Nursing Pharmacology:  Antiviral Drugs

• Antiviral Drugs

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

    • HIV-1 Pathophysiology/Pathogenesis:  HIV Disease Presentations

      • Pulmonary Disease (continued)

        • PCP Pneumonia

          • "Pneumocystis Pneumonia (PCP):  Part 1"¹³

            Wood BR (Medical Director, NW AETC ECHO, Asst. Professor of Medicine, University of Washington; Northwest AIDS Education and Training Center ;Last updated:  January 17, 2013) Pneumocystis Pneumonia (PCP):  Part 1 https://www.youtube.com/watch?v=I0fQupxy9uk Other Presentation from the Northwest AIDS Education and Training Center:  http://depts.washington.edu/nwaetc/echo/pres/#

           

          • The treatment for either PCP pneumonia (Pneumocystis jirovecii) or disseminated pneumocystosis is trimethoprim/sulfamethoxazole (TMP/SMX).² 

            • In patients with HIV infection the combination TMP/SMX exhibits a high incidence of side effects (20%-85%).

              • Side effects include, prominently:

                • Skin rash

                • Bone marrow suppression.

        • The treatment for either PCP pneumonia (Pneumocystis jirovecii) or disseminated pneumocystosis is trimethoprim/sulfamethoxazole (TMP/SMX).

          • In patients with HIV infection the combination TMP/SMX exhibits a high incidence of side effects (20%-85%).²

            • Side effects include, prominently, skin rash and bone marrow suppression.

          • Alternatives for management of mild to moderate Pneumocystis pneumonia include:

            • Dapsone + Trimethoprim

            • Clindamycin + Primaquine

            • Atovaquone.²

          • For patients with severe disease and who is unable to tolerate trimethoprim/sulfamethoxazole (TMP/SMX), IV pentamidine becomes the most appropriate treatment.²

          • In combination TMP/SMX is an effective antimicrobial with respect to many organisms.⁹ 

            • For example, Chlamydia diphtheriae and N. meningitidis (Neisseria meningitides) are both targets.

              • Most streptococcal pneumoniae remain susceptible, although an increase in resistance is observed.

            • A number of strains (50%-95%) of other organisms are inhibited by trimethoprim/sulfamethoxazole.

              • Some of these organisms include:

                • Staphylococcus aureus

                • Staphylococcus epidermidis

                • Streptococcus pyogenes

                • streptococci viridans group

                • E. coli

                • Proteus mirabilis

                • Proteus rettgeri

                • Enterobacter species

                • Salmonella

                • Shigella

                • Pseudomonas pseudomallei

                • Serratia

                • Alcaligenes species.

              • Other organisms sensitive include:

                • Klebsiella species

                • Brucella abortus

                • Pasteurella hemolytica

                • Yersinia pseudotuberculosis

                • Yersinia enterocolytica

                • Nocardia asteroides⁹

          • The effectiveness of trimethoprim with sulfamethoxazole rests on each agent inhibiting a different step in the pathway of a required bacterial enzymatic reaction.⁹

            • As noted, trimethoprim is most often used in combination with the sulfonamide sulfamethoxazole.¹¹  

              The ratio of trimethoprim to sulfamethoxazole is 1:5.

              • The combination takes advantage not only of synergism but also would be less likely to cause development of bacterial resistance, when compared to administration of either agent alone.

                • Bacterial resistance is likely due to integration of a plasmid coding for an altered form of dihydrofolate reductase.⁹

              • Use of these two agents together was based on both pharmacokinetic factors and availability.

                • Therapeutic effectiveness requires both agents to arrive at the tissue compartment describing infection localization, both at the proper time and in the correct ratio.

                  • The optimum ratio in vitro is 1:20.^11,9 

                  • Sulfamethoxazole was the closest to optimum for trimethoprim, noting that administration of the 1:5 combination of these agents orally resulted in a 1:20 ratio in the body at steady-state.^11,9

          • Pharmacokinetics:⁹

            • Pharmacokinetic profiles of sulfamethoxazole and trimethoprim are approximately matched in order to obtain the 20:1 concentration ratio in blood and tissues.⁹

              • The blood ratio may be >20:1 in blood, although the ratio in tissues is less.

            • Following single-dose administration of the combined trimethoprim-sulfamethoxazole preparation, trimethoprim exhibits more rapid absorption.⁹ 

              • For example, peak blood levels of trimethoprim usually occur at about two hours for most patients but peak sulfamethoxazole concentrations occur in about four hours.

              • Trimethoprim is both distributed and concentrated in tissues rapidly with about 40% bound to plasma protein in the presence of sulfamethoxazole.

