NRTI interactions

How do these NRRIs interact with their final target, the HCV RNA replicase They are phosphorylated to their 5 -triphosphate form, and then inhibit the HCV replicase. As they possess a 3 -hydroxyl function, they may not be considered as obligate chain terminators, but they may act as virtual chain terminators, viz. by steric hindrance exerted by the neighboring 2 -C-methyl and/or 4 -C-azido groups. Similar to their NRTI and NNRTI counterparts in the case of HIV reverse transcriptase, the NRRIs (2 -C-methylnucleosides) interact, upon their phosphorylation to the corresponding 5 -triphosphates, with a region of the HCV RNA replicase (or NS5B RNA-dependent RNA polymerase) that is clearly distinct from the site(s) of interaction of the NNRRIs (Tomei et al. 2005). 

C. Myelotoxicity is associated with certain NRTIs such as zidovudine. Fat redistribution, drug interactions involving CYP3A4, dyslipidemia, and diabetic symptoms are all side effects common to the protease inhibitors. 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

A close-up view showing the relative locations of the commonly identified drug-resistance mutations for NRTIs (in dark-gray) and for NNRTIs (in light-gray) with respect to the bound DNA. Most of the NRTI-resistance mutations are not located at the putative dNTP-binding site, but are at positions to have potential interactions with the nucleic acid template-primer. Conversely, all the NNRTI-re si stance mutations are clustered around the NNIBP and have direct contacts with NNRTIs or have direct effect on... 

At the present time, there are at least 14 compounds that have been formally approved for the treatment of human immunodeficiency virus (HIV) infections. There are six nucleoside reverse transcriptase inhibitors (NRTIs) that, after their intracellular conversion to the 5 -triphosphate form, are able to interfere as competitive inhibitors of the normal substrates (dNTPs). These are zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC), and abacavir (ABC). There are three nonnucleoside reverse transcriptase inhibitors (NNRTIs) — nevirapine, delavirdine, and efavirenz — that, as such, directly interact with the reverse transcriptase at a nonsubstrate binding, allosteric site. There are five HIV protease inhibitors (Pis saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir) that block the cleavage of precursor to mature HIV proteins, thus impairing the infectivity of the virus particles produced in the presence of these inhibitors. 

Many recreational drugs such as benzodiazepines, amphetamines, and opioids are also metabolized by the liver. Although information is scant about the clinical significance and interactions between these drugs and antiretroviral agents, unintentional overdoses with methamphetamine and gamma hydroxybutyrate have been reported in patients using Pis, particularly ritonavir. Pis and NRTIs may alter metabohsm of methadone and precipitate opioid withdrawal (McCance-Katz et al., 2003). 

D. Efavirenz This NNRTI has been shown to be effective in HIV treatment when used in combination with two NRTIs. Efavirenz is metabolized by hepatic cytochromes P450 and is frequently involved in drug interactions. Toxicity of efavirenz includes CNS dysfunction, skin rash, and elevations of plasma cholesterol. The drug should be avoided in pregnancy since fetal abnormalities have been reported in animals. 

The NNRTis are extensively metabolised by the cytochrome P450 isoenzyme system, particularly by CYP3A4. They are also inducers (nevirapine, efavirenz) or inhibitors (delavirdine) of CYP3A4. NNRTis would therefore be expected to interact with each other, and with protease inhibitors, but not with NRTIs (see below). They also have the potential to interact with other drugs metabolised by CYP3A4, and are affected by CYP3A4 inhibitors and inducers. Delavirdine and efavirenz may also inhibit some other P450 isoenzymes. For a summary, see Table 21.2 , (p.773). 

NRTIs are prodrugs, which need to be activated by phosphorylation within cells to a triphosphate anabolite. Drugs may therefore interact with... 

NRTIs are water soluble, and are mainly eliminated by the kidneys (di-danosine, lamivudine, stavudine, and zalcitabine) or undergo hepatie glu-curonidation (abacavir, zidovudine). The few important interactions with these drugs primarily involve altered renal clearance. For zidovudine (and possibly abacavir) some interactions occur via altered glucuronidation, but the clinical relevance of these are less clear (e.g. rifampicin , (p.792)). Cytochrome P450-mediated interactions are not important for this class of drugs. 

Probenecid reduces the nephrotoxicity of cidofovir, and it is recommended it should always be used concurrently. Therefore, when using cidofovir/probenecid the interactions of probenecid should be considered. Of particular note, zidovudine should be temporarily discontinued or the dosage halved when cidofovir/probenecid is used, see NRTIs + Probenecid , p.803. 

The manufacturer notes that there were no clinically significant pharmacokinetic interactions between efavirenz and zidovudine or iamivudine in patients with HIV. " No dosage adjustments are required on concurrent use. No pharmacokinetic interactions are anticipated with other NRTIs. ... 

Information seems to be limited to the papers cited, but an interaction between zidovudine and valproate would appear to be established. It would therefore seem prudent to monitor for any evidence of increased zidovudine effects and possible toxicity if valproate is added. The other NRTIs do not undergo significant glucuronidation (see Antivirals , (p.772)), and would therefore not be expected to interact with valproate. For a discussion of drug-disease considerations when using valproate in HIV infection, see under Importance and management in protease inhibitors ,... 

There is no pharmacokinetic interaction between stavudine and fluconazole. No interaction would be expected with other similar NRTIs such as lamivudine and zalcitabine (see Antivirals , (p.772)). 

Interferon alfa does not alter the pharmacokinetics of didanosine or lamivudine to a clinically relevant extent. Interferon alfa and, particularly, interferon beta can cause an increase in the serum levels of zidovudine. HIV-positive patients infected with hepatitis C and treated with interferon alfa and ribavirin may be at special risk of NRTI-associated lactic acidosis. Interleukin-2 appears not to interact significantly with zidovudine. 

Lamivudine is cleared predominantly from the body by the kidneys using the organic cationic transport system. Didanosine is not cleared by this mechanism and so is unlikely to interact with lamivudine by this mechanism. Didanosine does not affect the intracellular activation of lamivudine in vitro. In UK and US guidelines, the combination of didanosine with lamivudine is currently a recommended alternative dual NRTI option for use with an NNRTI or a protease inhibitor, for the treatment of HIV-infection in treatment naive patients. 

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