Antivirals Flashcards
how are viruses different from bacteria
intracellular rely on host cell for metabolismm simple few targets for chemo diverse no natural antivirals exist toxicity linked to thier therapeutic metabolism
which treatmetn has the most common cause of toxicity by antivirals
HIV
more likely to get toxic effects from acute or chronic
chronic
how do nucleoside analogs work
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
why is crucial in preventing toxicity with nucleoside analogs
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
why is zalcitabine extremely toxic (nucleoside analog)
very stimilar to the nucleotide but missing the hydroxy group so stops DNA elongation
why is lamivudine not that toxic
has a sulfer and the ribose is an enantiomer so the shap is different
(other enantiomer is toxic)
how does the activation of the pro drug work
why is it good and bad to stay in the intracellular space
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
example of drug that already has phosphate group and doesnt need to be phosphorylated
cidofovir
toxicity issues if polymerase beta is inhibited (inhibition of DNA repair)
mutagenesis
theratogenesis
bone marrow suppression
toxic effects if polymerase alpha/delta is inhibited (inhibition of host cell dna synthesis)
bone marrow suppression
toxic effects if polymerase gamma is inhibited - more common
inhibition of mitochondrial dna synthesis peripheral neuropathy liver damage myopathy lactic acidosis
what is thymidine kinase 2
TK isoenzyme found in the mitochondria
most abundant species of TK in non dividing cell with many mitochondria
why do a high concentration of phosphorylated analogs accumulate in the mitochondria
mitochondria has abundant thymidine kinase which phosphorylates nucleosides and nucleoside analogs
examples of non dividing cells with many mitochondria
muscle tissues, liiver cells, neural cells
hepatotoxicity pathogenesis (mitochondrial toxicity)
loss of mitochondrial function in liver cell causes reduced aerobic metabolism and liver cell damage
signs and symptoms of hepatitis
high enzymes
fatty liver and alteration of lipid metabolism
lactic acidosis
death
peripheral neuropathy pathogenesis (mitochondrial toxicity)
shortage of energy for transmission of action potential along myelinated axons
signs and symptoms of peripheral neuropathy
tingling and burning sensation starting in the feet
loss of sensation and reflexes
spontaneous pain
why is central neuropathy due to mitochondrial toxicity rare
blood brain barrier
signs of central neuropathy
central deafness
myopathies pathogenesis (mitochondrial toxicity)
loss of mitochondrial in muscle causes loss of contraction strength and disruption of muscle architecture
signs and symptoms of myopathies
weakness
fatigue
cardiomyopathy - loss of contractility, enlargement of the heart
how does bone marrow suppression occur
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
azathiopurine effect on bone marrow
erythroid series affected leading to anemia
ganciclovir effect on bone marrow suppression
anemia
myelosuppression
thrombocytopenia
drug that causes serious hypersensitivity of immmunological origin
abacavir
pancreatitis cause by
ddC, ddl
drug that cuases tubular renal toxicity
cidofovir
tenofovir
other common adverse effect of antivirals
skin rash
how do non nucleoside RT inhibitors work
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
toxicity symptoms in NNRTI
rash and hypersensitivity most common
dyslipidemia
usually mild
frequent 5-20%
example of protease inhibitor
saquinavir
how do protease inhibitors work
prevents proteinase from cutting apart gag-pol poyprotein? on HIV gene so cant form new virions
cardiovascular concerns with protease inhibitors
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
recommended treatment of naive HIV infected patients
1 INSTI + 2 NRTIs
explain abacavir hypersensitivity
delayed hypersensitivity reaction within first 6 weeks of treatment with at least 2 symptoms: fever, rash, gastrointestinal, constitutional, respiratory
what must you do in abacavir hypersensitivity
stop therapy otherwise becomes progressively worse and death may occur
why cant you introduce one drug at a time in antiretroviral drugs
resistant viruses would be quickly selected
abacavir genetic testing
should do testing for HLA-B*5701 as it has excellent predictive value for hypersensitivity
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acyclovir toxicity
very diff from anythign in our body non toxic
ganciclovir toxicity
not as virus specific
incorporated into dna and subsequent attempts at repair cause dna strand breaks and apoptosis
triple specificity of acyclovir
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
gangciclovir used to treat
CMV which has a unique protein kinase that can phosphorylate ganciclovir
main problems with ganciclovir
bone marrow toxicity
aplastic anemia
neutropenia and thrombocytopenia
toxicity of direct acting antivirals
rash
nausea
fatigue
headache
ribavirin (for hepC) MOA proven
competitive inhibitor of IMP dehydrogenase and therefore of de novo synthesis of GTP and dGTP
incorporated and acts as a mutagen for RNA viruses
toxicity of ribavirin
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
new treatment for Hep C
direct acting antivirals:
HCV polymerase inhibitors (telaprevir, boceprivir, simeprivir, sofosbuvir)
HCV NS5A protein inhibitors (ledipasvir)
