Antiretroviral Drugs Flashcards
Nucleoside/-tide Reverse Transcritpase Inhibitors (NRTIs)
"Lam Did Stav Ten Zebras while Eating Aba's NRTIs" Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine
Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
“REN”
Rilpivirine, Efavirenz, Nevirapine,
Protease Inhibitors
..NAVIR Atazanavir Darunavir Indinavir Lopinavir Nelfinavir
Entry Inhibitors
“MEn enter”
Enfuviritde, Maraviroc
Integrase Inhibitor
“RED”
Dolutegravir, Elvitegravir, Raltegravir
Pharmacokinetic enhancers
Cobicistat
Ritonavir
NRTIs
MOA
Didanosine, Emtricitabine, Lamivudine, Stavudine, Tenofovir, Zidovudine
MOA: analogs of native ribosides (lack 3’OH)
- Phosphorylated by cellular enzyme and incorporated into viral DNA by reverse transcriptase
- Lack of 3’OH terminates DNA elongation ie. they are competitive inhibitors of reverse transcriptase
- Most have activity against HIV 2 (africa) as well as HIV 1 (Western world)
NRTIs AE
> 1 NRTI causes toxicities to overlap
AE mainly due to inhibition of mitochondrial DNA polymerase: peripheral neuropathy, myopathy, lipoatrophy and lactic acidosis
Pancreatitis, myelosuppression and cardiomyopathy can also occur
Liver toxicity is rare but fatal (lactic acidosis, hepatomegaly with steatosis)
Zidovudine and stavudine may be particularly associated with dyslipidemia and insulin resistance
NRTIs DI
Didansosine and Tenofovir
Tenofovir increases plasma didanosine levels ~ 60%.
doses of didansosine have to be reduced
NRTIs are not metabolized by cytochrome enzymes.
Zidovudine (ZDV, AZT)
Nucleoside analog:
Pharmacokinetics:
Nucleoside Analog : Thymidine
Pharmacokinetics
- Oral
- Penetrates well across BBB
- Dosage adjustments required patients w/ cirrhosis
Zidovudine (ZDV, AZT) AE:
CI:
AE:
Bone marrow suppression (neutropenia, anemia)
GI intolerance, headaches, insomnia
CI:
- Toxicity potentiated by coadmin. of probenecid, acetaminophen, lorazepam, indomethacin and cimetidine. (PLACI)
- Stavudine and ribavirin activated by same pathways (might reduce active levels of zidovudine)
Stavudine (d4T): MOA/PK
what does it have high affinity for?
Strong inhibitor of beta and gama DNA polymerases (high affinity for mitochondrial DNA polymerase, which can lead to toxicity)
Nucleoside Analog:
Thymidine
PK: Oral, dosage adjustment required in renal insufficiency
Stavudine AE
Peripheral neuropathy, lactic acidosis
Hyperlipidemia, neuromuscular weakness
Didanosine (DDL)
Analogue?
Adenosine analogue
PK: Absorption best taken in fasting state (acid labile) or combined with antacid.
- penetrates into CSF
- Dosage adjustment acquired in renal insufficiency
Didanosine (DDL) AE:
what does it have high affinity for?
High affinity for mitochondrial DNA polymerase
- Pancreatitis (esp. alcoholics and patients w/ hypertrigglyceridemia) - highest risk
Peripheral neuropathy, diarrheas, hepatic dysfunction
CNS effects
Tenofovir (TDF)
Analog of?
Combos?
One of preferred NRTIs in currently recommended regimens
Nucleoside Analog
Adenosine
Fixed-dose combinations available
Tenofovir + emtricitabine
Tenofovir + emtricitabine + efavirenz
Tenofovir (TDF) PK/AE
PK: taken w/ food to increase bioavailability
- Long t1/2 (can dose once daily)
AE: GI (nausea, diarrhea, vomiting, flatulence)
Tenofovir (TDF) CI?
Serum creatinine monitored with renal insufficiency
Only NRTI with sig. drug interactions (increases didanosine concs. and dosage reductions are usually required)
- Decreases conc. of atazanavir (can be boosted with ritonavir.
Lamivudine (3TC) MOA what does it not affect? ANALOG? Resistance? PK? AE?
DOes not affect mitochondrial DNA synthesis or bone marrow precursor cells
CYTOSINE
High level of resistance with single amino substitutions.
dosage adjustment requirement w/ renal insufficiency
AE: Few significant (headache, dry mouth)
Emtricitabine (FTC) structurally related to? ANALOG? PK? AE?
lamivudine
One of the prefered NRTIs in currently recommended regimens
Nucleoside analogue: Cytosine
PK: One a day admin.
