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36 Cards in this Set
- Front
- Back
Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs)
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- ZDV/AZT, Stavudine, Didanosine, Tenofovir, Lamivudine, Abacavir
- MOA: termination of DNA elongation - PK: renally excreted - AE: mainly b/c of inhibition of mitochondrial DNA poly.; if more than one given --> overlapping toxicities; Liver toxicity** (lactic acidosis, hepatomegaly w/ steatosis) |
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Nucleoside/-tide Reverse Transcriptase Inhibitors (NRTIs) - Drug interactions / Resistance
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- Drug interactions: not many (except w/ ZDV + tenofovir)
- Resistance: most common mutation at viral codon 184: lamivudine (restores sensitivity to ZDV and Tenofovir) - cross-resistance b/w agents of same analog class |
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Zidovudine / 3'azido-3'deoxythymidine (ZDV, AZT)
-AE/CI |
- AE: bone marrow suppression (neutropenia, anemia), headaches; GI intolerance
- CI: toxicity potentiated by coadin of probenecid, acetaminophen, lorazepam, indomethacin, and cimetidine - stavudine and ribavirin activated by same pathways - Clinical app: prophylaxis in exposed and prevention of prenatal infection - PK: absorbed well orally, BBB, glucuronylated by liver --> urine |
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Stavudine (d4T)
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- strong inhibitor of beta and gamma DNA polymerases (decreases mitochondrial DNA synthesis --> toxicity)
- PK: completely absorbed orally, penetrates BBB - AE: peripheral neuropathy |
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Didanosine (ddl)
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- HIV adults/children in comb w/ other agents
- PK: absorption best if taken in fasting state (acid labile) or combined with antacid - penetrates into CSF (less than AZT) - AE: pancreatitis (can be fatal, monitor serum amylase); peripheral neuropathy - CI: Stavudine (similar toxicities) |
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Tenofovir (TDF)
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- PK: should be taken w/ food
- long half-life - most of drug recovered unchanged in urine - AE: GI (nausea, diarrhea, vomiting, flatulence) - CI: ONLY NRTI W/ SIG DRUG INTERACTIONS (increases [ddl] --> dosage reductions required) - DECREASES [atazanavir] --> boosted w/ ritonavir |
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Lamivudine (3TC)
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- terminates synthesis of proviral DNA chain and inhibits HIV and HBV RT (DOES NOT AFFECT MITOCHONDRIAL DNA synt or BONE MARROW PRECURSOR CELLS)
- approved for tx of HIV in comb w/ AZT - single amino acid substitution --> resistance - few AE - Emtricitabine (FTC) is a structural relative of 3TC |
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Abacavir (ABC)
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- guanosine analog
- may be cross-resistant w/ strains resistant to AZT + 3TC - AE: GI, headache, dizziness - 5%: HS RXN - SENSITIZED INDIV SHOULD NEVER BE RECHALLENGED (genetically screen) |
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Nonnucleoside Reverse Trancriptase Inhibitors (NNRTIs)
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MOA - highly-selective, non-competitive inhibitors of HIV-1 RT
- DO NOT REQUIRE ACTIVATION BY CELLULAR ENZYMES - Advantages = lack of effect on host blood-forming elements = lack of cross resistance with NRTIs - Disadvantages = cross-resistance w/ NNRTIs, drug interactions, high incidence of HS rxns - Nevirapine, Efavirenz, Delavirdine (Never Ever Deliver nucleosides) |
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Nevirapine (NVP)
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- used in comb w/ other anti-retrovirals for HIV-1 tx
- PK: well abs orally, wide tissue dist, BBB, excreted in urine as metabolites (CYP3A4 + CYP2B6) |
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Nervirapine (NVP) - AE
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- potential severe hepatotoxicity (dont use in women with CD4+ counts > 250 cells/mm and men >400)
- RASH (16%) - dermatologic effects (stevens-johnson syn + toxic epidermal necrolysis) |
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Nevirapine (NVP) - CI / Resistance
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CI
- INDUCER OF CYP3A4 --> inc metabolism of PI's, OCP, ketoconazole, methadone, metronidazole, quinidine, theophylline, and warfarin Resistance - target site is HIV-1 specific and not essential to enzyme --> resistance develops rapidly |
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Efavirenz (EFV)
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- preferred NNRTI on DHHS guidelines (results in inc CD4 counts and decrease in viral load)
- PK: well dist after oral admin (better w/ fatty meal); 99% bound to albumin; extensively metabolized to inactive products - AE: mostly CNS - dizziness, headache, vivid dreams; resolve in few weeks - RASH - CI = PREGNANCY - potent inducer of CYP450 enzymes |
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Protease Inhibitors (PIs) - MOA
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- reversible inhibitors of HIV aspartyl protease (enzyme responsible for cleavage of viral polyprotein into RT, protease, and integrase)
- inhibition prevents maturation and results in production of non-infectious virions |
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Protease Inhibitors (PIs) - PK
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- POOR oral bioavailability
