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2. HDS Pulmonary > Antivirals > Flashcards

Antivirals Flashcards

1
Q

Viral

Host Cell Killing

A
  • Interfere w/ host cell macromolecular synthesis
  • Decline of plasma membrane function
  • Failure of lysosomal membranes
  • Cell lysis
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2
Q

Antiviral

Targets

A

Goal to block viral replication only in infected cells.

  • Adsorption, penetration, uncoating
    • Amantadine ⇒ ⊗ uncoating of influenza
    • Gamma globulins against specific Ag on cell surface ⇒ modify infection
      • Ex. Measles
  • Replication of nucleic acids
    • Catalyzed by enzymes not present in normal cells
    • Nucleic acid analogues ⇒ ⊗ replication
      • Ex. Acyclovir
  • Integration of viral genome
    • Viral integrase vs host integrase
    • Target of HIV drugs, covered later
  • Viral mRNA synthesis
    • Viral vs host RNA polymerases
    • Some viral mRNA capped at 5’ end by viral enzymes
    • Ribavirin ⇒ ⊗ this step
      • Nucleoside analogue
  • Translation of viral mRNA
    • ⊗ by interferons
  • Viral morphogenesis
    • Large precursor viral proteins cleaved by virus specific proteases
    • ⊗ by HIV drugs
  • Viral escape
    • ⊗ by Neuraminidase inhibitors
      • Ex. Zanamivir, Oseltamivir
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3
Q

Influenza

Pathogenesis

A
  • Hemagglutinin ⇒ binds to sialic acid on target cell
    • Faciliates endocytosis
    • Binding on new virus after replication prevents virus from separating from parent cell
  • M2 protein ⇒ ion channel required for uncoating
  • Neuraminidase ⇒ cleaves sialic acid
    • Allows new virus to be separated from target cell
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4
Q

Uncoating Inhibitors

A

Amantadine & Rimantadine

  • ⊗ M2 proton channel in viral envelope
    • ⊗ uncoating
    • ⊗ viral replication @ early stage
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5
Q

Amantadine & Rimantadine

Indications

A
  • Treat influenza A
  • Can alleviate sx if given within first 48 hrs
  • Can be used prophylactically
  • Does not prevent Ab development w/ vaccine
  • No longer recommended in US d/t widespread resistance
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6
Q

Amantadine

Pharmacokinetics

A

Is not metabolized ⇒ almost all excreted into urine changed

Dose adjustment needed for renal impairment

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7
Q

Amantadine

Adverse Effects

A
  • Readily crosses BBB
    • Causes release of dopamine from CNS neurons
  • Neurological side effects:
    • Lightheadedness
    • Difficulty concentrating
    • Nervousness / anxiety
    • Insomnia
  • May be used during initial therapy for Parkinson’s disease
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8
Q

Rimantadine

Pharmacokinetics

A

Extensively metabolized before renal excretion

Dose adjustments not necessary until creatinine clearance

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9
Q

Rimantadine

Adverse Effects

A

Lower risk of CNS adverse effects

May cause ataxia or livedo reticularis (netlike pattern of reddish-blue skin discoloration)

Is not used for Parkinson’s

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10
Q

Release Inhibitors

A

Zanamivir (Relenza) & Oseltamivir (Tamiflu)

  • ⊗ Neuraminidase
    • ⊗ cleavage of sialic acid by newly synthesized virions
    • ⊗ budding from target cell
    • Virus remains tethered to parent cell
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11
Q

Zanamivir & Oseltamivir

Indications

A
  • Active against influenza A and B
    • Works best when given early
  • ↓ time to improvement in sx by one day
  • ↓ in influenza-related complications
  • Effective prophylactically
  • Oseltamivir ⇒ drug of choice for treatment and prevention of bird flu
    • Resistant strains have been identified
    • H1N1 epidemic in 2009
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12
Q

Oseltamivir

Pharmacokinetics

A
  • Ethyl ester prodrug
  • Well-absorbed in GI tract
  • Bioavailability 80% after desterification
  • Excreted unchanged in the urine
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13
Q

