Nucleoside reverse transcriptase inhibitors (NRTIs)

Definitions & Key takeaways

Nucleoside reverse transcriptase inhibitors (NRTIs) are a class of antiviral drugs used to manage HIV infection, which work by inhibiting HIV's reverse transcriptase enzyme. This enzyme prevents the multiplication of the virus and slows down the progression of the disease. Medications in this class include zidovudine, stavudine, lamivudine, didanosine, and tenofovir. Common side effects may include gastrointestinal disturbances like nausea, vomiting, abdominal pain, insomnia, and headache.

Chapters:

Watch video only

Introduction0:00–1:10

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. Based on their structure, they can be classified into nucleoside reverse transcriptase inhibitors, or NRTIs; and non-nucleoside reverse transcriptase inhibitors, or NNRTIs.
NRTIs resemble nucleosides, which are tiny molecules which when attached to a phosphate group give rise to nucleotides, which are building blocks of nucleic acids like DNA and RNA.
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.

Pathology1:10–3:33

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. NRTIs are structural analogues of nucleosides.

Mechanism of action3:33–4:56

So, when a NRTI molecule enters the cell, it gets phosphorylated, or a phosphate group is added, and it will resemble a nucleotide.
This fake nucleotide molecule now competes with the natural nucleotide in the infected cell for the attention of reverse transcriptase.
If it’s picked and inserted into the proviral DNA, it will screw up HIV’s entire plan. Think of DNA like a written instruction for synthesizing proteins, and the nucleotides are the letters.
The NRTI molecule are like random foreign letters that disrupts the instruction so viral proteins can’t be made. Also, additional nucleotides can not be added to the NRTI molecules inserted into the proDNA so this stops its synthesis.
So instead of the proviral DNA, what we end up with are a bunch of incomplete instructions full of gibberish. This stops new viruses from being created and keeps other CD4+ cells from getting infected.
However, it’s important to note that NRTIs have no effect on the completed proviral DNA already incorporated into the CD4+ cells, and the cells that are already infected remain infected.
So, NRTIs can only slow down the progression of the disease, but not cure it. Some commonly used NRTIs include zidovudine, stavudine, lamivudine, didanosine, abacavir, and tenofovir.

Indications4:56–6:25

Of these, tenofovir is an exception because it is a nucleotide analogue, so it does not need to be phosphorylated within the cell.
Typically, NRTIs are used as a part of the highly active antiretroviral therapy or HAART. This involves the use of two NRTIs along with one antiretroviral of another class which acts by a different mechanism, like non-nucleoside reverse-transcriptase inhibitors, or NNRTIs, and protease inhibitors.
For example, zidovudine and lamivudine can be given along with efavirenz, which is an NNRTI. This is so that, if HIV were to develop a mutation making it resistant to NRTIs, then it can still be killed by the NNRTI.
NRTI are also used alone in post-exposure prophylaxis, for example, in individuals who’ve recently been exposed to HIV infected blood in the past 72 hours.
They can also be used in children born to HIV infected mothers who are at the risk of developing the disease. In addition, lamivudine also inhibits the DNA polymerase of hepatitis B virus, and is used in the treatment of hepatitis B infection.

Side effects6:25–7:22

When NRTI molecules enter the CD4+ cells, they’re also at the risk of being picked up by cellular DNA polymerases, which are enzymes our cells use to make DNA.
Although reverse transcriptase has a way higher affinity for the NRTIs, some inhibition of cellular DNA polymerase is inevitable.
This disrupts the function of the normal cells in our body and can lead to side effects such as gastrointestinal disturbances like nausea, vomiting, and abdominal pain; bone marrow suppression leading to anemia and neutropenia; central nervous system toxicity leading to insomnia, headache, and peripheral neuropathy; and metabolic effects like lactic acidosis, which is when lactic acid builds up in the body causing a decrease in blood pH.
In addition, it’s important to know that abacavir can lead to sometimes fatal hypersensitivity reactions while didanosine can cause pancreatitis.
Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory palace7:22–8:49

Let’s have a bunch of animals enjoying a party next to a barrel of nuclear waste representing nucleoside. There’s a Zebra for zidovudine, a stag stavudine, and a lamb for lamivudine, and they’re all chatting with each other and having a great time.
Now the lamb is just a baby so it can be used to treat hepatitis B. A few of the party goers are having less fun.
There’s a dinosaur for didanosine, but he had too much to drink and developed pancreatitis! Just as unfortunate is the bear for abacavir who ate some shrimp and developed an allergic reaction (hypersensitivity reaction).
The tentacled octopus for tenofovir is splashing around in the pool making tidal waves since it’s a nucleotide analogue.
For the side effects of NRTIs, let’s look at the nuclear waste. First, it’s melting through the barrel like some kind of acid (lactic acidosis) and it’s strong enough to melt through bone!
(bone marrow suppression) The noxious fumes it’s giving off is causing vomiting (GI disturbance) in some animals, and some even passing out (Neurotoxicity).
They woke up later and were fine though, but they learned not to party next to nucleoside waste!” All right, as a quick recap, let’s look at a mind map that’ll help organize the information we covered.

Review8:49–9:33

Nucleoside reverse transcriptase inhibitors, or NRTIs, are nucleoside analogues that inhibit HIV reverse transcriptase enzyme and prevent multiplication of the virus.
Medications in this class include the nucleoside analogues like zidovudine, stavudine, lamivudine, didanosine, and abacavir, and nucleotide analogues like tenofovir.
These medications slow down the progression of the disease, and are commonly used along with other antiretroviral medication in HAART therapy, for post-exposure prophylaxis, and in children born to HIV infected mothers.