Question

Good afternoon! Hope you are having a great day.

I have a question about HIV treatments.

Could you please describe Nucleoside or nucleotide reverse transcriptase (NRTIs) and what is the difference between Non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Many thanks!

Answer 1

Solution to the Question:-

Reverse transcriptase is the enzyme which converts viral RNA to viral DNA (reversal of normal cycle of conversion taking place from DNA to RNA in human body). This enzyme is not found in human cells without Human immunodeficienct virus. In the absence of reverse transcriptase, HIV cannot replicate, thus it t is a good target for anti-HIV drugs such as NRTIs, NNRTIs etc.

Nucleoside reverse transcriptase inhibitors (NRTIs) and Nucleotide reverse transcriptase inhibitors (NtRTIs) are active inhibitors of reverse transcriptase enzyme found in retroviruses such as the human immunodeficiency virus (HIV). They compete with cellular triphosphates, which are substrates for proviral DNA by viral reverse transcriptase.

NRTI/NtRTIs Examples: (with dose indicated for HIIV/AIDS)

• Zidovudine (AZT) - 300 mg bid
• Didanosine (DDI) - If >60 kg, 400 mg od
• Stavudine (D4T) - If >60 kg, 40 mg bid
• Lamivudine (3TC) - 150 mg bid
• Abacavir (ABC) - 300 mg bid
• Emtricitabine (FTC) - 200 mg od

Mechanism of action of NRTIs/NtRTIs:

• The NRTIs require phosphorylation to the 5'-triphosphate moiety to become pharmacologically active.
• Intracellular phosphorylation occurs by cytoplasmic or mitochondrial kinases and phosphotransferases (not viral kinases)
• The 5'-triphosphate moiety acts in two ways:

(a) It competes with endogenous deoxyribonucleotides for the catalytic site of reverse transcriptase, and

(b) It prematurely terminates DNA elongation as it lacks the requisite 3'-hydroxyl for sugar-phosphate linking

• Thus NRTIs inhibit this process and conversion of RNA to DNA, as they are analogues of the natural ATGC nucleotides that are normally used by the reverse transcriptase to build DNA.But NRTIs lack the 3' hydroxyl group necessary for the next DNA base to attach.
• Therein NRTIs work by competitively inhibiting reverse-transcriptase.

Non-Nucleoside reverse transcriptase inhibitors:-

Examples: Nevirapine - 200 mg od for the first 14 days, then 200 mg bid

Delavirdine - 400 mg tid

Efavirenz - 600 mg od (usually at night)

Mechanism of action:-

NNRTIs also inhibit the viral reverse transcriptase enzyme but have a different mechanism of action compared to NRTIs. NNRTIs bind directly to the reverse transcriptase enzyme and inhibit their action by a non-competitive mechanism.

Note: Abbreviations: 1. od = once daily

2.bid = twice daily

3. tid =thrice daily