nrti mechanism of action

HIV Drugs Mode of Action | ImmunopaediaEMAIL: Action Mode ARV Action mode Action mode – NRTINucleoside Transcription Inhibitors (NRTIs) inhibiting by causing string termination after they have been incorporated into viral DNA. To make these drugs active they need to be intracellular phosphorylated. This was the first group of antiretroviral agents to use HIV. Normally two drugs of this class are used to form the spine of HAART. Antiretroviral Action Mechanisms against HIV and Drug ResistanceInhibitors of Neurology (NRTI)Inhibitors of Neurosurgery (NRTI)Mechanism of Action The class of antiretroviral drugs are chemical compounds that are . They function as during the extension of the DNA chain during the reverse transcription process carried out by the reverse transcriptase of HIV. NRTI compounds allow correct incorporation into the DNA chain, however, an important requirement for adding the following has been replaced by an unreactive chemical group. Action Mechanism With the exception of Tenofovir, NRTI compounds that are taken by the cell do not contain phosphate groups and require three phosphate groups to generate the triphosphate form of the cell before it can be used as an inverse transcriptase. Tenofovir contains a single phosphonate group to which only two phosphate groups need to be added to generate the active compound. The additional is carried out by host (kinases). Resistance Mechanism Antiretroviral Action Mechanisms against HIV and Drug Resistance Reverse Transcribase inhibitors (NRTI)Nucleoside (NRTI) Resistance mechanism There are two ways in which resistance can be achieved: Resistance mechanism1. Way of discrimination These are changes in the reverse transcriptase that increase the selective ability of the enzyme to incorporate the natural nucleotide on the (e.g. K65R, K70E, L74V, M184V and Q151M). There are two ways of achieving discrimination: two ways of achieving discrimination:2. Precision road These resistance mutations are amino acid changes in the primary structure of the reverse transcription that facilitate the removal of the NRTI-triphosphate chain terminals from end 3 of the DNA chain after it has been incorporated (e.g. M41L, D67N, K70R, L210W, T215F/Y and K219Q).2. The route of the split depends on adenosine triphosphate (ATP) or pyrophosphate therefore favor mutations that increase the affinity of the reverse transcription for ATP or increase the rate of elimination of the analog complex. Also changes in the wastes of the post-translocation site (P-site) as well as the dissociation rate of the enzyme template/firster can improve the pathway of excision. Mode of Action – NNRTINon-nucleoside Transcription inhibitors (NNRTIs) interfere with reverse transcription by directly binding with the enzyme and delaying its function. These are usually small chemical molecules with a long average life. This class typically combines with two NRTIs to form first-line HAART treatment in South Africa. Action Mechanism Antiretroviral Action Mechanisms of HIV and Drug Resistance Reverse Transcription Non-cores (NNRTI)Inhibitors of Reverse Transcription Without Cores (NNRTI)Active Mechanism The NNRTI class of antiretroviral drugs are small chemical compounds that have high affinity for a hydrophobic bond pocket located near the active site of the reverse HIV transcription. The union of the drug to the enzyme produces a change in the important residues necessary for the optimal capacity of the enzyme to catalyze the polymerization of the DNA. Action MechanismResistance Mechanism Antiretroviral Action Mechanisms against HIV and Drug Resistance Reverse transcriptase inhibitors without nuclei inverse transcriptase inhibitors without nucleus (NNRTI)Resistance Mechanism These resistance mutations affect the union of the drug to reverse the transcription by changing the association and the dissociation constants so that the reverse transcription can be achieved in the presence of the drug (e.g., K103N and Y181C). Resistance Mechanism Action Mode – Protease Protease Inhibitors Protease Inhibitors (PIs) are substrate analogs for the protease enzyme of HIV as part, which is involved in the processing of viral proteins. Once linked to the active site of the enzyme, the enzyme is blocked from another activity. This inhibits the process of viral maturation resulting in a lack of functional virion formation. These drugs are synergistic with reverse transcription inhibitors and are typically used in second-line HAART treatment in South Africa. Action Mechanism Antiretroviral Action Mechanisms against HIV and Drug ResistanceProtein inhibitors (PI) Action mechanism Protease inhibitors are small chemical compounds that mimic the natural substrate of the enzyme peptides, but do not allow a cut to be done due to chemical modifications. The binding of the inhibitor to the active site of the enzyme prevents the enzyme from orienting to its natural