Antiviral Agents

Question 1

Nucleobase, nucleoside and nucleotide. Describe the difference

Answer 1

Nucleobase: adenin, guanine, thymine etc. JUST THE BASE

Nucleoside: nulceobase+ribose sugar

Nucleotide: nucleoside+phosphate (1-3 P groups)

Question 2

What does acyclovir treat and how does it do its job?

Answer 2

It is the treatment for herpesviruses (HSV-1, HSV-2 and VZV). Mechanism: It is a guanosine analog that works as a chain terminator. It exist as a prodrug, and must be phosphorylated to it GMP form by VIRAL thymidine kinase. Cellular kinases turn it into its GTP form, which then terminates DNA replication. (without HSV infection, this drug stays in its prodrug form)

Question 3

How is valaciclovir different from acyclovir?

Answer 3

Differences: it has a valine group attached to it, and has higher bioavailability. Similarities: Treats Herpesvirus infections

Question 4

What are the 4 NRTIs we have to know for this exam

Answer 4

1. Zidovudine (AZT)
2. Lamivudine (3CT)
3. Emtricitabine
4. Abacavir

Remember, ZEAL. (I put them in a different order but you get the picture)

Question 5

Zidovudine (aka azidothymidine aka AZT) is what kind of HIV drug and how does it work?

Answer 5

It is a deoxythymidine analog that works as a nucleoside reverse transcriptase inhibitor (NRTI). So this is similar to acyclovir except that our cellular kinases do all of the phosphorylation to activate this prodrug. The drug will become activated whether or not the person has HIV. It is a better substrate for HIV RT (reverse transcriptase) than host polymerases which is good. It goes for the HIV infected cells only.

Question 6

What are the most common side effects of AZT?

Answer 6

Macrocytic anemia

Neutropenia

Lactic acidosis (common in all NRTIs–drugs inhibit mitochondrial gamma polymerase DNA that is responsible for mitochondrial DNA replication. Fewer mitochondria means that there is less OXPHOS and more lactic acidosis)

Question 7

What is the half life of AZT

Answer 7

1 hour (so terrible) but the phosphorylated form lasts 3-4 hours so that a bit better

Question 8

Based on structure, how can you tell you’re looking at an NRTI?

Answer 8

Its a nucleoside that has no 3’ hydroxyl group. Translation: you will see the pentagon with a O on top, but there will be NO OH at the carbon kitty corner to the nucleobase. Hope that makes sense.

Not having the OH group makes it impossible to form a phosphodiester bond with the next nucleotide, which results in chain termination.

Question 9

Tell me 4 things about Lamivudine (3CT)

Answer 9

1. Has fewer side effects compared to other NRTIs
2. Recommended in pregger ladies
3. M184V mutation is common in incompletely suppressive tx
4. ALSO USED TO TREAT HBV

Use LAMi in Tammy the pregnant lady who also has HBV that she got at 18 b4 she got pregnant. But she’s alright, she’s got few drug side effects.

Question 10

Tell me 2 things about Emtricitabine. Just 2. So easy.

Answer 10

1. It is a fluorinated analog of lamivudine that has a longer half life
2. Also works against HBV

EMily TRIs TA B (emtricitabine) like LAMi (lamivudine) by working against HBV too, but EMily lasts longer.

Question 11

Tell me 2 things about Abacavir

Answer 11

1. It can cause hypersensitivity rxns
2. Can cause hepatomegaly, esp. in HLA-B5701 pts so you give this drug only after genotyping

With an ABACAdabra, your liver gets huge.

Question 12

What is the activity of thymidine kinase (remember, the enzyme that puts the first P on the prodrug, activating it) like in resting cells

Answer 12

Real terrible. Almost no activity, so that drug remains in its prodrug state in resting cells.

Question 13

What kind of HIV drug is Tenofovir and how does it work?

Answer 13

This is a nucleotide analog (it has a monophosphate group on it, so it doesn’t have to deal with getting activated in the cell since it already has its P group ready to go). It gets converted to a di- and triphsohpate in resting cells which then inhibits HIV RT, leading to chain termination.

Can also be used for HBV

Watch out for renal toxicity with this one. Gets excreted unchanged in the kidney.

What’s the best time to get HBV? At TENOclock, when the TIDE (nucleotide) is low.

Question 14

What’s the difference between an NNRTI and an NRTI? Tell me 4.

Answer 14

1. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are allosteric HIV RT inhibitors (they bind to a different site than the active site, so they don’t compete with NTRIS or nucleotides).
2. They don’t require phosphorylation for activation
3. There is lot of resistance to these drugs though so consider genotyping
4. Lots of drug-drug interactions because of their effects on CYP3A4 (some inhibit, some enhance, some do both. Such a cluster fuck)

Question 15

What are the 4 NNRTIs we are responsible for knowing?

