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53 Cards in this Set
- Front
- Back
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What are the 2 main tests that pts with HIV are given?
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- Plasma HIV RNA levels which indicates viral load (goal of treatment is to reduce to undetectable levels)
- CD4 T cell count which shows immune damage |
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Which pts with HIV should be treated?
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- symptomatic pts -Thrush, wasting, or opportunistic infections.
- pts with rapid decrease in CD4 T cell ct - pts with plasma HIV RNA levels greater than 100K copies/mL - Special pop-- preg women, HIV related kidney disease, Hep B or C Every pt is not treated b.c high resistance rates with noncompliance and high toxicity |
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What classes of drugs should be combined in initial HAART treatment?
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- 2 NRTIs + NNRTIs or PI or intergrase inhibitor
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HIV Infection Mechanism
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HIV infects CD4+ cells by binding and fusing at the CD4+ receptor site
HIV inserts its viral RNA into the host cell along with other key enzymes involved in replication Enzyme reverse transcriptase catalyzes viral RNA to viral DNA Since it needs the host cell for survival and with the assistance of HIV unique enzyme, integrase, the viral DNA migrates into the host CD4+ cell DNA strands Host cell transcribes viral DNA to viral RNA Viral RNA is converted to viral polyproteins that are cleaved and activated by protease enzymes Once these essential proteins are formed, new virions are enveloped and depart the host CD4+ cells to infect others |
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NRTI Drugs MOA
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- Bacterial reverse transcriptase has to convert viral RNA into proviral DNA and insert into the host cell's genetic material.
- NRTIs can only protect newly infected cells MOA: NRTIs are substrates for reverse transcriptas adn will incorporate into false nucleic acids and into the newly produced proviral DNA - b/c NRTIs lack 3' hydroxyl group, thus incorporation into DNA terminates chain elongation |
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Zidovudine - AZT- Class, MOA, Tox
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- Class: NRTI
- MOA: thymidine analog which must be activated and then terminates chain elongation - Tox: Bone marrow suppression - NRTIs generally have a prob with hepatic steatosis due to increasd lactic acidosis |
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Lamivudine- Class, MOA, Tox
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Class: NRTI
MOA: cytosine analog Tox: Minimal toxicity |
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Stavudine- Class, MOA, Tox
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Class: NRTI
MOA: thymidine analog Tox: peripheral neuropathy, lipidystrophy, pancreatitis |
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Didanosine- Class, MOA, Tox
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Class: NRTI
MOA: adenosine analog Tox: pancreatitis, peripheral neuropathy |
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Abacavir - Class, MOA, Tox
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Class: NRTI
MOA: carbocylic nucleoside analog Tox: hypersensitivity which can be fatal, should not rechallenge |
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Emtricitabine - Class, MOA, Tox
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Class: NRTI
MOA: cytosine analog Tox: minimal toxicity |
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Tenofovir- Class, MOA, Tox
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Class: NRTI (nucleoTide RT inhibitor)
MOA: adenosine analog, which acts as a nucleoTIDE RT inhibitor Tox: Nephrotoxicity |
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NRTIs must be activated _____ and thus have a ______ half life
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1. intracellularly
2. short half life |
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Do NRTIs bind protein heavily?
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No, which decreases concerns about drug interactions
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Does the liver metabolize NRTIs? How is the drug excreted-- mainly in the parent form or in inactive form?
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Yes the liver metabolizes NRTIs to inactive forms. These inactive forms are then excreted by the kidney
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What is the importance of knowing renal excretion of certain drugs?
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If renal excretion of the parent drug is greater than normal than must lower the dose for your pt
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What is the MOA of NNRTIs?
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- Non nucleoside reverse transcriptase inhibitors, inhibit RT by binding to peripheral site on HIV-1 RT enzyme itself and induces conformational changes. NNRTIs can only protect newly infected cells. Liver toxicity is biggest problem. NNRTIs work only against HIV1
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Why do NNRTIs have longer half lives than NRTIs? Do NNRTIs have more or less drug interactions than NRTIs? Why?
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B/c NNRTIs do not have to be activated intracellularly like NRTIs do, so have much longer half lives.
NNRTIs have more drug interactions than NRTIs b/c they are bound to plasma proteins. |
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Is the liver the main metabolizer of NNRTIs or are NNRTIs excreted in mainly the parent form?
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Liver metabolizes NNRTIs to inactive form and thus are excreted in the inactive form by the kidney
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Delavirdine- Class, Tox
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Class: NNRTIs
Tox- rash, increased transaminase levels, headaches |
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Efavirenz- Class, Tox
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Class: NNRTIs
Tox: Rash (10%), CNS symptoms (VIVID dreams) >50% of pts, increased transaminase levels, contraindicated in pregnancy |
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Nevirapine- Class, Tox
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Class: NNRTIs
Tox: symptomatic hepatitis |
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Etravirine- Class, Tox
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Class: NNRTIs
Tox: Rash (severe and life threatening) within first 6 wks of therapy, hepatic failure |
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What is the MOA for the drug class Protease Inhibitors?
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MOA: HIV protease= essential enzyme for viral survival and infectivity. HIV protease cleaves viral polyprotein into active viral enzymes. PIs bind reversibly to the active site of HIV protease to make it inactive, viral particles then become immature and non infectious. PIs inhibit viral replication in any infected cells
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Do PIs as a class need to be activated intracellularly?
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No
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What liver metabolism pathway do PIs use? What significance does this have for dosing?
