HIV Pharmacology Flashcards
what is the life cycle of HIV (8 steps)?
- entry
- fusion and uncoating
- reverse transcription
- integration
- transcription
- translation
- virion assembly
- budding and maturation
MOA of miraviroc
binds specifically to CCR5 to prevent viral entry into the host cell
- miraviroc is not efficatious in viruses with a tropism for CCR5 and CXCR4 or just CXCR4
what surface receptors are usually seen in advanced HIV?
CXCR4
- this means miraviroc may not be useful in patients with advanced HIV (it only binds CCR5)
what are the pharmacokinetics of miraviroc?
- oral administration
- CYP450 metabolism
mechanisms of resistance to miraviroc
- mutations in the V3 loop of gp120
- emergence of CXCR4-tropic virus
what stage of the life cycle does miraviroc act on?
fusion
MOA of enfuvirtide
binds gp41, preventing the conformational changes needed for fusion of the viral envelope with the host cell membrane
what are the pharmacokinetics of enfuvirtide?
- subcutaneous injection
- metabolized by proteolytic hydrolysis, without involvement of CYP450
mechanisms of resistance of enfuvirtide
- mutations in gp41 to prevent enfuvirtide binding
adverse effects of enfuvirtide
- local injection site reactions
can NRTIs eradicate virus from cells that are already infected?
no, once the cells are infected the virus’ genetic material is integrated into the host cell DNA
what is the mechanism of action of nucleoside/tide reverse transcriptase inhibitors (NRTIs)?
competitive inhibition of HIV reverse transcriptase
- the NRTI is incorporated into the growing DNA, leading to premature chain termination
mechanisms of resistance to NRTIs
- point mutations in HIV reverse transcriptase
- impaired kinase activity to prevent phosphorylation and subsequent activation (only for nucleosides)
abacavir
guanosine nucleoside RT inhibitor
- drug combinations inculde
- abacavir + lamivudine
- abacavir + zidovudine
pharmacokinetics of abacavir
metabolized by alcohol dehydrogenase
- serum levels of abacavir can be increased with concurrent ingestion of EtOH
adverse effects of abacavir
hypersensitivity (consitutional sx, respiratory sx, skin rash)
- do not reintroduce abacavir if hypersensitivity occurs; may cause death
didanosine
adenosine nucleoside RT inhibitor
adverse effects of didanosine
-
dose-dependent pancreatitis
- contraindicated in alcoholism and hypertrigyceridemia
-
retinal changes
- mandated periodic retinal exams
- lactic acidosis and hepatic steatosis when combined with stavudine
lamivudine
cytosine nucleoside RT inhibitor
- active against HIV and HBV
- discontinuation could exacertbate HBV symptoms
- should not be used in conjuction with emtricitabine; since they are related, they select for the same point mutation in HIV reverse transcriptase
emtricitabine
cytosine nucleoside RT inhibitor
fluorinated analog of lamivudine
- active against HIV and HBV
pharmacokinetics of emtricitabine
has a long intracellular half-life that allows for once daily dosing
adverse effects of emtricitabine
- constitutional sx
- hyperpigmentation of the palms and soles
stavudine
thymidine nucleoside RT inhibitor
adverse effects of stavudine
- dose-dependent peripheral neuropathy
- dyslipidemia
- lactic acidosis and hepatic steatosis when combined with didanosine
zidovudine
deoxythymidine nucleoside RT inhibitor
adverse effects of zidovudine
- macrocytic anemia
- neutropenia
- constitutional symptoms
tenofovir
adenosine nucleoTide RT inhibitor
- active against HIV and HBV
what drugs enhance absorption of tenofovir?
disoproxil and alafenamide
MOA of non-nucleoside reverse transcriptase inhibitors (NNRTIs)?
