Reverse-transcriptase inhibitor

Nucleoside reverse transcriptase inhibitors ( engl. nucleosides reverse transcriptase inhibitor, NRTI) drugs from the group of medicines called antivirals. It is nucleoside analogue similar to the natural nucleosides. Its starting point is the enzyme reverse transcriptase of retroviruses, which circumscribes the viral RNA genome into DNA. They compete with natural nucleosides, but differ in some minor modifications of the ribose ( sugar molecule ), i.e. they do not have 3'-hydroxyl group, which takes place in the chain extension.

  • 4.1 HIV 4.1.1 Use / clinical studies
  • 4.1.2 Deprecated agents

Effect

Nucleoside analogues are taken up by the cell and are only valid after an intracellular phosphorylation. This gradual three phosphate groups are transferred. The incorporation of the nucleoside as a false DNA building block during reverse transcription results in a break in the DNA chain newly formed and leads to the termination of the polymerization and thus the reverse transcription.

Side effects

Long-term side effects are common myelotoxicity, lactic acidosis, neuropathy, lipoatrophy, or pancreatitis. You are likely to establish a toxicity of which are important for cell metabolism, mitochondria. Since mitochondria are also dependent on nucleosides also leads to the incorporation of false components to metabolic disorders and finally to degeneration. Between the substances there are large differences in the expression of mitochondrial toxicity.

Nucleoside analogs are primarily eliminated by the kidneys. You do not interact with substances that are metabolized by enzyme systems of the liver. A key interaction potential therefore exists. Concomitant administration of ribavirin or in patients with renal impairment, dose adjustment may be required.

Areas of application

They are used to control the replication of viruses. So far, there are drugs against HIV and HBV.

HIV therapy

Nucleoside analogues were 1987, the first drugs in HIV therapy. The application is simple and it is usually only a single daily dose. Common complaints in the first few weeks - despite relatively good compatibility - fatigue, headaches and gastrointestinal problems such as Bloating, nausea, vomiting, or diarrhea.

In HIV therapy, the drugs zidovudine ( azidothymidine, AZT) and stavudine correspond ( d4T ) the DNA building block thymidine, lamivudine ( 3TC ) the cytidine, while didanosine (DDI ) to inosine and a guanosine analogue abacavir is analogous.

In the Highly Active Antiretroviral Therapy ( HAART) are often combined two NRTIs with a non- nucleoside reverse transcriptase inhibitor ( NNRTI) or a protease inhibitor ( ritonavir as a booster ). There are often cross-resistance between different nucleoside analogues.

HBV therapy

Interferon - α has long been the only approved in Germany drug that has proven to have a positive effect on the course of hepatitis B. Under long-term therapy could be achieved in many patients already good results. Treatment with interferon is often accompanied by severe side effects of different types.

A major step forward in the treatment of hepatitis B, the introduction of the nucleoside analogues lamivudine and adefovir dar. Both substances are administered orally and has few side effects are usually. Recently, nucleotide analogs (such as, for example, tenofovir and entecavir ) is preferred. This rare lead to drug resistance and thus appear more suitable for long-term therapy.

NRTIs typically are combined with interferon in order to increase the effectiveness.

Prophylactic NRTI in combination with hepatitis B immune globulin for HBV carriers administered with a graft to prevent reinfection.

Agents

HIV

In use / clinical studies

  • Emtricitabine
  • Lamivudine
  • Zidovudine
  • Didanosine
  • Stavudine
  • Abacavir
  • Amdoxovir development currently unclear
  • Apricitabine
  • Elvucitabin
  • KP -1461
  • MIV -210
  • Dioxolane (DOT)
  • Fozivudin
  • Fosalvudin

Agents Deprecated

  • SPD -756
  • SPD -761
  • Adefovir dipivoxil Gilead little effect against HIV, nephrotoxicity
  • FddA ( Lodenosin ®) of Bioscience, 1999, liver / kidney damage
  • DOTC Biochem Pharma, toxicity in monkeys
  • Lobucavir BMS, carcinogenicity
  • GS 7340, Gilead, unsatisfactory clinical data
  • MIV -310 ( alovudine, FLT) Boehringer March 2005, after disappointing phase II study
  • Dexelvucitabin ( Reverset ) Incyte, 2006 pancreatitis

HBV

  • Lamivudine
  • Adefovir ( is a nucleotide analogue)
  • Tenofovir ( a nucleotide analogue )
  • Entecavir
  • Emtricitabine
  • Clevudin
Active ingredient Elvucitabine Clevudine The Lancet AIDS (journal) Drugs (journal) The Journal of Infectious Diseases
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