- high fat meals can increase (nelfanvir and saquinavir) and decrease (indinavir) bioavailability - SUBSTRATES FOR CYP3A4 |
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- Protease Inhibitors (PIs) - AE
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- parathesias, nausea, vomiting, diarrhea
- dist in lipid metabolism - chronic admin --> fat redistribution |
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- Protease Inhibitors (PIs) - Drug Interactions / Resistance
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Drug Interactions - Potent inhibitors of CYP isozymes **; eg: rhabdomyolysis (simvastatin or lovastatin), excessive sedation (midazolam or triazolam), resp depression (fentanyl)
- warfarin, sildenafil, and phenytoin --> dosage adjustments - Rifampicin and st. johns wort --> CI Resistance: acc of stepwise mutations of protease gene (can lead to high levels of resistance) |
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- Ritonavir (RTV)
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- PK enhancer
- Booster of other PI's - potent inhibitor of CYP3A4 |
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- Saquinavir (SQV)
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- given w/ low dose RTV
- high fat meals enhance abs |
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- Indinavir (IDV)
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- given w/ RTV to inc abs
- least protein bound - abs decreased with meals - dosage reduced with hepatic insufficiency - AE: nephrolithiasis + hyperbilirubinemia (adeq hydration imp) |
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Nelfinavir (NFV)
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- CANNOT be boosted by RTV
- met by several CYPs - can inhibit met of other drugs |
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Fosamprenavir (fAPV)
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- given w/ RTV
- prodrug = amprenavir |
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Lopinavir (LPVr)
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- one of the preferred PIs
- given w/ RTV - POOR intrinsic bioavailability - enzyme inducers (ex St. Johns Wort) should be avoided |
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Atazanavir (ATV)
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- ATV + RTV are only once-daily preferred PIs
- structurally unrelated to other PIs - well abs orally - high protein bound - PPI = CI - competitive inhibitor of glucuronyl transferase (benign hyperbilirubinemia and jaundice) - prolongs PR interval and slows heart |
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Tipranavir (TPV)
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- inhibits HIV protease resistant to other PIs
- SEVERE and FATAL HEPATITIS - FATAL and NONFATAL INTRACRANIAL HEMORRHAGES |
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Darunavir (DRV)
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- Inhibits HIV protease ressitant to other PIs
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Inhibition of Viral Attachment
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Enfuvirtide (T-20)
- use in tx-experienced adults w/ evidence of HIV replication |
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Enfuvirtide (T-20) - MOA
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- structurally similar to gp41 (HIV protein mediates membrane fusion)
- Prevents ability of virion to fuse membranes |
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Enfuvirtide (T-20) - PK and AE
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PK: admin parenterally twice daily subcutaneously
AE: injection-related, HS rxns, Eosinophilia |
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Inhibition of Viral Entry
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Maraviroc
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Maraviroc - MOA, PK, AE
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MOA: blocks CCR5 coreceptor that works w/ gp41 to facilitate HIV entry through cell membrane (only CCR5-expressing virus can be treated w/ maraviroc)
PK: orally, met by CYP3A4 (dose reduced when given w/ PIs) AE: well tolerated, risk of hepatotoxicity |
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Integrase Strand Transfer Inhibitor (INSTI)
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Raltegravir (RAL)
- in comb w/ other retrovirals is approved for tx-experienced and tx-naive pts w/ evidence of viral replication |
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Raltegravir (RAL)
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- MOA: inhibits final step in integration of viral DNA into host cell DNA
- PK: metabolism - UGT1A1-mediated glucuronidation --> no interactions w/ CYP450 inducers, inhibitors, etc - AE: well tolerated, nausea, headache, diarrhea |
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Current Recc for tx of Naive pts- Goals
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- maximally and durably suppress viral load replication
- restore and preserve immunologic fxn - reduce HIV-related morbidity and mortality INCREASE QUALITY OF LIFE |
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Current Recc for tx of Naive pts - Regimens
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1 of following
- NNRTI + 2 NRTI - PI (preferably boosted w/ ritonavir) + 2NRTI - INSTI + 2 NRTI |
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Current recc for use of antiretroviral drugs in pregnancy
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Ritonavir-boosted lopinavir (2 daily) + Zidovudine/lamivudine
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