Antivirals Flashcards
3 general areas to block with antivirals
1) viral attachment
2) stages internally (ex. NRTI, proteases)
3) block release
Resistance is higher with antivirals!! Also we don’t have a backup like in antibacterials
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Which drugs work on virus specific enzyme thymidine kinase?
acyclovir
penciclovir
ganciclovir
leads to chain termination
Which drug works on triphosphates for competitive inhibition of viral DNA polymerase?
Foscarnet
leads to inhibition of viral DNA synthesis
The host cell uses its own phosphates to get it from monophosphate that the virus specific enzyme created to triphosphate (where foscarnet acts).
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What works on host kinases? (2)
cidofovir
Trifluiridine
Acyclovir name?
Zovirax
Valacyclovir name?
Valtrex
Famciclovir name?
Famvir
What are acylcovir, valacyclovir, and famciclovir techinically?
MOA?
mechanisms of resistance?
guanosine analogs! (synthetic purine nucleosides) NOT ENZYMES.
Chain termination
- activated by viral specific thymidine kinase to mono phosphate
- host enzymes convert to di/triphosphates
- triphosphate analog inhibits viral DNA polymerase by inhibiting DNA chain elongation! (30x more specific for viral vs cellular DNA polymerase - why not as toxic)
MOR:
- deficient or mutant thymidine kinase
- mutant DNA polymerase
- cross resistance among agents
What do Acyclovir, Valacyclovir, and Famciclovir work on?
- HSV-1/2>VZV
**do not work for CMV!!
- Used in genital herpes (initial, recurrent, and supprision)
- used in varicella zoster (chicken pox/shingles)
- HSV encephalitis (inflame of brain)
**decreases the duration/severity of sx, time to lesion healing, viral shedding, and transmission!!
10 fold more drug is needed for VZV when using acyclovir - generally just less effective
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Shedding is what?
The contagious period!
Not necessarily having symptoms though in the individual
It is a period of rapid replication.
Formulations/Kinetics of topical acyclovir?
less effective than oral for primary infection; not effective for recurrent
Dosing is based on indication, severity, and immune function. (if immunodepressed give IV of full dose for ex)
Acyclovir is only given with an IV!!!
Formulations/kinetics for valcyclovir/famciclovir?
valcyclovir: acyclovir prodrug
famciclovir = penciclovir prodrug
Higher levels, less frequent dosing - only available orally! (really only once a day)
better pharmacokinetics
Dosing is based on indication, severity, and immune function.
Adverse effects of Acyclovir, Valcyclovir, and Famciclovir?
Well tolerated (HA - headache, GI side effects possible)
Renal (5%) - crystalline nephropathy with IV acyclovir —- REVERSIBLE WITH HYDRATION.
Neurologic (IV 1-4%) - lethargy, tremors, delirium, hallucinations, seizures.
Antiviral for cytomegalovirus (CMV)?
3
Ganciclovir/Valganciclovir
Foscarnet
Cidofovir (Vistide)
How can ganciclovir be given?
PO, IV, intravitreal injection, or implant
similar in structure to acyclovir
what is the prodrug of ganciclovir?
valganciclovir (PO) - this is generally given
activity for ganciclovir?
CMV»HSV-1, HSV-2, VZV
100x greater than acyclovir for CMV
Ganciclovir/Valganciclovir is generally way more toxic and will see more black box warnings!!
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Regular effects of Ganciclovir/Valganciclovir?
GI: NVD, pain
CNS: insomnia, HA, confusion
RASH!
Black box warnings for Ganciclovir/Valganciclovir?
- Bone Marrow Toxicity! (actual black box)
neutropenia (40%), thrombocytopenia (20%), and anemia (20%)
-Mutagenic, Embryotoxic - contraception 90 days post tx (use two diff types)
Potential interactions with ganciclovir/valganciclovir?
other myelosuprressive agents
Increased seizure potential with imipenem
Chemistry and MOA of Foscarnet
Pyrophosphate analog
Inhibits viral DNA polymerase
- competes for pyrophosphate binding site on DNA polymerase
- does not require activation by viral kinases!!
What is Foscarnet used for?
CMV
Acyclovir resistant HSV
How is Foscarnet given?
poorly absorbed, given IV, intravitreal
Adverse reactions for Foscarnet? (3 big ones - 2 smaller)
- NEPHROTOXCITY (50%)
- BONE MARROW TOXICITY
- ELECTROLYTE IMBALANCES
- GI (30-40%)
- CNS (fever, HA, hallucinations, seizures)
Drug Interactions with Foscarnet?
