Nucleoside reverse transcriptase inhibitors are nucleoside analogues that inhibit the action of the enzyme reverse transcriptase. This enzyme inhibition slows or prevents viral replication. Most of the NRTIs require multiple daily doses, do not interact with other drugs, and can be taken with or without food.
Full Answer
How do reverse transcriptase inhibitors work?
Reverse transcriptase inhibitors act through one of two mechanisms. First, as ‘chain terminators’, they block the elongation of the DNA chain through blockage of further nucleosides.
What are the different types of nucleoside reverse transcriptase inhibitors?
The six nucleoside reverse transcriptase inhibitors currently in clinical use include zidovudine, didanosine, stavudine, zalcitabine, lamivudine and abacavir. While their mechanism of action is similar, these drugs differ somewhat from one another with regard to pharmacokinetics and adverse effects.
What are the side effects of nucleotide reverse transcriptase inhibitors (RTPS)?
The most frequent adverse effects reported in association with nucleotide reverse transcriptase inhibitors include mild to moderate gastrointestinal side effects, such as diarrhea, nausea, vomiting, and flatulence.
How do antiviral drugs inhibit RNA virus replication?
The drugs inhibit RNA virus replication by reversible inhibition of viral HIV reverse transcriptase, which reverse transcribes viral RNA into DNA for insertion into the host DNA sequence (see Fig. 51.6 ).
What does reverse transcriptase inhibitors do?
Nucleoside reverse transcriptase inhibitors (NRTIs) block reverse transcriptase (an HIV enzyme). HIV uses reverse transcriptase to convert its RNA into DNA (reverse transcription). Blocking reverse transcriptase and reverse transcription prevents HIV from replicating.
Why does anti retroviral treatment include a number of different drugs?
Antiretroviral drugs HIV is treated with antiretroviral medicines, which work by stopping the virus replicating in the body. This allows the immune system to repair itself and prevent further damage. A combination of HIV drugs is used because HIV can quickly adapt and become resistant.
Do reverse transcriptase inhibitors harm patient cells?
The human immunodeficiency virus (HIV) contains genetic information in the form of RNA. When HIV infects a human T cell, it must convert this RNA to DNA. It does so by using an enzyme called reverse transcriptase. Reverse transcriptase inhibitors interfere with this process.
What are the side effects of nucleoside reverse transcriptase inhibitors?
NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS Asthenia, headache, diarrhea, nausea, vomiting, flatulence, renal toxicity, proteinuria, renal failure, decreased bone mineral density, risk of hepatitis B flare when stopped (also effective for treatment of hepatitis B)
What is the advantage of using multiple targets during Haart?
The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death.
What is the main reason why single drug antiretroviral therapies eventually fail at controlling a patient's viral load?
Poor adherence leads to a low level of antiretroviral effect in the body, and this causes insufficient to suppress viral replication, finally resulting in treatment failure.
Is reverse transcriptase harmful to humans?
Reverse transcriptase is central to the infectious nature of retroviruses, several of which cause disease in humans, including human immunodeficiency virus (HIV), which causes acquired immunodeficiency syndrome (AIDS), and human T-cell lymphotrophic virus I (HTLV-I), which causes leukemia.
What are the effects of reverse transcription?
More than 10 years of experience with NRTI therapy has revealed important adverse effects ranging from mild (myopathy) to fatal in some cases (pancreatitis, liver failure and lactic acidosis). Behind most of these side-effects there appears to be a common mechanism: a decreased mitochondrial energy-generating capacity.
What is a common side effect of Combivir?
Headache, tiredness, loss of appetite, nausea, vomiting, diarrhea, trouble sleeping, dizziness, or stuffy nose may occur.
How does reverse transcriptase inhibitors slow the replication of DNA?
Reverse transcriptase inhibitors are active against HIV, a retrovirus. The drugs inhibit RNA virus replication by reversible inhibition of viral HIV reverse transcriptase, which reverse transcribes viral RNA into DNA for insertion into the host DNA sequence (see Fig. 51.6).
What are the two most common adverse effects of antiretroviral drugs?
Side effects from antiretroviral HIV drugs can include appetite loss, diarrhea, fatigue, and mood changes. However, not sticking to a treatment plan can cause the virus to become resistant to drugs and harder to treat.
Which common adverse effect is associated with most nucleoside reverse transcriptase inhibitors NRTIs?
Answer. Adverse effects of the NRTI class include mitochondrial toxicities (e.g., lactic acidosis, pancreatitis, peripheral neuropathy, hepatic steatosis, lipoatrophy).
How do reverse transcriptase inhibitors work?
