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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

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2
Q

Do any natural antivirals exist?

A

nope

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3
Q

What is toxicity of most antivirals linked to?

A

their therapeutic mechanism

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4
Q

Acute toxicity of antivirals is very ___

A

low

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

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5
Q

Toxic effects of antivirals may not be easily ______

A

reversible

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6
Q

Acute toxicity is rare but _____ toxicity is common

A

chronic

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7
Q

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

A

HIV

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8
Q

Nucleoside analogs mimic the structure of what?

A

normal nucleosides

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9
Q

How do nucleoside analogs become active?

A

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

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10
Q

Nucleoside analogs compete with normal nucleosides for what?

A

the viral polymerase or reverse transcriptase

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11
Q

How do nucleoside analogs prevent viral replication?

A

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

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12
Q

_____ for the viral polymerase is crucial

A

Selectivity

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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)
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14
Q

Which is toxic?

-3TC) or (+3TC

A

+3TC

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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.

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16
Q

Why doesn’t Cidofovir need to be phosphorylated?

A

Bc it doesn’t have an oxygen ring?

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17
Q

Toxic and therapeutic effects are due to analog ______

A

triphosphate

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18
Q

What are some toxic effects of pol gamma?

A
  • peripheral neuropathy
  • liver damage
  • myopathy
  • lactic acidosis
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19
Q

What are some toxic effects of pol alpha/delta?

A

bone marrow suppression

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20
Q

What are some toxic effects of pol beta?

A
  • mutagenesis
  • teratogenesis (embryo or fetal malformations)
  • bone marrow suppression
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21
Q

What phosphorylates nucleosides and nucleoside analogs?

A

thymidine kinase (TK-1)

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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)

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23
Q

Bc phopsphorylation happens in the mitochondria - lots of ______ toxicity

A

mitochondrial

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24
Q

List 4 things that can hep from mitochondrial toxicity

A
  • Hepatotoxicity
  • Peripheral neuropathy
  • Central neuropathy (rare)
  • Myopathies (rare)
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25
Q

Mitochondrial toxicity:

Describe hepatotoxicity pathogenesis

A

loss of mitochondrial function in liver cell causes reduced aerobic metabolism and liver cell damage

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26
Q

Mitochondrial toxicity:

Describe hepatotoxicity signs and symptoms

A
  • Hepatitis (high enzymes)
  • Fatty liver and alteration of lipid metabolism
  • Lactic acidosis
  • Death
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27
Q

Mitochondrial toxicity:

Describe peripheral neuropathy pathogenesis

A

shortage of energy for transmission of action potential along myelinated axons

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28
Q

Mitochondrial toxicity:

Describe peripheral neuropathy signs and symptoms

A
  • Dysestesia (tingling, burning sensation) starting in the feet
  • Loss of sensation and reflexes
  • Spontaneous pain
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29
Q

Mitochondrial toxicity:

Describe central neuropathy

A

causes central deafness

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30
Q

Mitochondrial toxicity:

Describe pathogenesis of Myopathies

A

loss of mitochondrial in muscles causes loss of contraction strength, and disruption of muscle architecture

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31
Q

Mitochondrial toxicity:

Describe signs and symptoms of myopathies

A
  • weakness and fatigue

- cardiomyopathy (loss of contractility, enlargement of the heart)

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32
Q

How is bone marrow suppression believed to be caused?

A

by inhibition of DNA polymerases in bone marrow precursor cells

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33
Q

What will AZT cause?

A

mostly the erythroid series affected - leads to anemia

34
Q

What will ganciclovir cause?

A

anemia, myelosuppression, thrombocytopenia

35
Q

List some other adverse effects of nucleoside analogs

A
  • skin rash (frequent)
  • serious hypersensitivity of immunological origin (abacavir)
  • pancreatitis - mainly with ddC, ddI (mechanism is unknown)
  • tubular renal toxicity (cidofovir, tenofovir)
36
Q

List some NNRTIs (non-nucleoside reverse transcriptase inhibitors)

A
  • nevirapine
  • efavirenz
  • delavirdine
37
Q

Describe the binding of NNRTIs

A
  • 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
Q

NNRTIs are classic ___-________ inhibitors

A

non-competitive

39
Q

HIV that is resistant to NRTI are NOT resistant to _____

A

NNRTIs

40
Q

Describe the toxicity of NNRTIs

A
  • usually mild
  • total adverse events frequent (5-20%)
  • rash and hypersensitivity most common and troublesome event
  • dyslipidemia
41
Q

What are other events that can happen that are not “class” specific?