AE: Hyperpigmentation of palms and soles (occurs most frequently in dark-skinned)
Abacavir (ABC)
ANALOG?
RESISTANCE?
AE?
Nucleotide analog:
Guanosine
Resistance:
- HIV resistance requires several mutations and tends to develop slowly.
AE: GI, headache, dizzinesss
- 5% - hypersensitivity reation (one or more of rash, GI, malaise, respiratory distress).
- Sensitized individuals shoud NEVER be rechallenged!!!!! Can be genetically screened
Non-Nucleoside Reverse transcriptase inhibitors (NNRTIs) MOA?
MOA
- Highly selective, noncompetitive inhibitors of HIV 1 RT
- Bind at distinct sites away from active sites (NNRTI pocket)
- All NNRTIs bind within the same pocket
- All result in inhibition of RNA and DNA dependent DNA polymerase.
- DO NOT require phosphoryation by cellular enzyms***
Advantages of NNRTIs
lack of effect on host blood-forming elements
lack of cross resistance with NRTIs (binding sites are distinct)
Disadvantages of NNRTIs
Cross-resistance w/ NNRTIs
Drug interaction
HIGH incidence of hypersensitivity reactions (eg. rash)
NNRTIs AE
SKin rash (including stevens-johnson syndrome) GI intolerance ALL are CYP3A4 substrates and can act as inducers, inhibitors or both of CYPs.
Nevirapine (NVP) Pharmacokinetics
AE?
excreted in urine as metabolites (CYP 3A4 and CYP 2B6)
AE: Potential severe hepatotoxicity ( DON’T use in women w/ CD4+ counts >250 and men >400)
RASH (16%), dermalogic effects (stevens johnson syndrome and toxic epiderml necrolysis)
14 day titration at 1/2 dose is mandatory to reduce risk of serrious epidermal reactions.
Nevirapine (NVP)
what enzyme does it induce?
Inducer of CYP 3A4
Increases metabolism of PIs (no dosage adjustment necssary), oral contracpetives, Ketoconazole, methadone, metronidazole, quinidine, theophylline and warfarin).
Efavirenz (EFV)
clinical appliations?
PK?
results in increased CD4+ counts and decreased viral load
Not a first line agent in new guidelines (2015)
PK:
Oral, t1/2 >40hrs (once a day dosing)
Extensively metabolized to inactive products
Efavirenz (EFV) AE?
High rate of CNS toxicity (50%): dizziness, headache, vivid dreams, loss of concentration- possible association with suicidality.
RASH (25%)
Increased triglycerides, HDL and total cholesterol (lipid levels must be monitored at beginning of and during therapy).
Efavirenz (EFV) CI:
Potent inhibitor of CYP 450 enzymes.
Pregnancy (D) (can be used after 1st trimester if considered best choice)
Rilpivirine PK/AE
Oral, extensively metabolized to inactive products
AE: RASH, INSOMNIA, DEPRESSION, INCREASED Live enzymes!
Protease Inhibitors (PIs) MOA
Reversible inhibitors of aspartyl protease of HIV
- inhibition prevents viral maturation and results in production of non-infectious virions!
DO NOT require intracellular activation
Active against both HIV-1 and HIV-2
Protease Inhibitors (PIs) PK?
Poor oral bioavailability
High fat meals increase (nelfinavir) or decrease (indinabir) bioavailabilty
- Substrate for CYP 3A4 (most require enhancing w/ a PK enhancer).
- Substrates for P-glycoprotein pump
- Bound to plasma proteins (alpha1-acid glycoprotein which can increase in response to trauma and surgery).
Protease Inhibitors AE
Parathesias, nausea, vomiting diarrhea
- disturbances in lipid metabolism (diabetes, hypertriglycerodemia, hypercholesterolemia)
- Chronic admin –> fat redistribution and accumulation resulting in central obesity, dorsocervical fat enlargement, peripheral and facial wasting, breat enlargement and a cushingoid appearance.***
Protease Inhibitors DI:
- Potent inhibitors and substrates of CYP isoforms:
eg, rhabdomyolysis (simvastatin or lovastatin), excessive sedation (midazolam or triazolam), respiratory depression (fentanyl) - Warfarin, sildenafil and phenytoin require dosage adjustments
- Rifampin and st. johns wort are CI.
Entry/fusion inhibitors
Fusion inhibitor?
Entry inhibitor?