- nephrotoxic agents
- imipenem (seizures increased), ciphroflaxin (also increase seizures)
Other name for cidofovir?
Vistide
Chemistry/MOA of cidofovir?
Used for?
cytosine nucleotide analog
inhibits viral DNA polymerase (like foscarnet)
Used for CMV/acyclovir-resitant HSV
How is cidofovir given?
IV with probenecid (blocks tubular secretion)
Adverse side effects of Cidofovir (Vistide) (3)?
- Nephrotoxicity (BLACK BOX!)
concentration dependent, proximal tubule
requires, pre and post hydration AND probenecid
avoid other nephrotoxic agents - Bone marrow toxicity
- carcinogenic/mutagenic (avoid getting pregnant 3 mos post administration!)
Brincidofovir… what is it? what is it used for?
Lipid conjugate of cidofovir
phase 3 for CMV, Emergency IND - investigational new drug -for Ebola virus
cidofovir/foscarnet are virus non specific!!
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Cidofovir/foscarnet/ganciclovir are used in CMV disease in immunosuppressed pts.
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Cidofovir is given IV only for retinitis.
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foscarnet is given IV only for intravitreal.
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Infleunza meds that only work on Infleunza A?
Must be given 1-2 before symptoms start! or may be given prophylatically
Rimantidine (Flumadine)
Amantadine (Symmetrel)
THESE ARE RARELY USED ANYMORE - OLDER MEDS.
Chemistry/MOA for Rimantidine and Amantidine?
Work on viral uncoating
Adamantanes
Kinetics of amantadine and rimantidine?
Rimantidine is extensively metabolized! (less SE)
Well absorbed, high nasal, salivary, lung levels
ADRs of amantadine/rimandtidine?
(lower with rimantidine)
CNS (5-33%) - alters dopamine transmission
- HA, dizziness, nervousness, dificulty concentrating, insomnia, depression, fatigue
GI/GU (1-10%) nvd, dry mouth, urinary retention
TERATOGENIC, EMBRYOTOXIC!!
Influenza A is more common early in the flu season.
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Antivirals for Influenza A and B?
must be given within 1-2 days of symptoms but also may be given prophylatically
Oseltamvir (Tamiflu)
Zanamivir (Relenza)
Peramivir (Rapivab)
Oseltamivir, Zanamivir, and Peramivir…. MOA/Chemistry/MOR?
silica acid analogs
inhibit viral neuraminidase (causes clumping of virions preventing release from respiratory epithelial cells)
MOR = aa changes to viral neuraminidase
Kinetics (how are they given) for influenza A/B drugs?
ADRs for each?
Oseltamivir (tamiflu) - orally - GI
Zanamivir (Relenza) - Nasally
-cough, bronchospaasm, may exacerbate asthma/COPD (give bronchodilator before use!)
Peramivir (Rapivab) - IV
skin reactions
viral turnover is greatest at 1-2 days!!
We stretch this number for elderly patients.
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There is high resistance in amantadine/rimantidine!!! They are poorly tolerated also…. why we don’t use them anymore!
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Baloxavir marboxil (Xofluza) - FDA approved in October 2018.
MOA?
USes?
Adverse effects?
How often?
polymerase acidic endonuclease inhibitor
post exposure prophylaxix/A and B strains/Avian and swine flues
GI (n/d)
single oral dose!
useful for strains resistant to neuraminidase inhibitors
Antivirals used against Hep B (3)
Inteferons
-peglyated interferon - MULTIPLE TOXICITIES
Nucleoside Reverse Transcriptase Inhibitors (given orally) - works on DNA pol
- Lamivudine (Epivir HBV) - restance
- Telbivudine (tyzeka) - resitance/$$
- Entecavir (Baraclude) - most commonly used
Nucleotide Reverse Transcriptase Inhibitors (given orally) - works on DNA poly
- Adefovir (Hepsera) - nephrotoxicity
- Tenofovir (Viread) - most commonly used
Interferons have to be injected! - subcutaneous injection
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Which two drugs are most commonly used for Hep B?
Entecavir (Barclude) - nucleoside - oral
Tenofovir (Viread) - nucleotide - oral
What is the MOA of interferons…normally?
- small glycoproteins released by macrophages, lymphocytes, and tissue cells infected with a virus
- diffuse to surrounding cells and bind receptors on the cells
- produces antiviral proteins
(this works in paracrine manner… normally!)
