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TOXICOLOGY > Antivirals > Flashcards

Antivirals Flashcards

1
Q

how are viruses different from bacteria

A 
intracellular
rely on host cell for metabolismm
simple few targets for chemo
diverse
no natural antivirals exist
toxicity linked to thier therapeutic metabolism
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2
Q

which treatmetn has the most common cause of toxicity by antivirals

A

HIV

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3
Q

more likely to get toxic effects from acute or chronic

A

chronic

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4
Q

how do nucleoside analogs work

A

mimic the stucture of normal nucleoside but must be phosphorylated by cellular or viral enzymes to nucleotides to become active so have to compete with the normal nucleoside for viral polymerase or reverse transcriptase
after that they are incorporated into the viral DNA to stop DNA replication

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5
Q

why is crucial in preventing toxicity with nucleoside analogs

A

selectivity for VIRAL polymersae
host polymerase are less sensitive usually able to proof read out analogs once theyre incorporated if this doesnt happen have a problem

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6
Q

why is zalcitabine extremely toxic (nucleoside analog)

A

very stimilar to the nucleotide but missing the hydroxy group so stops DNA elongation

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7
Q

why is lamivudine not that toxic

A

has a sulfer and the ribose is an enantiomer so the shap is different
(other enantiomer is toxic)

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8
Q

how does the activation of the pro drug work

why is it good and bad to stay in the intracellular space

A

analog with 5’OH enters the intracellular space and get converted by thymine kinase into nucleotide(3phosphates) and stays in the cell until metabolized
good to accumulate and kill virus but bad for toxicity

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9
Q

example of drug that already has phosphate group and doesnt need to be phosphorylated

A

cidofovir

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10
Q

toxicity issues if polymerase beta is inhibited (inhibition of DNA repair)

A

mutagenesis
theratogenesis
bone marrow suppression

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11
Q

toxic effects if polymerase alpha/delta is inhibited (inhibition of host cell dna synthesis)

A

bone marrow suppression

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12
Q

toxic effects if polymerase gamma is inhibited - more common

A 
inhibition of mitochondrial dna synthesis
peripheral neuropathy
liver damage
myopathy
lactic acidosis
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13
Q

what is thymidine kinase 2

A

TK isoenzyme found in the mitochondria

most abundant species of TK in non dividing cell with many mitochondria

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14
Q

why do a high concentration of phosphorylated analogs accumulate in the mitochondria

A

mitochondria has abundant thymidine kinase which phosphorylates nucleosides and nucleoside analogs

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15
Q

examples of non dividing cells with many mitochondria

A

muscle tissues, liiver cells, neural cells

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16
Q

hepatotoxicity pathogenesis (mitochondrial toxicity)

A

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

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17
Q

signs and symptoms of hepatitis

A

high enzymes
fatty liver and alteration of lipid metabolism
lactic acidosis
death

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18
Q

peripheral neuropathy pathogenesis (mitochondrial toxicity)

A

shortage of energy for transmission of action potential along myelinated axons

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19
Q

signs and symptoms of peripheral neuropathy

A

tingling and burning sensation starting in the feet
loss of sensation and reflexes
spontaneous pain

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20
Q

why is central neuropathy due to mitochondrial toxicity rare

A

blood brain barrier

21
Q

signs of central neuropathy

A

central deafness

22
Q

myopathies pathogenesis (mitochondrial toxicity)

A

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

23
Q

signs and symptoms of myopathies

A

weakness
fatigue
cardiomyopathy - loss of contractility, enlargement of the heart

24
Q

how does bone marrow suppression occur

A

inhibition of dna polymerases in bone marrow precursor cells causes mutations and inhibition of repair leading to cell death and inhibition of dna replication in rapidly multiplying cells

25
Q

azathiopurine effect on bone marrow

A

erythroid series affected leading to anemia

26
Q

ganciclovir effect on bone marrow suppression

A

anemia
myelosuppression
thrombocytopenia

27
Q

drug that causes serious hypersensitivity of immmunological origin

A

abacavir

28
Q

pancreatitis cause by

A

ddC, ddl

29
Q

drug that cuases tubular renal toxicity

A

cidofovir

tenofovir

30
Q

other common adverse effect of antivirals

A

skin rash

31
Q

how do non nucleoside RT inhibitors work

A

binds to reveres transcriptase or polymerase at sites other than the nucleotide triphosphate binding site causing distortion of the polymerase which becomes unable to catalyze dna elongation
aka non competitive inhibitors

32
Q

toxicity symptoms in NNRTI

A

rash and hypersensitivity most common
dyslipidemia
usually mild
frequent 5-20%

33
Q

example of protease inhibitor

A

saquinavir

34
Q

how do protease inhibitors work

A

prevents proteinase from cutting apart gag-pol poyprotein? on HIV gene so cant form new virions

35
Q

cardiovascular concerns with protease inhibitors

A

redistribution of fat - buffalo hump, peripheral wasting, lipodystophy(loss of fat in strips)
dyslipidemia increases risk of heart disease
increase risk of MI 16% per year of treatment

36
Q

recommended treatment of naive HIV infected patients

A

1 INSTI + 2 NRTIs

37
Q

explain abacavir hypersensitivity

A

delayed hypersensitivity reaction within first 6 weeks of treatment with at least 2 symptoms: fever, rash, gastrointestinal, constitutional, respiratory

38
Q

what must you do in abacavir hypersensitivity

A

stop therapy otherwise becomes progressively worse and death may occur

39
Q

why cant you introduce one drug at a time in antiretroviral drugs

A

resistant viruses would be quickly selected

40
Q

abacavir genetic testing

A

should do testing for HLA-B*5701 as it has excellent predictive value for hypersensitivity
l

41
Q

acyclovir toxicity

A

very diff from anythign in our body non toxic

42
Q

ganciclovir toxicity

A

not as virus specific

incorporated into dna and subsequent attempts at repair cause dna strand breaks and apoptosis

43
Q

triple specificity of acyclovir

A

phosphorylates exclusively by the herpes thymidine kinase
strong specificity for the viral dna polymerase
cellular polymerases proofread acyclovir out of the dna but viral polymerase does not

44
Q

gangciclovir used to treat

A

CMV which has a unique protein kinase that can phosphorylate ganciclovir

45
Q

main problems with ganciclovir

A

bone marrow toxicity
aplastic anemia
neutropenia and thrombocytopenia

46
Q

toxicity of direct acting antivirals

A

rash
nausea
fatigue
headache

47
Q

ribavirin (for hepC) MOA proven

A

competitive inhibitor of IMP dehydrogenase and therefore of de novo synthesis of GTP and dGTP
incorporated and acts as a mutagen for RNA viruses

48
Q

toxicity of ribavirin

A

hemolytic anemia!!
ribavirin phosphates accumulate in erythrocytes because they lack the phsphatases to hydrolyze them
deplretion of normal high energy phosphates
sensitivity to oxidative damage
haemolysis and enhanced clearance of erythrocytes

49
Q

new treatment for Hep C

A

direct acting antivirals:
HCV polymerase inhibitors (telaprevir, boceprivir, simeprivir, sofosbuvir)
HCV NS5A protein inhibitors (ledipasvir)

TOXICOLOGY (24 decks)

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