Reverse transcriptase inhibitors RTIs

FIGURE 34-3 T Schematic illustration of HIV replication and the site of action of the reverse transcriptase inhibitors [RTIs], These drugs interfere with the process of reverse transcription by inhibiting the enzyme that converts viral RNA [vRNA] to viral DNA (vDNA). See text for further discussion. 

Viral dynamic modeling has been described for the effects of two classes of anti-HIV drugs, namely, reverse-transcriptase inhibitors (RTIs) that prevent infection of new cells and protease inhibitors (Pis) that decrease production of infectious virions by blocking the release of virions from infected cells, leading to the production of... 

Pancreatic dysfunction, heralded by large increases in serum amylase and lipase, is associated with the use of several reverse-transcriptase inhibitors (RTIs). Didanosine appears to be the worst offender, and pancreatitis is the most characteristic adverse effect of this particular NRTI. Conditions enhancing susceptibility to drug-induced pancreatic dysfunction include hypertriglyceridemia, hypercalcemia, and history of excessive ethanol use. Liver dysfunction including hepatitis may occur with the antitu-bercular drugs, isoniazid, and pyrazinamide. Cholestasis is associated with the estolate form of erythromycin. 

NNRTI, nonnucleoside reverse transcriptase inhibitor NRTI, nucleoside reverse transcriptase inhibitor PI, protease inhibitor RTI, reverse transcriptase inhibitor. 

More recently, RTIs that are chemically distinct from zidovudine and other NRTIs have also been developed (see Table 34-3). These agents are known as nonnucleoside reverse transcriptase inhibitors (NNR-TIs), and include drugs such as delavirdine (Rescrip-tor), efavirenz (Sustiva), and nevirapine (Viramune).32 These drugs also inhibit the reverse transcriptase enzyme, but act at a different site on the enzyme than do their NRTI counterparts. 

Nonnucleoside RTIs that do not require metabolic activation (e.g., delavirdine and nevirapine, efavirenz, which are not myelosuppressants) and a nucleotide reverse-transcriptase inhibitor (adefovir) have been introduced. Resistance emerges rapidly if these drugs are used as individual agents for management of HIV infection. However, they may provide additive or synergistic activity against HIV if used in combination regimens with NRTIs and/or Pis. 

The sites at which anti-HIV drugs may. in principle, act, are dealt with in detail under a main heading (see ANTIVIRAL agents). In summary, currently, of the drugs actually in use, a number are reverse transcriptase (enzyme) inhibitors (RTIs). Examples of nucleoside RTIs include zidovudine, didanosine and zalcitabine. Some non-nucleoside RTIs include foscarnet sodium, nevirapine, carbovir and TIBO analogues (some of these are at trial stage only). 

Nonnudeoside inhibitors of reverse transcriptase (NNRTIs) and a nucleotide RTI are also used in j combinations for treatment in an HIV-positive patient. j... 

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