1. ANTIVIRAL/ANTIFUNGAL AGENTS MA. LENY ALDA G. JUSAYAN, MD Department of Pharmacology

2. ANTIVIRAL AGENTS VIRUSES: • Single or double stranded DNA or RNA enclosed in a protein – CAPSID • Obligate intracellular parasite • Replication depends on synthetic processes of the host cell • Antiviral drugs must either block entry or exit from cell or be active inside the host cell

3. VIRAL REPLICATION: • Adsorption and penetration into susceptible host cells • Uncoating of viral nucleic acid • Synthesis of early regulatory proteins • Synthesis of RNA or DNA • Synthesis of late regulatory proteins • Assembly (maturation) of viral particles • Release from cells

6. ANTI-HERPES/ ANTI VZV

7. ACYCLOVIR • Acyclovir (9-[2-hydroxy) methyl]-9-H- guanine • Acyclic guanosine derivative against HSV1, HSV2, & VZV • Weaker activity against EBV, CMV, Human Herpes Virus 6

8. MECHANISM OF ACTION: • REQUIRES 3 PHOSPHORYLATION STEPS: • Converted to monophosphate derivative by virus-specified thymidine kinase • Converted to di and triphosphate compounds by the host’s cellular enzymes • Acyclovir triphosphate inhibits viral DNA synthesis

9. Cont. • Acts as a chain terminator because it lacks 3’ hydroxyl group • Competitive inhibition of deoxyGTP for viral DNA polymerase RESISTANCE: • HSV: absence of partial production of viral thymidine kinase, altered thymidine kinase substrate specificity, altered viral DNA polymerase • VZV: mutation in VZV thymidine kinase , mutations in viral DNA polymerase

10. PHARMACOKINETICS: • Oral bioavailability ranges from 10-30% and decreases with increasing dose • Relative oral bioavailability increases to 3-5 fold approx. 70% following valacyclovir administration • Distributes widely in body fluids including vesicular fluid, aqueous humor & CSF • Concentrated in breast milk, amniotic fluid, & placenta • Percutaneous absorption is low

11. THERAPEUTIC USES: • First and recurrent genital herpes: • 200 mg 5x daily for 10 days – oral • 5 mg/kg per 8 hrs – IV • Recurrent: 400 mg 2x daily or 200 mg 3x daily

12. THERAPEUTIC USES: • ACUTE HERPES ZOSTER (SHINGLES) • SYSTEMIC ACYCLOVIR PROPHYLAXIS • HSV ENCEPHALITIS • VARICELLA ZOSTER VIRUS INFECTION • CMV PROPHYLAXIS

13. SIDE EFFECTS: • TOPICAL PREPARATIONS- mucosal irritation & transient burning to genital lesions • ORAL – nausea, diarrhea, rash, headache,renal insufficiency, neurotoxicity • IV- renal insufficiency, CNS side effects

14. PENCICLOVIR • Penciclovir (9-[4-hydroxy-3-hydroxymethylbut-1-yl]guanine • An acyclic guanine nucleoside • Active metabolite of famciclovir • Spectrum of activity & potency against HSV & VZV is similar to acyclovir • Inhibitory activity to HBV

15. MECHANISM OF ACTION: • Inhibitor of viral DNA synthesis • Initially phosphorylated by viral thymidine kinase • Penciclovir triphosphate is a competitive inhibitor of viral DNA polymerase • 100 fold less potent in inhibiting DNA polymerase than acyclovir but present in higher concentration and prolonged periods in infected cells

16. THERAPEUTIC USES: • Intravenous form- 5 mg/kg per 8-12 hrs for 7 days is comparable to acyclovir in tx of mucocutaneous HSV infection • Topical 1% penciclovir cream applied every 2 hrs while awake for 4 days shortens healing time and symptoms by about 1 day in recurrent labial HSV

17. SIDE EFFECTS: • Mutagenic at high concentrations • No clinically important drug interactions have identified

18. FAMCICLOVIR • Diacetyl ester prodrug of 6 deoxy penciclovir and lacks intrinsic viral activity • Oral form is approved for managing HSV & VZV infections • First episode genital herpes – 250 mg TID x 5-10 days • Recurrent genital herpes – 250 mg BID for 1 year • Herpes zoster of 3 days – 500 mg TID x 10 days is as effective as acyclovir in reducing healing time and zoster asso. pain

