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Infectious Disease > Antivirals > Flashcards

Antivirals Flashcards

1
Q

What is a virus made of?

A

No cell wall, made up of nucleic acid components:

  • protein coat (capsid)
  • nucleic acid core, or genome
  • some have lipoprotein envelope
  • viruses containing envelope are antigenic in nature
  • Viruses are obligate intracellular parasites
  • Use host enzymes, don’t have metabolic machinery of their own.
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2
Q

Where do viruses replicate in the host?

A

certain ones multiply in cytoplasm and others do so in the nucleus
-most have to replicate so many times before they illicit symptoms in the host and before the dx is made.

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3
Q

Process of viral infection and replication?

A
  1. Absorption: binds to host cell
  2. Penetration: virus injects genome into host cell
  3. Viral genome replication: viral genome replicates using the host’s cellular machinery
  4. Assembly: viral components and enzymes are produced and begin to assemble.
  5. Maturation: viral components assemble and viruses fully develop.
  6. Release: newly produced viruses are expelled from the host cell.
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4
Q

What must antiviral drugs do to be effective?

A

must either:

  • block viral entry into or exit from the cell
  • be active inside the host cell
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5
Q

What is the MOA of most anti-viral drugs?

A

many are purine or pyrimidine analogs.

  • Many are prodrugs: so they must be phosphorylated by viral or cellular enzymes in order to become active.
  • anti-viral agents inhibit active replication so the viral growth resumes after drug removal.
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6
Q

What is an important part of fighting viral infections?

A

current anti-viral agents don’t eliminate non-replicating or latent virus

  • **Effective host immune response remains essential for recovery from viral infection.
  • clinical efficacy depends on achieving inhibitory concentration at site of the infection within the infected cells
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7
Q

What are the anti-HSV/VZV agents?

Herpes/Varicella/Zoster

A

acyclovir (zovirax)
famciclovir (famvir)
valacyclovir (valtrex)

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8
Q

MOA of anti-HSV/VZV agents?

A

All 3 are guanine nucleoside analogs.

  • all are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs.
    • The analog inhibits viral DNA-polymerase and only actively replicating viruses are inhibited
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9
Q

Acyclovir (zovirax)

A

guanosine analog

-topical, oral, and IV

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10
Q

Spectrum of Acyclovir?

A

HSV 1 and 2, VZV, and possible EBV
*DOC for HSV genital infections, herpes labialis/orolabial, HSV encephalitis, HSV infections in immunocompromised and pregnant pt

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11
Q

Pharmokinetics of acyclovir?

A 
oral bioavailability: 20-30%
distribution to all tissues including CNS
-renal excretion: >80%
-half life: 2-5 hours
-topical, oral and IV
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12
Q

Acyclovir safety

A

Pregnancy: B
lactation: safe
renal dosing: adjust if CrCl

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13
Q

Acyclovir MOA

A

inhibition of viral synthesis of DNA

  • uptake by infected cell
  • competes with deoxyguanosine triphosphate for viral DNA polymerases:
  • chain termination -> inactivated viral DNA polymerase
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14
Q

What cells is acyclovir selectively activated in?

A

in cells infected with herpes virus

-uninfected cells don’t phosphorylate acyclovir.

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15
Q

When would you take acyclovir for genital/mucocutaneous HSV?

A

Take it for first episode: frequent dosing (trying to prevent it from reocurring)
Recurrence and suppression if pt has frequent recurrence.

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16
Q

Adverse effects of Acyclovir

A
  • reversible renal toxicity
  • Neuro symptoms: encephalopathic changes - somnolence, hallucinations, confusion and coma.
  • TTP/HUS in immunocompromised
  • GI sxs
  • HA
  • rash
  • photosensitivity
  • anemia
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17
Q

Resistance to acyclovir and MOA of resistance

A

MIC>2-3 mcg/mL

  • mostly occurs in immunocompromised
  • 3 basic resistance mechanisms exist:
    1. reduced or absent thymidine kinase
    2. altered TK substrate specifity
    3. alterations in DNA poly.
  • there is cross resistance to famciclovir and valacyclovir
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18
Q

Why tx with acyclovir?

A

genital herpes: shortens duration of sxs, viral shedding time, and time to resolution of lesions

recurrent genital herpes: shortens course of time by 1-2 days

long term tx: decreases frequency of both symptomatic recurrences and asymptomatic viral shedding -> decreases sexual transmissions.

Varicella Zoster: decreases total number of lesions and duration of varicella (if begun w/in 24 hours after onset of rash).

