Term
HIV/AIDS: susceptible cells include CD4 T lymphocytes
Human T-cell leukemia viruses |
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Definition
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Term
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CCR5 inhibitors: Maraviroc, inhibits the penetration and uncoating of the virus
nucleoside analog reverse transcriptase inhibitors: zidovudine, didanosine, lamivudine, zalcitabine, stavudine, abacavir
non-nucleoside analog reverse transcriptase inhibitors: nevirapine, delavirdine, efavirenz
integrase inhibitors: raltegravir; inhibit integration of viral RNA with host chromosomes
protease inhibitors: amprenavir, nelfinavir, indinavir, ritonavir, atazanavir, saquinavir; inhibits last part of viral replication |
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Definition
| 4 classes of antiretroviral drugs |
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Term
combination therapy:
to prevent resistance, HIV will mutate/change very quickly
attack the virus from different fronts = stronger activity
most HIV drugs have a narrow therapeutic index, if given in combination there is a synergistic effect so that there can be decreased doses given |
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Definition
| what is the treatment strategy of the treatment of HIV? |
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Term
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Definition
| nucleoside reverse transcriptase inhibitors |
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Term
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first class of agents approved for treating HIV infection
block the initial phase of viral replication
they prevent the infection of NEW CELLS - do not affect chronically infected cells
dideoxynuceloside analogs
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inhibition of reverse transcriptase -> prevents conversion of viral RNA genome into a double stranded copy prior to integration into the cell genome
occurs early in the replication (better for acute infections than chronic ones)
INHIBITORS AND SUBSTRATES for the reverse transcriptase enzyme
selective toxicity
binding to the enzyme template primer
reverse transcriptase has a higher affinity for NRTIs than the natural substrate
NRTIs have to compete with the natural substrate for host cell enzymes to be phosphorolated and for the enzyme (reverse transcriptase)
each nucleoside (and each analog of that nucleoside) have there own set of enzymes in the cell to become activated. because of this, 2 NRTIs can be given together because they will be working on 2 different biosynthetic pathways |
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Definition
| MOA of nuceloside analog reverse transcriptase inhibitors |
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Term
associated with point mutations -> aa substitutions in the reverse transcriptase enzyme
AZT resistance -> deoxynuceloside triphosphate binding site decreased affinity
if a strain becomes resistant, there will not be cross resistance with other NRTIs because different enzymes are used for each nucleoside
cross resistance will develop if the same enzymes are being targeted |
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Definition
| mechanism of resistance to nucleoside reverse transcriptase inhibitors |
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Term
absorption: good systemic bioavailability after oral administration, didanosine has low and variable absorption (acid liable), high fat protein meal slows zidovudine absorption
distribution: low plasma protein binding, well distributed to tissues and cells, penetration into CSF and CNS
metabolism: rapidly cleared, metabolized in the liver
excretion: kidneys |
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Definition
| ADME of nucleoside analog reverse transcriptase inhibitors |
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Term
toxicity is related to incorporation and inhibition of NON-VIRAL DNA polymerases
dose-limiting toxicities = narrow therapeutic window
BONE MARROW TOXICITIES:
neutropenia and anemia - inhibits hematopoietic cells growth in the bone marrow
reversible and dose-dependent
PERIPHERAL NEUROPATHY:
painful, slow onset, tingling, burning, pain at rest
resolves after termination of therapy
related to mitochondrial DNA synthesis
MYOPATHY:
long lasting and debilitating
muscle mitochondrial toxin - interferes with oxidative phosphorylation and respiratory chain activity
PANCREATITIS:
mainly associated with didanosine
progressive abdominal pain, nausea, vomiting
HEPATIC TOXICITY:
hepatomegaly with fatty degeneration of the liver
metabolic acidosis
inhibition of mitochondrial DNA synthesis |
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Definition
| ADRs of nucleoside analog reverse transcriptase inhibitors |
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Term
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Definition
| non-nucleoside reverse transcriptase inhibitors |
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Term
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structurally diverse class of antivirals
directly bind to reverse transcriptase (unlike nucleoside analog reserve transcriptase which bind at the catalytic site replacing the natural substrate)
allosteric inhibition of enzyme function (changes the conformation of the enzyme still allowing substrate to bind, but inhibiting catalytic activity)
disrupts enzyme's catalytic site, blocking transcription
non-competitive with respect to substrates
minimal cellular toxicity
no phosphorylation needed
quite specific to HIV
rapid emergence of resistance
cross-resistance between them
no cross-resistance to NRTIs or protease inhibitors |
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Definition
| MOA non-nucleoside analog reverse transcriptase inhibitor: nevirapine, delavirdine, efavirenz |
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Term
rapidly absorbed PO
highly lipophilic - binding to plasma proteins (whereas NRTI have low protein binding)
extensively metabolized by CYP450 enzymes
excreted renally and in feces (efavirenz) |
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Definition
| ADME of non-nucleoside reverse transcriptase inhibitor |
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Term
low toxicity
skin rashes: maculopapular
headache, fatigue, GI complaints, and hepatic enzyme elevation |
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Definition
| ADRs of non-nucleoside reverse transcriptase inhibitors |
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Term
metabolism by and effect on CYP450 enzymes
nevirapine INDUCES CYP3A
delavirdine INHIBITS CYP450
efavirenz INDUCES CYP3A4 |
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Definition
| drug interactions of non-nucleoside analog reverse transcriptase inhibitors |
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Term
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HIV protease (proteinase):
essential component of the replicative cycle
post-translational modification of core proteins
activates reverse transcriptase
release of infectious viral particles
dimer - monomer has 2 conserved aspartic residues at the active site
inhibitors prevent post-translational processing and budding
transition state mimetics |
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Definition
| MOA of protease inhibitors: amprenavir, ritonavir, nelfinavir, indinavir, atazanavir, saquinavir |
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Term
absorption: indinavir, ritonavir, and nelfinavir - good absorption PO; saquinavir - low absorption PO (differences due to 1st pass metabolism)
distribution: highly bound to plasma proteins
metabolism: CYP450
excretion: urine |
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Definition
| ADME of protease inhibitors |
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Term
GI disturbances
hemorrhages
hypertriglyceridemia, glucose intolerance and abnormal fat distribution |
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Definition
| ADRs of protease inhibitors |
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Term
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CCR5 receptor antagonist: entry inhibitor
for the treatment of adults with CCR5 receptor (have to be tested to see if they have the receptor) which high viral load of HIV in their blood despite treatment with other HIV medications |
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Definition
| MOA of CCR5 inhibitors (maraviroc) |
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Term
good absorption after oral administration
highly bound to plasma proteins |
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Definition
| ADME of CCR5 inhibitor (maraviroc) |
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Term
upper respiratory tract infection
rash
cough
abdominal pain
dizziness
pyrexia
drug interactions: CYP3A4 substrate |
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Definition
| ADRs of CCR5 inhibitor (maraviroc) |
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Term
inhibits insertion of viral DNA into human DNA
rapidly absorbed
no drug interactions due to CYP450 metabolism
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Definition
| MOA of integrase inhibitor (raltegravir) |
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