19. FAMCICLOVIR: • Comparable to valacyclovir in treating zoster and reducing associated pain in older adults • 500 mg TID x 10 days is comparable to high dose of acyclovir in treating zoster in immunocompromised patients & in opthalmic zoster • Associated with dose-related reductions in Hepatitis B Virus DNA and transaminase levels in patients with chronic HBV hepatitis

20. TRIFLURIDINE • Flourinated pyrimidine nucleoside that has an in vitro inhibitory activity against HSV 1 & 2 , CMV, vaccinia certain adenoviruses • Inhibits viral DNA synthesis • Phosphorylated intracellularly into its active form by cellular enzymes • Incorporation into both viral and cellular DNA prevents its systemic use

21. MECHANISM OF ACTION: • Trifluridine monophosphate irreversibly inhibits thymidylate synthetase • Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate incorporation into DNA by DNA polymerases

22. CLINICAL USES: • Primary keratoconjunctivitis & recurrent epithelial keratitis due to HSV 1 & 2 • Topical trifluridine is more active than idoxuridine & comparable to vidarabine in HSV ocular infections

23. ADVERSE EFFECTS: • Discomfort upon instillation • Palpebral edema • Hypersensensitivity reaction, irritations & superficial punctate or epithelial keratopathy

24. VALACYCLOVIR • L- valyl ester of acyclovir • Rapidly converted to acyclovir after oral administration • Serum levels are 3-5x greater than acylcovir • Treatment of primary and recurrent genital herpes & herpes zoster infections • Prevents CMV disease in postransplant patients

25. VIDARABINE • Adenosine analog with an in vitro activity against HSV, VZV, & CMV • Phosphorylated intracellularly by host enzymes to form ara-ATP and then inhibits viral DNA polymerase • Vidarabine triphosphate is incorporated into both vial & cellular DNA • Rapidly metabolized in vivo to hypoxanthine arabinoside through removal of 6-amino group by adenosine deaminase – dec. viral activity

26. Cont. • 3% ointment – acute keratoconjunctivitis, superficial keratitis, recurrent epithelial keratitis (HSV1 &2) • IV vidarabine – HSV encephalitis,neonatal herpes, VZV infection

27. ANTI-CMV AGENTS

28. GANCICLOVIR • (9-[1,3-dihydroxy-2-prpoxymethyl]guanine) • Cyclic guanosine analog that requires triphosphorylation for activation prior to inhibiting viral DNA polymerase • Similar structure to acyclovir except in having additional hydroxymethyl group on the acyclic side chain

29. MECHANISM OF ACTION: • Monophosphorylated intracellularly by a virus-induced enzyme • Phosphorylation is catalyzed by a viral thymidine kinase during HSV, phosphotransferase encoded gene during CMV infection • Ganciclovir di & triphosphate formed by cellular enzymes • Triphosphate is a competitive inhibitor of deoxyguanosine triphosphate incorporation into DNA, inhibits viral rather than cellular DNA polymerase • Viral DNA incorporation causes cessation of DNA chain elongation

30. PHARMACOKINETICS: • Oral bioavailability is 6-9% following ingestion with food & less in the fasting state • CSF concentration are approximately 50 % of those in serum

31. CLINICAL USES: • Delay progression of CMV retinitis in AIDS • CMV colitis & esophagitis • CMV infection in transplant patient • CMV pneumonitis • CMV retinitis • CMV, HSV1, HSV2, EBV & HHV-8

32. ADVERSE REACTIONS: • Myelosuppression • CNS toxicity • Vitreous hemorrhage, retinal detachment • Neutropenia (2nd wk) • CNS (headache, behavioral changes, convulsions, coma) • Infusion related phlebitis, azotemia, anemia, rash, fever, liver function test abnormalities

33. VALGANCICLCOVIR • L- valyl ester prodrug of ganciclovir • Hydrolyzed to active compound ganciclovir by intestinal & hepatic enzymes • Well absorbed & rapidly metabolized in intestinal walls & liver to gancilovir • CMV retinitis

34. CIDOFOVIR • (1-[(S)-3-hydroxy-2-(phosphonomethoxy)-propyl]cytosine dihydrate) • Cytidine nucleoside analog with inhibitory activity against human herpes, papiloma, polyoma, pox, & adenoviruses • Phosphorylation to active diphosphate is independent of viral enzymes • After phosphorylation it acts as potent inhibitor to viral DNA polymerase

35. PHARMACOKINETICS: • Penetration into the CNS or eye have not been well characterized • Terminal half-life is 2.6 hrs , cidofovir diphosphate half-life is 17-65 hrs • IV administration must be administered with probenicid to block active tubular secretion & decrease nephrotoxicity

36. CLINICAL USES: • CMV, HSV 1, HSV 2, VZV, EBV, HHV-6, HHV-8, adenoviruses, poxvirus, poliomyxoviruses, HPV • CMV retinitis • Polyoma virus associated progressive multifocal leukoencephalopathy syndrome associated with AIDS • Topical – recurrent genital herpes, anogenital warts

37. FOSCARNET • Phosphonoformic acidinorganic pyrophosphate analog that inhibits viral DNA polymerase, RNA polymerase & HIV transcriptase directly without requiring activation by phosphorylation • Taken up slowly by cells & does not undergo significant intracellular metabolism • Reversibly blocks the pyrophosphate binding site of the viral polymerase • Inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates

38. SIDE EFFECTS: • Nephrotoxicity • Symptomatic hypocalcemia • Saline loading may reduce the risk of nephrotoxicity • Concurrent administration with pentamidine exacerbates both nephrotoxicity & hypocalcemia

39. CLINICAL USES: • CMV retinitis, colitis, esophagitis • Acyclovir- resistant HSV infection & VZV infection • HSV, VZV, CMV, EBV, HHV-6, HHV-8, HIV

40. FOMIVERSEN • 21mer-phosphorothioate oligonucleotide • First FDA approved antisense therapy Binding to target mRNA results in inhibiton of immediate early region 2 protein synthesis – inhibiting viral replication • Injected intravitreally in CMV retinitis

41. ANTIVIRAL DRUGS – DNA & RNA VIRUSES

43. ANTIRETROVIRAL AGENTS

44. NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS: • Competitive inhibition of HIV 1 reverse transcriptase & can be incorporated into the growing viral DNA chain to cause termination • Bind directly to HIV reverse transcriptase, block both DNA & RNA dependent DNA polymerase activities • Prevent transfer of information that would allow virus to replicate & survive • Activity against HIV 1, HIV 2 • Lactic acidosis & severe hepatomegaly with steatosis

45. ZIDOVUDINE (Azithymidine, AZT) • Deoxythymidine analog • Decrease rate of clinical disease progression & prolong survival of HIV infected individuals • Well absorbed from the gut & distributed to most body tissues & fluids • Eliminated by renal excretion following glucorinadation in the liver • Combination therapy with other retroviral agents enhance potency and delay resistance

46. CLINICAL USES: • HIV – associated dementia & thrombocytopenia • Reduce rate of vertical transmission (mother-newborn) by 23%

47. ADVERSE EFFECTS: • Myelosuppression – most common • Thrombocytopenia, hyperpigmentation of nails, myopathy, anxiety, confusion & tremulousness • Fatal lactic acidosis & severe hepatomegaly w/ steatosis

48. DIDANOSINE (ddl) • Synthetic analog of deoxyadenosine • Activity is potentiated by hydroxyurea due to depletion of intraocular pools of dATP • Chewable, dispersable tablet, enteric coated • Contains phenylalanine & Na • Should be taken on an empty stomach • Food, fluroquinolones & tetracycline should be given 2 hrs before didanosine

49. ADVERSE EFFECTS: • Dose –dependent pancreatitis • Painful peripheral distal neuropathy • Diarrhea, hepatitis, esophageal ulceration, cardiomyopathy • CNS toxicity • Precipitate gouty attacks • Optic neuritis

50. LAMIVUDINE (3TC) • Cytosine analog ,synergistic with other antiretroviral nucleoside – Stavudine, Zidovudine • Oral bioavailability exceeds 80% & is not food dependent • Used in combination therapy • Approved for the treatment of chronic Hepatitis B infection