A
  • 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
Q

Protease inhibitors:

give an example

A

Saquinavir

43
Q

Protease inhibitors themselves are not very toxic, but they must be taken for life in combination with other ____ meds

A

toxic

44
Q

Why must protease inhibitors be taking in combination?

A

when given as monotherpay, they rapidly cause onset of resistant viruses

45
Q

List 2 things that PIs can cause

A

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
Q

Protease inhibitors increase the risk of MI by ___% per year of treatment

A

16

47
Q

The risk of PI causing MI is similar to the risk of a _____ or a _____

A

smoker or a diabetic

48
Q

Who is anti-retroviral therapy recommended for?

A

for treatment-naive HIV-infected patients

*this is always a combo of 3 drugs

49
Q

Describe some problems with HIV therapy

A

-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
Q

Describe some kidney problems in those with HIV

A

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
Q

Abacavir hypersensitivity is a _____ reaction

A

delayed

52
Q

Abacavir hypersensitivity is more common in what race

A

Caucasian patients

53
Q

Abacavir hypersensitivity should happen within ___ weeks of treatment

A

6

54
Q

Abacavir hypersensitivity: list some symptoms

A

At least 2 of the following:

  • fever
  • fash
  • GI
  • constitutional
  • respiratory
55
Q

Abacavir hypersensitivity linked to ___ alleles

A

HLA

56
Q

Which alleles had a positive predictive value for Abacavir hypersensitivity of 70-100% and a negative predictive value of 97%

A

HLA-B*5701, HLA-DR7 and HLA-DQ3

57
Q

testing of _______ should be performed in every new HIV patient

A

HLA-B*5701

58
Q

List 2 antivirals against herpes virus and their active derivatives

A
  • acyclovir
  • ganciclovir

Active derivatives:
-famcyclovir, valacyclovir (Valtrex) and valaganciclovir

59
Q

What is acyclovir used for?

A
  • herpes simplex (genital/oral herpes, encephalitis)

- varicella-zoster (chicken pox, shingles)

60
Q

Describe how acyclovir has triple specificity

A

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
Q

Ganciclovir used mainly to treat ______

A

cytomegalovirus (AIDS retinitis, transplant patients)

62
Q

CMV does not have the ______ _____

A

thymidine kinase

63
Q

What does CMV have

A

a unique protein kinase that can phosphorylate ganciclovir

64
Q

Ganciclovir is more toxic than ______

A

acyclovir

*ganciclovir is not as virus specific as acyclovir

65
Q

how does ganciclovir work

A

it is incorporated in the DNA (not a good chain terminator) and the subsequent attempt at repair cause DNA strand breaks and apoptosis

66
Q

What is the main toxicity of ganciclovir

A

bone marrow toxicity

  • aplastic anemia
  • neutropenia
  • thrombocytopenia
67
Q

describe hep C virus

A

an RNA virus replicated by an RNA/RNA polymerase

68
Q

___% of hep C cases progress to chronic disease

A

80

69
Q

__% of hep C cases develop cirrhosis after 25 years of infection, of which 20% develop hepatoma

A

25

70
Q

Which genotype is more difficult to treat and perhaps more malignant?

A

genotype 1

71
Q

What used to be the treatment for hepatitis C?

A

combination of RBV and pegylated interferon alpha

72
Q

How effective was RBV/IFN combo?

A

Genotype 1 and 4: 48 weeks of therapy - response in 42%

Genotype 2 and 3: 24 weeks of therapy - response in 82%

73
Q

list 3 HCV protease inhibitors

A
  • telaprevir
  • boceprivir
  • simeprivir
74
Q

What do HCV protease inhibitors need to be combined with?

A

interferon + ribavirin for 24 weeks

75
Q

give an example of HCV polymerase inhibitor

A

sofosbuvir

76
Q

What are HCV polymerase inhibitors given with?

A

just ribavirin for 12 weeks

77
Q

give an example of HCV NS5A protein inhibitors

A

ledipasvir

78
Q

What is ledipasvir given with?

A

sofosbuvir x 12 weeks

79
Q

Describe the toxicity symptoms of direct acting antivirals

A
  • rash
  • nausea
  • fatigue
  • headache
80
Q

What are 2 proven mechanisms of action of ribavirin

A
  • 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
Q

Describe the toxicity of ribavirin

A

Hemolytic anemia (27% of patients, 10-13% significant anemia)

82
Q

how does ribavirin cause anemia

A
  • 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)

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