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Pharmacology

1. Pharmacology of Antiviral Agents

2. LEARNING OBJECTIVES At the end of this lecture each student should be able to: State the features of viruses and the features of antiviral agents. Outline the pharmacology of antiviral agents. 2/13/2024 . 2

3. Herpes Zoster 2/13/2024 3

4. Features of Viruses Obligate intracellular pathogens Enter and release genome (DNA or RNA) inside host cells Hijack and utilize host cell metabolic processes for replication 2/13/2024 . 4

5. Features of Antiviral Agents Antiviral agents exhibit the following features: Selectively active inside host cell Block viral entry into host cells Block viral release from host cell 2/13/2024 . 5

6. Major Targets of Antiviral Action 2/13/2024 6

7. Nucleoside Analogues: e.g Acyclovir Active against herpes simplex viruses, Varicella- zoster, and CMV Other guanosine analogs: Valacyclovir , Famciclovir , Penciclovir 2/13/2024 . 7

8. Acyclovir MoA; Metabolic activation inside infected cells by virus encoded thymidine kinase Subsequent conversion of the monophospate to a triphosphate ACYC-TP ACYC-TP inhibits viral DNA synthesis by chain termination 2/13/2024 8

9. Clinical Uses Treatment of herpes infections and varicella-zoster Prophylaxis in patients with recurrent or risk of herpes infections Oral or IV treatment preferred; topical therapy often not effective 2/13/2024 9

10. DOSE Primary genital herpes simplex virus (HSV) infection. Adult: 200 - 800mg P.O. every 4 hours while awake five times a day for 10 days 5mg/kg I.V. every 8 hours ( infused over 1 hour for 5 – 7 days in patients with a creatinine clearance greater than 50ml/minute Recurrent Genital HSV infection 200 – 800mg P.O. five times a day for 5 days 2/13/2024 10

11. DOSE Varicella Zoster Infection 5 – 10mg/kg I.V. every 8 hours ( infused over 1 hour) for 5 days Herpes Simplex Encephalitis 10mg/kg I.V every 8 hours (infused over 1 hour) for 10 days. 2/13/2024 11

12. Adverse Effects Well tolerated Nephrotoxicity with IV infusion Neurotoxicity 2/13/2024 . 12

13. PRECAUTIONS Closely monitor the patient’s renal function, especially the serum creatinine level, during parenteral therapy. I.V. infusion of Acyclovir or Gancyclovir to be administered slowly (usually over 1hr) to prevent drug crystals from precipitating in the renal tubules. 2/13/2024 13

14. Ganciclovir MoA; Acyclic guanosine analogue Converted in infected cells to triphosphate by protein kinase phosphotransferase Metabolite inhibits viral DNA polymerase Concentrated X10 in infected cells 2/13/2024 . 14

15. Clinical Uses & Adverse Effects CMV infections (retinitis, oesophagitis, pneumonitis, colitis) Acyclovir resistant herpes infections. A/E: Marrow suppression, inhibition of gametogenesis, phlebitis, pain, rash, fever, GI disorders. 2/13/2024 . 15

16. Contraindications & Drug Interactions Pregnancy: Reported to be teratogenic Cancer drugs, Amphotericin B, & Zidovudine may enhance toxicity 2/13/2024 . 16

17. Foscarnet Active against HIV, HSV, CMV MoA; Irreversibly inhibit viral DNA & RNA polymerases, and reverse transcriptase Does not inhibit human polymerase* 2/13/2024 . 17

18. Clinical Uses/ Resistance CMV infections – retinitis, pneumonitis, colitis, esophagitis Acyclovir resistant strains HIV and HSV infections 2/13/2024 18

19. DOSE 60mg/kg every 8 hours for 2 – 3 weeks depending on clinical response; For maintenance dosage, 60 to 120mg/kg I.V. daily. 2/13/2024 . 19

20. PRECAUTIONS Closely monitor the patient’s renal function, especially the serum creatinine level, during therapy. Because Foscanet can cause renal dysfunction, the dosage must be adjusted to changes in renal function. Do not administer Foscanet by I.V. or bolus infusion because high plasma levels are associated with toxicity. An infusion pump is recommended. 2/13/2024 20

21. PRECAUTIONS CONT’ Closely monitor serum electrolyte levels because transient changes may increase the risk of cardiac disturbances and seizures. Closely monitor for signs and symptoms of infection, such as fever, chills, cough and purulent drainage, if the patient develops Leucopenia . Take infection control measures until the patients WBC count returns to normal. 2/13/2024 . 21

22. INFLUENZA VIROLOGY They are classified according to their core proteins – A, B, C Group A causes most flu diseases Group A classified and named based on haemagglutinin H (16) and neuraminidase N (9) subtypes; Examples: H1N1, H1N2, H5N1 Most infect poultry; Some mutants cause human disease 2/13/2024 . 22

23. Anti-Influenza Drugs Amantadine, Rimantadine, M2 inhibitors Oseltamivir, Zanamivir Neuraminidase inhibitors 2/13/2024 23

24. Adamantanes Amantadine and Rimantadine Inhibit M2 protein required by type A viruses for uncoating inside the host cell Effective only against type A viruses Amantadine is not metabolized; excreted unchanged by tubular secretion 2/13/2024 24

25. 2/13/2024 . 25 Rimantadine is extensively metabolized in the liver Activities of both similar against type A viruses A/E: Neurological and GI related

26. Neuraminidase Inhibitors Oseltamivir and Zanamivir Active against types A and B viruses Neuraminidases facilitate the release of newly assembled viruses from the infected cells NIs promote clumping of the viruses on cell surface – reduced spread; 2/13/2024 26

27. Side effects They are relatively less toxic than Adamantanes A/E: Mainly GI related – reduced by taking with food; fatigue, headache, delirium 2/13/2024 27

28. Zanamivir Orally not bioavailable Given by oral inhalation Spectrum similar to Oseltamivir A/E: Cough, bronchospasm, depressed respiratory function. *Not to be given to patients with airways diseases 2/13/2024 . 28

29. Agents for Viral Hepatitis: Interferon- α Immunomodulators play significant roles in the mgt of viral hepatitis Preparations of interferon- α are used often in combination therapy Includes interferon – α 2a & interferon – α 2b 2/13/2024 . 29

30. Interferon Alfa Interferon is host cell derived cytokine Binds to receptor to induce signals for antiviral activity Inhibition of penetration, transcription, translation, protein synthesis, and viral release Available for parenteral use only 2/13/2024 . 30

31. Interferon Alfa A/E: Flu-like symptoms, changes in liver function parameters, myelosuppression, weight loss, retinopathy, neurotoxicity, pneumonitis, aggravation of autoimmune diseases. 2/13/2024 . 31

32. HBV Therapy Goals: To suppress HBV replication, slow disease progression and prevent complications. Interferon derivatives ( α -2a and α -2b) Nucleoside and nucleotide analogues Lamivudine, Adefovir , Tenofovir, Entecavir 2/13/2024 . 32

33. HCV Therapy Major goal – Eradication of HCV to achieve zero viraemia Rx with interferon preparations + Ribavirin. 2/13/2024 33

34. Ribavirin MoA; Guanosine analogue Inhibits viral RNA and DNA polymerases A/E: Dose-dependent, hemolytic anaemia , depression, cough, rash, nausea, insomnia C/I: heart disease, severe anaemia , pregnancy 2/13/2024 34