Antiviral drugs

1. Antiviral drugs Mr. OLORO JOSEPH.

2. Viruses • Obligate intracellular parasites • Consist of a core genome in a protein shell and some are surrounded by a lipoprotein • lack a cell wall and cell membrane • do not carry out metabolic processes • Replication depends on the host cell machinery

3. Viruses • Steps for Viral Replication • 1) adsorption and penetration into cell • 2) uncoating of viral nucleic acid • 3) synthesis of regulatory proteins • 4) synthesis of RNA or DNA • 5) synthesis of structural proteins • 6) assembly of viral particles • 7) release from host cell

4. Antiviral Agents • General mechanism of action • Block viral entry into the cell • Inhibits uncoating • Inhibit synthesis of nucleic acid • Inhibit release of new virions • Most agents are pyrimidine or purine nucleoside analogs

5. Sites of Drug Action

6. Antiherpes Agents • Acyclovir- prototype • Valacyclovir • Famciclovir • Penciclovir • Trifluridine • Vidarabine

7. Acyclovir • An acyclic guanosine derivatives. • Mechanism of action • Undergoes initial phosphorylation by viral specific thymidinekinase enzyme • Then di- and triphosphate by host cell enzymes • Triphosphate inhibit viral replication by; • Competition with dGTP. • Chain termination following icoporation

9. Mechanism of Resistance toAcyclovir • Alteration in viral thymidinekinase • Alteration in viral DNA polymerase • Cross-resistance with valacyclovir, famciclovir, andganciclovir

10. Acyclovir • Oral, IV, and Topical formulations • Cleared by glomerular filtration and tubular secretion • Uses: • Herpes Simplex Virus 1 and 2 (HSV) • Varicella-zoster virus (VZV) • Side Effects: nausea, diarrhea, headache, tremors, and delirium

11. Valacyclovir • L-valyl ester of acyclovir • Converted to acyclovir when ingested • M.O.A.: same as acyclovir • Uses: • 1) recurrent genital herpes • 2) herpes zoster infections • Side Effects: nausea, diarrhea, and headache

12. Famciclovir • Prodrug of penciclovir (a guanosine analog) • M.O.A.: same as acyclovir • does not cause chain termination • Uses: HSV-1, HSV-2, VZV, EBV, and hepatitis B • Side Effects: nausea, diarrhea, and headache

13. Trifluridine • Trifluridine- fluorinated pyrimidine • inhibits viral DNA synthesis same as acyclovir • incorporates into viral and cellular DNA • Uses: HSV-1 and HSV-2 (topically)

14. Vidarabine • An adenosine analog • inhibits viral DNA polymerase • incorporated into viral and cellular DNA • metabolized to hypoxanthine arabinoside • Side Effects: GI intolerance and myelosuppression

15. Anti-Cytomegalovirus Agents • Gancyclovir • Valgancyclovir • Cidofovir • Foscarnet • Fomivirsen

16. Ganciclovir • An acyclic guanosine analog • requires a 3 step phosphorylationfor activation • monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidinekinase in HSV cells • M.O.A.: same as acyclovir • Uses: CMV*, HSV, VZV,and EBV • Side Effect: myelosuppression

17. Valgancyclovir • Monovalyl ester prodrug of gancyclovir • Metabolized by intestinal and hepatic esterases when administered orally • M.O.A.: same as gancyclovir • Uses: CMV* • Side Effect: myelosuppression

18. Cidofovir • [si-DOE-foe-veer] • A cytosine analog • phosphorylationnot dependent on viral enzymes • Uses: CMV*, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus • Side Effects: nephrotoxicity (prevented by admin. of probenecid) • Resistance: mutation in DNA polymerase gene

19. Foscarnet • [fos-KAR-net] • An inorganic pyrophosphate • inhibits viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase • Does not undergo phosphorylation. • Uses: HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV • Resistance: due to mutations in DNA polymerase gene • Side Effects:hypo- or hypercalcemia and phosphotemia

20. Fomivirsen • [foe-MI-veer-sen] • An antisenseoligonucleotide • M.O.A.: binds to mRNA and inhibits protein synthesis and viral replication • Uses: CMV retinitis in pts who cannot tolerated other agents. • Side effects: iritis and vitritis, and changes in vision.

21. Neuraminidase inhibitors. • Oseltamivir[os-el-TAM-i-veer] and Zanamivir[za-NA-mi-veer] • Are sialicacid analogs • They prevent the release of new virions and their spread from cell to cell. • are effective against both Type A and Type B influenza viruses

22. Mode of action • Inhibits neuraminidase, an enzyme necessary for the release of newly formed virions from infected cells Resistance: due to Mutations of the neuraminidase Pharmacokinetics • Oseltamivir, orally active pro-drug that is rapidly hydrolyzed by the liver to its active form. • Zanamivir, is administered either inhaled or intranasally. • Both are eliminated unchanged in urine

23. Adverse effects: • Oseltamivir are gastrointestinal discomfort and nausea, alleviated by taking the drug with food. • Zanamivir. Irritation of the respiratory tract does occur, however. • Caution: avoid in individuals with severe reactive asthma or chronic obstructive respiratory disease, because bronchospasm may occur with the risk of fatality. • No clinically significant drug interactions reported on both drugs.

24. Ant influenza agents. • Amantadine [a-MAN-ta-deen] and Rimantadine [ri-MAN-ta-deen] • Their activity is limited to influenza A infections

25. Mode of action: • Block the viral membrane matrix protein, M2, • A channel for hydrogen ion. • This channel is required for the fusion of the viral membrane with the cell membrane forming the endosome • Note: The acidic environment of the endosome is required for viral uncoating. • The drugs may also interfere with the release of new virions.

26. Pharmacokinetics: • Both are well absorbed orally. Amantadine distributes throughout the body including CNS, rimantadine does not cross the BBB. • Amantadine is not extensively metabolized. • excreted into the urine and may accumulate to toxic levels in patients with renal failure. • rimantadine is extensively metabolized by the liver, metabolites and the parent drug are eliminated by the kidney

27. Adverse effects: • insomnia, dizziness, and ataxia Resistance: • Due to a change in one amino acid of the M2 matrix protein. • Cross-resistance occurs between the two drugs.

28. Drugs active against respiratory syncitial virus (RSV) Ribavirin [rye-ba-VYE-rin] • A synthetic guanosine analog. • Mode of action: converted to ribavirin-triphosphate, which inhibits guanosinetriphosphate formation, preventing viral mRNA capping, and blocking RNA-dependent RNA polymerase. • [Note: Rhinoviruses and enteroviruses, which contain preformed mRNA and do not need to synthesize mRNA in the host cell to initiate an infection, are relatively resistant to the action of ribavirin.]

29. Pharmacokinetics: • Effective p.o, iv & aerosol. • Absorption ↑sed if taken with a fatty meal. • Retained in all tissues, except brain. • The drug and its metabolites are eliminated in the urine Clinical use • Treatment of RSV infection

30. Adverse effects: • oral or parenteral: included dose-dependent transient anemia, elevated bilirubin has been reported. The • Aerosol: safer, but respiratory function in infants can deteriorate quickly after initiation of aerosol treatment. • Contraindication: pregnancy (teratogenic)

31. Reference • Lippincotts illustrated review pharmacology 4th edition. • B. G. Katzung: Basic & Clinical Pharmacology • Katzung & Trevor; Examination review Pharmacology.

32. THANKS