Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

Definitions & Key takeaways

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a type of antiviral medication used to treat HIV infection. They work by inhibiting the HIV's reverse transcriptase enzyme, thus preventing the multiplication of the virus.

Some NNRTIs such as efavirenz and delavirdine are teratogenic. Non-teratogenic NNRTIs include nevirapine and etravirine. Common side effects of NNRTIs include hypersensitivity reactions, dizziness, hallucinations, vivid dreams, and in some cases, there may be toxic epidermal necrolysis and Stevens-Johnson syndrome.

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Introduction0:00–1:04

Reverse transcriptase inhibitors are an important part of HAART, or highly active antiretroviral therapy, which is the combination of medications used in the treatment of AIDS.
AIDS is caused by a RNA containing retrovirus called human immunodeficiency virus, or HIV. The “retro” part of retrovirus isn’t referring to its style, but refers to it needing to use an enzyme called reverse transcriptase to transcribe a piece of “proviral” DNA from its RNA.
As the name suggests, reverse transcriptase inhibitors go and inhibit this enzyme, and prevent HIV replication. They can either be nucleoside reverse transcriptase inhibitors, or NRTIs, which resemble nucleosides, which are the building blocks of nucleic acids like DNA and RNA; or non-nucleoside reverse transcriptase inhibitors, or NNRTIs, which dont resemble nucleosides.HIV is a single-stranded, positive-sense, enveloped RNA retrovirus that targets cells in the immune system that have a molecule called CD4 on their membrane.

Pathology1:04–3:45

These include macrophages, dendritic cells, and especially CD4+ T-helper cells. Normally, the CD4 molecule helps these cells attach to and communicate with other immune cells, which is particularly important when the cells are launching attacks against foreign pathogens.
HIV attaches to the CD4 molecule via a protein called gp120 found on its envelope. Now, inside its envelope, HIV contains a nucleocapsid which is a capsule containing a single-stranded RNA and some viral enzymes, like reverse transcriptase and integrase.
As HIV bind to the receptors, the viral envelope fuses with the cell membrane of the immune cell, releasing the contents of the nucleocapsid into the helpless host cell’s cytoplasm.
Once it’s inside the CD4+ cell, reverse transcriptase gets to work immediately. It uses the single stranded viral RNA as a template, and uses the nucleotides present in the cytoplasm of the CD4+ cell to transcribe a complementary double-stranded “proviral” DNA.
Proviral just means that it’s ready to be integrated into the host’s DNA, so it enters the T-helper cell’s nucleus and pops itself into the cell’s DNA, ready to be transcribed into new viruses, pretty sneaky, huh?
Well, here’s the actual sneaky part—when the immune cells become activated, they start transcribing and translating proteins needed for the immune response.
Ironically, this means that whenever the immune cell is exposed to something that causes it to start up an immune response, like any infection, the immune cell ends up inadvertently transcribing and translating new HIV viruses, which bud off from the cell membrane to infect more cells.
Very sneaky indeed! Over time, more and more immune cells are infected, and the immune system begins to fail, which is called immunodeficiency, and this increases the risk of infections and tumors that a healthy immune system would usually be able to fend off.These complications are referred to as AIDS, or acquired immunodeficiency syndrome.
Now there are two distinct types of HIV—HIV-1 and HIV-2, which have slightly different proteins and enzymes. HIV-1 is the more commonly associated with AIDS in the US and worldwide, HIV-2 is more rare, and typically restricted to areas in western Africa and southern Asia.
NNRTIs are allosteric inhibitors of reverse transcriptase, particularly that of HIV-1. This means that they bind to the allosteric site of the enzyme, which is a tiny regulatory switch next to the active site, or nucleoside binding site.

