HAART_and_Kidney[1]

HAART_and_Kidney[1] - HAART AND KIDNEY Nephrology Grand...

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HAART AND KIDNEY Nephrology Grand Rounds Tuesday, December 22 nd 2009 Aditya Mattoo
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Outline HIV Life Cycle Antiretroviral Pharmacokinetics Dosing Adjustments in Kidney Disease Antiviral Renal Tubular Handling Antiretroviral Renal Toxicities Indinavir Crystalluria Tenofovir Nephrotoxicity
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HIV Life Cycle HIV is internalized by binding to CD4 surface receptors on T cells. HIV RNA is released from nucleocapsid, then RT copies genomic RNA into proviral DNA. Proviral DNA is then inserted into host cell DNA. The inserted HIV genome is transcribed into RNA, including new proviral RNA that will be packaged into new virions as viral RNA. Other RNA are translated into viral capsid and regulatory proteins. Post-translational cleaving of polyproteins by viral protease. Viral RNA is packaged in new capsid envelopes and released from the cell as newly formed Berns et al. HAART and the kidney: An update on antiretroviral medications for nephrologists. CJ ASN, 1:117-129, 2006.
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ANTIRETROVIRALS
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Antiretrovirals Initial HAART regimens include combinations of drugs from at least two different of the three major classes of antiretroviral agents. The new fusion inhibitor, enfurvirtide, and the new integrase inhibitor, raltegravir, are not recommended as part of an initial HAART regimen at this time. Many ART agents are eliminated at least partly by the kidneys and require dosage adjustments in patients with reduced GFR.
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Protease Inhibitors Primarily metabolized in the liver Urinary excretion accounts for 10% of clearance for indinavir and <5% for other drugs in this class. PIs are highly protein bound, most being >90% protein bound in serum, however indinavir is approximately 60% protein bound. Not cleared by any significant extent by HD or PD. None of the currently available PI requires dose adjustment for patients with impaired kidney function.
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Nucleoside vs Nucleotide Structure NRTI and NtRTI is essentially the same; they are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with them for incorporation into the growing viral DNA chain. NNRTI block reverse transcriptase by binding at a different site on the enzyme, compared to NRTIs and NtRTIs. NNRTIs are not incorporated into the viral DNA but instead inhibit the movement of protein domains of reverse transcriptase that are needed to carry out the process of DNA synthesis (i.e. non-competitive inhibition).
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Nucleoside Reverse Transcriptase Inhibitors (NRTI) All of the NRTI except abacavir require dosage adjustment in patients with impaired kidney function and in patients on dialysis. NRTI are small molecules with volumes of
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  • Fall '11
  • Dr.Aslam
  • Antiretroviral drug, lactic acidosis, Reverse transcriptase inhibitor, severe lactic acidosis, NRTI, NRTI Lactic

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HAART_and_Kidney[1] - HAART AND KIDNEY Nephrology Grand...

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