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Unit 3 D&D > DD 02-28-14 08-09am Non-HIV Antiviral Agents - French > Flashcards

DD 02-28-14 08-09am Non-HIV Antiviral Agents - French Flashcards

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
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2
Q

Primary means to control viral spread

A
  • use of public health measures

- use of prophylactic vaccines

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3
Q

Major barrier to the development of effective antiviral agents

A
  1. Viruses are intracellular & undergo replication / propagation by commandeering host’s cell metabolic machinery.
  2. Broad spectrum antiviral agents has proved difficult to achieve b/c viruses are highly heterogeneous.
  3. Viral polymerases typically exhibit poor fidelity during genome replication, increasing mutagenesis & the speed of resistance developement to antiviral therapies.
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4
Q

Viral Life Cycle steps

A
  1. Attachment / Entry
  2. Penetration
  3. Uncoating
  4. Early protein synthesis
  5. Nucleic Acid synthesis
  6. Late protein synthesis & processing
  7. Packaging & Assembly
  8. Viral release
    (see pic in notes)
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5
Q

Antiviral agents that block Viral Attachment/Entry

A

Enfuvirtide (HIV)
Maraviroc (HIV)
Docosanol (HSV)
Palivizumab (RSV)

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6
Q

Antiviral agents that block Viral Penetration

A

Interferon-alpha (HBV, HCV)

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7
Q

Antiviral agents that block Viral Uncoating

A

Amantadine, Rimantadine (influenza)

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8
Q

Antiviral agents that block Nucleic Acid Synthesis of Virus

A

NRTIs (HIV, HBV)
NNRTIs (HIV)
Acyclovir (HSV)
Foscarnet (CMV)

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9
Q

Antiviral agents that block Late Protein Synthesis & Processing

A

Protease inhibitors (HIV)

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10
Q

Antiviral agents that block Viral Release

A

Neuraminidase inhibitors (influenza)

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11
Q

Influenza Life Cycle

A
  1. Binds cell surface of airway epithelial cell
  2. Is endocytosed & internalized into endosomes.
  3. Acidified endosomal environment promotes conformational change in hemagglutinin structure
  4. –> fusion btwn influenza viral envelope & endosomal membrane.
  5. Activation of & proton influx through viral M2 proton channel
  6. –> release of RNA genome
  7. Replication & Assembly into new virus particles.
  8. Egress of new virions results in their being tethered to the plasma member via intrxn w/ hemagglutinin & cellular sialic acid moieties
  9. Viral envelope-bound neuraminidases cleave sequestered sialic acid moieties, resulting in virion release.
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12
Q

Viral Neuraminidase Inhibitors - Examples

A

Oseltamivir (Tamiflu)

Zanamivir (Relenza)

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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
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14
Q

Resistance to Viral Neuraminidase Inhibitors

A
  • Relatively rare (1-4%)

- from mutations in either viral hemagglutinin or neuraminidase

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15
Q

Oseltamivir (Tamiflu) - Pharmacokinetics

A
  • PO prodrug
  • given twice daily
  • Plasma half-life of 6-10 hours
  • Elimination via renal tubular secretion
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16
Q

Zanamivir (Relenza) - Pharmacokinetics

A
  • Poor oral bioavailability
  • Administered via inhalation
  • Renal elimination
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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
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18
Q

Adverse Reactions of Oseltamivir (Tamiflu)

A
  • minor, occasional nausea & vomiting (reduced by taking with food)
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19
Q

Adverse Reactions of Zanamivir (Relenza)

A
  • Uncommonly, bronchospasm in pts w/ asthma or COPD
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20
Q

Agents that Inhibit of Uncoating

A

Amantadine (Symmetrel)

Reimantadine (Flumadine)

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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
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22
Q

Resistance to Inhibitors of Uncoating

A
  • Occurs to both amantadine & rimantadine

- Due to mutations in transmembrane domains of M2 proton channel

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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
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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.
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25
Q

Use of Inhibitors of Uncoating in Influenza

A
  • 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
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26
Q

Adverse Reactions of Amantadine

A
  • insomnia
  • concentration difficulty
  • lightheadedness / dizziness
  • headache
  • teratogenic in animals (Pregnancy Category C, but generally not recommended)
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27
Q

Adverse Reactions of Rimantadine

A
  • better tolerated than Amantadine due to poor CNS penetration (more highly protein bound)
  • teratogenic in animals (Pregnancy Category C , but generally not recommended)
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28
Q

Herpes Virus Replicative Cycle

A
  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
Q

Immediate-early vs. Late transcribed genes in Herpes Viruses

A

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
Q

Inhibitors of Viral Genome Replication - Overview

A
  • ## 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
Q

Antiviral actions of purine and pyrimidine analogs

A
  • involve passage of lipid soluble analog across cell membrane
  • it is then converted to active triphosphate form by intracellular kinases
32
Q

