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Toxicology Final > Toxicology of Antivirals > Flashcards

Toxicology of Antivirals Flashcards

1
Q

What are the main differences btw bacteria and viruses?

A
  • bacteria is extracellular, viruses are intracellular
  • viruses rely on the host cell for most of their metabolism (bacteria depend on their own metabolic machinery)
  • viruses are very diverse
  • bacteria have many targets for chemotherapy- viruses have very few
  • toxicity of antivirals is linked to their therapeutic mechanism- toxicity is independent of their therapeutic target
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2
Q

What is the rate of toxicity with antiviral medications?

A

low rate

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3
Q

Nucleoside analogs mimic the structure of _________

A

normal nucleosides

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4
Q

What needs to happen to allow for nucleoside analogs to be active?

A
  • must be phosphorylated by cellular or viral enzymes to nucleotides inorder to be active
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5
Q

How do nucleoside analogs work?

A

-they compete with normal nucleosides for the viral polymerase or reverse transcriptase - incorporated into the viral DNA and stops the DNA replication

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6
Q

Host polymerases are _____ sensitive and are usually able to proof read out analogs that are incorporated

A

less

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7
Q

Phosphorylation of nucleosides is crucial for what?

A

to allow them to be incorporated into the DNA chain

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8
Q

What confirmation of the nucleoside analogs causes toxicity to the mitochondria?

A
  • the + confirmation- our mitochondria like this confirmation
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9
Q

Does cidofovir need to be phosphorylated to get into the cell?

A

NO

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10
Q

What enzyme is typically involved in the inhibition of DNA repair?

A
  • polymerase beta
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11
Q

What is the role of polymerase gamma?

A
  • aids in mitochondrial DNA synthesis
  • polymerase gamma- does not have proofreading activity
  • not able to remove things once they’re incorporated
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12
Q

What is the action of TK-1 enzyme?

A

phosphorylates nucleosides and nucleoside analogs

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13
Q

What is the action of TK-2 enzymes?

A

TK isoenzymes found in the mitochondria - most abundant species of TK

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14
Q

What are some of the manifestations of mitochondrial toxicity?

A
  1. Hepatotoxicity
  2. Peripheral neuropathy
  3. Central neuropathy
  4. Myopathies
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15
Q

Explain the hepatotoxicity involved in antiviral toxicities

A
  1. Hepatotoxicity
    - loss of mitochondrial fx in liver cell causes reduced aerobic metabolism and liver cell damage
    - s/s: hepatitis, fatty liver and alteration of lipid metabolism, lactic acidosis, death
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16
Q

Explain the peripheral neuropathies involved in antiviral toxicities

A
  • pathogenesis: shortage of energy for transmission of action potential along myelinated axons
  • s/s: dysestesia (tingling, burning sensation) starting in the feet, loss of sensation and reflexes, spontaneous pain
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17
Q

Explain the myopathies that are involved in antiviral toxicities?

A
  • pathogenesis: loss of mitochondrial in muscles causes loss of contraction strength and disruption of muscle architecture
  • s/s: weakness, fatigue, cardiomyopathy (loss of contractility, enlargement of heart)
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18
Q

What is the mechanism in which bone marrow suppression is thought to work?

A
  • caused by inhibition of DNA polymerases n bone marrow precursor cells
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19
Q

AZT affects mostly in _____ series in bone marrow supp/

A

erythroid

20
Q

Ganciclovir causes what with regard to bone marrow suppression?

A
  • anemia, myelosuppression, trombocytopenia
21
Q

What antiviral causes serious hypersensitivity of immunological origin?

A
  • abacavir
22
Q

What antiviral causes serious tubular renal toxicity?

A
  • cidofovir

- tenofovir

23
Q

What medications are considered NNRTIs?

A
  • nevirapine
  • efavirenz
  • delaviridine
24
Q

What is the MOA of NNRTIs?

A
  • bind the reverse transcriptase or polymerase at sites other than the nucleoside-triphosphate binding site
  • binding results in the distortion of the polymerase, which becomes unable to catalyze DNA elongation
25
Q

NNRTIs are _________ inhibitors

A

non-competitive

26
Q

What is the toxicity of NNRTIs?

A
  • usually mild
  • rash and hypersensitivity are common, also dyslipidemia
  • ALSO can be psychiatric problems, dizziness, hepatic problems, etc
27
Q

What is the MOA of PIs?

A
  • inhibit HIV protease in a very specific manner
28
Q

Why can’t you give PI’s are mono therapy?

A
  • they rapidly cause onset of resistant viruses if given alone
  • NOT very toxic
29
Q

What is the “designer drug” of the PIs

A

saquinavir

30
Q

What are the s/s or cardiovascular disease and PIs

A
  • redistribution of fat - called the buffalo hump, peripheral wasting, lipodystrophy
  • dyslipidemia- increase in serum lipids, increase risk of HD
  • high cholesterol, high TG
31
Q

PI increase the risk of ____ disease? Specifically what?

A
  • cardiovascular
  • myocardial infarction (increases risk by 16% per year of tx) - NNRTI does not have the same increase in TG and cholesterol
32
Q

What is the combo of drugs usually used as anti-retroviral tx?

A
  • INSTI (1) and NRTIs (2)
33
Q

What are the 2 drugs that can cause an AKI?

A

indinavir and tenofovir

34
Q

What is HIV associated neuropathy caused by?

A
  • caused by the HIV infection directly
35
Q

What is the grouping of sx caused by abacavir hypersensitivity?

A
  • fever
  • rash
  • GI
  • constitutional
  • respiratory
36
Q

Hypersensitivity to abacavir is linked to what?

A
  • specific HLA alleles (HLA-B*5701 in particular)
37
Q

What is acyclovir used for?

A
  • herpes simplex virus

- varicella- zoster

38
Q

What is the triple specificity of acyclovir?

A

1) phosphorylated exclusively by herpes thymidine kinase
2) strong specificity for viral DNA polymerase
3) cellular polymerases proofread acyclovir out of the DNA, but viral polymerases cannot

39
Q

What is the MOA of ganciclovir?

A
  • ganciclovir is incorporated into the DNA (not a good chain terminator) and the subsequent attempts at repair cause DNA strand breaks and apoptosis
40
Q

What are the main SE of bone marrow toxicity?

A
  • aplastic anemia
  • neutropenia
  • trombocytopenia
41
Q

What is more toxic- ganciclovir and acyclovir?

A
  • ganciclovir
42
Q

What is hepatitis C?

A
  • an RNA virus replicated by an RNA/RNA polymerase
43
Q

What is the historical treatment of hepatitis C?

A
  • ribavirin (inhibits viral replication)
  • pegylated interferon 2 alpha
    (double tx boosts the immune system)
44
Q

What is the toxicity of direct acting antivirals?

A
  • rash
  • nausea
  • fatigue
  • headache
45
Q

What is the MOA of ribavirin?

A
  • competitive inhibitor of IMP dehydrogenase and therefore of de novo synthesis of GTP and dGTP
  • inhibitor of viral guanylyltransferase of HCV (reduces viral RNA capping)
  • incorportated and acts as a mutagen for RNA viruses (mutation catastrophe)
  • direct inhibition of viral RNA/RNA polymerase
  • shift toward Th1 response
46
Q

What is the main toxicity of ribavirin?

A
  • hemolytic anemia (27% of patients)
    • ribavirin phosphates accumulate in erythrocytes, because they lack the phosphatases to hydrolyze
    • depletion of normal high energy phosphates
  • -sensitivity to oxidative damage
    • haemolysis and enhanced clearance of erythrocytes

Toxicology Final (14 decks)

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