Antivirals Flashcards
What is a virus made of?
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.
Where do viruses replicate in the host?
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.
Process of viral infection and replication?
- Absorption: binds to host cell
- Penetration: virus injects genome into host cell
- Viral genome replication: viral genome replicates using the host’s cellular machinery
- Assembly: viral components and enzymes are produced and begin to assemble.
- Maturation: viral components assemble and viruses fully develop.
- Release: newly produced viruses are expelled from the host cell.
What must antiviral drugs do to be effective?
must either:
- block viral entry into or exit from the cell
- be active inside the host cell
What is the MOA of most anti-viral drugs?
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.
What is an important part of fighting viral infections?
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
What are the anti-HSV/VZV agents?
Herpes/Varicella/Zoster
acyclovir (zovirax)
famciclovir (famvir)
valacyclovir (valtrex)
MOA of anti-HSV/VZV agents?
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
Acyclovir (zovirax)
guanosine analog
-topical, oral, and IV
Spectrum of Acyclovir?
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
Pharmokinetics of acyclovir?
oral bioavailability: 20-30% distribution to all tissues including CNS -renal excretion: >80% -half life: 2-5 hours -topical, oral and IV
Acyclovir safety
Pregnancy: B
lactation: safe
renal dosing: adjust if CrCl
Acyclovir MOA
inhibition of viral synthesis of DNA
- uptake by infected cell
- competes with deoxyguanosine triphosphate for viral DNA polymerases:
- chain termination -> inactivated viral DNA polymerase
What cells is acyclovir selectively activated in?
in cells infected with herpes virus
-uninfected cells don’t phosphorylate acyclovir.
When would you take acyclovir for genital/mucocutaneous HSV?
Take it for first episode: frequent dosing (trying to prevent it from reocurring)
Recurrence and suppression if pt has frequent recurrence.
Adverse effects of Acyclovir
- reversible renal toxicity
- Neuro symptoms: encephalopathic changes - somnolence, hallucinations, confusion and coma.
- TTP/HUS in immunocompromised
- GI sxs
- HA
- rash
- photosensitivity
- anemia
Resistance to acyclovir and MOA of resistance
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
Why tx with acyclovir?
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).
Famciclovir (Famvir)
cyclic guanine analong:
- converted to penciclovir in the liver and intestines
- penciclovir is used only topically whereas famciclovir can be administered orally.
- PO only
Spectrum of famciclovir
HSV 1 & 2, VZV, maybe in EBV
- in vitro to HBV
Pharmacokinetics of famciclovir
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
Famciclovir safety
Pregnancy: B
lactation: unknown, caution advised
Renal dosing: adjust dose for CrCl
MOA of famciclovir
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
Famciclovir uses
zoster (shingles), and genital and orolabial HSV (for 1st occurence, recurrence and suppression)
Famciclovir adverse effects
- neutropenia
- thrombocytopenia
- neurological sxs: encephalopathic changes -> somnolence, hallucinations and delirium
- GI sxs
- HA, fatigue
- abnormal LFT’s
Resistance to Famciclovir
- 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)
Valacyclovir (Valtrex)
Prodrug of acyclovir:
rapidly and almost completely converted to a acyclovir, same MOA, same spectrum, same mechanism of resistance
Pros and cons of Valacyclovir
Advantage: more convenient dosing, better oral bioavailability (55%)
cons: more pricey than acyclovir
Pharmokinetics of Valacyclovir
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
Valacyclovir safety
Pregnancy: B
lactation: safe
renal dosing: adjust for CrCl
dosing of Valacyclovir
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
Adverse effects of Valacyclovir
- reversible renal toxicity
- neuro sxs: encephalopathic changes -> somnolence, hallucinations, confusion, coma
- TTP/HUS: immunocompromised
- GI, HA, rash, photosensitivity, elevated LFTs
What is the cheapest of the 3 HSV drugs and most preferred?
