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Download NRTIs NNRTIs PIs Entry Inhibitor Integrase Inhibitors MOA Inhibits
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ANTIRETROVIRAL DRUGS FOR HIV AND AIDS NRTIs MOA NNRTIs Inhibits HIV reverse transcriptase enzyme by competing with adenosine, guanosine, thymidine, and cytosine to grow proviral DNA chain. -Lactic Acidosis and hepatic steatosis (abdominal distention, n/v/d, low CO2, anion gap >16) -Stavudine and Didanosine have the greatest risk for ADR Inhibits HIV-1 reverse transcriptase by binding adjacent to the active site, inducing a conformational change that inactivates the enzyme Indications HIV-1 and HIV-2 Comments ADR DRUG: PIs Entry Inhibitor Integrase Inhibitors Inhibits the enzyme HIV protease by binding to its active site. Prevents the cleavage of gag-pol precursorincomplete & noninfectious “virions” -Significant GI effects -Paresthesia -Hyperglycemia & insulin resistance -Dyslipidemia -Hepatotoxicity -Lipohypertrophy CCR5 receptor antagonist— prevents CCR5 tropic HIV entry into cells HIV integrase strand transfer inhibitor Maraviroc- Dizziness, orthostatic hypotension, hepatoxicity N/D, h/a HIV-1 only HIV-1 and HIV-2 CCR5-trophic HIV-1, any pt resistant to multiple AR agents Combination therapy in pts resistant to other ARV drugs -NRTIs must undergo phosphorylation to be active vs. virus -First class of ARV drug approved. -All are renally eliminated -Parent molecule is active (unlike NRTIs) -2nd class of drug to be approved - CYP3A4 substrate -CI in CVD, Liver disease, Infection -CYP450 substrate -Expensive ($900-$1000 per month) Raltegravir (Isentress) Zidovudine (AZT) Lamivudine (3TC) Abacavir (ABC) Emtricitabine (FTC) Tenofovir (TDF) Efavirenz (EFZ) Ritonavir (RTV) Nelfinavir (NFV) Lopinavir-Ritonavir Atazanavir (ATV) Maraviroc (Selzentry) Enfuvirtide (Fezeon) Raltegravir All can cause rashes and hepatotoxicity -Ritonavir is most potent inhibitor (Boosted therapy--used in combo with other PIs to increase their levels) Enfuvirtide- Inj site Rxn. Expensive ($1000 per month) Nucleoside/Nucleotide Analogue Reverse Transriptase Inhibitors (NRTIs) MOA: Inhibits HIV reverse transcriptase enzyme by competing with adenosine, guanosine, thymidine, and cytosine to grow proviral DNA chain. ZIDOVUDINE(Retrovir) LAMIVUDINE(Epivir) ABACAVIR(Ziagen) EMTRICITABINE(Emtriva) TENOFOVIR DF (Viread) Indications -Adults & Children -Post-exposure prophylaxis -Prenatal/perinatal transmission to baby by HIV infected mother, NOT as monotherapy for mother -HIV 1, 2 pts -Hep B ADR -h/z, n/v/d, anorexia, fatigue -Bone marrow suppression -Nail discoloration -Lipoatrophy GI effects-(biggest complaint) Comments -First ARV for HIV -Post exposure prophylaxis (basic) in combo with Lamivudine -Cytosine analogue -Best tolerated of all NRTIs -HIV 1, 2 -Dual NRTI drug -Preferred initial HAART regimen QD dosing -Hep B -Dual NRTI -Preferred intial HAART regimen -Fatal hypersensitivity rxn (35% of pts)fever, rash, GI, cough -Black box warning -Similar to other NRTIs -Caution with h/a and unique hyperpigmentation of the palms -Renal insufficiency –RARE -Osteoporosis -Guanosine Analogue -Cytosine analogue -Long half-life- Can take w/o regards to meals -Adv: Already has one phosphate group so it only requires diphosphorylation to be activated -Adenosine analogue -Hep B Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTIs) MOA: Inhibits HIV-1 reverse transcriptase by binding adjacent to the active site, inducing a conformational change that inactivates the enzyme Indications EFAVIRENZ (Sustiva) EFZ -NNRTI portion of initial preferred HAART regiment -HIV-1 ONLY ADR -Rash (MC) -CNS effects: dizziness, h/a, insomnia, AMS, vivid dreams, nightmares, hallucinations Comments Adm: MUST be taken on an empty stomach CI in 1st trimester of preg Use with caution in pts with unstable psychiatric dz. Protease Inhibitors (PIs) MOA: Inhibits the enzyme HIV protease by binding to its active site. Prevents the cleavage of gag-pol precursorincomplete & non-infectious “virions” RITONAVIR (RTV) NELFINAVIR(NFV) LOPINAVIR-RITONAVIR ATAZANAVIR (ATV) Indications HIV 1,2 HIV 1,2 HIV 1,2 -Can be used as PI portion for initial preferred HAART regimen HIV 1,2 ADRs -GI effects -Altered taste sensation -Paresthesias -Hypertriglyceridemia -Pancreatitis -Diarrhea -Flatulence -Hyperlipidemia -Diarrhea -Similar to other PI except less dyslipidemia -Hyperbilirubinemia (d/c if total BIR >5x ULN or Jaudice) Comments -Not well tolerated in high doses Boosted therapy—used, in low dose, in combo with other PIs to increase their levels -Potent CYP3A4 inhibitor, also CYP2D6 **Does not have to be boosted with Ritonavir—Can boost with food** -No cross resistance to other PIs -Ritonavir inhibits the rapid inactivation of Lopinavir by CYP3A4 -Greater specificity for HIV protease than other available PIs -Do not use once-daily in preg -Metabolized/Inhibitor of CYP3A4 -Requires an acidic medium -CI with PPI -Separate dosing required w/ H2 blockers & antacids Entry/Fusion Inhibitors MOA: CCR5 receptor antagonist—prevents CCR5 tropic HIV entry into cells MARAVIROC (MVC) ENFUVIRITIDE (T-20) Indications CCR5-trophic HIV-1, any pt resistant to multiple AR agents Pts resistant to multiple ARV agents Preg Cat (B) ADRs -Injection site RXN -Dizziness, orthostatic hypoTN, hepatotoxicity Comments Inj Adm: -Supplied as Dry powder for reconstitution -Stored as room temp prior to reconstitution -Syringe, diluents, alcohol supplied with product -Caution in CVD, Liver Dz, Infxn -CYP450 substrate Integrase Inhibitors MOA: HIV integrase strand transfer inhibitor- Prevents HIV from getting into host DNA RALTEGRAVIR (ISENTRESS) Indications Combination therapy in pts resistant to other ARV drugs ADRs N/V, Headache Comments -Less DDIs -$1,000 per month ARV TX FAILURE: VIROLOGIC FAILURE (MC!) o HIV RNA is still in the blood 1 year after initiation of treatment OR if it is detected again after ARVs had previously lowered it to undetectable. IMMUNOLOGIC FAILURE o CD4 increase of <25-50 cells/uL in the first year of therapy, or a decline in CD4 count to below the baseline. CLINICAL PROGRESSION o The occurrence of HIV-related events or a decline in physical health after >3 months of therapy CAUSES OF TX FAILURE Patient factors o CD4, Viral load, co -morbidities) Suboptimal adherence ARV toxicity and intolerance Pharmacokinetic problems Suboptimal drug potency Viral resistance Antiretroviral Combination Regimen consists of either: 1-NNRTI + 2-NRTI OR 1-PI(w/ boost of ritonavir) + 2-NRTI NNRTI: Efavirenz PI: Atazanavir + Ritonavir (CI in PPIs) Darunavir + Ritonavir Fosamprenavir + Ritonavir Lopinavir/Ritonavir 2-NRTI: Tenofovir + Emtricitabine