Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

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Non-nucleoside reverse transcriptase inhibitors (NNRTIs)

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A 40-year-old man comes to the physician for a follow-up examination. Two-months ago, the patient was diagnosed with HIV infection and started on combined antiretroviral therapy. Recently, the patient began experiencing anxiety and difficulty concentrating at work. The patient is concerned that they may end up losing their job. The patient has recently been having intense dreams that “feel as if they were real.” The patient does not consume alcohol, tobacco, or illicit substances. Vitals are within normal limits. Physical examination is unremarkable. Which of the following drugs is most likely responsible for this patient’s current symptoms?  

Transcript

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.

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.

Summary

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.

Sources

  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "HIV-1 Antiretroviral Drug Therapy" Cold Spring Harbor Perspectives in Medicine (2012)
  5. "Emerging reverse transcriptase inhibitors for HIV-1 infection" Expert Opinion on Emerging Drugs (2018)
  6. "NNRTI-induced HIV-1 protease-mediated cytotoxicity induces rapid death of CD4 T cells during productive infection and latency reversal" Retrovirology (2019)
Elsevier

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