Agents to treat HSV and VZV?
Acyclovir
Valacyclovir
Acyclovir MOA
- guanosine analog active against
herpes simplex virus (HSV-1, HSV-2) - The drug is activated initially by the viral kinase —> acyclovir triphosphate –> interferes with viral synthesis:
1. Competitive substrate for DNA polymerase
2. chain termination after its incorporation into viral DNA - Resistance: changes in viral DNA polymerase
Acyclovir PharmacoKinetix?
- administeration: topical, oral, I.V. routes
- 1/2 life: short (oral administration requires multiple daily doses)
- Elimination: Renal excretion (dosage should be reduced in patients with renal impairment)
Acyclovir clinical uses?
- Oral: mucocutaneous and genital herpes and for prophylaxis in immunocompromised patients
- I.V. administration: severe herpes disease (including encephalitis)
- neonatal HSV infection
Acyclovir Toxicity?
- The oral drug: is well tolerated but may cause GI distress and headache
- the I.V. drug:
delirium, tremor, seizures, hypotension, and nephrotoxicity
Valacyclovir MOA?
- same as Acyclovir
- prodrug converted to acyclovir by hepatic metabolism after oral administration
- reaches plasma levels 3–5x greater than those achieved by acyclovir
- longer duration of action than acyclovir
Ganci.cyclovir MOA?
it is guanine derivative –> triphosphorylated –> inhibits DNA polymerases of CMV and HSV –> chain termination
Gancicyclovir PharmacoKinetix?
- Bioavailability: given intravenously and penetrates well into tissues
- Elimination: renal elimination
- Oral bioavailability: is less than 10%
- intraocular implant: used in CMV retinitis
what about Valganciclovir?
- prodrug of ganciclovir
- high oral bioavailability
- alternative to I.V. ganciclovir, cidofovir and foscarnet (in end-organ CMV)
Gancicyclovir Clinical uses?
- prophylaxis and treatment of CMV retinitis
- other CMV infections in immunocompromised
Gancicyclovir Toxicity?
- Systemic toxic effects:
1. leukopenia
2. thrombocytopenia
3. mucositis
4. hepatic dysfunction
5. severe neutropenia (if used with zidovudine or other myelosuppressive agents)
Cidofovir MOA?
activated by host cell kinases –> active diphosphate –> inhibits DNA polymerases of HSV, CMV, Adenovirus, and HPV.
Cidofovir Pharmacokinetix?
- given intravenously a
- elimination: kidney
- Dosage is adjusted in proportion to creatinine clearance
- full hydration must be maintained
Cidofovir clinical uses?
- in CMV retinitis
- in mucocutaneous HSV
- in genital warts.
Cidofovir Toxicity?
Nephrotoxicity
major dose-limiting toxicity
Phosphonoformate drug used for CMV?
Foscarnet
Foscarnet MOA?
- does not require phosphorylation for antiviral activity!
- inhibits viral RNA polymerase, DNA polymerase, and HIV reverse transcriptase.
Foscarnet Pharmacokinetix?
- bioavailability: given I.V.
- distribution: penetrates well into tissues (also CNS).
- Elimination: kidney (in direct proportion to creatinine clearance)
Foscarnet clinical uses?
an alternative for prophylaxis and treatment of CMV infections
Foscarnet Toxicity?
- severe
- nephrotoxicity
- disturbances in electrolyte balance (especially hypocalcemia)
- genitourinary ulceration
- CNS effects (headache, hallucinations, seizures)
drugs RSV?
palivizumab
what about palivizumab ?
- Antibody to surface protein of RSV
- used for prophylaxis and treatment of RSV infection
Anti-influenza agents?
Oseltamivir
Oseltamivir MOA?
- inhibitors of neuraminidases produced by influenza A and B a
- cleave sialic acid residues from viral proteins and surface proteins of infected cells –> inhibit virion release and prevent clumping of newly released virions –> impede viral spread
