Nursing Pharmacology:  Antiviral Drugs

Non-nucleoside/Nucleotide Reverse Transcriptase Inhibtors (NNRTI)

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Non-nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NNRTI):  Introduction

    • Sites of Antiretroviral Drug Actions¹⁴

      a: The lifecycle of HIV-1, showing the step at which enfuvirtide acts, and also the steps targeted by other drugs.14  b:  "Simplified schematic of the mechanism by which enfuvirtide inhibits viral entry into host cells.14    The envelope glycoprotein of HIV-1 consists of two non-covalently associated subunits, gp120 and gp41. After attachment of HIV-1 to its target cells carrying the CD4 receptor, gp120 interacts with the CD4 receptor, which initiates a series of conformational changes in gp41 and gp120 that lead to the insertion of a region of gp41 into the membrane of the host cell, and formation of a ' pre-hairpin intermediate' (top). Further changes in the confirmation of gp41 bring the viral and cellular membranes into close enough proximity for membrane fusion (bottom left). Abbreviations: NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor" Attribution:  Slight modification of Figure 1 from:  LaBonte J Lebbos J Kirkpatrick nature Reviews Drug Discovery 2, 345-346 (May 2003).14

    •  

      NNRTI:  Site of Action in HIV Viral Replication

      Optigan13 "Non-nucleoside reverse transcriptase inhibitors (NNRTIs) work by inhibiting the reverse transcriptase enzyme."

     

    • 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 

    • 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.

      •  

        Mixed Function Oxidase System (Cytochrome P450 System):  Phase I Reactions

     

    • Currently, FDA-approved non-nucleoside reverse transcriptase inhibitors include:⁹

      • Delavirdine (DLV)

      • Efavirenz (EFV)

      • Etravirine (ETR)

      • Nevirapine (NVP) and

      • Rilpivirine (RPV).

    • 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-naïve 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

References

Flexner C Antiretroviral Agents and Treatment of HIV Infection, Chapter 59  in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Fauci AS Lane HC Chapter 226, Human Immunodeficiency Virus Disease:  AIDS and Related Disorders, in Harrison's Online   (Kasper DL Fauci AS Hauser SL Longo DL Jameson JL Loscalzo J, Eds.),  Harrison's Principles of Internal Medicine, 19th edition, The McGraw-Hill Companies, Inc. 2015 (on-line edition) Longo DL Fauci AS  188, The Human Retroviruses, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Woster PM Chapter 43:  Antiviral Agents and Protease Inhibitors in Foye's Principles of Medicinal Chemistry 6e, Lemke, TL Williams DA, eds; Roche VG Zito SW, asst eds) Wolters Kluwer|Lippincott Williams & Wilkins 1214, 2008. HIV Overview:  The HIV Life Cycle, Education Materials, AIDSinfo, NIH http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Tsibris AMN Hirsch MS Chapter 130 Antiretroviral Therapy for Human Immunodeficiency Virus Infection in Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, 8e (Bennett JE Bolin R Blaser, eds) Elsevier, Inc/Saunders 2015, online version. Safrin S Chapter 49:  Antiviral Agents:  Antiretroviral Agents in Basic & Clinical Pharmacology 13e (Katzung BG Trevor AJ, eds) 2015, online edition. Wensing AM Calvez V Gunthard JF Johnson VA Paredes R Pillay D Shafer RW Richman DD Special Contribution:  2014 Update of the Drug Resistance Multations in HIV-1 Topics in Antivral Medicine 22(3)  June/July 2014, https://www.iasusa.org/sites/default/files/tam/22-3-642.pdf AIDSinfo:  Guidelines for the Use of Antriretroviral Agents in HIV-1-Infected Adults and Adolescents https://aidsinfo.nih.gov/guidelines (2015) Madrid M Ribbon Representation of the Viral Reverse Transcriptase Active Domain (the p66 monomer) http://en.wikipedia.org/wiki/File:RTenzyme-hand.jpg de Bethune M-P Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection:  A review of the last 20 years (1989-2009) Antiviral Research 85:  75-90 2010. http://www.ncbi.nlm.nih.gov/pubmed/19781578 Optigan13 "Non-nucleoside reverse transcriptase inhibitors (NNRTIs) work by inhibiting the reverse transcriptase enzyme." http://en.wikipedia.org/wiki/File:HIVlifecycle-NNRTIs.png Havlir D McLaughlin MM Richman DD A Pilot Study to Evaluate the Development of Resistance to Nevirapine in Asymptomatic Human Immnodeficiency Virus-Infected Patients with CD4 Cell Counts o f >500/mm3:  AIDS Clinical Trials Group Protocol 28 J Infect Dis 172(5):  1379-1283 Nov. 1995. http://www-ncbi-nlm-nih-gov.proxy.kumc.edu:2048/pubmed/7594683 LaBonte J Lebbos J Kirkpatrick nature Reviews Drug Discovery 2, 345-346 (May 2003). (Slight modification of Fig. 1) http://www.nature.com/nrd/journal/v2/n5/fig_tab/nrd1091_F1.html; Original figure attribution:  Kilby JM Hopkins S Venetta TM

 

Disclaimer

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.