DD 02-28-14 08-09am Non-HIV Antiviral Agents - French Flashcards
Viruses - outcomes of infection in host cell
- Lysis - typically RNA virus (e.g., influenza)
- Persistently infected - chronically detectable disease; may recur
- Latently infected - undetectable disease; may recur; not targeted by current antiviral therapies
Primary means to control viral spread
- use of public health measures
- use of prophylactic vaccines
Major barrier to the development of effective antiviral agents
- Viruses are intracellular & undergo replication / propagation by commandeering host’s cell metabolic machinery.
- Broad spectrum antiviral agents has proved difficult to achieve b/c viruses are highly heterogeneous.
- Viral polymerases typically exhibit poor fidelity during genome replication, increasing mutagenesis & the speed of resistance developement to antiviral therapies.
Viral Life Cycle steps
- Attachment / Entry
- Penetration
- Uncoating
- Early protein synthesis
- Nucleic Acid synthesis
- Late protein synthesis & processing
- Packaging & Assembly
- Viral release
(see pic in notes)
Antiviral agents that block Viral Attachment/Entry
Enfuvirtide (HIV)
Maraviroc (HIV)
Docosanol (HSV)
Palivizumab (RSV)
Antiviral agents that block Viral Penetration
Interferon-alpha (HBV, HCV)
Antiviral agents that block Viral Uncoating
Amantadine, Rimantadine (influenza)
Antiviral agents that block Nucleic Acid Synthesis of Virus
NRTIs (HIV, HBV)
NNRTIs (HIV)
Acyclovir (HSV)
Foscarnet (CMV)
Antiviral agents that block Late Protein Synthesis & Processing
Protease inhibitors (HIV)
Antiviral agents that block Viral Release
Neuraminidase inhibitors (influenza)
Influenza Life Cycle
- Binds cell surface of airway epithelial cell
- Is endocytosed & internalized into endosomes.
- Acidified endosomal environment promotes conformational change in hemagglutinin structure
- –> fusion btwn influenza viral envelope & endosomal membrane.
- Activation of & proton influx through viral M2 proton channel
- –> release of RNA genome
- Replication & Assembly into new virus particles.
- Egress of new virions results in their being tethered to the plasma member via intrxn w/ hemagglutinin & cellular sialic acid moieties
- Viral envelope-bound neuraminidases cleave sequestered sialic acid moieties, resulting in virion release.
Viral Neuraminidase Inhibitors - Examples
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
Viral Neuraminidase Inhibitors - Mechanism of Action
- Inhibit enzyme neuraminidase (NA) that cleaves N-acetyl neuraminic acid (sialic acid) from host cell receptors for influenza virus (A & B)
- w/out NA activity, virus aggregates at cell surface (can’t be un-tethered from plasma membrane) decreasing both intracellular viral translocation & viral budding, resulting in reduced viral infectivity
- Inhibition of NA also impairs viral penetration through mucin secretions, reducing infection of other respiratory epithelial cells
Resistance to Viral Neuraminidase Inhibitors
- Relatively rare (1-4%)
- from mutations in either viral hemagglutinin or neuraminidase
Oseltamivir (Tamiflu) - Pharmacokinetics
- PO prodrug
- given twice daily
- Plasma half-life of 6-10 hours
- Elimination via renal tubular secretion
Zanamivir (Relenza) - Pharmacokinetics
- Poor oral bioavailability
- Administered via inhalation
- Renal elimination
Use of Viral Neuraminidase Inhibitors
- Started w/in 48 hours of symptom onset
- Can decrease severity / duration (by 1-2 days) of symptoms caused by either influenza A or B in adults and children
- Effective (80-90%) as prophylactic measure in contacts
- Indicated to control influenza institutional outbreaks & protect high-risk individuals until vaccination effective
Adverse Reactions of Oseltamivir (Tamiflu)
- minor, occasional nausea & vomiting (reduced by taking with food)
Adverse Reactions of Zanamivir (Relenza)
- Uncommonly, bronchospasm in pts w/ asthma or COPD
Agents that Inhibit of Uncoating
Amantadine (Symmetrel)
Reimantadine (Flumadine)
Inhibitors of Uncoating - Mechanism of Action
- Blocks virally-encoded H+ ion channel (M2 protein)
- -> Prevents changes in intracellular pH necessary for uncoating
- -> prevents subsequent release of virion ribonucleoprotein & RNA genome for replication in the cytosol
Resistance to Inhibitors of Uncoating
- Occurs to both amantadine & rimantadine
- Due to mutations in transmembrane domains of M2 proton channel
Amantadine (Symmetrel) - Pharmacokinetics
- Effective orally w/ accumulation in lungs.
