Nursing Pharmacology: Antiviral Drugs

Nursing Pharmacology: Antiviral Drugs

Antiviral Drugs

Anti-viral drugs with activity against HIV (Human Immunodeficiency Virus)

HIV-1 Pathophysiology/Pathogenesis: HIV Disease Presentations

Cardiovascular Diseases

Drug-Induced Myocardial Disease (continued)

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

The HIV viral genome contains the base sequence for an RNA-dependent DNA polymerase or reverse transcriptase.¹
- This enzyme catalyzes conversion of viral RNA into proviral DNA which may be incorporated into the host cell chromosome.¹
- An example drug from this class is zidovudine (AZT).
  - Zidovudine exhibits pharmacological activity against RNA tumor retroviruses, causative of AIDS and T-cell leukemia.⁶
    - The enzyme reverse transcriptase of retroviruses catalyzes synthesis of a DNA genome.
      - As noted above, proviral "HIV" DNA integrates into the normal cell genome and upon expression results in HIV infection.
      - Zidovudine may be classified as a prodrug in that the parent compound is converted by host cell thymidine kinases to 5'-mono-,di-and triphosphate derivatives.
      - These phosphorylated derivatives are then incorporated into proviral DNA, since reverse transcriptase uses zidovudine-triphosphate as a substrate.
        
        As a consequence, normal cellular 5', 3'-phosphodiester bonding is prevented and DNA chain elongation terminated as a result of the azido group in AZT (zidovudine).
        
        This process results in preventing new HIV virion synthesis. ⁶
    - Zidovudine not only inhibits HIV-1 but also HIV-2 and Epstein-Barr virus.⁶
- One important class of anti-HIV drugs act by inhibiting this enzyme.
- Reverse transcriptase inhibitors include both nucleoside/nucleotide analogues or non-nucleoside inhibitors.

**Mechanism of Nucleoside Reverse-Transcriptase Inhibitors⁸**

"Nucleoside reverse-transcriptase inhibitors are similar in structure to the building blocks that make up DNA.⁸ "By incorporating themselves into the DNA nucleoside chain being produced by reverse transcriptase, they stop attachment of further nucleosides and so prevent ongoing viral DNA synthesis."⁸ This figure corresponds to Figure 3A in reference 8.

**Mechanism of Non-nucleoside Reverse Transcriptase Inhibitors^8,7**

"Non-nucleoside reverse transcriptase inhibitors attach to the reverse transcriptase and affect the activity of the enzyme by restricting its mobility and making it unable to function."⁸ This figure corresponds to figure 3B in reference 8.

Nucleoside/nucleotide reverse transcriptase inhibitors have been evaluated with respect to possible adverse cardiovascular effects.⁵
- Generally, with the possible exception of abacavir, nucleotide/nucleoside reverse transcriptase inhibitors have not been found associated with increased cardiovascular risk.
- There has been evidence indicative of cardiotoxicity associated with azidothymidine (AZT) which is both a nucleotide reverse transcriptase inhibitor and a component of cART (HAART).⁵
  - This cardiotoxicity has been described as due to mitochondrial damage; however, despite initial reports, this association has not been replicated in larger clinical studies.
  - Nucleoside/nucleotide reverse transcriptase inhibitors may have effects on lipids, described as increased total cholesterol, increase low-density lipoprotein cholesterol (LDL), increased triglycerides and decreased high-density lipoprotein cholesterol (HDL.
    - Effects on glucose, when noted, have been represented in terms of varying degrees of insulin resistance.⁵

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 189, Human Immunodeficiency Virus Disease: AIDS and Related Disorders, 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. 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. Lewis W Currie PF Chapter 93 HIV/AIDS and the Cardiovascular System (in Hurst's The Heart, 13 e Fuster V, Walsh RA Harrington RA, eds; Hunt AS King III SB Nash IS Prystowsky EN Roberts R Rose E, Assoc eds) The McGraw-Hill Companies, Inc 2011. Thienemann F Sliwa K Rockstroh JK HIV and the heart: the impact of antiretroviral therapy: a global perspective. Eur Heart J 34(46): 3538-3546 Dec. 2013 http://www.ncbi.nlm.nih.gov/pubmed/24126882 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. Davidson College Reverse Transcriptase http://www.bio.davidson.edu/Courses/Molbio/MolStudents/spring2005/Koike/RT protein.htm Richman DD HIV Chemotherapy (Insight review articles) Nature 410: 995-1001, 19 April 2001 Stowell D Reverse Transcriptase http://www.mcld.co.uk/hiv/?q=reverse transcriptase

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