substrate as the inhibitor can only be released from the enzyme after the substrate has been polished. Fat inhibitors (PI) Action MechanismResistence Mechanism Antiretroviral Action Mechanisms against HIV and Drug ResistanceInhibitors of Disease (PI) Resistance mechanism These resistance mutations affect the union of the drug to the active site of the protease by changing the association and the dissociation constants so that the protease is available for action in the presence of the drug. Fat inhibitors (PI) Resistance Mechanism Action Mode – Integration InhibitorInhibitors Integrase inhibitors are a new class of medications that aim to integrate the HIV enzyme. This is the enzyme responsible for the integration of viral genetic material into human DNA, a crucial step in the HIV replication cycle. Raltegravir (Isentress) is the first medication to be approved in the class of antiretroviral drugs called integration inhibitors. It was approved by the United States Food and Drug Administration (FDA) in October 2007. Raltegravir is approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adult patients with treatment experience that have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. It is still not approved for people with drug-sensitive HIV strains, such as those that begin for the first time and have not been approved for use in children. Action Mechanism Antiretroviral Action Mechanisms against HIV and Drug ResistanceInhibitors of Integrasis Action mechanism The integration enzyme brings with it the insertion of HIV DNA into human DNA, thus helping to hide the HIV DNA within the amphibian cell's DNA (see figure 1). Once this provirus forms the cell begins to produce genetic material for new viruses. Raltegravir inhibits the integration of this essential function that limits the ability of the virus to replicate and infect new cells, thus preventing the DNA of HIV from mechanizing with healthy cell DNA (see figure 2). There are drugs in use that inhibit two other enzymes critical of the HIV replication process – inverse protease and transcriptase – but Raltegravir is the only approved drug that inhibits the integrative enzyme. For this reason, Raltegravir is an important milestone in the history of HIV/AIDS therapy. Integration inhibitors Action mechanism Side effects The most commonly reported adverse experiences of any severity (leve, moderate or severe) regardless of the drug relationship were diarrhea, nausea, headache and fever. Cinase elevations of crematin were observed in subjects who received Raltegravir. Myopathy and rhabdomiolysis have been reported; however, Raltegravir's relationship with these events is not known but should be used with caution in patients who receive known concomitant medications to cause these conditions. Side effects Drug interactions Based on the results of drug interaction studies and clinical trial data, no Raltegravir dose adjustment is required when administered with other antiretroviral agents. Preclinical studies show that Raltegravir is not metaboly per cytochrome enzymes P450. Caution should be used when co manages Raltegravir with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 (e.g. rifampicin) due to the reduction of plasma concentrations of Raltegravir. Drug Interactions Resistance Mechanism Antiretroviral Action Mechanisms against HIV and Drug ResistanceInhibitors of Integrasis Resistance mechanism Genetic mutations in the gene of viral integration can produce a drug-resistant enzyme that can catalyze the integration of viral DNA. Integration inhibitor s Resistance mechanism Action Mode – Input inhibitorsInput inhibitors interfere with the mediated entry by virus receptors into a cell. Two subclasses known as "Merge inhibitors" and "antagonists" are new classes of antiretroviral drugs used in combination therapy for the treatment of HIV infection. This kind of drugs interferes with the process of union, merger and entry of HIV into a human cell. Mechanism of Action – Enfuvirtida Antiretroviral Action Mechanisms against HIV and Drug ResistanceInvention inhibitors (a) Subclass: fusion inhibitor (e.g., Enfuvirtide)Input inhibitors (a) Subclass: fusion inhibitor (e.g., Enfuvirtide) Action mechanism The FDA Enfuvirtide approved fusion inhibitor is a peptide chain that mimics the structure of the HR2 region of gp41 that binds to the HR1 region and facilitates the fusion of the viral envelope with the cell membrane. The union of the inhibitor to the HR1 region prevents the HR2 region from having access to HR1 and inhibits the fusion process. Action MechanismResistence Mechanism – Enfuvirtide Antiretroviral Action Mechanisms against HIV and Drug ResistanceInhibitors of Entry (a) Subclass: fusion inhibitor (e.g. Enfuvirtide)Input inhibitors (a) Subclass: fusion inhibitor (e.g., Enfuvirtidade) Resistance mechanism These are resistance mutations in the HR1 region of gp41 that affect the binding affinity of the drug. A drug