Antivirals Flashcards
The basic process of viral infection and virus replication occurs in 6 main steps:
Absorption Penetration Viral genome replication Assembly Maturation Release
To be effective, antiviral agents must either?
2
Block viral entry into or exit from the cell
Be active inside the host cell
Name the kind of drugs most antivirals are?
1 and 2
Purine or Pyrimidine analogs.
They are prodrugs –must be phosphorylated by viral or cellular enzyme
One step do anti-viral drugs work on of the viral attack?
Anti-viral agents inhibits active replication so the viral growth resumes after drug removal (when you stop them the virus will not be coontrolled anymore)
–nucleic acid synthesis specifically
What is needed for antiviral drugs to work?
3
- Current anti-viral agents do not eliminate non-replicating or latent virus (if they go into a latent stage)
- Effective host immune response remains essential for the recovery from the viral infection
- Clinical efficacy depends on achieving inhibitory concentration at the site of infection within the infected cells
- Must be actively replicating
- Host must have effective immune response
- Clinical efficacy = achieving inhibitory concentration
What are the Anti-HSV/VZV ((Herpes/Varicella/Zoster) agents?
3
Acyclovir (Zovirax)
Famciclovir (Famvir)
Valacyclovir (Valtrex)
MOA of Anti-HSV/VZV (Herpes/Varicella/Zoster) agents
2
The analog inhibits viral DNA-polymerase
Only actively replicating viruses are inhibited
What is Acyclovir (Zovirax®) used to treat?
mostly 2 and sometimes two others
Herpes simplex 1 (mouth) and 2 (genital)
varicella-zoster virus, possibly the Epstein-Barr Virus
Acyclovir (Zovirax®) is treatment of choice for?
4
- HSV Genital infections,
- Herpes labialis/orolabial (cold sores),
- HSV encephalitis,
- HSV infections in immunocompromised and pregnant patient
What dosage forms does it come in?
3(one main one)
Topical, ORAL, and intravenous formulations
Pharmacokinetics of Acyclovir : Oral bioavailability: Distribution in: Renal excretion: Half life: Administration:
~ 20-30% all body tissues including CNS > 80% 2-5 hours Topical, Oral , IV
Acyclovir safety/monitoring:
Renal Dosing?
Hepatic dosing?
- IV route CrCl 25-50 give q 12hrs: CrCl
Acyclovir Mechanism of Action?
2
Inhibition of viral synthesis of DNA
- Uptake by infected cell
- Competes with deoxyguanosine triphosphate for viral DNA polymerases (Chain termination)
Acyclovir is thus selectively activated in cells that are?
infected with herpes virus.
Uninfected cells do not phosphorylate acyclovir.
Acyclovir Adverse effects ?
3 big ones
5 others
Reversible renal toxicity Neurological symptoms TTP/HUS GI symptoms Headache Rash Photosensitivity Anemia
WHat kind of patient does Acyclovir Resistance most often occur in?
Three basic resistance mechanism exist?
What drugs are cross resistant to acyclovir?2
Mostly occurs in immunocompromised host
MIC > 2-3 mcg/mL
Reduced or absent thymidine kinase
Altered TK substrate specificity
Alterations in DNA polymerase
Cross resistance to famciclovir and valacyclovir
Acyclovir (Zovirax®) Why treat with it? Primary genital herpes:3 Recurrent genital herpes:1 Long term treatment:3 Varicella Zoster:2
- Shortens duration of symptoms, time of viral shedding and time to resolution of lesions by approximately 5 days.
- Shortens time course by 1-2 days
- Decreases frequency of both symptomatic recurrences and asymptomatic viral shedding, thus decreasing sexual transmissions
- Decreases total number of lesions and duration of varicella (if begun within 24 hours after the onset of rash)
What do we treat with Famciclovir (Famvir®)?
3
HSV 1 and 2, VZV,
to a lesser extent, EBV, in vitro activity to HBV
Pharmacokinetics of Famciclovir: Oral bioavailability: Metabolism: Renal excretion: Half life: Administration:
~ 77% First-pass metabolism in the intestine and liver results in conversion to penciclovir. > 80% 2-3 hours Oral
Famciclovir safety/monitoring:
Pregnancy Category?
Lactation?
Renal dosing?
Hepatic dosing?
