Pharmacology & Med Chem of HIV Antivirals Study Set | Quizlet

Abacavir

Emtricitabine

Lamivudine

Tenofovir

Nucleoside reverse transcriptase inhibitors (NRTI)

Nevirapine

Efavirenz

Etravirine

Rilpivirine

non-nucleoside reverse transcriptase inhibitors

Enfuvirtide

Maraviroc

Fusion inhibitors

Atazanavir

Darunavir

Lopinavir

Nelfinavir

Ritonavir

Tipranavir

Protease inhibitors

Raltegravir

Elvitegravir

Dolutegravir

Integrase inhibitors

What is the MOA of nucleoside reverse transcriptase inhibitors?

competitively inhibit viral RNA-dependent DNA polymerase to TERMINATE the chain

Are NRTIs chain terminators?

Yes

Virucidal or static: Nucleoside reverse transcriptase inhibitor.

virustatic

What is the mechanism of resistance against NRTIs?

active site mutations that decrease affinity

Zidovudine (Retrovir) MOA

azidothymidine that gets converted into triphosphate to get incorporated and terminate DNA chains

ADRs of Zidovudine

Hyperpigmentation of oral mucosa and nail beds

GI upset

Anemia

Didanosine (Videx) MOA

purine dideoxynucleoside analog of inosine that acts through competitive inhibition of RT by incorporating into a growing DNA chain (NRTI)

ADRs of Didanosine

Peripheral neuropathy

Pancreatitis

Stavudine (Zerit) MOA

pyrimidine nucleoside analog that acts through competitive RT inhibitiona nd DNA chain termination (NRTI)

Can you combine Stavudine with Didanosine?

NO - can lead to fatal prancreaitits

ADRs of Stavudine

Peripheral neuropathy

Fat wasting

Lamivudine (Epivir) MOA

competitive inhibition of RT that results in DNA chain termination (NRTI)

True or false: NRTIs are DNA chain terminators.

True

What key structural feature is missing from NRTIs that is typically present in nucleotides?

3' OH group

Abacavir (Ziagen) MOA

carbocyclic guanosine analog NRTI

Abacavir (Ziagen) ADRs

Hypersensitivity reactions

Tenofovir disoproxil (Viread) MOA

prodrug NRTI that competes with deoxyadenosine triphosphate that results in chain termination

ADRs of Tenofovir

Flatulence

Tenofovir Alafenamide Fumarate MOA

new prodrug formulation of Tenofovir that has improved retroviral activity with less ADRs

What is an advantage of Tenofovir Alafenamide Fumarate?

imrpoved distribution allows for lowered dosing than TDF

Emtricitabine (Emtriva)

cytidine analog NRTI

What is a big concern with Emtricitabine?

Cross-resistance

ADRs of Emtricitabine

Hyperpigmentation of palms and soles

True or false: NRTIs are metabolized by CYP450 enzymes.

False

1st gen NNRTIs

Nevirapine

Delavirdine

Efavirenz

2nd gen NNRTIs

Etravirine, Rilpivirine, Doravirine

MOA of non-nucleoside reverse transcriptase inhibitors (NNRTIs)

allosteric inhibition of HIV reverse transcriptase that reduces activity of RT

What is the SOA of NNRTIs?

HIV-1

What is done to overcome resistance with NNRTIs?

Always used in combination

Nevirapine (Viramune)

dipridodiazepinone derivative NNRTI

How are NNRTIs metabolized?

CYP enzymes

Delavirdine (Rescriptor)

bisheteroarylpiperazine derivative NNRTI

Delavirdine is pH _________________.

dependent

Which NNRTI increases plasma concentration of most other HIV protease inhibitors?

Delavirdine

ADRs of NNRTIs

Rash

Efavirenz (Sustiva) MOA

1,4-dihydro-2H-3,1-benzoxazin-2-one NNRTI

ADRs of Efavirenz

Vivid dreams

Nightmares

Suicidality

Rash

Etravirine (Intelence) MOA

diarylpyrimidine NNRTI

Which NNRTI is NOT cross-resistant to Nevirapine, Delavirdine, Efavirenz?