- Excreted unchanged in urine (90%) requiring dosage adjustment if impaired renal function.
- Excreted in breast milk: Not recommended if breast feeding due to potential to cause urinary retention, vomiting, skin rash in the nursing infant
Rimantadine (Flumadine) - Pharmacokinetics
- Effective orally, with accumulation in lungs.
- Hepatic elimination for rimantadine (t1/2 = ~12 hrs, 1-2 daily doses)
- Excreted in breast milk: Not recommended if breast feeding due to potential to cause urinary retention, vomiting, skin rash in the nursing infant.
Use of Inhibitors of Uncoating in Influenza
- Prophylaxis & treatment of influenza A infections (influenza B lacks M2 protein target)
- Can be given for 2-3 weeks in conjunction w/ flu vaccine in high risk populations
- If given 1-2 days prior to & 6-7 days during infection, reduces incidence & severity of symptoms
- If given 48 hours after, only slight therapeutic effect
- NOTE: In 2012, most seasonal A H3N2 and A H1N1 isolates were resistant limiting current use
Adverse Reactions of Amantadine
- insomnia
- concentration difficulty
- lightheadedness / dizziness
- headache
- teratogenic in animals (Pregnancy Category C, but generally not recommended)
Adverse Reactions of Rimantadine
- better tolerated than Amantadine due to poor CNS penetration (more highly protein bound)
- teratogenic in animals (Pregnancy Category C , but generally not recommended)
Herpes Virus Replicative Cycle
- Attachment
- Entry
- Viral uncoating
- Transfer of viral DNA into host nuclei wherein viral immediate-early genes are transcribed
- Upon completion of replication, late viral encoded genes direct assembly & packaging of virion progeny.
- Progeny undergo budding to facilitate their ultimate release from host cells
Immediate-early vs. Late transcribed genes in Herpes Viruses
Immediate-Early:
- Direct synthesis of viral genome replicating genes
- e.g., thymidine kinase, DNA polymerase, etc
Late:
- Direct assembly & packaging of viron progeny after replication is complete
Inhibitors of Viral Genome Replication - Overview
- ## Vast majority of antiviral agents are nucleoside analogs (purine, pyrimidine) that specifically target viral genome replication by inactivating viral DNA polymerases, or viral reverse transcriptases
Antiviral actions of purine and pyrimidine analogs
- involve passage of lipid soluble analog across cell membrane
- it is then converted to active triphosphate form by intracellular kinases
Degree of selective toxicity in nucleoside analogs
- Highest in those analogs (e.g., acyclovir) activated by viral kinases rather than host cell kinases
- Selective toxicity can also be achieved w/ differences in affinity of analog for viral vs mammalian enzymes
Anti-Herpes Drugs - Inhibitors of Viral Genome Replication (Nucleoside Analogs) - Examples
Acyclovir (Zovirax) Valacyclovir (Valtrex) Penciclovir (Denavir) Famciclovir (Famvir) rufluridine (Viroptic)
Anti-Herpes Drugs - Mechanism of Action
- Initial phosphorylation is mediated by viral thymidine kinase
= primary mechanism of viral vs. host selectivity (i.e., 200-fold difference in affinity) - Cellular protein kinases convert acyclovir-MP (monophosphate) to its TP (triphosphate) form.
- Acyclovir-TP competes w/ cellular dGTP for viral DNA polymerase
- DNA polymerase then incorporates nucleotide analog into replicating viral DNA strands.