change allows the HR2 region to start the merger process. Resistance MechanismMechanism of Action – MaravirocAn antiretroviral Action Mechanisms against HIV and Drug ResistanceInhibitors of Entry (b) Subclass: antagonist of CCR5 (e.g., Maraviroc)Inhibitors of entry b) Subclass: antagonist of CCR5 (e.g., Maraviroc)Mechanism of action The recently approved FDA antagonist CCR5 Maraviroc is a small chemical compound that binds to the external part of the CCR5 transmembrane receptor that serves as a co-receptor for the entry of the virus. The union of this CCR5 inhibitor prevents HIV gp120 from having access to co-receptor and prevents the fusion process involving gp41 from moving forward. Action MechanismResistance Mechanism – MaravirocAn antiretroviral action mechanisms against HIV and drug resistanceInvention inhibitors (b) Subclass: antagonist of CCR5 (e.g., Maraviroc)Entry Inhibitors b) Subclass: antagonist CCR5 (e.g., Maraviroc)Resistance Mechanism Resistance mechanism© 2014 - 2021 - - Website designed by in association with . This work is licensed.

Warning: The NCBI website requires JavaScript to operate. NCBI Bookshelf. Service of the National Library of Medicine, National Institutes of Health. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan... StatPearls [Internet]. Parth H. Patel; Hassam Zulfiqar.AuthorsAfiliations Last updated: November 30, 2020. Continuous educational activityFacial transcription inhibitors are drugs used in the management and treatment of HIV. He's in the antiretroviral class of drugs. This activity examines the indication, action and contraindications for ICR as a valuable agent in HIV management (and other disorders where appropriate). This activity will highlight the mechanism of action, profile of adverse events and other key factors (e.g., out-of-label usages, dosage, pharmacokinetics, pharmacokinetics, monitoring, relevant interactions) relevant to members of the interprofessional health care team in the (management of HIV patients and related conditions. Objectives:Indictions With the rise in the HIV/AIDS epidemic, many companies have created drugs in the hope of reducing the spread and potentially healing this problem. At the forefront of these drugs are reverse transcription inhibitors. To date, FDA has approved the use of reverse transcription inhibitors for two main viral infections. The first approved use is for the treatment of HIV, specifically HIV-1 strain. The second virus is hepatitis B. Converse transcription inhibitors have also been used for post-exposure prophylaxis when there is concern about the possible infection of HIV patients. Finally, reverse transcription inhibitors are being used to decrease the spread of mother-to-child HIV during pregnancy, as well as childbirth and childbirth. The medicine of choice for the treatment of HIV of the mother during pregnancy is antiretroviral therapy based on zidovudine. Research and testing is currently being conducted to assess the effectiveness of the use of reverse transcription inhibitors for pre-exposure prophylaxis. Studies show that there is a reduction of 67 per cent to 75 per cent of the risk of infection through the use of pre-exposure prophylaxis. While the results have been promising, some have raised strong concerns about the emergence of drug-resistant strains due to the lack of adherence to the pre-exposure prophylaxis protocol by patients. The most important factor in the success of these therapies has been the lack of adherence to the protocol by patients. Mechanism of ActionIn the class of reverse transcription inhibitors are two subclasses of drugs. The first class is nucleoside/nucleotide reverse transcriptase inhibitors, and the second class is non-nucleoside reverse transcription inhibitors. Inverse nucleoside/nucleotide (NRTIs) inhibitors were the first class of antiretroviral drugs to be approved by the FDA. NRTIs are taken as prodrug drugs and must be taken to the host and phosphorylated cell before they become active. Once inside the host cell, cellular kinases will activate the drug. The drug exerts its effect through its structure. NRTIs lacks a 3'-hydroxyl group in the 2'-deoxyribosyl mix and will have a core or nucleotide as a base. Due to the missing 3'hydroxil group, NRTI avoids the formation of a 3'-5'-phosphodiester bond in growing DNA chains and can thus prevent the replication of the virus. An interesting feature of these drugs is that their incorporation during the DNA synthesis dependent on RNA or DNA, which inhibits the production of positive or negative strands of DNA. Inverse transcribase inhibitors (NNRTIs) not nucleosides are the second class of reverse transcription inhibitors. The main action mechanism is by binding the NNRTI to the reverse transcriptase and creating a proximal hydrophobic pocket to the active site. This pocket creates a new spatial configuration of the substrate binding site to reduce the overall activity of the