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