Nursing Pharmacology:  Antiviral Drugs

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

    • Sites of Antiretroviral Drug Actions¹⁶

      a: The lifecycle of HIV-1, showing the step at which enfuvirtide acts, and also the steps targeted by other drugs.16  b:  "Simplified schematic of the mechanism by which enfuvirtide inhibits viral entry into host cells.16    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).16

       

    • Nucleoside Reverse Transcriptase Resistance¹⁷

      Attribution: Wood BR Nucleoside Reverse Transcriptase Resistance (NRTI Resistance) https://www.youtube.com/watch?v=UHNcx6zrZwc (5/2014) MWAETC:  Project ECHO https://www.youtube.com/channel/UCqgJ2z1oIAhA-ZB_WocHibw

       

    • Zidovudine (AZT)

      • Zidovudine (AZT) is a thymidine analogue suitable for oral administration. Usually, zidovudine is formulated along with lamivudine for daily dosing (2X).⁶ 

        • Dosage adjustment for zidovudine may be required for those patients with sufficient renal impairment requiring hemodialysis, peritoneal dialysis or continuous venovenous hemofiltration.

          • Zidovudine has an oral bioavailability of about 65% as a result of first pass (phase II) hepatic glucuronidation.

            • Phase II characteristics: Parent drug participates in conjugation reactions that: Form covalent linkage between a parent compound functional group and: Glucuronic acid Sulfate Glutathione Amino acids Acetate

          • Zidovudine does not induce the microsomal cytochrome P450 drug metabolizing system and is not a substrate for that system either.

        • Zidovudine should not be co-administered with stavudine a.k.a. d4T as a result of in vivo (and in vitro) antagonism..⁶  

          • The assessment of this antagonism was based on a randomized clinical study which involved adding stavudine (d4T) or didanosine (DDI) to HIV-infected individuals receiving zidovudine.⁹ 

            • Since both zidovudine and stavudine require thymidine kinase-mediated phosphorylation for activation, the parent compound are "prodrugs".

            • Furthermore zidovudine exhibits a >100-fold affinity for thymidine kinase compared to stavudine.

            • This characteristic was reflected in measurements of intracellular stavudine-triphosphate.

            • In absence of zidovudine, intracellular stavudine triphosphate levels were about 65 fmol/10⁶ cells (stavudine alone).

              • By contrast, levels of stavudine triphosphate levels in patients also receiving zidovudine were about 10 fmol/10⁶ cells or about 6-fold less.

            • These results, albeit in a small clinical study, were consistent with findings in the in vitro setting.⁹ 

      • Combination of zidovudine and stavudine represented a theoretical risk, since both drugs depend on intracellular phosphorylation by cellular thymidine kinase.⁴ 

        • The phosphorylation step is important because zidovudine is sequentially converted to 5'-mono-, di-, and triphosphates by thymidine kinase.

          • Zidovudine so phosphorylated is incorporated into proviral DNA, important because viral reverse transcriptase uses zidovudine-triphosphate as a substrate.

          • The tri-phosphorylated form prevents normal 5', 3'-phosphodiester bonding, thus resulting in DNA chain elongation termination due to the presence of the azido group in zidovudine (AZT).⁴ 

            • Chain termination occurs because zidovudine 5'-triphosphate which is incorporated into nascent DNA lacks a 3'-hydroxyl group.¹ 

              • The first phosphorylation step of zidovudine, yielding the monophosphate, results in a form that competitively inhibits cellular thymidylate kinase.¹ 

                • This competitive inhibition reduces quantities of intracellular thymidine triphosphate.

              • Zidovudine 5'-triphosphate slightly inhibits cellular DNA polymerase-α; however, this compound is a stronger inhibitor of mitochondrial polymerase-γ.¹ 

                • Conversion of zidovudine 5' monophosphate to diphosphate is relatively slow, resulting in monophosphate accumulation in cells.

                • Elevated concentrations of intracellular monophosphate acts as a reservoir and as a result, elevation in plasma zidovudine may not proportionally increase intracellular zidovudine triphosphate.¹

        • Mutations and Zidovudine Resistance

          • Clinical resistance to zidovudine anti-retroviral activity is due to mutations in the viral reverse transcriptase enzyme.¹ 

             

            • Development of Antiretroviral Resistance (nucleoside analogue class)¹⁴

              Attribution:  Wainberg M Mechanisms of Nucleoside Analogue Antiretroviral Resistance:  NRTI Resistance, https://www.youtube.com/watch?v=Hrd1kNmqEOs (5/2014) MWAETC:  Project ECHO https://www.youtube.com/channel/UCqgJ2z1oIAhA-ZB_WocHibw

            • These mutations have been localized to specific regions.¹¹ 

              • When used as a single antiretroviral drug, zidovudine is associated with clinical resistance has mutations gradually develop.¹ 

              • About 30% of patients experience zidovudine resistance after 1 year of zidovudine monotherapy.

                • Prolonged therapy, however, results in cross-resistance to various nucleoside analogues.

            • Administration of lamivudine or emtricitabine results in a particular mutation at codon 184 (a methionine to valine substitution) in the viral reverse transcriptase gene that restores zidovudine sensitivity.¹⁰ 

            • Combination treatment of zidovudine and lamivudine has been shown to extend long-term plasma HIV RNA suppression compared to zidovudine by itself.¹³ 

              • Consequently, zidovudine may be combined with lamivudine in the clinical setting.¹

        • Pharmacokinetics:¹

          • Following oral administration, zidovudine is rapidly absorbed, reaching peak plasma levels in about an hour.