polymerase. By creating a different configuration, DNA synthesis is generally slowed down. Because of NNRTI's non-competitive inhibitive action, it is not effective against reverse HIV-2 transcriptase. Administration The standard of care for HIV treatment requires the combination of NRTI, NNRTI, protease, and integration chain transfer inhibitors. Currently, the recommended regime consists of a "2+1" method where the patient should start at 2 NRTIs followed by an NNRTI, a protease inhibitor (with ritonavir boost), or an integration inhibitor. In terms of the selection of NRTI, various factors such as HIV strain sensitivity, contraindications, adverse reactions and current medicines must be taken into account. The International Antiretroviral Society recommends that treatment begin the day of diagnosis to have the maximum efficacy and slow progression of the disease as quickly as possible. According to IAS, for new HIV infections, recommended initial treatments are integration inhibitors: For pre-exposure prophylaxis cases, recommended treatment regimen: Post-exposure prophylaxis is achievable through any of the following regimens for four weeks: The following list contains some of the approved drugs falling into the NRTI and NNRTI categories of transcribase inhibitors as well. All RTIs come in an oral tablet or solution form with certain medicines that come in other formulations. Nucleoside/Nucleotide Retroceder TranscriptionInhibitorsNucleoside/Nucleoide Retroceder TranscriptionInhibitorsNo-nucleoside Reverse transcription inhibitors While total safe medicines, ICRs have a variety of side effects that should be taken into account when prescribed. Most adverse effects are observed in chronic situations rather than sudden occurrence and associated with each subcategory of the medication. NRTINRTI The most common adverse effect, as well as the most significant adverse effect associated with the use of INA, is mitochondrial toxicity. While new NRTIs have less incidence of mitochondrial toxicity, they still have some risk of causing it. Mythochondrial toxicity due to the use of NRTIs can be manifested as one of the following: myopathy, lipoatrophy, neuropathy and lactic acidosis with or without liver steatosis. Myopathy is more commonly associated with zidovudine and can manifest as proximal muscle tenderness and myalgia. Lipoatrophy (also known as lipodystrophy) is the loss of body fat from the face and limbs. The loss of fat in the areas of cheek, temples and periorbital regions gives patients an empathy appearance. Although this effect correlates strongly with the use of protease inhibitors in HAART, it may also appear in association with the use of stavudine. Peripheral neuropathy associated with NRTI is more common with chronic use of zalcitabine, didanosine and lamivudine. Lactic acidosis occurs more commonly with the use of zidovudine, lamivudine, stavudine and didanosine. Hepatic steatosis usually occurs accompanied by lactic acidosis due to the decrease in mitochondrial beta-oxidation of fatty acids resulting in sterified triglycerides that accumulate in the liver. NNRTINNRTI Compared to NRTIs, NNRTIs have been correlated with less adverse effects. As a group, all NNRTIs are known to cause rash. The most severe of these eruptions are Stevens-Johnson syndrome, as well as toxic epidermal necrolysis. In addition to the complications of dermatitis by using NNRTIs, some NNRTIs are known to cause other adverse effects. In comparison, nevirapin has been shown to cause significant transaminitis. Efavirenz, unlike the other NNRTIs, has shown CNS alterations. These CNS effects include mood problems, insomnia and disturbing dreams. Finally, it is known that delavirdine causes neutropenia when administered with zidovudine. Contraindications While reverse transcription inhibitors are generally safe to use, there are contraindications to prevent serious adverse effects associated with their use. First, a previous history of hypersensitivity to ICRs is a contraindication to its use. If a patient has had an adverse reaction to an RTI, he must suspend the medication and a different prescribed agent. Abacavir is explicitly associated with a hypersensitivity reaction that threatens life in 5% of patients. Specifically, patients who carry the HLA-B*5701 allele have the greatest chance to experience a severe reaction to the medication. Patients with HLA-DR7 and HLA-DQ3 should also avoid the use of abacavir. Patients with high or abnormal LTA or AST should avoid the use of nevirapin-based antiretroviral therapy due to severe hepatotoxicity and hepatotoxicity associated with rash. Didanosine has also shown a clinically significant interaction with the medication when taken concomitantly with alopurinol. MonitoringMonitoring for RTIs and HAART, in general, is essential due to the disastrous effects of medication noncompliance and suboptimal therapy. Surveillance is performed mainly through