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Agents for Influenza A
Adamantanes: Amantidine and Rimantidine
Amantadine and Rimantidine MoA, MoR, antiviral activity
- MoA: Inhibits early stage of viral replication presumably by uncoating of the viral genome in the lysosome
- MoR: Occurs easily in the lab through unclear mechanisms
- Antiviral activity: Influenza A ONLY!
Amantadine and Rimantidine Adverse reactions
- Anticholinergic: dry mouth, papillary dilatation, toxic psychosis
- Side effects are common especially with increased age and decreased renal function
- CNS Toxicity: !
- GI disturbance
- Dehydration increases drug levels. Drug-Drug interaction with the diuretic triamterene and HCTZ
- Rimantidine has longer half-life and less side effects: .
Amantadine and Rimantidine: Clinical use
- Prevention and treatment of sensitive strains of Influenza A
- NOT effective against influenza B
- Rapid selection of resistant virus during treatment (excretion of resistant virus)
- Recommendation to NOT use for both treatment and prophylaxis in the same household
Neuraminidase Inhibitors: MoA, MoR, Antiviral activity
- 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: .
- Peripheral neuropathy
- 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
- Drug-drug interactions
- 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
- MoR: unclear
- 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
Anivirals against CMV