Medical Pharmacology Chapter 36: Antiviral Drugs
Non-nucleoside/Nucleotide Reverse Transcriptase Inhibtors (NNRTI)
Antiretroviral Drugs Used in Treating HIV Infection
→Non-nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRTI): Introduction
Non-nucleoside reverse transcriptase inhibitors bind to a "hydrophobic pocket" in the "p66" subunit of the heterodimeric protein.1,11
This site is about 10 ┼ removed from the enzyme catalytic site. The binding of an NNRTI induces a conformational change which rotates specific side chains in the protein towards the catalytic site.11
This structural change causes additional structural changes directly affecting three catalytic aspartic acid residues.
The magnitude of the change at the catalytic site appears to be of the order of about 2 ┼.
These confirmation alterations caused by NNRTI binding to the retroviral reverse transcriptase are likely to be the inhibitory mechanisms exhibited by drugs belonging to this class.11
Non-nucleoside reverse transcriptase inhibitors are classified as noncompetitive, acting by inducing a conformational change in the enzyme as opposed to competing with other molecules at the binding site (competitive inhibition).1
Binding site specificity for these drugs results in their activity against HIV-1 but these agents are not active against HIV-2 or other retroviruses.
Furthermore the non-nucleoside reverse transcriptase inhibitors did not exhibit activity with respect to cell DNA polymerases.1
Efavirenz and nevirapine are examples of drugs in this category and represents the two agents most frequently administered.1
Employed as monotherapy, administration of these drugs may decrease in HIV RNA plasma concentrations by a factor of 100 or more, although resistance typically rapidly develops.13
For example, a clinical study utilizing nevirapine involved asymptomatic patients with CD4+ T cell counts >500 cells/cc.
Using a dosage of 400 mg of nevirapine once a day, HIV plasma RNA decreased with a mean reduction of 0.73 log10 and a median reduction of 0.51 log10 copies/cc.
The study involved 17 seropositive individuals.
After 12 weeks of nevirapine administration, all HIV viral isolates exhibited drug resistance.13
Non-nucleoside reverse transcriptase inhibitors (presently approved) utilize the liver microsomal metabolizing system for elimination.1
The cytochrome P450-dependent system describes a variety of cytochrome P450 similar enzymes or "isoforms".
For example, delavirdine and nevirapine are primarily metabolized by an important drug metabolizing isoform, CYP3A4.
By contrast, efavirenz is mainly metabolized by CYP2B6 and CYP3A4.
Elimination half-times for efavirenz and nevirapine extend from 1 to 3 days which permits daily dosing.
Sometimes drugs are also able to induce cytochrome P450 enzymes, resulting usually and elevated enzyme cellular concentrations.
In this instance, efavirenz, etravirine, and nevirapine are classified as moderately potent inducers of the cytochrom P450 system.1
In particular, these agents elevate CYP3A4 levels; however, delavirdine has been shown to be a CYP3A4 inhibitor.
A further complication is that a drug may inhibit some cytochrome P450 isoforms while inducing others.
This effect, "mix metabolism", describes the case noted for etravirine.1
Changes in concentrations or activities of cytochrome P450 isoforms may result in drug-drug interactions.1
For example, if one drug increases the concentration of the cytochrome P450 isoform mainly responsible for the metabolism of the second drug, the plasma concentration of the second drug may decrease to below therapeutic levels.
Should one drug decrease the concentration of a cytochrome P450 isoform which metabolizes a second drug, plasma concentration of the second drug may be increased resulting in toxicities.
Microsomes have been used to study mixed function oxidases
Drug metabolizing enzymes are located in lipophilic, hepatic endoplasmic reticulum membranes. Smooth endoplasmic reticulum contains those enzymes responsible for drug metabolism.
One molecule oxygen is consumed per substrate molecule
One oxygen atom -- appears in the product; the other in the form of water
Two important microsomal enzymes:
Flavoprotein is NADPH cytochrome P450 reductase
Cytochrome P450, a terminal oxidase:
Consists of multiple forms
Named cytochrome P450 because:
Note in the Figure below the conversion of RH to ROH represents drug oxidation.
Currently, FDA-approved non-nucleoside reverse transcriptase inhibitors include:9
Nevirapine (NVP) and
Genotypic testing is suggested prior to initiating NNRTI treatment because of relatively high resistance rate: 2%-8%.7
NNRTI resistance, as noted, develops quickly with monotherapy and may occur following a single mutation.7
Examples of mutations include K103N, a substitution of lysine by asparagine, noted in resistance to nevirapine and Y181C, a substitution of a tyrosine by a cysteine.
These mutations appear more likely to induce resistance to the first-generation NNRTI agents while not affecting newer drugs such as rilpivirine and etravirine.
Some mutations induce cross-resistance to drugs belonging to the NNRTI drug group.7
With the exception of etravirine, other NNRTI agents may exhibit significant drug resistance due to single-amino-acid substitutions in the drug-binding allosteric region.1
By contrast, other HIV-1 antiretroviral drugs belonging to the nucleoside analog or protease inhibitor classes, efavirenz or nevirapine resistance and associated virologic relapse may occur quickly, within a few days or weeks, if the drug is administered as monotherapy.
As monotherapy, a single dose of nevirapine may be associated with mutations resulting in drug resistance in as many as 33% of patients.1
As a result of these considerations, NNRTI antiretroviral drugs must be administered in combination with a minimum of two other active drugs in order to avoid drug resistance.1
Efavirenz or nevirapine administration along with other antiretroviral agents results in long-term suppression of viremia and increases in CD4+ T lymphocyte counts.1
Efavirenz is frequently used as a component of the first drug regimen in treatment-na´ve patients.
Efavirenz is favored in this setting as a result of convenience of use, patient's ability to tolerate the drug, and drug potency.
A common side effect associated with NNRTIs, most likely occurring within the first month of treatment is a mild, self-limited rash.
Rare cases of potentially fatal Stevens-Johnson syndrome have been documented with nevirapine, efavirenz, and etravirine.1
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