Oseltamivir

Adverse Effects

A

Nausea, vomiting, and headache in 15%

↑ risk of psychiatric disturbances and renal events

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14
Q

Zanamivir

Pharmacokinetics

A
  • Poor oral bioavailability
  • Given as dry powder that is inhaled
  • < 20% absorbed systemically
  • 90% excreted unchanged in urine
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15
Q

Viral Replication

Inhibitors

A

Acyclovir, Valacyclovir, Famciclovir

  • Nucleoside analogues
    • Mechanism similar for all 3 drugs
  • Phosphorylated by viral thymidine kinase
    • 200x greater affinity for viral enzyme than mammalian enzyme
    • Resistance d/t alterations in viral thymidine kinase
  • Acyclovir-monophosphate → acyclovir-triphosphate by cellular kinases
  • Acyclovir-℗3
    • Acts as substrate for viral DNA polymerase ⇒ ⊗ DNA polymerase
    • Incorporated into DNA ⇒ terminates chain elongation
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16
Q

Keratitis

A

Inflammation of the cornea.

Causes sudden and severe pain, blurred vision, or corneal lesions.

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17
Q

Herpes Encephalitis

A
  • Fever
  • Headache
  • Stiff neck
  • Seizures
  • Partial paralysis
  • Stupor
  • Coma
18
Q

Acyclovir, Valacyclovir, Famciclovir

Indications

A
  • Herpes keratitis
    • Topical acyclovir mostly
    • May be given PO if eye is sensitive
    • Trifluridine also used topically
      • Unacceptable toxicity if used systemically
  • Herpes encephalitis
    • Begin Acyclovir therapy immediately after biopsy
    • Discontinue if biopsy negative for Herpes
  • Primary and recurrent genital herpes
    • Herpes simplex type 2 most common cause
    • Topical used for mild disease
      • Not effective for recurrent herpes
    • PO used for more serious disease
      • Can prevent recurrence for up to 1 year
      • Protective effect disappears when drug is stopped
  • Mucocutaneous infections
    • Acyclovir IV used in immunocompromised pts
  • Varicella-zoster
    • Used in immunocompromised pts
19
Q

Acyclovir

Pharmacokinetics

A
  • Given IV, PO, or topically
    • Systemic absorption minimal w/ topical
  • 15-30% bioavailability w/ PO
    • Prodrug valacyclovir has greater bioavailability
  • Widely distributed in tissues
  • Metabolized to a small extent
  • Eliminated by glomerular filtration and tubular secretion
20
Q

Acyclovir, Valacyclovir, Famciclovir

Adverse Effects

A

Obstructive crystallin nephropathy if not properly hydrated

21
Q

Cytomegalovirus Retinitis

Treatments

A
  • Ganciclovir
  • Foscarnet
  • Cidofovir
22
Q

Ganciclovir

MOA

A
  • Similar structure to acyclovir w/ additional hydroxymethyl group
  • Same MOA as acyclovir
  • 100x more active against CMV than acyclovir
23
Q

Ganciclovir

Indications

A

CMV retinitis & other viral manifestations

  • Ganciclovir + anti-CMV Ab ⇒ CMV PNA in renal transplant pts on immunosuppressants
    • Significant improvement in survival rate
24
Q

Ganciclovir

Pharmacokinetics

A
  • Oral availability very low
    • Used for maintenance treatment
    • Valganciclovir ⇒ prodrug that can be used PO
  • IV used for acute treatment
  • Ocular implant used for retinitis
25
Q

Ganciclovir

Adverse Effects

A
  • Bone marrow suppression ⇒ most common
  • CNS effects ⇒ 5-15%
  • Renal toxicity
    • Only used to treat serious CMV infections
26
Q

Foscarnet

MOA

A
  • Phosphonate derivative
  • ⊗ DNA polymerase & HIV reverse transcriptase
    • Binds pyrophosphate site on enzymes
27
Q