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
What is used to treat HSV keratoconjunctivitis?
trifluridine (viroptic -> ophthalmic application)
- this is active against acyclovir resistant strains
Anti-CMV agents
Ganciclovir
Spectrum of Ganciclovir
oral, IV, intraocular
CMV, EBV, HSV/VZV, human herpesvirus 6
(for CMV and EBV: 10x more potent than acyclovir)
Ganciclovir is DOC for?
CMV retinitis in immunocompromised pt, and prevention of CMV disease in transplant patients
pharmacokinetic of Ganciclovir
oral bioavailability: 50% is excreted unmodified in urine renal excretion: >90% half life: 2-4 hours admin: oral, IV, intraocular
Ganciclovir safety
pregnancy: C (adverse fetal effects in animal studies)
lactation: unsafe
renal dosing: adjust dose for CrCl
MOA of Ganciclovir
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
Adverse effects of Ganciclovir
reversible pancytopenia, fever, rash, phlebitis (IV), confusion, renal dysfunction, psychiatric disturbances, seizures
Influenza agents
- oseltamivir
- zanamivir
- amantadine (used in parkinsons now)
- Rimantadine
MOA of influenza and neuraminidase inhibitors -> oseltamivir/zanamavir
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.
Neuraminidase inhibitors effectiveness
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
Oseltamivir (Tamiflu) MOA
oral neuraminidase inhibitor: cleaves terminal sialic acid residues on glycoconjugates and destroys receptors
-newly formed visions adhere to cell surface and limit spread.
Spectrum of Oseltamivir (Tamiflu)
Influenza A and B in kids and adults, avian flu, H5N1 disease
Adverse effects of Tamiflu
N/V, HA
When do you want to administer Oseltamivir (Tamiflu)
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
Zanamivir (Relenza)
Neuraminidase inhibitor, given via inhalation
spectrum: uncomplicated influenza A and B and some strains of Avian influenza
Adverse effects of Zanamivir (Relenza)
nasal and throat discomfort
-bronchospasm
Amantadine (Symmetrel) and Rimantadine (Flumadine)
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
Is Amantadine or Rimantadine recommended in US?
NO not currently recommended for influenza because too much resistance
- it is being used for extrapyramidal sx and parkinsonism though
Pharmacokinetics of Amantadine
oral bioavailability: 50-90%
- crosses BBB extensively, and Rimantadine doesn’t.
- PO
Ribavarin
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
Therapeutic uses of Ribavarin
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
Safety of Ribavarin
Available: PO and inhalation
IV available through CDC
Preg: X (teratongenic)
lactation: probably unsafe
Adverse effects of Ribavirin
BBW-hemolytic anemia resp. deterioration depression suicidal ideation bacterial infections psych. effects anxiety, fatigue, dizziness
Hepatitis?
swelling or inflammation of the liver in response to:
drugs, toxins, excessive alcohol, infections from bacteria or viruses
Hepatitis A
typically spreads when infected individuals improperly handle food or water
Hepatitis B
often transmitted by sexual intercourse, sharing of needles or contact with contaminated blood (vaccine available)
Hepatitis C
more likely to cause permanent liver damage, genes mutate very fast, new genotypes make developing an effective vaccine impossible so far
Hepatitis A tx
clears on its own with rest and adequate hydration
Hepatitis B tx
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)
Hepatitis C epidemiology
chronic infection that afflicts about 170 million people worldwide
-annual mortality: 350,000
15,000 in the US
Hepatitis C standard treatment
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
Anti-viral drugs for hepatic viral infections
- interferons
- lamivudine - cytosine analog - HBV
- Entecavir - guanosine analog- HBV (lamivudine resistance strains)
- Ribavarin - Hep C (w/ interferons)
New drugs for Hep C
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
New formulation for Hepatitis
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
Sofosbuvir paired with ledispasvir
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.
What is downfall of new drugs for Hep C
> $100,000 for 12 week course of treatment.
Many people with Hep C poor and/or incarcerated
Cost of sofasbuvir?
$594 dose, treatment would run nearly $12 billion dollars
- much cheaper in Canada and Germany
- What the heck U.S.?