            • The elimination t_½ for the parent compound (prodrug) is about an hour, which is shorter than that of the intracellular triphosphate active compound by about a factor of four (i.e. about 3-4 hours).

            • Zidovudine exhibits first-pass hepatic metabolism (phase II glucuronidation), reducing bioavailability to about 65%.

            • The pharmacokinetic characteristics of zidovudine is not notably affected in pregnancy with the drug concentration in the newborn similar to that in the mother.

            • The parent agent, zidovudine, crosses the blood brain barrier fairly well with a CSF to plasma ratio (cerebrospinal fluid: plasma ratio) of about 0.6.

              • Zidovudine can be detected in breast milk, fetal tissue and semen.¹

        • Adverse Effects:⁷

          • The most common zidovudine adverse effect is myelosuppression associated with macrocytic anemia (about 2%) or neutropenia (about 5%).⁷ 

          • Some adverse effects develop initially and then resolve during continued treatment.

            • Examples of these effects include headaches, insomnia, and gastrointestinal issues.

            • Lipoatrophy appears more frequently in patients receiving zidovudine or other thymidine analogue agents.

              • "Lipoatrophy:  Facial Fat Loss"¹⁵

                Chow DC Day LJ Shikuma CM Lipoatrophy: facial fat loss

                 

          • Less frequently observed toxicities include thrombocytopenia, nail hyperpigmentation and myopathy.

          • CNS effects may be noted at high doses, presenting as anxiety, confusion and tremor.

          • Co-administration of zidovudine with certain other agents result in increased zidovudine serum concentrations.

            • Elevated zidovudine in this setting can occur by:

              • Reduction of first-pass metabolism or by

              • Decreased drug clearance.

            •  Drugs which can, upon concurrent zidovudine administration, result in elevated zidovudine serum levels

              Probenecid	Methadone		Phenytoin
              Fluconazole	Atovaquone	Valproic acid	Lamivudine

            • By contrast, zidovudine administration may reduce phenytoin levels.

            • Increased hematological toxicity may be observed upon co-administration of other myelosuppressive agents such as:

              • Ganciclovir

              • Ribavirin

              • Cytotoxic drugs

            • As discussed earlier, combination protocols containing zidovudine and stavudine should be avoided because of drug-drug antagonism (competition for intracellular phosphorylation).⁷

        • Therapeutics:¹

          • Zidovudine (Retrovir, AZT) is approved (FDA) both for treating adults and children infected with HIV and for preventing mother-to-child HIV transmission.¹ 

            • Given the long time and broad experience with zidovudine, zidovudine remains recommended for post-exposure prophylaxis in HIV-exposed health-care workers.

              • This conclusion has been described in a 2005 Centers for Disease Control and Prevention (CDC) report (here) which has been slightly modified in 2013 (here).

                • Zidovudine is available as oral tablets, capsules, syrup and solution, including a solution suitable for intravenous injection.¹

                •  

                  Examples of Zidovudine Formulations

              • Zidovudine is also available in coformulation tablets with other antiretroviral drugs.¹  

                • For example, zidovudine may be compounded with lamivudine (Combivir) or with lamivudine and abacavir (Trizivir).

                  • As monotherapy, zidovudine decreases perinatal HIV transmission risk by about 67%.

                    • In this application use of zidovudine with other antiretroviral drugs is even more effective in preventing HIV perinatal transmission.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. HIV Overview:  The HIV Life Cycle, Education Materials, AIDSinfo, NIH http://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Havlir DV Tierney C Friedland GH Pollard RB Smeaton L Sommadossi J-P Fox L Kessler H Fife KH Richman DD  Iv vivo Antagonism with Zidivudine plus Stavudine Combination Therapy. The Journal of Infectious Disease, 182(1) (July., 2000) 321-325. http://www.ncbi.nlm.nih.gov/pubmed/10882616 Gallant JE Gerondelis PZ Wainberg MA Shulman NS Haubrich RH St Clain M Lanier ER Hellmann NS Richman DD Nucleoside and nucleotide analogue reverse transcriptase inhibitors:  a clinical review of antiretroviral resistance.  Antiviral Therapy 8:  489-506. http://www.intmedpress.com/journals/avt/abstract.cfm?id=1027&pid=88; http://www.ncbi.nlm.nih.gov/pubmed/14760883. (second sourced from reference 1 above) 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 Naeger LK Margo NA Miller MD ATP-Dependent Removal of Nucleoside Reverse Transcriptase Inhibitors by Human Immunodeficiency Virus Type 1 Reverse Transcriptase.  Antimicrobial Agents and Chemotherapy, July 2002, p. 2179-2184, http://www.ncbi.nlm.nih.gov/pubmed/12069972 (second sourced from reference 1 above). Eron JJ Benoid SL Jemsek J MacArchur RD Santana J Quinn JB Kutitzkes DR Fallon MA Rubin M Treatment with Lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. The New England Journal of Medicine 333(25): 1662-1669, 1995, http://www.ncbi.nlm.nih.gov/pubmed/7477218 . (second sourced from reference 1 above) Wainberg M Mechanisms of Nucleoside Analogue Antiretroviral Resistance, 2013 https://www.youtube.com/watch?v=Hrd1kNmqEOs Chow DC Day LJ Shikuma CM Lipoatrophy: facial fat loss.  HIV/AIDS,  U.S. Department of Veterans Affairs:  Image Library | Lipoatrophy/Lipoaccumulation http://www.hiv.va.gov/provider/image-library/lipodystrophy.asp?post=1&slide=21 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 Wood BR NRTI Resistance https://www.youtube.com/watch?v=UHNcx6zrZwc (5/9/13; published 5/29/14)

 

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