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CYP3A4 pathway. This is significant for dosing b/c when PIs are given together they have a synergistic effect b/c less of each drug is metabolized to the inactive form in the liver thus a smaller dose of each PI is required making it more likely that pt will tolerate the drugs well
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Do PIs generally bind to plasma proteins?
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Yes, thus must be careful about drug interactions
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Saquinavir- Class, Tox
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Class: PI
Tox: GI, headache, *elevated transaminase enzymes |
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Indinavir- Class, Tox
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Class: PI
Tox: GI, Kidney stones, hyperbilirubinemia, alopecia |
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Ritonavir- Class, Tox
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Class: PI
Tox: hepatitis, increased triglycerides |
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Nelfinavir- Class, Tox
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Class: PI
Tox: GI, asthenia, elevated transaminase enzymes |
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Tipranavir- Class, Tox
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Class: PI
Tox: GI, intracranial hemorrhage, hepatotoxicity |
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Lopinavir- Class, Tox
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Class: PI
Tox: GI, asthenia, elevated transaminase enzymes |
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Atazanavir- Class, Tox
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Class: PI
Tox: Hyperbilirubinemia, prolongs PR interval, nephrlitiasis |
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Fosamprenavir- Class, Tox
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Class: PI
Tox: GI, CNS, rash, elevated transaminase enzymes |
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What is a common adverse rxn for PI drugs?
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Endocrine distrubances leading to hyperglycemia, fat redistribution (40-50%), and lipid abnormalities (70%). Also ostopenia and osteoporosis
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What is the MOA of Fusion Inhibitor class of drugs?
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MOA: New med which inhibs fusion of virus to cellular membranes, thus prevents conformational changes required by virus transmembrane glycoprotein to attach to the CD4+ cells
- FIs only work against HIV1 |
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Enfuvirtide (Fuzeon)- Indication, PK, Tox
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Indication: advanced HIV 1 infection pts, or pts who are not responding to antiretroviral therapy. Is very expensive
PK: IV (not an inhibitor of CYP450 enzymes) Tox: Injection site rxns |
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Maraviroc- Class, MOA, Indic, Tox
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Class: New agent
MOA: chemokine coreceptor 5 antagonist (must do genetic testing of pt to see if effective option for pt) Indications: For pts with MDR HIV Tox: general but BLACK BOX warning for hepatotoxicity |
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Raltegravir- Class, MOA, Indic, Tox
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Class: New agent
MOA: HIV integrase inhibitor, integrase is needed for insertion of the Viral DNA into the human chromosome Tox: general and myopathy |
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What is better for HIV treatment monotherapy or polypharmacy?
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Polypharmacy b/c otherwise there is rapid development of viral resistance
- must use 3-4 different agents - sequential therapy is the worst b/c there is even more rapid resistance development |
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NRTIs require how many codon substitutions in order for the virus to become resistant? Is this a high or low genetic barrier?
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3-4 codons, which is relatively high genetic barrier
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NNRTIs require how many codon substitutions in order for the virus to become resistant? High or low genetic barrier to mutn?
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A single codon substn, this is low genetic barrier to mutn. resistance can occur QUICKLY (days to weks)
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PIs require how many codon substitutions in order for the virus to become resistant? High or low genetic barrier to mutn?
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4-5 codon substn, takes mos for mutn to occur, this is high genetic barrier to mutn
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Entry inhibitors require how many codon substitutions in order for the virus to become resistant? High or low genetic barrier to mutn?
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- single aa substn can increase resistance at GP 41 site, this low genetic barrier to resistance
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What are two methods to monitor HIV ?
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1. HIV RNA levels-- indicates viral load, must get down to undetectable levels, must have 1.5- 2.0 log decline after beginning therapy, target should be met in 4-6 mos, If decline is not seen evaluate adherence, drug absorption, or drug resistance
2. CD4 count |
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How often must therapy be monitored with HAART?
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Within 1 month of therapy and monthly till goal is met. After goal is met must monitor every 2-3 mos
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Resistance Tests for antiretrovirals, phenotype test? Genotype test?
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Phenotype= determined by concentration of antiretroviral necessary to inhibit 50% replication of pts viral isolate
Genotype: Determine genetic mutns associate with codon changes |
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What is a general toxicity associated with NRTIs
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Inhibition of cellular DNA polymerase, enzyme responsible for mitochondrial DNA synthesis
Mitochondrial dysfunction leads to: - Hepatic steatosis (fatty liver) - Lactic acidosis- a, n/v, abdominal pain, shortness of breath, extreme fatigue, myalgias b. Excess serum lactate & multi-organ dysfunction c. Uncommon complication but fatal - Peripheral neuropathy, myopathy, anemia, thrombocytopenia |
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What is the defintn of hepatotoxicity? Which class of antiretrovirals are most often ass. with hepatotoxicity?
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- 3-5 fold increase in serum transaminase, w/ or w/o clinical hepatitis
- Associated with NNRTIs and PIs |
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What is the toxicity ass with PI?
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- HIV ass lipodystrophy syndrome
- fat redistribution around peripheral extermities and increased ab fat - metabolic complications-- abnormal glucose metabolim, hyperlipidemia, hypertrigliceridemia. within wks of therapy must monitor metabolic panels - Ostopenia and osteoporosis is also associated with PIs, must increase Ca+2 and vit D intake |
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HIV associated lipidystrophy syndrome associated with which drugs?
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PIs and stavudine, HIV itself can also cause
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What are the potential drug interactions of PIs?
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Cyt P450 inhibitor, substrate
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