Mechanism of action3:45–4:42

Binding of NNRTI to the allosteric site sets forth a series of changes in enzyme, which alters the structure of its active site.
The end result is that the nucleosides cannot bind to the enzyme anymore, and new proviral DNA is not transcribed. This stops new viruses from being created and keeps other CD4+ cells from getting infected.
However, it’s important to note that NNRTIs have no effect on the completed proviral DNA already incorporated into the CD4+ cells, and the cells that are already infected remain infected.
So, NNRTIs can only slow down the progression of the disease, but not cure it.Some commonly used NNRTIs include efavirenz, etravirine, delavirdine, and nevirapine.
These medications are rarely used alone, since HIV quickly develop resistance to them by point mutation of the enzyme. Typically, NNRTIs are used as a part of the highly active antiretroviral therapy, or HAART, along with nucleoside reverse-transcriptase inhibitors, or NRTIs, like zidovudine and lamivudine.

Indications and Contraindications4:42–5:45

This is so that, if HIV were to become resistant to the NNRTIs, then it can still be killed by the NRTI. Because there’s so many medications to take, Efavirenz has the advantage of having the longest half-life, so it only need to be taken once a day.
Nevirapine is sometimes used during pregnancy to prevent vertical transmission, from mother to foetus, as it easily crosses the placenta.
However, efavirenz and delavirdine are contraindicated during pregnancy as they can cause congenital malformations in the fetus.
Most common side effects of NNRTI are hypersensitivity reactions, which commonly result in a skin rash. In case of nevirapine, this may rarely progress to threatening conditions like toxic epidermal necrolysis, and Stevens-Johnson syndrome.
In addition, NNRTI may also cause damage to the liver, resulting in increased liver transaminases, and rarely hepatitis.

Side effects5:45–6:52

Severe hepatitis is most commonly seen with the use of nevirapine. In addition to these, efavirenz also affects the central nervous system, which causes side effects like dizziness, hallucinations, vivid dreams, or depression.
NNRTIs are metabolized by a class of enzymes called cytochrome p450 so they have a lot of drug interactions, especially delavirdine.
Medications that inhibit the enzyme, like cimetidine and macrolides, increase NNRTIs concentration in the blood, while medications that induce the enzyme’s activity, like rifampin, decrease their concentration.
We want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these crazy pharmacology facts!
Let’s divide these drugs into two groups, on the left are the teratogenic medications. There’s an elf for efavirenz, and she’s a delivery girl with chinese food for dinner for delavirdine.

Memory palace6:52–8:21

She’s a bit overworked so she’s having a vivid daydream about the beach to help you remember its CNS toxicity that causes vivid dreams and hallucinations.
On the right, let’s put the medications safe for pregnancy. Nevirapine is a pine tree in november, so it has a bunch of halloween decoration on it.
There are 2 spooky figures by the tree to represent its severe side effects. There’s a 2 headed man named Steve and John to represent Stevens-Johnson syndrome, and a zombie with his flesh falling off for toxic epidermal necrolysis.
For etravarin, let’s have a traveler’s luggage left by the tree because the traveller got scared off! The problem is he also left his baby there!
The baby is amused by the whole situation and is laughing, since both of these medications are safe for pregnancy. Now, NNRTIs share a few side effects, so let’s put them in the middle.
There’s a large, liver shaped rock to help you remember the liver toxicity, and it’s covered in patches of red moss to represent the rash.
A large chrome colored cell is trying to eat the rock since NNRTIs are metabolized by cytochrome p450. All right, as a quick recap… Non-nucleoside reverse transcriptase inhibitors, or NNRTIs, are allosteric inhibitors of HIV reverse transcriptase enzyme and prevent multiplication of the virus.
This class includes medications that are teratogenic like efavirenz and delavirdine, and those that are not like nevirapine and etravarin.
They are all metabolized by cytochrome p450 and cause are hepatotoxic and cause rashes. They are commonly used along with other antiretroviral medication in HAART therapy to slow down the progression of the disease.But wait, there's more: Here's a mind map with all of the mnemonics from the video.

Review8:21–8:58

Go ahead and pause the video so you can test yourself to see what you remember. Stay tuned for the answers at the end.
with other antiretroviral medications, in heart therapy to slow, down the progression of the disease. There's more.

Mind map8:58–9:08

Here's a mind map with all the pneumatics from the video. Go ahead and pause a video so you can test yourself to see what you remember.
They tuned for the answers at