Antiretrovirals Flashcards
what are the six classes of antiretrovirals
- nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)
- non nucleoside/nucleotide reverse transcriptase inhibitors (NNRTIs)
- Protease Inhibitors (PIs)
- Fusion Inhibitors (FIs)
- CCR5 antagonists
- Integrase Strand Transfer Inhibitors (INSTIs)
what drugs are used to improve the pharmacokinetic profiles of some antiretrovirals
pharmacokinetic enhancers
-ex: PIs and the INSTIs, elvitegravir
what does a typical antiretroviral regimen consist of
- two NRTIs
- usually abacavir + lamivudine
- or tenofivir + emtricitabine
- with a third antiretroviral from the classes NNRTIs, INSTIs, or PIs
- with a pharmacokinetic enhancer
what are the NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors)
TADELSZ
Tenofovir Abacavir Didanosine Emtricitabine Lamivudine Stavudine Zidovudine
mechanism of NRTIs
TADELSZ - tenofovir, abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine
- enters the cells and undergoes phosphorylation to generate synthetic substrates for the HIV RNA dependent DNA polymerase enzyme aka reverse transcriptase
- phosphorylated analogue competitively inhibits incorporation of native nucleotides and prevents elongation of nascent provirus because they lack a 3’ OH
- essentially prevents formation of provirus from HIV RNA
what are most of the adverse effects of NRTIs associated with (name them)
TADELSZ - tenofovir, abacavir, didanosine, emtricitabine, lamivudine, stavudine, zidovudine
-some NRTIs have an affinity for human DNA polymerase-gamma, a mitochondrial enzyme –> anemia, granulocytopenia, myopathy, peripheral neuropathy, lipatrophy, lactic acidosis, and pancreatitis
adverse effects of abacavir and what drug should be avoided
hypersensitivity rash with fever, rash, malaise, respiratory and or GI symptoms
avoid alcohol
adverse effects of didanosine and what drug should be avoided
PANCREATITIS (insulin disturbance)
Peripheral Neuropahty
Retinal Changes
avoid Tenofovir because it increases the concentration of didanosine –> more likely cause side effects
of all the NRTIs which are nucleoside and which are nucleotide
Tenofovir is a nucleotide while the rest are nucleosides and hence need to be phosphorylated to be active
adverse effect of emtricitabine
hyperpigmentation of palms and soles especially in darker skinned people
adverse of Staduvine and what drug to avoid
FATAL LACTIC ACIDOSIS
Peripheral Neuropathy
Diabetes
Pancreatitis
avoid concurrent neuropathic drugs
drug interactions of Tenofovir
- lowers serum conc of atazanavir
- increases conc of didanosine
- together with didanosine –> decreased CD4 T cells
adverse effects of Tenofovir
Renal Toxicity
Decreased bone density
Osteomalacia
adverse effects of Zidovudine and what drugs should be avoided
Myelosuppression (bone marrow suppression)
avoid co-administration with doxorubicin and stavudine; also avoid other myelosuppressive drugs
what are the NNRTIs (non nucleoside/nucleotide reverse transcriptase inhibitors)
REN
Rilpivirine
Efavirenz
Nevirapine
mechanism of NNRTIs (name them)
REN - Rilpivirine, Efavirenz, Nevirapine
they non-competitively bind to reverse transcriptase distant from the active site and cause conformational changes hence reducing its activity without the need for phosphorylation
adverse effect of Efavirenz
DVN’T (DON’T
Difficulty concentrating
Vivid Dreams
Nightmares
Teratogenic (avoid in 1st trimester)
adverse effects of Rilpivirine
Insomnia
Depression
adverse effects of Nevirapine
Severe Hepatotoxicity
Hepatic Failure
what are inducers of both CYP3A4 and CYP2B6
Nevirapine and Efavirenz
what are the protease inhibitors
NAVIR tease a Protease LIDAN
Lopinavir Indinavir Darunavir Atazanavir Nelfinavir
which protease inhibitor is not a substrate for CYP3A4
Nelfinavir
mechanism of protease inhibitors (name them)
NAVIR tease a protease LIDAN - lopinavir, indinavir, darunavir, atazanavir, nelfinavir
competitively inhibits virus aspartyl protease hence inhibiting proteolytic cleavage of HIV gag and pol that includes enzymatic and structural component of HIV
adverse effects of Lopinavir, Indinavir, and Darunavir
Lopinavir - Asthenia (lack of energy) and Pancreatitis
Indinavir - increased indirect bilirubin, nephrolithiasis, cholelithiasis, rash, blurred vision
Darunavir - Rash
who should avoid darunavir
those with sulfa allergy
adverse effects of Atazanavir and Nelfinavir
Atazanavir - Hyperbilirubinemia and PR elongation
Nelfinavir - nausea and flatulence
in general what are adverse effects of protease inhibitors (name them)
NAVIR tease a protease LIDAN - lopinavir, indinavir, darunavir, atazanavir, and nelfinavir
disorders of fat and carb distribution - hyperglycemia, insulin resistance, hyperlipidemia, truncal obesity etc
what are the integrase strand transfer inhibitors (INSTIs)
Integrase RED GRAVIR
Raltegravir
Elvitegravir
Dolutegravir
how is raltegravir eliminated and what can increase its elimination hence decreasing its con
eliminated by glucuronidation mediated by UDP glucuronosyltransferase 1A1 aka UGT1A1
conc can be decreased by strong inducer of UGT1A1 for ex rifampin
adverse of INSTIs (name them)
Integrase RED Gravir - Raltegravir, Elvitegravir, Dolutegravir
increase in creatinine phosphokinase, myopathy, rhabdomyolysis, and systemic hypersensitivity reactions
what is the CCR5 antagonist and its mechanism
Maraviroc binds to CCR5 co receptor and prevents entry of CCR5 tropic viruses into CD4 T cells
what is the fusion inhibitor and its mechanism
Enfuvirtide binds to gp41 and prevents conformational change that would allow HIV virus to fuse to host cell
what are the pharmacokinetic enhancers
Cobicistat
Ritonavir
mechanism of pharmacokinetic enhancers (name them)
Cobicistat and Ritonavir
both potent inhibitors of CYP3A4 hence increasing plasma conc of antiretroviral drugs that are broken down by CYP3A4 leading to higher efficacy and less frequent dosing
difference between Cobicistat and Ritonavir
- Ritonavir has its own antiretroviral activity although it is not used for that but rather for its pharmacokinetic enhancing ability while cobicistat has no antiretroviral activity
- Ritonavir is mainly used with PIs while Cobicistat is used with INSTIs
antiretroviral drugs that should be avoided during pregnancy
- Efavirenz due to its teratogenic activity
- Nevirapine in those with CD4 greater than 250 due to its increased risk of hepatotoxicity
preferred regimen for occupational post exposure prophylaxis of HIV
superficial: 2 NRTIs
Deep: 2 NRTIs and one from another group
Raltegravir + Tenofovir + Emtricitabine
general recommended treatment for HIV patients (also be specific)
2 NRTIs and INSTI (highly effective with fewer side effects and no CYP3A4 drug interactions0
(Tenofovir + Emtricitabine + Raltegravir)
(Tenofovir + Emtricitabine + Daltegravir)
2 NRTIs and PI
(Tenofovir + Emtricitabine + Darunavir or Ritonavir)
what are HIV prophylactic vaccines
Strep pneumonia
Hep A and B
Influenza