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19
Q

Famciclovir (Famvir)

A

cyclic guanine analong:

  • converted to penciclovir in the liver and intestines
  • penciclovir is used only topically whereas famciclovir can be administered orally.
  • PO only
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20
Q

Spectrum of famciclovir

A

HSV 1 & 2, VZV, maybe in EBV

- in vitro to HBV

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21
Q

Pharmacokinetics of famciclovir

A 
oral bioavailability: 77%
1st pass metabolism in intestine and liver: results in conversion to penciclovir 
Renal excretion: > 80%
half life: 2-3 hours
- Just PO
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22
Q

Famciclovir safety

A

Pregnancy: B
lactation: unknown, caution advised

Renal dosing: adjust dose for CrCl

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23
Q

MOA of famciclovir

A

Similar to acyclovir -> inhibition of viral synthesis of DNA, uptake by infected cell and competes with deoxyguanosine triphosphate for viral DNA polymerases -> inactivates viral DNA polymerase
-it is converted to penciclovir triphosphate and compared to acyclovir triphosphate, penciclovir 3xP has lower affinity for viral DNA polymerase but does have longer intracellular half life

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24
Q

Famciclovir uses

A

zoster (shingles), and genital and orolabial HSV (for 1st occurence, recurrence and suppression)

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25
Q

Famciclovir adverse effects

A
  • neutropenia
  • thrombocytopenia
  • neurological sxs: encephalopathic changes -> somnolence, hallucinations and delirium
  • GI sxs
  • HA, fatigue
  • abnormal LFT’s
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26
Q

Resistance to Famciclovir

A
  • mutations in viral TK or DNA polymerase
  • cross resistance with acyclovir in TK negative strains
  • May still have activity in TK altered strains
  • resistance to HBV due to pt mutation (viral DNA polymerase)
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27
Q

Valacyclovir (Valtrex)

A

Prodrug of acyclovir:

rapidly and almost completely converted to a acyclovir, same MOA, same spectrum, same mechanism of resistance

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28
Q

Pros and cons of Valacyclovir

A

Advantage: more convenient dosing, better oral bioavailability (55%)
cons: more pricey than acyclovir

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29
Q

Pharmokinetics of Valacyclovir

A 
oral bioavailability: 55%
-undergoes rapid and extensive 1st pass effect to yield acyclovir
-food doesn't affect absorption
-renal excretion: >50%
Half life: 2-3 hours
Administration: oral
30
Q

Valacyclovir safety

A

Pregnancy: B
lactation: safe

renal dosing: adjust for CrCl

31
Q

dosing of Valacyclovir

A

varies with infection type/severity

  • 1st episode of HSV: hit em’ hard -> 1000 mg PO bid x 7-10 days
    shingles: PO tid x 7 days
32
Q

Adverse effects of Valacyclovir

A
  • reversible renal toxicity
  • neuro sxs: encephalopathic changes -> somnolence, hallucinations, confusion, coma
  • TTP/HUS: immunocompromised
  • GI, HA, rash, photosensitivity, elevated LFTs
33
Q

What is the cheapest of the 3 HSV drugs and most preferred?

A

Acyclovir cheapest, but you have to admin more often.
Can tx encephalitis with this too by IV
- used b/c it has broader spectrum -> recommended for varicella or zoster in immunocompromised

34
Q

What is used to treat HSV keratoconjunctivitis?

A

trifluridine (viroptic -> ophthalmic application)

- this is active against acyclovir resistant strains

35
Q

Anti-CMV agents

A

Ganciclovir

36
Q

Spectrum of Ganciclovir

A

oral, IV, intraocular
CMV, EBV, HSV/VZV, human herpesvirus 6

(for CMV and EBV: 10x more potent than acyclovir)

37
Q

Ganciclovir is DOC for?

A

CMV retinitis in immunocompromised pt, and prevention of CMV disease in transplant patients

38
Q

pharmacokinetic of Ganciclovir

A 
oral bioavailability: 50%
is excreted unmodified in urine
renal excretion: >90% 
half life: 2-4 hours
admin: oral, IV, intraocular
39
Q

Ganciclovir safety

A

pregnancy: C (adverse fetal effects in animal studies)
lactation: unsafe

renal dosing: adjust dose for CrCl

40
Q

MOA of Ganciclovir

A

competes with deoxyguanosine triphosphate similar to acyclovir

  • but in CMV -> viral encoded phosphotransferase coverts to ganciclovir triphosphate
  • unlike acyclovir, ganciclovir contains 3’ OH group allowing for DNA to continue
41
Q

Adverse effects of Ganciclovir

A

reversible pancytopenia, fever, rash, phlebitis (IV), confusion, renal dysfunction, psychiatric disturbances, seizures

42
Q

Influenza agents

A
  • oseltamivir
  • zanamivir
  • amantadine (used in parkinsons now)
  • Rimantadine
43
Q

MOA of influenza and neuraminidase inhibitors -> oseltamivir/zanamavir

A

influenza: contains an enzyme neuraminidase which is essential for the replication of the virus
- so neurominidase inhibitors prevent the release of new visions and their spread from cell to cell.

44
Q

Neuraminidase inhibitors effectiveness

A

effective against both types of influenza A and B

  • don’t interfere with immune response to influenza A vaccine
  • can be used for both prophylaxis and acute tx
45
Q

Oseltamivir (Tamiflu) MOA

A

oral neuraminidase inhibitor: cleaves terminal sialic acid residues on glycoconjugates and destroys receptors
-newly formed visions adhere to cell surface and limit spread.