Answer 15

1. Nevirapine
2. Rilpivirine
3. Etravirine
4. Efavirenz

Remember, the NNRTIs work NEER the active site of HIV RT, not in it. Or remember, all NNRTIs have an internal “VIR”

Question 16

Tell me some things about Nevirapine: who should we give it to and what are the side effects

Answer 16

1. It is used prophylactically for pregger women
2. Side effects: Stevens Johnson Syndrome, hepatotoxicity, (moderate inhucer of CYP3A4, may reduce levels of other HIV drugs)

NEVer leave a pregnant lady without giving her NEVirapine

Question 17

Rilpivirine. Why is this drug RILy (really) annoying?

Answer 17

High rates of cross resistance, don’t give with other NNTRIs

Question 18

Tell me about Etravirine, who do we use it with and what are the risks of using it

Answer 18

1. Use when pt is resistance to other NNRTIs
2. High risk of drug-drug interactions through CYPs

Question 19

Efavirenz: why is this my FAVorite HIV drug so far

Answer 19

1. 1x/day dosing (long half life), very commonly used in ARTs
2. Few toxic side effects: NS disturbanse, nightmares, dizziness, insomnia
3. Don’t use in pregger ladies, causes fetal abnormalities

A PREGNANCT lady’s FAVorite thing is definitely not NIGHTMARES, so don’t give it to her, for the sake of her fetus.

Question 20

What’s the big deal about HBV and HIV?

Answer 20

A typical immunocompetent patient will celar HBV from their system, but HIV patients very commonly become co-infected (same routes of transmission. and also both use RT).

This is why we are so excited about some of the NRTIs that are also effective against HBV

Remember: drugs that target HBV

use LAMi in tammy the pregnancy lady (Lamivudine)

EMily TRIs to be like LAMi (Emtricitabine)

What’s the best time to get HBV? TENOclock when the TIDE is low (Tenofovir)

Question 21

What are the 2 attachment inhibitors we have to know?

Answer 21

1. Maraviroc
2. Enfuvirtide

These are peptide drugs that must be injected (can’t be taken orally)

I am very ATTACHed to ROCk FUsion music. It’s just my favorite. What rock fusion sound like I could not tell you. But now that I’ve talked about it so much hopefully you’ll remember it.

Question 22

What kind of HIV drug is Maraviroc? What does it specifically target?

Answer 22

It is an attachment inhibitor that binds to CCR5 on the CD4 T-cell (now gp120 can’t bind to it HA). You genotype before giving this to make sure HIV isn’t targeting the CXCR4 recetpor because in that case this drug would be pointless.

You put a ROC on the CCR5 receptor, and it blOCs gp120.

Question 23

What kind of drug is Enfuvirtide? How does it work?

Answer 23

It is another attachment inhibitor. It blocks gp41 in its extended form so that it can’t pull the HIV virus to the CD4 T-cell.

This is not a first line drug because it is a peptide so it has to be infected subcutaneously

EnFUvirtide effects the FUsion of HIV with CD4 cell.

Question 24

HIV Integrase inhibitors. Name the ones we have to know

Answer 24

1. Raltegravir

Question 25

How specifically does Raltegravir work?

Answer 25

It does not prevent the double stranded viral DNA from entering the nucleus, but it does stop the integrase-bound DNA from being incorporated into the host DNA.

This is a generally well tolerated drug

ralTEGravir inhibitrs inTEGrase

Question 26

HIV protease inhbitors

Answer 26

1. Atazanavir (Get an A, b/c it has lower incidence of lipodystrophies)
2. Ritonavir (Most inhibition of CYP3A4)
3. Saquinavir (Least inhibition of CYP3A4)

*These are all metabolized by CYP3A4 (so they will be affected by the NNRTIs that can either induce or inhibit CYP3A4)

RAS. That’s all I got. Losing steam.

Question 27

What are some common side effects of protease inhibitors

Answer 27

1. Lidopystrophies: redistributed body fat (central obesiy, buffalo hump, facial wasting)
2. Increased LDL, decreased HDL, increased triglycerides, hyerpglyemia, insulin resistance
3. Cardiac conduction abnormalities

Question 28

Why do we never treat HIV with monotherapy?

Answer 28

Because HIV will develope resistance supah fast. So we use drugs that target HIV with different mechanisms which reduces the chances that the drug will become resistance to both of them.

Question 29

What’s the random HCV drug they threw into this lecture and how does it work

Answer 29

Sofosbuvir

It is a nucleotide analog (has a 3’ OH group and a mock phosphate group) that inhibits HCV RNA synthesis

Is a fantastic drug and in some studies have shown 100% SVR in combination therapy but it is SUPER EXPENSIVE