6. Antiretroviral agents. Flashcards
Antiretroviral agents
Nucleoside Reverse Transcriptase Inhibitors (NRTI)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Protease inhibitors
Entry inhibitors
Integrase inhibitors
NRTIs can be divide to …
Thymidine analogs
Purine analogs
Cytidine analogs
Cytidine analogs
Lamivudine (3TC)
Emtricitabine (FTC)
Thymidine analogs
ZIdovudine (AZT)
Stavudine (d4T)
Purine analogs
Didanosine (ddI)
Tenofovir (TDF)
Abacavir (ABC)
NNRTIs can be divide to …
2 generations
Nevirapine
Efavirenz
Etravirine
Rilpivirine
NNRTI
MOA: noncompetitive inhibition of reverse transcriptase
binds to an hydrophobic allosteric site
only effective against HIV-1 (highly selective inhibitors of HIV-1 RT)
Pharmacokinetics: catabolized in the liver by CYP enzymes
Administration: oral
General adverse effects:
Liver and GI disorder
Skin reactions – up to Stevens-Johnson syndrome
1st generation NNRTI
Resistance to the drug is A single point-mutation causes total cross-resistance for all 1st generation agents
drugs …
Nevirapine
Efavirenz
2nd generation NNRTI
Etravirine
Rilpivirine
Nevirapine
NNRTI
penetrates well in the CNS
urine excretion
AE: Liver and GI disorder
Skin reactions & CNS problem !!!
Rilpivirine
NNRTI
pH dependant absorption (given with PPIs)
feces excretion
Efavirenz adverse effects
Liver and GI disorder
Skin reactions
and can cause CNS problems and it is highly teratogenic, nightmares
Thymidine analogs
ZIdovudine (AZT)
Stavudine (d4T)
Purine analogs
Didanosine (ddI)
Tenofovir (TDF)
Abacavir (ABC)
Cytidine analogs
Lamivudine (3TC)
Emtricitabine (FTC)
ZIdovudine (AZT) Stavudine (d4T) Didanosine (ddI) Tenofovir (TDF) Abacavir (ABC) Lamivudine (3TC) Emtricitabine (FTC)
MOA: terminate DNA chain elongation
Kinetics: Primarily renally excreted abacavir metabolized in the liver All except tenofovir penetrate the CNS Administration: oral
Adverse effects: Lactate acidosis (damage of mitochondria), liver toxicity
Protease inhibitors
suffix -navir
Ritonavir Lopinavir Atazanavir Darunavir Tipranavir
Ritonavir Lopinavir Atazanavir Darunavir Tipranavir
MOA: HIV protease cleaves Gag and Gag-Pol polyproteins of HIV
Pharmacokinetics:
The bioavailability is different can be increased by P-glycoproteins
They do not penetrate CNS
They are metabolized in the liver primary through CYP3A4
!!!In low dose Ritonavir block CYP2C19 and P-glycoprotein
There is no general cross-resistance between PIs
Adverse effects:
Insulin-resistance (after 5 years 5% new diabetic patients)
Hyperlipidemia (LDL, total cholesterol and triglyceride elevation)
GI disorders
Entry inhibitors
Maraviroc
Enfuvirtide
Integrase inhibitors
inhibits integration of proviral DNA to host chromosome
Administration: oral
Adverse effects: GI intolerance, headache
Resistance: A single point-mutation (of integrase gene)
drugs ..
Raltegravir
Elvitegravir
Dolutegravir
Raltegravir
Elvitegravir
Dolutegravir
Integrase inhibitors
Raltegravir
Kinetics: conjugated to glucuronic acid (CYP450) | forms complex with bivalent cations (reduces bioavailability
Well tolerated (GI problems, CK elevation due to myopathy, rhabdomyolysis)
Relative fast resistance development
Elvitegravir
Cross-resistance with raltegravir
Combined tablet:
elvitegravir (+cobicistat = “booster”) + emtricitabine + tenofovir
!!!Administered once a day with “booster” (CYP3A inhibitor: ritonavir or cobicistat) increases duration of action from 3 to 9 hours
Dolutegravir
Extensive hepatic metabolism (glucuronidation)
Low cross-resistance, high genetic barrier
Maraviroc
Entry inhibitors (CCR5 coreceptor antagonist) - CCR5 viruses are mainly present in earlier stage of the disease
Prior to use a test to determine viral tropism is required to distinguish if the drug will have any effect (CCR5 / CXCR4/dual)
Orally administered,
metabolized in the liver (CYP3A4, note drug interactions)
Adverse effects: Generally well tolerated (Headache, dizziness, orthostatic hypotension)
Enfuvirtide
Polypeptide
Entry inhibitors
Binds to gp41 HIV and inhibits the binding to the cells (a fusion inhibitor)
Administration: subcutaneous administered
Mainly well tolerated (local reactions on injection site, headache, nausea)