- Once incorporated, acyclovir-TP terminates further DNA replication & strand elongation.
- DNA containing acyclovir-TP also irreversibly binds & inactivates viral DNA polymerase (i.e., suicide inactivation).
Acyclovir - Selective Toxcity
Two layers:
- Initial phosphorylation is mediated by viral thymidine kinase (rather than host kinases)
- Binds w/ greater affinity to viral DNA polymerase than host enzyme
Resistance to Anti-Herpes Drugs (Nucleoside Analogs)
Mainly in immunosuppressed patients receiving extended treatment regimens.
Due to:
- Most commonly: reduced / lost of expression of viral thymidine kinase
- Altered viral thymidine kinase substrate specificity (kinase loses activity)
- Altered affinity of viral DNA polymerase activity
Pharmacokinetics of Acyclovir (Anti-Herpes)
- Oral absorption poor (15-30%)
- Not affected by food
- Also available in topical & IV
- Renal elimination (adjust dosage w/renal impairment)
- Neonatal clearance only 1/3 of adults
Pharmacokinetics of Valacyclovir
= Valyl ester prodrug of acyclovir
- Given PO achieves plasma levels 3-5 times higher than acyclovir (equivalent to IV administration)
- Neonatal clearance only 1/3 of adults
Pharmacokinetics of Peniciclovir
= Acyclic guanosine analog
- Poor oral absorption
- Topical only (more effective than topical acyclovir)
- Neonatal clearance only 1/3 of adults
Pharmacokinetics of Famiciclovir
- Penciclovir prodrug that increases oral bioavailability to 70%
- Neonatal clearance only 1/3 of adults
Pharmacokinetics of Vidarabine-trifluridinne
- ONLY topical (toxicity associated w/ IV use)
- Neonatal clearance only 1/3 of adults
Agents for Herpes Simplex Virus (HSV) - Primary & Recurrent herpes
- ORAL acyclovir shorted duration of primary & recurrent herpes
Agents for Herpes Simplex Virus (HSV) - Recurrent Herpes labialis
ORAL acyclovir reduces mean duration of pain (NOT time to healing)
Agents for Herpes Simplex Virus (HSV) - Herpes Simplex Encephalitis
IV acyclovir
Agents for Herpes Simplex Virus (HSV) - Neonatal HSV infection
IV acyclovir
Agents for Herpes Simplex Virus (HSV) - Serious HSV/ VZV Infections (esp. in immunsuppressed)
IV acyclovir
Agents for Herpes Simplex Virus (HSV) - HSV keratoconjunctivitis & recurrent epithelia keratitis
TOPICAL Vidarabine & trfluridine
- for limited use
- effective against acyclovir-resistant strains
Agents for Varicella Zoster Virus (VZV)
Oral acyclovir
- decreases number of lesions & duration of varicella (chicken pox) and zoster (shingles) but higher doses are required
- suppression to reduce VZV reactivation in immunocompromised patients
Adverse Reactions of Anti-Herpes agents
- Minor toxicities include H/A, n/v, reversible renal dysfunction (rare w/ adequate hydration)
- IV acyclovir has been associated with encephalopathy (tremors, hallucinations, seizures, and coma)
- Pregnancy category B
Inhibitors of Viral Penetration - Example
Docosanol (Abreva cream - OTC)
Docosanol (Abreva cream - OTC)
- Long chain saturated alcohol
- Inhibits replication of many lipid-enveloped viruses (including HSV)
- Acts to prevent fusion between cellular & viral envelop membranes, blocking viral entry into cell
Use Docosanol (Abreva cream, OTC)
- Topical treatment
- 5X daily to lips or face
- begun w/in 12 hours of prodomal symptoms or lesion onset reduces healing time ~1 day (4.8 days to 4.1 days, similar to penciclovir)
- Administration at papular or later stages fails to elicit therapeutic responses
- Appears to be well tolerated
Drugs for Cytomegalovirus Infections
Inhibitors of Viral DNA Polymerase
- Ganciclovir (Cytovene)
- Valganciclovir (Valcyte)
Inhibitors of Viral DNA Polymerase (Anti-CMV drugs) - Overview
- All of the current agents for treatment of CMV infections exert their antiviral activity via inhibition of viral DNA polymerase
