HIV Pharmacology Flashcards
binds specifically and selectively to CCR5 to prevent viral ENTRY into the host cell
- co-receptor tropism should be tested prior to initiating treatment
maraviroc
approved for use in combination with other antiretroviral agents infected only with CCR5-tropic HIV
maraviroc
binds to GP41 preventing the conformational and structural changes needed to allow fusion of the viral envelope with the host cell membrane
enfuvirtide
what drug is the ONLY parenteral (subQ) antiviral agent?
enfuvirtide
- it is a large, 36 AA peptide
side effects:
- local injection site reactions
- insomnia, HA, dizziness, nausea
- hypersensitivity is rare
enfuvirtide
competitive inhibition of HIV reverse transcriptase
- incorporation into the growing viral DNA chain (leads to premature chain termination d/t inhibition of binding with incoming nucleotide
NRTI’s
name the 6 nucleoSIDE reverse transcriptase inhibitors
- abacavir
- didanosine
- lamivudine
- emtricitabine
- stavudine
- zidovudine
what is the 1 nucleoTIDE reverse transcriptase inhibitor?
tenofovir
guanosine analog
- available in fixed dosage combinations with lamivudine or zidovudine
- serum levels can be increased with concurrent ethanol ingestion
abacavir
what are the adverse effects of abacavir?
- hypersensitivity (8% in the first 6 weeks of therapy)
- fever, fatigue, nausea, vomiting, diarrhea, abdominal pain
- respiratory: dyspnea, pharyngitis, cough
- skin rash (50%)***
synthetic analog of deoxyadenosine
- causes dose dependent pancreatitis***
- retinal changes with optic neuritis
- increased risk of lactic acidosis and hepatic steatosis when combined with stavudine
didanosine
cytosine analog
- active against both HIV and HBV
- HA, dizziness, insomnia, fatigue, dry mouth, hsrxn rare
lamivudine
fluorinated analog of lamivudine
- active against both HIV and HBV
- long intracellular half-life allows for once daily dosing
- causes HA, diarrhea, nausea, rash
- hyperpigmentation of palms/soles may be observed, especially in African Americans
emtricitabine
thymidine analog
- causes dose dependent peripheral sensory neuropathy
- causes dyslipidemia
- increased risk of lactic acidosis and hepatic steatosis when combined with didanosine
stavudine
deoxythymidine analog
- first antiretroviral drug to be approved
- causes: macrocytic anemia, neutropenia, GI intolerance
zidovudine
acyclic analog of adenosine
- active against both HIV and HBV
- disoproxil or alafenamide prodrugs enhance oral absorption
- generally well tolerated, can cause flatulence
tenofovir
bind directly to HIV reverse transcriptase in site distant from active site
- binding induces conformational change in enzyme (reducing activity)
- acts as noncompetitive inhibitors
NNRTI’s
develops rapidly with monotherapy
- HIV transcriptase point mutations alter binding
- no cross resistance between these and NRTI’s
NNRTI’s
what are the adverse effects of NNRTI’s?
GI intolerance, skin rash
what drug class is metabolized by the CYP450 system, leading to many drug-drug interactions?
NNRTI’s
what are the first generation NNRTI’s? (3)
- delavirdine
- efavirenz
- nevirapine
what are the second generation NNRTI’s? (2)
- etravirine
- rilpivirine
this drug not used often d/t decreased potency relative to other NNRTI’s
- causes skin rash (up to 38% of pts)
- HA, fatigue, nausea, diarrhea, increased aminotransferase
delavirdine
- extensively metabolized by CYP3A and CYPD6
can be given once daily d/t increased half-life
- metabolized by CYP3A4 and CYP2B6
- CNS adverse effects HA, dizziness, drowsiness, INSOMNIA, NIGHTMARES
- skin rash in up to (28%)
efavirenz
the first NNRTI to be approved for HIV
- metabolized for CYP3A
- used in preventing transmission of HIV from mother to child
- causes rash (20%), can be dose limiting
- liver toxicity (4%)
nevirapine
diarylpyrimidine
- designed to overcome HIV resistance to first generation NNRTI’s
- can cause rash, nausea, diarrhea
etravirine
- substrate and inducer of CYP3A4 and an inhibitor of CYP2C9 and CYP2C19
diarylpryrimidine
- coformulated with entricitabine and tenofovir
- metabolized with CYP3A4
- can cause rash, depression, HA< insomnia, increased serum aminotransferase
- high doses associated with QT prolongation
rilpivirine
bind HIV integrase
- inhibits strand transfer and prevents ligation of reverse-transcribed HIV DNA into the xsome of the host cell
INSTI’s
what are the adverse effects of INSTI’s?
