DD 02-28-14 08-09am Non-HIV Antiviral Agents - French Flashcards
(68 cards)
1
Q
Viruses - outcomes of infection in host cell
A
- 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
2
Q
Primary means to control viral spread
A
- use of public health measures
- use of prophylactic vaccines
3
Q
Major barrier to the development of effective antiviral agents
A
- 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.
4
Q
Viral Life Cycle steps
A
- Attachment / Entry
- Penetration
- Uncoating
- Early protein synthesis
- Nucleic Acid synthesis
- Late protein synthesis & processing
- Packaging & Assembly
- Viral release
(see pic in notes)
5
Q
Antiviral agents that block Viral Attachment/Entry
A
Enfuvirtide (HIV)
Maraviroc (HIV)
Docosanol (HSV)
Palivizumab (RSV)
6
Q
Antiviral agents that block Viral Penetration
A
Interferon-alpha (HBV, HCV)
7
Q
Antiviral agents that block Viral Uncoating
A
Amantadine, Rimantadine (influenza)
8
Q
Antiviral agents that block Nucleic Acid Synthesis of Virus
A
NRTIs (HIV, HBV)
NNRTIs (HIV)
Acyclovir (HSV)
Foscarnet (CMV)
9
Q
Antiviral agents that block Late Protein Synthesis & Processing
A
Protease inhibitors (HIV)
10
Q
Antiviral agents that block Viral Release
A
Neuraminidase inhibitors (influenza)
11
Q
Influenza Life Cycle
A
- 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.
12
Q
Viral Neuraminidase Inhibitors - Examples
A
Oseltamivir (Tamiflu)
Zanamivir (Relenza)
13
Q
Viral Neuraminidase Inhibitors - Mechanism of Action
A
- 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
14
Q
Resistance to Viral Neuraminidase Inhibitors
A
- Relatively rare (1-4%)
- from mutations in either viral hemagglutinin or neuraminidase
15
Q
Oseltamivir (Tamiflu) - Pharmacokinetics
A
- PO prodrug
- given twice daily
- Plasma half-life of 6-10 hours
- Elimination via renal tubular secretion
16
Q
Zanamivir (Relenza) - Pharmacokinetics
A
- Poor oral bioavailability
- Administered via inhalation
- Renal elimination
17
Q
Use of Viral Neuraminidase Inhibitors
A
- 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
18
Q
Adverse Reactions of Oseltamivir (Tamiflu)
A
- minor, occasional nausea & vomiting (reduced by taking with food)
19
Q
Adverse Reactions of Zanamivir (Relenza)
A
- Uncommonly, bronchospasm in pts w/ asthma or COPD
20
Q
Agents that Inhibit of Uncoating
A
Amantadine (Symmetrel)
Reimantadine (Flumadine)
21
Q
Inhibitors of Uncoating - Mechanism of Action
A
- 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
22
Q
Resistance to Inhibitors of Uncoating
A
- Occurs to both amantadine & rimantadine
- Due to mutations in transmembrane domains of M2 proton channel
23
Q
Amantadine (Symmetrel) - Pharmacokinetics
A
- 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
24
Q
Rimantadine (Flumadine) - Pharmacokinetics
A
- 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.
25
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
26
Adverse Reactions of Amantadine
- insomnia
- concentration difficulty
- lightheadedness / dizziness
- headache
- teratogenic in animals (Pregnancy Category C, but generally not recommended)
27
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)
28
Herpes Virus Replicative Cycle
1. Attachment
2. Entry
3. Viral uncoating
4. Transfer of viral DNA into host nuclei wherein viral immediate-early genes are transcribed
5. Upon completion of replication, late viral encoded genes direct assembly & packaging of virion progeny.
6. Progeny undergo budding to facilitate their ultimate release from host cells
29
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
30
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
-
31
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
32
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
33
Anti-Herpes Drugs - Inhibitors of Viral Genome Replication (Nucleoside Analogs) - Examples
```
Acyclovir (Zovirax)
Valacyclovir (Valtrex)
Penciclovir (Denavir)
Famciclovir (Famvir)
rufluridine (Viroptic)
```
34
Anti-Herpes Drugs - Mechanism of Action
1. Initial phosphorylation is mediated by viral thymidine kinase
= primary mechanism of viral vs. host selectivity (i.e., 200-fold difference in affinity)
2. Cellular protein kinases convert acyclovir-MP (monophosphate) to its TP (triphosphate) form.
3. Acyclovir-TP competes w/ cellular dGTP for viral DNA polymerase
4. DNA polymerase then incorporates nucleotide analog into replicating viral DNA strands.
5. Once incorporated, acyclovir-TP terminates further DNA replication & strand elongation.
6. DNA containing acyclovir-TP also irreversibly binds & inactivates viral DNA polymerase (i.e., suicide inactivation).
35
Acyclovir - Selective Toxcity
Two layers:
1. Initial phosphorylation is mediated by viral thymidine kinase (rather than host kinases)
2. Binds w/ greater affinity to viral DNA polymerase than host enzyme
36
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
37
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
38
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
39
Pharmacokinetics of Peniciclovir
= Acyclic guanosine analog
- Poor oral absorption
- Topical only (more effective than topical acyclovir)
- Neonatal clearance only 1/3 of adults
40
Pharmacokinetics of Famiciclovir
- Penciclovir prodrug that increases oral bioavailability to 70%
- Neonatal clearance only 1/3 of adults
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Pharmacokinetics of Vidarabine-trifluridinne
- ONLY topical (toxicity associated w/ IV use)
| - Neonatal clearance only 1/3 of adults
42
Agents for Herpes Simplex Virus (HSV) - Primary & Recurrent herpes
- ORAL acyclovir shorted duration of primary & recurrent herpes
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Agents for Herpes Simplex Virus (HSV) - Recurrent Herpes labialis
ORAL acyclovir reduces mean duration of pain (NOT time to healing)
44
Agents for Herpes Simplex Virus (HSV) - Herpes Simplex Encephalitis
IV acyclovir
45
Agents for Herpes Simplex Virus (HSV) - Neonatal HSV infection
IV acyclovir
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Agents for Herpes Simplex Virus (HSV) - Serious HSV/ VZV Infections (esp. in immunsuppressed)
IV acyclovir
47
Agents for Herpes Simplex Virus (HSV) - HSV keratoconjunctivitis & recurrent epithelia keratitis
TOPICAL Vidarabine & trfluridine
- for limited use
- effective against acyclovir-resistant strains
48
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
49
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
50
Inhibitors of Viral Penetration - Example
Docosanol (Abreva cream - OTC)
51
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
52
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
53
Drugs for Cytomegalovirus Infections
Inhibitors of Viral DNA Polymerase
- Ganciclovir (Cytovene)
- Valganciclovir (Valcyte)
54
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
55
Setting of CMV infections
In advanced immunosuppression (HIV & organ transplantation)
| - most commonly as result of reactivation of latent infection
56
Results of CMV infections
End organ disease including:
- retinitis
- colitis
- esophagitis
- CNS disease
- pneumonitis
57
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
58
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
59
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)
60
Valganciclovir (Valcyte) - Pharmacokinetics
- Prodrug
| - Rapidly deesterified & converted to ganciclovir by GI and hepatic esterases
61
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
62
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)
63
Foscarnet (Foscavir)
- Inorganic pyrophosphate analog, unique amongst all antiviral agents
64
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
65
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
66
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
67
Foscarnet (Foscavir) - Clinical Uses
- Effective against CMV retinitis, esp. in immunocompromised pts
- Effective against ganciclovir-resistant CMV infections and acyclovir-resistant HSV & VZV infections
68
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
