Nursing Pharmacology: Antiviral Drugs

• Antiviral Drugs

  • Anti-viral drugs with activity against influenza.

    • Amantadine and Rimantadine

      • Introduction: 

        • Amantadine (Symmetrel) and an associated drug, rimantadine (Flumadine), the α-methyl derivative of rimantadine are both tricyclic amines.¹ 

        • These agents inhibit influenza A viral replication with rimantadine generally being up to 10 times more active compared to amantadine.¹

          • Rimantadine also exhibits inhibition for a causative agent of African sleeping sickness, Trypanosoma brucei.

        • The efficacy of amantadine or rimantadine is dependent on possible resistance of the influenza strain.¹ 

          • For example, nearly all strains of influenza A H1N1 (2008-2009 influenza season) were resistant oseltamivir (neuraminidase inhibitor).

            • Most of the 2009 H1N1 "swine" isolate, however, were susceptible to oseltamivir but this viral isolate exhibit resistance to amantadine and rimantadine.¹

              •  

                Swine Flu: Example of Antigenic Shift

                Mouagip (derivative work):  Illustration of Antigenic Shift (National Institute of Allergy and Infectious Diseases) http://commons.wikimedia.org/wiki/File:AntigenicShift_HiRes_vector.svg

              • Earlier, resistance to amantadine and rimantadine was noted in influenza A/H3N2 viruses during the 2005-2006 influenza season, also seen in the strain in 2008-2009.² 

                • Pandemic A/H1N1 viruses in 2009-2010 also exhibit resistance to both agents.

                  • As a result, these drugs are not typically recommended for clinical use unless the particular influenza A isolate is known to exhibit sensitivity.² 

                    • In that case, amantadine/rimantadine might be viewed as an option.

                • Amantadine and rimantadine appear effective in influenza A prophylaxis based on "large-scale" clinical studies of young adults and smaller studies involving children and the elderly.

                  • Using these agents to prevent influenza-like disease was associated with efficacy rates of about 55-80%. Higher rates were noted when virus-specific "attack rates" were computed.²

      • Mechanism of Action:  Amantadine and Rimantadine

        • Amantadine and rimantadine exhibit two mechanisms accounting for their antiviral effects.

          • These agents inhibit an early step in viral replication most likely related to viral uncoating.¹ 

            • This finding was suggested by Davies and associates who identified amantadine as an agent producing dose-related inhibition of influenza infection in three systems: tissue culture, chick embryos and mice.⁷ 

            • It was concluded that the agent at least in part acted by interfering with penetration of the host cell by the virus.⁷  

            • The amantadine effect of inhibiting viral uncoating is shared by rimantadine.⁸

            • Other structurally-related compounds such as benzyl-substituted amantadine derivatives, also classified as viral uncoating inhibitors have also been identified.⁹ 

          • Inhibition of Viral Uncoating¹⁰

            • Amantadine was later found to target specifically the M2 influenza A viral protein and affecting its antiviral activity at that site.

              • Rimantadine acts similarly.

              • These drugs are part of a general class, adamantanes.

              • Influenza A viral isolates resistant to amantadine and rimantadine which renders these drugs ineffective results from a single amino acid change in the M2 protein, given that this alteration appears to have no or limited effect on viral activity.

              • Newer agents (9) are in development that can block both adamantane-sensitive and-resistant isolates.

            • Amantadine-Mediated Blockade of the Endosomal Acidification Step in the Influenza A Virus Replication Sequence

              Figure Attribution:  Adapted from "Release of influenza viral RNAs into Cells (6 May 2009)12.  Racaniello V:  Virology blog about viruses and viral disease http://www.virology.ws/2009/05/06/release-of-influenza-viral-rnas-into-cells/ 12

            • Accordingly, blockade of the M2 channel by e.g. amantadine or rimantadine is sufficient to block this step and confers the antiviral activity associated with these drugs.

              • As noted earlier however, a mutation, even a single mutation, in the M2 channel protein may be sufficient to confer resistance of the virus to the adamantane effects.¹⁰

          • These agents also affect a late step in viral assembly, related to hemagglutinin processing.¹

References

Acosta EP Flexner C Antiviral Agents (Nonretroviral) Chapter 58 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. Baden LR Dolin R, Chapter 178, Antiviral Chemotherapy, Excluding Antiretroviral Drugs, 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. Safrin S Antiviral Agents, Chapter 49 in Basic & Clinical Pharmacology, 12 e (Katzung BG Masters SB Trevor AJ) The McGraw-Hill Companies, 2012 (on-line edition) Briedis DJ  Chapter 18:  Influenza Viruses  (in Acheson NH,  Fundamentals of molecular virology, 2nd edition) p. 210-220 2011. Dolin R Chapter 187, Influenza , 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. Mouagip (derivative work):  Illustration of Antigenic Shift (National Institute of Allergy and Infectious Diseases) http://commons.wikimedia.org/wiki/File:AntigenicShift_HiRes_vector.svg Davies WL Brunert RR Haff RF McGahen JW Neumayer EM Paulshock M Watts JC Wood TR Hermann EC Hoffmann CE Antiviral Activity of 1-Adamantanamine (Amantadine) Science 144 (3620): 862-863, May 15, 1964. Rabinovich S Baldini JT Bannister R Treatment of influenza.  The therapeutic efficacy of rimantidine HCl in a naturally occurring influenza A2 outbreak.  Am J Med Sci 257:  328-355, 1969. Wang J Ma C Wang J Jo H Canturk B Fiorin G Pinto LH Lamb RA Klein ML DeBrado WF Discovery of novel dual inhibitors of the wild-type and the most prevalent drug-resistant mutant, S31N of the M2 protein channel from influenza A virus. J Med Chem 56:  2804-2812, 2013. Eeinger TO Pohl MO Stertz S Entry of influenza A virus:  host factors and antiviral targets Journal of General Virology 95:  263-277 (2014). Krug RM Aramini JM Emerging antiviral targets for influenza A virus.  Trends in Pharmacological Sciences 30(6): 266-277 June 2009. Racaniello V:  Virology blog about viruses and viral disease. Adapted from "Release of influenza viral RNAs into Cells (6 May 2009).  http://www.virology.ws/2009/05/06/release-of-influenza-viral-rnas-into-cells/

 

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