46
Q

Spectrum of Oseltamivir (Tamiflu)

A

Influenza A and B in kids and adults, avian flu, H5N1 disease

47
Q

Adverse effects of Tamiflu

A

N/V, HA

48
Q

When do you want to administer Oseltamivir (Tamiflu)

A

for tx of Influenza A and B:
w/in 48 hours of sx onset, if high risk -> 72 hours
- prophylaxis: w/in 48 hours of exposure

49
Q

Zanamivir (Relenza)

A

Neuraminidase inhibitor, given via inhalation

spectrum: uncomplicated influenza A and B and some strains of Avian influenza

50
Q

Adverse effects of Zanamivir (Relenza)

A

nasal and throat discomfort

-bronchospasm

51
Q

Amantadine (Symmetrel) and Rimantadine (Flumadine)

A

MOA: prevents release of viral nucleic acid into host cell
spectrum: influenza A, however resistance is frequent (Symmetrel not as effective anymore -> doesn’t work on B)

Adverse effects: seizures, anticholinergic, CNS, edema, blurry vision

52
Q

Is Amantadine or Rimantadine recommended in US?

A

NO not currently recommended for influenza because too much resistance
- it is being used for extrapyramidal sx and parkinsonism though

53
Q

Pharmacokinetics of Amantadine

A

oral bioavailability: 50-90%

  • crosses BBB extensively, and Rimantadine doesn’t.
  • PO
54
Q

Ribavarin

A

purine nucleoside analog
MOA: not fully understood, inhibition of RNA polymerase

Spectrum: DNA and RNA viruses are susceptible, including influenza, HCV, parainfluenza, RSV, Lassa virus

55
Q

Therapeutic uses of Ribavarin

A

DOC for: RSV bronchitis and pneumonia in hospitalized children (aerosol), lassa fever

alternate drug: influenza, parainfluenza, measles virus in immunocompromised pts
- used in combo with interferons for HCV

56
Q

Safety of Ribavarin

A

Available: PO and inhalation
IV available through CDC
Preg: X (teratongenic)
lactation: probably unsafe

57
Q

Adverse effects of Ribavirin

A 
BBW-hemolytic anemia
resp. deterioration
depression
suicidal ideation
bacterial infections
psych. effects
anxiety, fatigue, dizziness
58
Q

Hepatitis?

A

swelling or inflammation of the liver in response to:

drugs, toxins, excessive alcohol, infections from bacteria or viruses

59
Q

Hepatitis A

A

typically spreads when infected individuals improperly handle food or water

60
Q

Hepatitis B

A

often transmitted by sexual intercourse, sharing of needles or contact with contaminated blood (vaccine available)

61
Q

Hepatitis C

A

more likely to cause permanent liver damage, genes mutate very fast, new genotypes make developing an effective vaccine impossible so far

62
Q

Hepatitis A tx

A

clears on its own with rest and adequate hydration

63
Q

Hepatitis B tx

A 
May clear on its own.
Chronic cases may be tx with:
- interferon
- Nucleoside Reverse Transcriptase inhibitors (NRTI) such as ->
emtricitabine
tenofavir
entacavir
lamivudine 
(some patients may need liver transplant)
64
Q

Hepatitis C epidemiology

A

chronic infection that afflicts about 170 million people worldwide
-annual mortality: 350,000
15,000 in the US

65
Q

Hepatitis C standard treatment

A

synthetic, injectable version of interferon plus the antiviral drug ribavarin

  • this combo shows benefit or cure in 25-75% of patients
  • SE: significant or intolerable -> severe flu-like sxs, fatigue, depression, anemia
  • Virus often becomes resistant to medication, allowing disease to worsen
66
Q

Anti-viral drugs for hepatic viral infections

A
  • interferons
  • lamivudine - cytosine analog - HBV
  • Entecavir - guanosine analog- HBV (lamivudine resistance strains)
  • Ribavarin - Hep C (w/ interferons)
67
Q

New drugs for Hep C

A

To be effective - drug has to incorporate itself in the virus’s genetic code so as to halt replication
- to avoid potentially debilitating side effects the med needs to enter the liver quickly and directly avoiding as many other organs as possible

68
Q

New formulation for Hepatitis

A 
called sofosbuvir (Sovaldi)
study showed 295/327 patients treated with sofosbuvir as well as ribavarin and interferon showed no signs of virus in blood after 12 weeks -> approved by FDA in 2013 in combo with rivabarin
69
Q

Sofosbuvir paired with ledispasvir

A

cured at least 94% of patients with genotype 1 disease, mixed in single daily pill (Harvoni) -> cure rates >90% with 12 weeks and no significant SE’s.

70
Q

What is downfall of new drugs for Hep C

A

> $100,000 for 12 week course of treatment.

Many people with Hep C poor and/or incarcerated

71
Q

Cost of sofasbuvir?

A

$594 dose, treatment would run nearly $12 billion dollars

  • much cheaper in Canada and Germany
  • What the heck U.S.?

Infectious Disease (27 decks)

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