(interfere with spread of virus from one cell to another)
Why are interferons pegylated?
longer half life
Interferon alpha….
recombinant version of one or more proteins that are naturally produced by the body in response to a viral infection
antiviral, antiproliferative, immunomodulatory, and antifibrotic
MOA - not well defined
resistance is low because it is not well tolerated!
Most common interferon used?
Pegylated IFN alpha-2a (pegasys)
Given SQ once weekly for 48 weeks
Other interferons are used for cancer, MS, and granulomatous disease. Oral interferons are being developed…
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Adverse effects of Peg-interferon alpha-2a (pegasus)?
- flu like illness, fever, HA, myalgia, fatigue
- bone marrow suppression - leukpenia and thrombocytopenia
- hair loss
- change in mood
**Side effects worse than the Hep B disease itself
Follow renal function for Tenofovir… (Hep B) - If renal dysfunction, do not use!
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Entecavir and Tenofovir can almost cure patients! Reduces viral load by 67-90/80-95
Have little viral resistance
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Increased serum creatinine in what drug?
Tenofovir! - why watch renal?
Entecavir/Adefovir/Telbivudine.Tenofovir/Lamivudine class effects?
lactic acidosis
hepatic steatosis
rebound hepatitis
HCV agents…
Immunomodulator?
Inhibit RNA poly?
Direct acting antiviral (DAA) agents? (3) - when using this target two areas to avoid resistance - medical miracle
peg-interferon
Ribavirin (rebetol,copegus)
NS 3/4 A protease inhibitor
NS5B polymerase inhibitior
NS5a replication complex inhibitor
NS 3/4 A protease inhibitors for HCV
simeprevir
paritaprevir
telaprevir
boceprevir
NS 3/4 A protease inhibitors for HCV
they inhibit cleavage of non-functional polypeptides into functional proteins
simeprevir
paritaprevir
telaprevir
boceprevir
have a lot of p’s!
NS5B polymerase inhibitors for HCV?
binds to polymerase actie site (chain termination!)
sofosbuvir
dasabuvir
Have b’s!!!! NS5B!!!!
NS5A replication complex inhibitor for HCV?
prevents creation of new sites of RNA synthesis! (inhibits assembly)
well tolerated!!! (fatigue, GI, HA, anemia)
ledipasvir
daclatasvir
ombitasvir
velpatasvir
have a’s!!! NS5A
Oral Ribavirin (Rebetol, Copegus)
Chemistry?
Use?
MOA?
HCV tx
Oral guanosine analog
in combination with interferons and other drugs
MOA:
-phosphorylated intracellular by host enzymes
- inhibits viral RNA dependent RNA polymerases
- inhibits replication of DNA and RNA viruses
Oral Ribavirin (Copegus, Rebetol) Adverse effects? (2)
HCV tx
1) Hemolytic anemia
- decline in hemoglobin within 1-2 weeks of initiation
- hemoglobin decrease usually approx 3.0 g/dl
- contraindicated in patients with significant or unstable cardiac disease
2)teratogencity and embryotoxicity
Ribavarin Inhalation (virazole)
Used for what disease?
Used for RESPIRATORY SYNCYTIAL VIRUS (RSV) - seen primarily in children
inhalation with a small particle aerosol generator (1.3 microns)
Adverse effects of Ribavarin Inhalation (Virazole) used for respiratory syncytial virus seen in children?
for person?
healthcare workers?
precautions taken for eye?
Rash, wheezing, eye irritation
Healthcare workers:
- HA (51), conjunctivitis (32)
- Rhinitis, dizzines, nausea, lacrimation (10-20)
- MUTAGENIC, TERATOGENIC, EMBRYOGENIC - PREGNANT WOMEN SHOULD NOT RECEIVE OR GIVE CARE
-precautions - may absorb in contact lenses
NS-5B polymerase inhibitors have what adverse effects?
black box warning?
Well tolerated (fatigue, GI, HA, anemia) - same as NS-5A
Interaction with Amidarone (fatal arrhythmias)
NS3/4A
adverse effets?
black box warning?
SE: not well tolerated! - flu-like symptoms, serious liver injury
(also anemia, leukopenia, rash, pruritus, photosensitivity)
Black box:
hyperlipidemia, fat redistribution
CONTRAINDICATED IN MODERATE - SEVERE LVIER IMPAIRMENT. POTENT P450 3A4 INHIBITOR (many interactions)
Should screen all patients for HBV before starting DAA (direct-acting antivirals) for HCV! There is a risk of HBV reactivation
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