- Differences btwn agents in activation step can sometimes limit cross-resistance between agents
- W/ availability of oral valganciclovir & intraocular ganciclovir, usage of IV ganciclovir & foscarnet has decreased
Setting of CMV infections
In advanced immunosuppression (HIV & organ transplantation)
- most commonly as result of reactivation of latent infection
Results of CMV infections
End organ disease including:
- retinitis
- colitis
- esophagitis
- CNS disease
- pneumonitis
Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Mechanism of Action
- Cellular uptake & initial phosphorylation is mediated by viral protein kinase UL97 in CMV (or by viral thymidine kinase in HSV)
= Primary mechanism of viral vs. host selectivity - Cellular protein kinases then convert ganciclovir-MP (mono-phosphate) to its TP (triphosphate) form (10x higher than in non-CMV-infected cells)
- Ganciclovir-TP competes w/cellular dGTP for viral DNA polymerase
- DNA pol incorporates nucleotide analog into replicating viral DNA strands
- -> eventually slows & ceases further viral DNA chain elongation
Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Resistance
- Mutations in UL97 protein kinase decrease ganciclovir phosphorylation & activation (most common)
- Mutations in viral DNA pol activity (UL54) that alters its activity
- Possible cross-resistance to cidofovir possible with UL 54 mutations
Ganciclovir (Cytovene) - Pharmacokinetics
- Poor oral bioavailability
- Good distribution in bodily fluids
- Usually IV
Half-life: 4 hours (intracellular half-life of 16-24 hours)
Elimination: primarily excreted unchanged via urine (clearance related to renal function)
Valganciclovir (Valcyte) - Pharmacokinetics
- Prodrug
- Rapidly deesterified & converted to ganciclovir by GI and hepatic esterases
Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Clinical uses
- Effective for treatment & chronic suppression of CMV retinitis in immuno-compromised patients
- Also effective in controlling CMV in transplant patients
- Ophthalmic gel is effective in treating HSV keratitis
- Some activity against HBV when administered PO
Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Adverse Rxns
- Less selective toxicity than acyclovir b/c host kinase can also perform 1st phosphorylation step.
Major Side Effect / Concern:
- Myelosuppression w/ neutropenia & thrombocytopenia (20-40%)
- Reversible w/ drug cessation
Also:
- GI disturbances & nausea also are reported
- Rare CNS toxicity (H/A, mental status changes, seizures)
- Rare bnormal liver function
Ganciclovir = Pregnancy Category C (risk cannot be ruled out)
Foscarnet (Foscavir)
- Inorganic pyrophosphate analog, unique amongst all antiviral agents
Foscarnet (Foscavir) - Mechanism of Action
- Does NOT require cellular activation
- Noncompetitively binds to pyrophosphate binding site of RNA & DNA polymerases
- Appears to inhibit cleavage of pyrophosphate from deoxy-TPs –> block of viral replication
Foscarnet (Foscavir) - Resistance
- Resistant strains exhibit alterations in DNA polymerase
- Combined use of ganciclovir & foscarnet can benefit some CMV patients, but strains resistant to both agents have been reported
Foscarnet (Foscavir) - Pharmacokinetics
- Poor oral bioavailability
- Primarily IV infusion
Plasma half-life is bimodal & complex:
- initial t1/2 is 4-8 hours
- terminal t1/2 is 3-4 days
Elimination: Primarily unchanged in urine
Foscarnet (Foscavir) - Clinical Uses
- Effective against CMV retinitis, esp. in immunocompromised pts
- Effective against ganciclovir-resistant CMV infections and acyclovir-resistant HSV & VZV infections
Foscarnet (Foscavir) - Adverse Reactions
Major side effect: Nephrotoxicity & hypocalcemia
- can be severe & even fatal
Also:
- CNS abnormalities (H/A, tremor, seizures, & even hallucinations)
- Rash
- Fever
- Nausea
