Toxicology of Antivirals Flashcards
What are the main differences btw bacteria and viruses?
- 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
What is the rate of toxicity with antiviral medications?
low rate
Nucleoside analogs mimic the structure of _________
normal nucleosides
What needs to happen to allow for nucleoside analogs to be active?
- must be phosphorylated by cellular or viral enzymes to nucleotides inorder to be active
How do nucleoside analogs work?
-they compete with normal nucleosides for the viral polymerase or reverse transcriptase - incorporated into the viral DNA and stops the DNA replication
Host polymerases are _____ sensitive and are usually able to proof read out analogs that are incorporated
less
Phosphorylation of nucleosides is crucial for what?
to allow them to be incorporated into the DNA chain
What confirmation of the nucleoside analogs causes toxicity to the mitochondria?
- the + confirmation- our mitochondria like this confirmation
Does cidofovir need to be phosphorylated to get into the cell?
NO
What enzyme is typically involved in the inhibition of DNA repair?
- polymerase beta
What is the role of polymerase gamma?
- aids in mitochondrial DNA synthesis
- polymerase gamma- does not have proofreading activity
- not able to remove things once they’re incorporated
What is the action of TK-1 enzyme?
phosphorylates nucleosides and nucleoside analogs
What is the action of TK-2 enzymes?
TK isoenzymes found in the mitochondria - most abundant species of TK
What are some of the manifestations of mitochondrial toxicity?
- Hepatotoxicity
- Peripheral neuropathy
- Central neuropathy
- Myopathies
Explain the hepatotoxicity involved in antiviral toxicities
- 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
Explain the peripheral neuropathies involved in antiviral toxicities
- 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
Explain the myopathies that are involved in antiviral toxicities?
- 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)
What is the mechanism in which bone marrow suppression is thought to work?
- caused by inhibition of DNA polymerases n bone marrow precursor cells
AZT affects mostly in _____ series in bone marrow supp/
erythroid
Ganciclovir causes what with regard to bone marrow suppression?
- anemia, myelosuppression, trombocytopenia
What antiviral causes serious hypersensitivity of immunological origin?
- abacavir
What antiviral causes serious tubular renal toxicity?
- cidofovir
- tenofovir
What medications are considered NNRTIs?
- nevirapine
- efavirenz
- delaviridine
What is the MOA of NNRTIs?
- 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
NNRTIs are _________ inhibitors
non-competitive
What is the toxicity of NNRTIs?
- usually mild
- rash and hypersensitivity are common, also dyslipidemia
- ALSO can be psychiatric problems, dizziness, hepatic problems, etc
What is the MOA of PIs?
- inhibit HIV protease in a very specific manner
Why can’t you give PI’s are mono therapy?
- they rapidly cause onset of resistant viruses if given alone
- NOT very toxic
What is the “designer drug” of the PIs
saquinavir
What are the s/s or cardiovascular disease and PIs
- redistribution of fat - called the buffalo hump, peripheral wasting, lipodystrophy
- dyslipidemia- increase in serum lipids, increase risk of HD
- high cholesterol, high TG
PI increase the risk of ____ disease? Specifically what?
- cardiovascular
- myocardial infarction (increases risk by 16% per year of tx) - NNRTI does not have the same increase in TG and cholesterol
What is the combo of drugs usually used as anti-retroviral tx?
- INSTI (1) and NRTIs (2)
What are the 2 drugs that can cause an AKI?
indinavir and tenofovir
What is HIV associated neuropathy caused by?
- caused by the HIV infection directly
What is the grouping of sx caused by abacavir hypersensitivity?
- fever
- rash
- GI
- constitutional
- respiratory
Hypersensitivity to abacavir is linked to what?
- specific HLA alleles (HLA-B*5701 in particular)
What is acyclovir used for?
- herpes simplex virus
- varicella- zoster
What is the triple specificity of acyclovir?
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
What is the MOA of ganciclovir?
- ganciclovir is incorporated into the DNA (not a good chain terminator) and the subsequent attempts at repair cause DNA strand breaks and apoptosis
What are the main SE of bone marrow toxicity?
- aplastic anemia
- neutropenia
- trombocytopenia
What is more toxic- ganciclovir and acyclovir?
- ganciclovir
What is hepatitis C?
- an RNA virus replicated by an RNA/RNA polymerase
What is the historical treatment of hepatitis C?
- ribavirin (inhibits viral replication)
- pegylated interferon 2 alpha
(double tx boosts the immune system)
What is the toxicity of direct acting antivirals?
- rash
- nausea
- fatigue
- headache
What is the MOA of ribavirin?
- 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
What is the main toxicity of ribavirin?
- 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