Foscarnet

Indications

A
  • Cytomegalovirus retinitis
    • In ganciclovir resistant disease
    • In pts unable to tolerate ganciclovir
  • Some activity against Herpes
28
Q

Foscarnet

Adverse Effects

A
  • Reduced renal function
  • More expensive and generally less well tolerated than ganciclovir
29
Q

Cidofovir

MOA

A
  • Nucleotide analogue that mimics deoxycytidine monophosphate
  • Does not require viral kinases for phosphorylation
30
Q

Cidofovir

Indications

A
  • Alternative for CMV retinitis
  • Herpes infections resistant to acyclovir
31
Q

Cidofovir

Adverse Effects

A

Nephrotoxicity

Must be given IV w/ probenecid (⊗ renal uric acid tubular transport)

32
Q

SARS-CoV-2

A
  • ⊕-sense ssRNA virus
  • Codes for a RNA replicase (RNA-dependent RNA polymerase)
    • Makes a complementary ⊖ strand of RNA
    • Reads ⊖ RNA to make ⊕-sense RNA copy & small pieces of ⊕-sense mRNA for viral structural proteins
33
Q

Remdesivir

MOA

A
  • Adenosine analogue
  • Inserts into RNA chain resulting in conformational changes
  • Prevents RNA from entering RNA dependent RNA polymerase
34
Q

Remdesivir

Indications

A
  • Approved by FDA for emergency use
  • Treat COVID-19, including all hospitalized pts
  • Median recovery time decreased by 5 days
  • Overall odds of clinical improvement at day 15 greater in treated group
35
Q

Remdesivir

Adverse Effects

A
  • ↑ Liver enzymes
  • Infusion related reaction
    • Low BP
    • N/V
    • Sweating
    • Shivering
36
Q

Ribavirin

MOA

A

Mixed mechanism of action:

  • Competes with GTP and ATP ⇒ ⊗ RNA polymerase
  • ⊗ inosine monophosphate dehydrogenase ⇒ depletes virally infected cell of GTP
  • ⊗ N7 methyl transferase ⇒ ⊗ capping of mRNA

Development of resistant strains less likely.

37
Q

Ribavirin

Indications

A
  • Active in tissue culture against 85% of all animal viruses studies
  • Is not toxic to cells
  • Uses
    • Used as an aerosol for RSV
    • In combo w/ interferon for Hep C
    • Influenza
38
Q

Ribavirin

Adverse Effects

A
  • Aerosol for RSV ⇒ upper airway irritation
  • Combo w/ IFN for Hep C ⇒ hemolytic anemia
  • Teratogenic
39
Q

Fomivirsen

A
  • Second-line treatment for CMV retinitis
  • An anti-sense mRNA for a protein necessary for viral replication
40
Q

Interferons

Overview

A
  • Viral nucleic acids ⇒ de-repression of host genes ⇒ induction of IFN production
  • IFN released into extracellular space ⇒ binds to receptors on nearby cells
  • IFN induces proteins that ⊗ viral replication
    • Induces a protein kinase ⇒ ⊗ initiation factor ⇒ ⊗ viral protein synthesis
    • Activates cellular endonuclease ⇒ degrades viral mRNA
    • Activates phosphodiesterase ⇒ degrades terminal nucleotides of tRNA ⇒ ⊗ peptide elongation
41
Q

Interferon

Treatment

A
  • Glycoprotein ⇒ give SubQ or IM
  • Indications:
    • Chronic Hep B and C ⇒ most common
      • Combo w/ ribavirin for Hep C ⇒ synergistic effects w/ decreased replapse
    • Hairy cell leukemia
    • Kaposi’s sarcoma 2/2 AIDS
    • Genital warts (condyloma acuminatum)
    • Prevent dissemination of herpes zoster in cancer pts
    • Topical admin in combo w/ other antivirals for herpes keratoconjunctivitis
42
Q

Interferons

Adverse Effects

A

Neutropenia

Results in flu-like sx, fever, chills, fatigue.

2. HDS Pulmonary (28 decks)

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