generally well tolerated
- HA and GI effects most common
what is the suffic for INST’s?
** all end in -gravir **
what are the INST’s?
- dolutegravir
- elvitegravir
- raltegravir
preferred agent for treatment of treatment-naive patients when combined with:
- tonofovir/emtricitabine
- abacavir/lamivudine
dolutegravir
- adverse effects infrequent
approved in 2012
- only available as combination pill (stribild= elvitegravir, cobicistat, emtricitabine, tenofovir)
- requires boosting to be efficacious -> combine with cobicistat
elvitegravir
- few adverse effects
preferred treatment option for treatment-naive patients
- hald life is 9 hrs
- adverse effects uncommon
raltegravir
this group blocks the HIV protease and prevents the maturation of the final structural proteins that make up that mature virion core
- specifically and competitively inhibit the action of HIV aspartyl protease
protease inhibitors
resistance develops quickly with monotherapy
- causes: GI intolerance, lipodystrophy (hyperglycemia/hyperlipidemia, lipoatrophy/fat deposition), redistribution and accumulation of body fat
protease inhibitors
- metabolized by CYP3A4
which protease inhibitor has the most pronounced inhibitory effect on CYP3A4 metabolism?
ritonavir
which protease inhibitor has the least inhibitory effect of CYP3A4 metabolism?
saquinavir
what are the 9 protease inhibitors?
- atazanavir
- darunavir
- fosamprenavir
- indinavir
- lopinavir
- nelfinavir
- ritonavir
- saquinavir
- tipranavir
frequently prescribed
- once daily dosing
- causes diarrhea and nausea, skin rash
atazanavir
- inhibits CYP3A4, CYP2C9, UGT1A1
must be co-administered with ritonvir or cobististat
- causes rash, potential hsrxn in pt with sulfa allergy
- metabolized by CYP3A4
darunavir
prodrug of amprenavir
- often administere with low dose ritonavir
- causes hA, N/D, paresthesias, depression
- potential hsrxn in pt with sulfa allergy
fosamprenavir
this protease inhibitor causes unconjugated bilirubinemia and nephrolithiasis
- drinking 1.5L of water daily helps prevent kidney stones
- boosting with ritonavir allows for twice daily dosing (increase chance for kidney stones)
indinavir
this protease inhibitor only available in combination with low dose ritonavir
- generally well tolerated
lopinavir
this protease inhibitor causes diarrhea and flatulence
nelfinavir
- *high rate of GI side effects at standard doses**
- very potent CYP450 inhibitor, used primarily as booster
- lower dose used for inhibitorion of CYP3A4
ritonavir
first approved protease inhibitor
- reformulated for once daily dosing with ritonavir
- causes N/D, GI discomfort, dyspepsia (less effects when boosted by ritonavir)
saquinavir
indicated in pts resistant to other protease inhibitors
- combined with ritonavir
- causes NVD, abd pain
- urticarual or maculopapular rash
- potential hsrxn in pt with sulfa allergy
tipranavir
what are the HAART’s?
2 NRTI’s plus either:
- 1 protease inhibitor
- 1 NNRTI
- 1 INSTI
- abacavir + lamivudine + dolutegravir
- (tenofovir + emtricitabine) + dolutegravir
- (tenofovir + emtricitabine) + darunavir/ritonavir
- (tenofovir + emtricabine) + elvitegravir/cobicistat
examples of HAART’s