Degree of selective toxicity in nucleoside analogs

A
  • 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
Q

Anti-Herpes Drugs - Inhibitors of Viral Genome Replication (Nucleoside Analogs) - Examples

A 
Acyclovir (Zovirax)
Valacyclovir (Valtrex)
Penciclovir (Denavir)
Famciclovir (Famvir)
rufluridine (Viroptic)
34
Q

Anti-Herpes Drugs - Mechanism of Action

A
  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
Q

Acyclovir - Selective Toxcity

A

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
Q

Resistance to Anti-Herpes Drugs (Nucleoside Analogs)

A

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
Q

Pharmacokinetics of Acyclovir (Anti-Herpes)

A
  • 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
Q

Pharmacokinetics of Valacyclovir

A

= 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
Q

Pharmacokinetics of Peniciclovir

A

= Acyclic guanosine analog

  • Poor oral absorption
  • Topical only (more effective than topical acyclovir)
  • Neonatal clearance only 1/3 of adults
40
Q

Pharmacokinetics of Famiciclovir

A
  • Penciclovir prodrug that increases oral bioavailability to 70%
  • Neonatal clearance only 1/3 of adults
41
Q

Pharmacokinetics of Vidarabine-trifluridinne

A
  • ONLY topical (toxicity associated w/ IV use)

- Neonatal clearance only 1/3 of adults

42
Q

Agents for Herpes Simplex Virus (HSV) - Primary & Recurrent herpes

A
  • ORAL acyclovir shorted duration of primary & recurrent herpes
43
Q

Agents for Herpes Simplex Virus (HSV) - Recurrent Herpes labialis

A

ORAL acyclovir reduces mean duration of pain (NOT time to healing)

44
Q

Agents for Herpes Simplex Virus (HSV) - Herpes Simplex Encephalitis

A

IV acyclovir

45
Q

Agents for Herpes Simplex Virus (HSV) - Neonatal HSV infection

A

IV acyclovir

46
Q

Agents for Herpes Simplex Virus (HSV) - Serious HSV/ VZV Infections (esp. in immunsuppressed)

A

IV acyclovir

47
Q

Agents for Herpes Simplex Virus (HSV) - HSV keratoconjunctivitis & recurrent epithelia keratitis

A

TOPICAL Vidarabine & trfluridine

  • for limited use
  • effective against acyclovir-resistant strains
48
Q

Agents for Varicella Zoster Virus (VZV)

A

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
Q

Adverse Reactions of Anti-Herpes agents

A
  • 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
Q

Inhibitors of Viral Penetration - Example

A

Docosanol (Abreva cream - OTC)

51
Q

Docosanol (Abreva cream - OTC)

A
  • 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
Q

Use Docosanol (Abreva cream, OTC)

A
  • 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
Q

Drugs for Cytomegalovirus Infections

A

Inhibitors of Viral DNA Polymerase

  • Ganciclovir (Cytovene)
  • Valganciclovir (Valcyte)
54
Q

Inhibitors of Viral DNA Polymerase (Anti-CMV drugs) - Overview

A
  • 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
Q

Setting of CMV infections

A

In advanced immunosuppression (HIV & organ transplantation)

- most commonly as result of reactivation of latent infection

56
Q

Results of CMV infections

A

End organ disease including:

  • retinitis
  • colitis
  • esophagitis
  • CNS disease
  • pneumonitis
57
Q

Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Mechanism of Action

A
  • 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
Q

Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Resistance

A
  • 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
Q

Ganciclovir (Cytovene) - Pharmacokinetics

A
  • 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
Q

Valganciclovir (Valcyte) - Pharmacokinetics

A
  • Prodrug

- Rapidly deesterified & converted to ganciclovir by GI and hepatic esterases

61
Q

Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Clinical uses

A
  • 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
Q

Ganciclovir (Cytovene) & Valganciclovir (Valcyte) - Adverse Rxns

A
  • 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
Q

Foscarnet (Foscavir)

A
  • Inorganic pyrophosphate analog, unique amongst all antiviral agents
64
Q

Foscarnet (Foscavir) - Mechanism of Action

A
  • 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
Q

Foscarnet (Foscavir) - Resistance

A
  • 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
Q

Foscarnet (Foscavir) - Pharmacokinetics

A
  • 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
Q

Foscarnet (Foscavir) - Clinical Uses

A
  • Effective against CMV retinitis, esp. in immunocompromised pts
  • Effective against ganciclovir-resistant CMV infections and acyclovir-resistant HSV & VZV infections
68
Q

Foscarnet (Foscavir) - Adverse Reactions

A

Major side effect: Nephrotoxicity & hypocalcemia
- can be severe & even fatal

Also:

  • CNS abnormalities (H/A, tremor, seizures, & even hallucinations)
  • Rash
  • Fever
  • Nausea

Unit 3 D&D (18 decks)

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