Etravirine

Rilpivarine (Edurant) MOA

diarylpyrimidine 2nd gen NNRTI

ADRs of Rilpivarine

Depression

Insomnia

Rash

QT prolongation at high doses

Doravirine (Pfeltro) MOA

pyridinone NNRTI that inhibits HIV-1

Which NNRTI is both a CYP and P-gp substrate?

Doravirine

ADRs of Doravirine

Immune reconstitution syndrome

Nausea

Fatigue

Dizziness

MOA of HIV Protease Inhibitors

competitively inhibit HIV protease by mimicking the transition state of the cleavage complex

SOA of HIV Protease inhibitors

HIV-1 and HIV-2

What is the mechanism of resistance against HIV protease inhibitors?

active site mutations that result in decreased binding affinity

True or false: Resistance with HIV protease inhibitors is lower than NRTIs.

False - it is greater

ADRs of HIV Protease inhibitors

GI effects

Insulin resistance

Lipodystrophy

Elevated TG and cholesterol

Saquinavir (Invirase) MOA

HIV protease inhibitor that is an analog of phenylalanine proline cleavage site

Why does Saquinavir need to be combined with Ritonavir?

It has very low oral absorption (4%)

Ritonavir (Norvir) MOA

very potent 3A4 inhibitor that is typically used as a PK booster for other HIV protease inhibitors

Fosamprenavir (Lexiva) MOA

protease inhibitor that is a phosphate prodrug of amprenavir

Lopinavir (Kaletra) MOA

HIV protease inhibitor that is a fixed combo with Ritonavir

ADRs of Lopinavir

PR and QT interval prolongation

Atazanavir (Reyataz) MOA

aza-peptide protease inhibitor

ADRs of Atazanavir

PR interval prolongation

Kidney stones

Indinavir (Crixivan) MOA

peptidomimetic hydroxyethylene HIV protease inhibitor

Which HIV protease inhibitor has the highest CSF penetration?

Indinavir

ADRs of Indinavir

Ingrown toenails

Nephrollithiasis

Cholelithiasis

Darunavir (Prezista) MOA

non-peptidic protease inhibitor

Can Darunavir or Tipranavir be used in patients with sulfonamide allergies?

use with caution

What are the non-peptidic protease inhibitors?

Darunavir

Nelfinavir

Tipranavir

Nelfinavir (Viracept) MOA

non-peptidic HIV protease inhibitor

Which protease inhibitor is NOT affected by Ritonavir?

Nelfinavir

Tipranavir (Aptivus) MOA

non-peptidic HIV protease inhibitor

Which protease inhibitor is nearly 100% protein bound?

Tipranavir

Raltegravir (Isentress) MOA

inhibits HIV integrase through metal chelation

ADRs of Raltegravir

CPK elevations, myopathy and potential for rhabdomyolysis

Elvitegravir (Stribild) MOA

used as a fixed dose combination HIV integrase inhibitor

ADRs of Elvitegravir

BBW - Lactic acidosis, severe hepatomegaly, and HBV exacerbation

Cobicistat (Tybost) MOA

potent CYP3A enzyme that acts as a antiretroviral boosting agent

Describe the structure of Cobicistat

peptidomimetic drug WITHOUT hydroxyethylene

HIV fusion inhibitors

Maraviroc

Enfuvirtide

Maraviroc (Selzentry) MOA

chemokine receptor antagonist that prevents virus entry into the host cell

Enfuvirtide (Fuseon) MOA

36-amino acid peptide that binds to gp41 and prevents the conformational change that is required for membrane fusion

What is the core structure of NRTIs?

Nucleosides

What is the core structure of HIV protease inhibitors?

hydroxyethylene

Lenocapravir MOA

"multistage"

1. Inhibits capsid nuclear import

2. Inhibits capsid uncoating

3. Inhibits capsid formation

Lenocapravir

Capsid inhibitor