binds HIV reverse transcriptase at a site distant from the active site
- binding leads to reduced activity
- non-competitive inhibitor
mechanisms of resistance to NNRTIs
- point mutations in HIV reverse transcriptase that alter NNRTI binding
- there is no cross resistance between NNRTIs and NRTIs since they bind such different sites
pharmacokinetics of NNRTIs
metabolized by CYP450 system
delavirdine
first generation NNRTI
adverse effects of delavirdine
- skin rash
- constitutional symptoms
- increased aminotransferase levels
efavirenz
first generation NNRTI
pharmacokinetics of efavirenz
can only be given once daily d/t increased t1/2
adverse effects of efavirenz
- CNS symptoms - dizziness, drowsiness, insomnia, nightmares, HA
- skin rash
nevirapine
first generation NNRTI
- used in preventing transmission of HIV from mother to child
- single dose to mother at onset of labor, and a dose to the baby within 3 days after birth
adverse effects of nevirapine
- rash (can be dose-limiting)
- liver toxicity
etravirine
second generation NNRTI
- increased potency, increased t1/2, and less adverse effects
- has a higher genetic barrier to resistance; designed to overcome resistance to first generation NNRTIs
pharmacokinetics of etravirine
metabolized by CYP450 system
- induces CYP3A4
- inhibits CYP2C9 and CYP2C19
rilpivirine
second generation NNRTI
- increased potency, increased t1/2, and less adverse effects
- coformulated with emtricitabine + tenofovir; allows for once daily oral administration
adverse effects of rilpivirine
- rash, depression, HA, insomnia, increased serum aminotransferases
- high doses associated with QT prolongation
what stage of the HIV life cycle do integrase strand transfer inhibitors (INSTIs) work at?
integration
MOA of integrase strand transfer inhibitors (INSTIs)
bind HIV integrase to inhibit strand transfer and ligation of reverse-transcribed HIV DNA into the chromosomes of the host cell
dolutegravir
integrase strand transfer inhibitor (INSTI)
- used for treatment of naïve patients in combination with:
- tenofovir + emtricitabine
- abacavir + lamivudine
elvitegravir
integrase strand transfer inhibitor (INSTI)
- only available as a combination pill
- elvitegravir + cobicistat + emtricitabine + tenofovir
- requires boosting with cobicistat
raltegravir
integrase strand transfer inhibitor (INSTI)
- preferred treatment for treatment naïve patients
what stage of the HIV life cycle do protease inhibitors work on?
budding and maturatino
MOA of protease inhibitors
competitively inhibit HIV aspartyl protease to prevent maturation of final structural proteins that make up the mature virion core
- prevents production of gag and pol polypeptides
adverese effects of protease inhibitors
- GI intolerance (can be dose-limiting)
-
lipodystrophy
- metabolic - hyperglycemia + hyperlipidemia
- morphologic - lipoatrophy + fat depositino
- redistribution and accumulation of body fat
- central obesity, buffalo hump, facial wasting, breast enlargment, cushingoid appearance
pharmacokinetics of protease inhibitors
- metabolized by CYP450 system
- ritonavir has the strongest inhibitory effect on CYP3A4
- saquinavir has the weakest
atazanavir
protease inhibitor
- once daily dosing
adverse effects of atazanavir
- diarrhea and nausea
- skin rash
- not associated with dyslipidemia or hyperglycemia (unlike most protease inhibitors)
pharmacokinetics of atazanavir
inhibits CYP3A4, CYP2C9, UGT1A1
darunavir
protease inhibitor
- must be boosted with ritonavir or cobicistat
adverse effects of darunavir
sulfa drug
fosamprenavir
protease inhibitor
adverse effects of fosamprenavir
sulfa drug
- personal parasthesias
- depression
indinavir
protease inhibitor
adverse effects of indinavir
unconjugated hyperbilirubinemia and nephrolithiasis
- consuming 1.5L of water each day helps prevent kidney stones
pharmacokinetics of indinavir
boosting with ritonavir allows for twice daily dosing
- this carries increased risk for kidney stones–drink lots of water!
lopinavir
protease inhibitor
- available only in combination with low-dose ritonavir
nelfinavir
protease inhibitor
ritonavir
protease inhibitor
pharmacokinetics of ritonavir
- at standard dosing for protease inhibitors, it has a high rate of GI side effects
- very potent CYP450 inhibitor; used primarily as a booster
- lower doses are used for inhibition of CYP3A4
saquinavir
protease inhibitor
- formulated for once daily dosing with ritonavir
tipranavir
protease inhibitor
- indicated in patients resistant to other protease inhibitors
- combined with ritonavir
adverse effects of tipranavir
sulfa drug
what is highly active antiretroviral therapy (HAART)?
combinations of 3-4 drugs used to treat HIV and prevent resistance by inhibiting various steps of the life cycle
what drug combinations are used in HAART?
2 NRTIs plus either:
- 1 protease inhibitor (sometimes 2 for boosting)
- 1 NNRTI
- 1 INSTI