir, radio contrast agents, NSAID, lithium) HIV associated nephropathy - caused by HIV infection directly - 90% of patients are African American
51
Abacavir hypersensitivity is a _____ reaction
delayed
52
Abacavir hypersensitivity is more common in what race
Caucasian patients
53
Abacavir hypersensitivity should happen within ___ weeks of treatment
6
54
Abacavir hypersensitivity: list some symptoms
At least 2 of the following: - fever - fash - GI - constitutional - respiratory
55
Abacavir hypersensitivity linked to ___ alleles
HLA
56
Which alleles had a positive predictive value for Abacavir hypersensitivity of 70-100% and a negative predictive value of 97%
HLA-B*5701, HLA-DR7 and HLA-DQ3
57
testing of _______ should be performed in every new HIV patient
HLA-B*5701
58
List 2 antivirals against herpes virus and their active derivatives
- acyclovir - ganciclovir Active derivatives: -famcyclovir, valacyclovir (Valtrex) and valaganciclovir
59
What is acyclovir used for?
- herpes simplex (genital/oral herpes, encephalitis) | - varicella-zoster (chicken pox, shingles)
60
Describe how acyclovir has triple specificity
1) it is phosphorylated exclusively by the herpes thymidine kinase 2) it has a strong specificity for the viral DNA polymerase 3) cellular polymerases proofread acyclovir out of the DNA, but viral polymerase does not
61
Ganciclovir used mainly to treat ______
cytomegalovirus (AIDS retinitis, transplant patients)
62
CMV does not have the ______ _____
thymidine kinase
63
What does CMV have
a unique protein kinase that can phosphorylate ganciclovir
64
Ganciclovir is more toxic than ______
acyclovir *ganciclovir is not as virus specific as acyclovir
65
how does ganciclovir work
it is incorporated in the DNA (not a good chain terminator) and the subsequent attempt at repair cause DNA strand breaks and apoptosis
66
What is the main toxicity of ganciclovir
bone marrow toxicity - aplastic anemia - neutropenia - thrombocytopenia
67
describe hep C virus
an RNA virus replicated by an RNA/RNA polymerase
68
___% of hep C cases progress to chronic disease
80
69
__% of hep C cases develop cirrhosis after 25 years of infection, of which 20% develop hepatoma
25
70
Which genotype is more difficult to treat and perhaps more malignant?
genotype 1
71
What used to be the treatment for hepatitis C?
combination of RBV and pegylated interferon alpha
72
How effective was RBV/IFN combo?
Genotype 1 and 4: 48 weeks of therapy - response in 42% Genotype 2 and 3: 24 weeks of therapy - response in 82%
73
list 3 HCV protease inhibitors
- telaprevir - boceprivir - simeprivir
74
What do HCV protease inhibitors need to be combined with?
interferon + ribavirin for 24 weeks
75
give an example of HCV polymerase inhibitor
sofosbuvir
76
What are HCV polymerase inhibitors given with?
just ribavirin for 12 weeks
77
give an example of HCV NS5A protein inhibitors
ledipasvir
78
What is ledipasvir given with?
sofosbuvir x 12 weeks
79
Describe the toxicity symptoms of direct acting antivirals
- rash - nausea - fatigue - headache
80
What are 2 proven mechanisms of action of ribavirin
- competitive inhibitor of IMP dehydrogenase and therefore of de novo synthesis of GTP and dGTP - it is incorporated and acts as a mutagen for RNA viruses (mutation catastrophe)
81
Describe the toxicity of ribavirin
Hemolytic anemia (27% of patients, 10-13% significant anemia)
82
how does ribavirin cause anemia
- ribavirin phosphates accumulate in erythrocytes, because they lack the phosphates to hydrolyze them - depletion of normal high energy phosphates (ATP) - sensitivity to oxidative damage - haemolysis and enhanced clearance of erythrocytes

Year 4 - Toxicology (24 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions