MoA: Inhibition of neuraminidase activity decreases release of virus from infected cells, increases formation of viral aggregates and decreases viral spread
MoR: mutation in the pocket of neuraminidase site – can become resistant to Oseltamivir
Antiviral activity: active against BOTH Influenza A and B in the absence of resistance
Neuraminidase inhibitors: use
Oseltamivir – ORAL; Zanamivir – inhalation
Therapy of Influenza A or B of less than 48 hours duration
Decrease duration of influenza approximately 24 hours on average
Approval for prophylaxis with both zanamivir and oseltamivir; won’t secrete drug-resistant viruses!
Neuraminidase Inhibitors: Adverse effects
Children: w high doses – psychosis, neurologic toxicity
Adults: tracheal irritation
Can get Oseltamivir Resistance
Oseltamivir resistsnt, zanamivir-sensitive
Ribavarin: MoA, MoR, Antiviral activity
MoA: Not fully defined, interferes with initiation and elongation of capped mRNA primer fragments
MoR: none to date
Antiviral activity: wide range of DNA and RNA viruses in lab
Clinically useful for RSV and Hep C: .
Ribavarin Adverse Reactions
Aerosolized form: bronchospasm and reversible pulmonary deterioration
Systemic form: can cause bone marrow toxicity, hemolysis and anemia!
Ribavarin clinical use
Use carefully risk vs. benefit…
RSV bronchiolitis in children: . (respiratory syncithial virus)
Combination therapy for hepatitis C with interferon: .
Lassa fever, hantavirus, and other viral hemorrhagic fevers…
Acyclovir MoA, MoR, Antiviral activity
MoA: Acyclovir uptake and intracellular phosphorylation are facilitated by HSV-induced thymidine kinase. Acyclovir triphosphate is present in 40-100 fold higher concentrations in HSV infected cells. The triphosphate form inhibits DNA polymerase and is incorporated into viral DNA and FUNCTIONS AS A CHAIN TERMINATOR
MoR: can occur through altered expression of deficiency of thymidine kinase (lack not a very severe disease) or through altered sensitivity of the DNA polymerase to triphosphate acyclovir.
Antiviral activity: Herpes simplex types I and II, Varicella-Zoster virus, animal herpesviruses (including Herpes B simian virus – monkeys)
Acyclovir: Excretion and Adverse effects
Renal excretion – major pathway
Oral, IV, ointment
Adverse effects: Generally well-tolerated
Reversivle renal dysfunction in ~5% of patients treated with high doses for HSV encephalitis – secondary to tubular precipitation of acyclovir: .
Less than 1 % have CNS dysfunction
Acyclovir: Clinical Use
Primary and recurrent genital herpes: .
Herpes simplex encephalitis!:
Acyclovir ointment use
Modest utility in the treatment of primary genital HSV disease – only useful in primary!
Documented effective in primary HSV disease
Use during primary episode does NOT alter the likelihood of recurrence.
Only modest effect in treatment of recurrent disease
Esteryfied acyclovir for oral administration
Hydrolyzed to acyclovir
Longer half-life and better oral absorption: .
Documented efficacy in discordant sexual partners. Well-done study
Topical formulation of famciclovir
May have activity in herpes labialis but the effect is clinically small but statistically significant
Agents for CMV
Ganciclovir MoA, MoR, Antiviral activity
MoA: Inhibitor of viral DNA synthesis; CHAIN TERMINATION is the eventual mechanism of action
MoR: altered or deficiency of thymidine kinase or altered sensitiviry of DNA polymerase to triphosphate ganciclovir; rare clinically
Antiviral activity: cytomegalovirus; still retains potent HSV activity
BUT: poor oral bioavailability with <5% absorbed – NEW, Valganciclovir ester – has much better absorption – can now be oral
Ganciclovir Adverse Reactions
Leukopenia!!!: major adverse reaction
Thrombocytopenia also a major problem
CNS toxicity, headache, psychosis, seizures, and behavioral changes
Ganciclovir Clinical Use
CMV retinitis: – useful in decreasing the progression of the disease but can’t cure it, AIDS patients generally require life-long therapy
Oral therapy limited prophylaxis – NOW VALGANCICLOVIR HIGHLY EFFECTIVE ORALLY
TREATMENT AND PROPHYLAXIS OF SYSTEMIC CMV INFECTIONS: .
Cidofovir MoA, MoR, Antiviral activity
MoA: Inhibitor of viral DNA synthesis
Antiviral activity: CMV and HSV, Other viruses – maybe JC virus, small pox??
Cidofovir adverse reations
Nephrotoxicity: major toxicity – renal excretion the major pathway, ½ life of 33 hours! “rat poison”
Co-Administration of probenicid reduces renal toxicity along with hydration.
Probenicid competes with cidofovir for tubular uptake and blocks some of the renal tubular accumulation of the drug.
Cidofovir Clinical use
CMV retinitis: very useful, but limited use because of renal toxicity
Foscarnet MoA, Antiviral activity
MoA: Inhibits DNA polymerase of most herpes group viruses, including CMV. The drug also inhibits the reverse transcriptase of HIV!
Antiviral activity: CMV, and some HIV
Foscarnet Adverse reactions
Impaired renal function, generally reversible: most common dose-limiting side effect
Anemia seen in 20-50% of patients
Thrombocytopenia and leucopenia have been reported