                • The volume of distribution of trimethoprim is almost an order of magnitude higher than that for sulfamethoxazole.

                • The combined preparation partitions readily into spinal fluid.

                • About 65% of sulfamethoxazole is plasma protein bound.

              • Approximately 60% of administered trimethoprim and about 25% to 50% of administered sulfamethoxazole are excreted by the kidney, found in the urine within 24 hours.

                • Sulfamethoxazole is recovered primarily (66%) as unconjugated.

                • Trimethoprim metabolites are also excreted.⁹

            • For patients with uremia, rates of excretion and urinary concentration of both compounds are markedly reduced.⁹

            • Trimethoprim:  Site of Action¹¹

              Dihydrofolate reductase is an important enzyme in the conversion of dihydrofolate (dihydrofolic acid) on to tetrahydrofolic acid which is an important cofactor for thymidine biosynthesis and accordingly DNA synthesis.11 This enzyme also reduces endogenously synthesized dihydrofolate. Trimethoprim inhibits tetrahydrofolic acid biosynthesis, resulting in bacteriostasis. Furthermore, Trimethoprim selectivity discriminates between bacterial and mammalian dihydrofolate reductases as a result of "architectural differences" between these enzyme systems.11 For example, although the bacterial enzyme and the mammalian enzyme are effective catalysts for dihydrofolic acid to tetrahydrofolic acid conversion, the bacterial enzyme is much more sensitive to trimethoprim inhibition (the differences about 40,000-fold lower in the bacterial case).11  This observation provides the basis for trimethoprim selective toxicity in comparing mammalian and bacterial systems.11 Figure attribution: The figure above is a slight modification of Fig. 38.5 from reference 11.

            • "Action of Trimethoprim and Sulfamethoxazole"¹⁰

              Figure attribution Carter P  Action of Trimethoprim and Sulfamethoxazole Midlands Technical College (Courses: Bio225) http://classes.midlandstech.edu/carterp/Courses/bio225/chap20/lecture5.htm

            •  

              "Pneumocystis Pneumonia (PCP):  Part 2"¹⁴

              Wood BR (Medical Director, NW AETC ECHO, Asst. Professor of Medicine, University of Washington; Northwest AIDS Education and Training Center ;Last updated:  January 24, 2013) Pneumocystis Pneumonia (PCP):  Part 2 https://www.youtube.com/watch?v=IFCBymReZeA Other Presentation from the Northwest AIDS Education and Training Center:  http://depts.washington.edu/nwaetc/echo/pres/#

         

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. 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). Cochrane A Retroviruses Chapter 28 in Fundaments of Molecular Virology, 2e, Acheson NH, ed., John Wiley & Sons pp 342-353 2011. Cochrane A Human Immunodeficiency Virus Chapter 29  in Fundaments of Molecular Virology, 2e, Acheson NH, ed., John Wiley & Sons pp 354-364 2011. Ryan KJ, Ray C. Chapter 18. Retroviruses: Human T-Lymphotropic Virus, Human Immunodeficiency Virus, and Acquired Immunodeficiency Syndrome. In: Ryan KJ, Ray C. eds. Sherris Medical Microbiology (Part editor, Ahmad N Ray CG Drew WL), 5e. New York, NY: McGraw-Hill; 2010. Butel JS Chapter 44:  AIDS and Lentiviruses (Brooks FG, Carroll KC Butel JS Morse SA, Mietzner TA in Jawetz, Melnick & Adelberg's Medical Microbiology, 26th edition), 2013, on-line edition. Petri Jr WA Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections  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. Carter P  Action of Trimethoprim and Sulfamethoxazole Midlands Technical College (Courses: Bio225); http://classes.midlandstech.edu/carterp/Courses/bio225/chap20/lecture5.htm Mitscher LA Lemke TL Genry EJ Section 5:  Chemotherapeutic Agents.  Chapter 38 in Foye's Principles of Medicinal Chemistry, 6e Lemke TL; Williams DA, eds; Roche VF Zito SW, asst. eds), Lippincott Williams & Wilkins, a Wolters Kluwer business, 1038-1039, 2008. Olson RP Harrell LJ Kay KS Antibiotic Resistance in Urinary Isolates of E. coli from Collge Women with Urinary Tract Infectinos.  Antimicrob Agents Chemother, 53:  1285-1286, 2009. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2650563/  (second sourced from reference 9) Wood BR (Medical Director, NW AETC ECHO, Asst. Professor of Medicine, University of Washington; Northwest AIDS Education and Training Center (Last updated:  January 17, 2013) https://www.youtube.com/watch?v=I0fQupxy9uk

 

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