Reverse transcriptase inhibitors are active against HIV, a retrovirus. The drugs inhibit RNA virus replication by reversible inhibition of viral HIV reverse transcriptase, which reverse transcribes viral RNA into DNA for insertion into the host DNA sequence (see Fig. 51.6 ). The nucleos (t)ide reverse transcriptase inhibitors (NRTIs) are activated by phosphorylation in two steps to the 5′-triphosphate form by cellular kinases. Inhibition of viral replication is achieved by competitive binding of the activated drug to the enzyme–template–primer complex in place of the natural 5′-deoxynucleoside triphosphates. The drugs lack the 3′-hydroxyl group on the deoxyribose moiety required for normal formation of a phosphodiester bond with the next nucleotide, so they terminate further DNA chain elongation.
What is a nucleoside reverse transcriptase inhibitor?
Nucleoside reverse transcriptase inhibitors are nucleoside analogues that inhibit the action of the enzyme reverse transcriptase. This enzyme inhibition slows or prevents viral replication. Most of the NRTIs require multiple daily doses, do not interact with other drugs, and can be taken with or without food.
What order of potency of NRTIs/NtRTIs in inhibiting mtDNA?
The order of potency of the NRTIs/NtRTIs in inhibiting mtDNA synthesis in vitro is didanosine (ddI) > stavudine (d4T) > zidovudine (ZDV) > lamivudine (3TC), abacavir (ABC), and tenofovir. 4 ddI and d4T are not used as first-line agents because of these toxicities.
What are the effects of NRTI on the liver?
NRTI-induced liver injury includes hepatic cytolysis, microvesicular and/or macrovacuolar steatosis, steatohepatitis, cirrhosis, and cholestasis. 2, 36 Numerous clinical and experimental investigations showed that NRTI-induced hepatotoxicity and other adverse effects are the consequence of an impairment of mtDNA replication. 22, 27, 30, 49, 50 By impairing mtDNA replication, these drugs can induce severe mtDNA depletion and OXPHOS impairment ( Fig. 2 ). NRTIs actually act as chain terminators because their incorporation into the growing chain of mtDNA does not allow the addition of endogenous nucleotides by the DNA polymerase γ. 22, 30, 50 Therefore, the lack of a 3′-hydroxyl group is responsible not only for the antiretroviral activity of NRTIs, but also explains their mitochondrial toxicity. Zalcitabine is not used anymore because of its much higher toxicity than other NRTIs.
What are the mechanisms of NRTI?
In mitochondria, various mechanisms appear to be involved with NRTI-induced toxicity, including (1) inhibition of mitochondrial DNA polymerase γ leading to truncation of mitochondrial DNA replication and subsequent mitochondrial DNA depletion as well as inhibition of DNA repair ( Lewis 1998 ), (2) incorporation into mitochondrial DNA, resulting in potentially pathogenic point mutations and deletions that may persist , and (3) alterations in oxidative phosphorylation (OXPHOS) activity, resulting in the generation of reactive oxygen species (ROS) that, in turn, damage cellular DNA, proteins, and lipid membranes ( Dagan et al. 2002; Walker et al. 2004 ). Mitochondria are a basic component of the cell’s ATP generating mechanism. Thus, mutations or deletions in mitochondrial genes that encode polypeptides involved in OXPHOS could affect the energy generating capacity of the cell ( Schon 2004 ). This dysfunction becomes of great concern in mitochondrial rich tissues such as the heart and brain, particularly if damage occurs during growth and development.
Does NRTI cause neurotoxicity?
A mechanism for NRTI neurotoxicity has recently been suggested and is strictly related to NRTIs’ pharmacological properties. These compounds have been designed to be phosphorylated and then to compete with natural substrates for the HIV reverse transcriptase. Unfortunately, they react also with γ-deoxyribonucleic acid (γ-DNA) polymerase, which is an enzyme required for mitochondrial DNA replication. This interference reduces mitochondrial DNA and mitochondrial DNA-encoded enzymes, and it subsequently depletes neuronal energy during NRTI treatment [ 6 ]. An indirect confirmation of mitochondrial dysfunction during NRTI administration is represented by the analysis of the most common side effects associated with NRTI-induced peripheral neuropathy—that is, myopathy, pancreatitis, lactic acidosis, cardiomyopathy, and bone marrow suppression, which closely resemble the clinical features of mitochondrial diseases. Reduced acetyl- l -carnitine levels have been demonstrated in symptomatic patients as further evidence of mitochondrial damage, and the effectiveness of the exogenous administration of this substance in the treatment of NRTI-induced neuropathy has been reported.
Can NRTI be diagnosed with HIV?
A typical clinical feature of NRTI neuropathy is pain, a symptom that may make it difficult to differentially diagnose NRTI neuropathy from HIV painful neuropathy (which occurs in at least one-third of HIV patients at the beginning of their history), although the latter is generally more insidious in its onset.