Fusion inhibitor:
- Emfuvirtide
Entry inhibitor
- Maraviroc
Enfuvirtide (T-20)
whats special about Enfuvirtide
MOA?
• First approved drug that inhibits viral fusion
• Approved for use in treatment-experienced adults
with evidence of HIV replication**
• No activity against HIV-2
MOA
• Structurally similar to gp41 (HIV protein mediates
membrane fusion)
• Binds to GP41**subunit of the viral envelope glycoprotein,
preventing ability of virion to fuse cell membrane
Enfutvirtide (T-20) PK/AE
Pharmacokinetics
• Parenteral admin. only
Adverse Effects
• Injection-related (3% discontinue)
• Hypersensitivity reactions & eosinophilia rarely
• No drug interactions with other antiretrovirals have
been noted
MARAVIROC MOA
AE?
Binds specifically to CCR5**
Blocks HIV entry (only CCR5 tropic viruses can be treated with MARAVIROC doesnt work with CXCR4)
Well tolerated, risk of hepato toxicicity
Metabolized by CYP 3A4
Integrase Strand Transfer Inhibitors (INSTI’s)
Clinical applications?
Clinical Applications Clinical Applications
• In combination with other antiretrovirals, INSTI’s are
approved for treatment-experienced and treatment-naive
patients with evidence of viral replication
• Currently most popular antiretroviral class due to good
side-effect profile and favorable effects on lipid
metabolism
Dolutegravir PK?
AE
DI?
Pharmacokinetics
• Primarily eliminated by glucoronidatoin via UGT1A1
enzyme but some contribution from CYP 3A4.
Adverse Effects Adverse Effects
• Well tolerated (nausea, headache, diarrhea)
• Some reports of organ dysfunction (if so, discontinue
drug)
Drug Interactions
• Can occur due to CYP3A interactions
Elvitegravir
PK?
AE?
DI?
Pharmacokinetics
• Primarily metabolized by CYP3A enzymes
• May require ‘enhancing’ with a PK enhancer (Cobicistat)
Adverse Effects
• Well tolerated ( nausea, headache, diarrhea)
Drug Interactions
• Can occur due to CYP interactions
Raltegravir
Pk?
AE?
DI?
Pharmacokinetics
• Primarily eliminated by glucoronidation via UGT1A1
enzyme
Adverse Effects
• Well tolerated (nausea, headache, diarrhea)
• Can cause increases in creatine phosphokinases
DI i rug Interactions
• Rifampin, tipranavir & efavirenz may decrease [raltegravir]
• PPI’s may increase [raltegraivr]
Pharmacokinetic enhancers
MOA?
- Ritonavir (protease inhibitor)- never used a a protease inhibitor, mostly enhancer
- Cobicistat
MOA • Potent inhibitors of CYP 3A4 • Increase plasma concentrations of ARV allowing for lower and/or less frequent dosing • Improve tolerability of ARV
Ritonavir
how is it used?
Used in combo with most protease inhibitors (NOT nelfinavir
Never used alone
Cobicistat
Used commonly in combination with the INSTI elvitegravir
Also found in combo w/ darunavir and atazanavir
Current recommendations for Tx-naive patients:
Regimens
- 2*NRTI + INSTI
2. 2*NRTI + PI
Current recommendations for Tx-naive patients:
Selection based on:
• Avoiding the use of 2 agents of the same nucleotide
analog
• Avoiding overlapping toxicities and genotypic and
phenotypic characteristics of the virus
• Patient factors such as disease symptoms and concurrent
illnesses
• Impact of drug interactions; and
• Ease of adherence to a frequently complex administration
regimen
Current recommendations for Tx-naive patients:
Prefered regimens
INSTI - based regimens
- Raltegravir + tenofovir + emtricitabine
- Dolutegravir + tenofovir + emtricitabine
PI-based regimen
1. Ritonavir-boosted darunavir + tenofovir + emticitabine
Current recommendations for Infant born to HIV infected mother:
Zidovudine (start immediately after birth and administer for 6 weeks)
HIV prophylaxis following a needle stick
Postexposure prophylaxis:
regimen containing atleast 3 antiretroviral drugs
Raltegravir + tenofovir + emtricitabine
for 28 days and can be stopped if source is shown to be HIV negative
What Vaccines are recommeded for all HIV patients
Strep. Pneumoniae
Hep A
Hep B
Influenza
What Vaccines are CI’d in HIV+ patients w/ CD4+ count
Live vaccines eg, MMR Varicella and Zoster other vaccines may be administered w/out regard to the patients CD4+