assessments such as CD4 count and viral load. The CD4 count is useful for measuring because it is the main goal of HIV. Patients with low CD4 counts may be expected to have severe immunodeficiencies leading to opportunistic infections. Viral charge looks at how many copies of HIV RNA is present in the patient. The higher the viral load, the greater the presence of HIV infection. The current IAS recommendations indicate that patients should have a level of HIV RNA (viral charge) within six weeks of starting HAART to evaluate the adhesion and tolerability of therapy, while observing that the proper suppression of NR may take up to 24 weeks. Once the viral load has fallen below 50 copies/mL, the recommendation is to repeat the viral load every three months until it reaches a year of suppression. After one year of successfully suppressed viral load, the patient may have their HIV RNA levels measured every six months. IAS recommends checking the CD4 cell count every six months until the levels are above 250/microliter for at least one year. After achieving these objectives, the measurement of the CD4 account can cease. Unless the patient is subjected to steroid or immunosuppressive treatments, or the patient experiences HAART failure, the CD4 count does not need to be measured. The definition of HAART failure is IAS as a level of HIV RNA over 200 copies/mL at least two consecutive measurements. After diagnosing HAART's failure, the recommendation is a re-evaluation of the HIV genotype and drug susceptibility, and making changes in the patient's regime. When talking about the HAART fault, it is important to consider drug resistance as a causative agent. Drug resistance is a serious complication that should be considered and associated with poor drug compliance. In addition, factors such as the cost of treatment, accessibility to medicines and access to adequate follow-up all play an important factor in the upbringing of resistance to standard HIV regimes. Studies have shown that low adherence and interruptions in treatment for more than two consecutive days in the first three months with NNRTI and NRTI-based regimes increased the risk of resistance in the first six months of treatment. Studies have shown that while both measures help to determine the effectiveness of treatment, each variable offers different views on the condition of the patient. The CD4 count, when presented at a normal level through treatment, is associated with a lower risk of mortality. When the viral load becomes undetectable, it means that the drug regime in which the patient is working is most effectively. In addition, monitoring of viral load is considered to be a better predictor of HIV progression to AIDS than CD4. ToxicityToxicity to RTIs occurs mainly through adverse reactions with which the patient may present (see above for a list of severe reactions). Patients should understand the serious adverse effects that may cause the drugs that make up their HAART regime. If a patient has an adverse effect, then the medication should be interrupted and replaced by another of the same inverse transcription inhibitor subclass. Specifically for stavudine, studies suggest that changing to abacavir will help improve lipodistrophy and maintain the effectiveness of the optimal regime. All other drugs that cause adverse reactions need to change to a drug that your specific HIV genotype is susceptible to. Improve the results of the health care team Patients in STDs, and more importantly, HAART, should have close follow-up with the primary doctor who cares for them. Doctors should work closely with nurses to follow the appropriate follow-up of patients to ensure optimal therapy provision along with the search for possible adverse effects. Doctors can also work closely with pharmacists to help optimize treatment and give the best medications to patients to achieve optimal therapy; the pharmacist can consult the best combinations of agents, as well as optimal dosage and administration. The nursing and pharmacy should emphasize the importance of strict patient compliance, since lack of compliance can be devastating for therapy and, subsequently, their life. The attention of the doctor who immediately describes compliance must be drawn. All members of the inter-professional medical care team are responsible for providing the best care to their patients, as well as for finding adverse effects. An interprofessional team will result in the best results. [Level 5]Continuing Education / Review QuestionsReferences This book is distributed under the terms of the Creative Commons 4.0 International License (), which allows use, duplication, adaptation, distribution and reproduction in any medium or format, provided that you give appropriate credit to the original author(s) and source, a link to the Creative Commons license is provided, and the changes made are indicated. 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