B Safety Unknown (inadequate literature to assess risk: caution advised)
Adjust dose for CrCl
Famciclovir MOA?
how does it compare to acyclovir?
famciclovir is converted to penciclovir triphosphate and compared to acyclovir triphosphate,
penciclovir triphosphate has a lower affinity for viral DNA polymerase but a longer intracellular half-life.
Famciclovir Adverse effects
3 serious
4 general symptoms
Neutropenia
Thrombocytopenia
Neurological symptoms
GI symptoms
Headache
Fatigue
Abnormal LFT’s
Famciclovir Resistance mechanism?
Cross resistance with what drug and in what strains?
Mutations in viral TK or DNA polymerase
Cross resistance with acyclovir in TK negative strains
Valacyclovir (Valtrex®)
is what?
Dosage forms?
Valacyclovir is a prodrug of Acyclovir
Rapidly and almost completely converted to acyclovir
Orally only
WHat makes Valacyclovir different then from Acyclovir?
Why is it not used as often then?
Advantage: better oral bioavailability (55%)
More convenient dosing
Expensive
Valacyclovir (Valtrex®) Pharmacokinetics of Valacyclovir: Oral bioavailability? Metabolism? Renal excretion? Half life? Administration?
- ~ 55%
- undergoes rapid and extensive first-pass intestinal and hepatic hydrolysis to yield acyclovir
Food does not affect absorption - > 50%
- 2-3 hours
- Oral
Valacyclovir safety/monitoring
Pregnancy Category?
Lactation?
Renal Dosing?
Hepatic Dosing?
B
Safe
Adjust dose for CrCl
Valacyclovir (Valtrex®) adverse affects?
3 major
5
Reversible renal toxicity
Neurological symptoms
TTP/HUS
GI symptoms Headache Rash Photosensitivity Elevated LFT’s
What disease is acyclovair only used for and not Valacyclovir or Famciclovir? A. Primary Genital B. Recurrent Genital C. Encephalitis D. Chronic Suppressive
C
What do we use to treat varicella?
Acyclovir
What can we use to treat herpes zoster/
Valacyclovir
Famciclovir
Acyclovir
What can we use to treat Varicella or Zoster in Immunocompromised?
Acyclovir
What other Topicals for HSV do we treat orolabial herpes with?
2
- Penciclovir (Denavir® 1% cream)
-Topical guanine analog similar to acyclovir - Docosanol (Abreva® OTC)
Active against a broad range of lipid-envelop viruses
MOA: interferes with viral fusion to host cell
What do we use to treat HSV Keratoconjuctivitis?
Trifluridine (Viroptic® 1% ophthalmic)
1 drop q2h (max 9 drops/day)
Active against acyclovir resistant strains
Also active against vaccinia virus and smallpox
What is our antiCMV agent?
Dosage forms?3
Ganciclovir
Oral, intravenous, and intraocular
Ganciclovir is the drug of choice for?
2
- CMV retinitis in immunocompromised patient
2. Prevention of CMV disease in transplant patients
Ganciclovir (Cytovene®) Pharmacokinetics of Ganciclovir: Oral Bioavailability Excretion? Renal excretion? Half life?
- 50%
- Is excreted unmodified in the urine
- > 90%
- 2-4 hours
Ganciclovir Safety/Monitoring
Pregnancy Category?
Lactation?
Renal Dosing?
Hepatic Dosing?
C (animal studies show adverse fetal effects)
Unsafe
Adjust dose for CrCl
Ganciclovir MOA?
Competes with deoxyguanosine triphosphate similar to acyclovir
However in CMV, viral-encoded phosphotransferase converts to ganciclovir triphosphate
Unlike acyclovir, ganciclovir contains a 3’-hydroxyl group, allowing for DNA to continue
Ganciclovir
Adverse affects?
LOTS OF THEM(only used for CMV) reversible pancytopenia Fever Rash Phlebitis (IV) Confusion Renal dysfunction Psychiatric disturbances Seizures
Influenza Agents?
4
Oseltamivir
Zanamivir
Amantadine
Rimantadine
Neuraminidase inhibitors are which influenza agents?
Oseltamivir / Zanamavir
What makes influenza virus suceptible to antivirals?
Influenza contains an enzyme neuraminidase which is essential for the replication of the virus.
How do Neuraminidase inhibitors, Oseltamivir / Zanamavir, work against influenza?
Neuraminidase inhibitors prevent the release of new virions and their spread from cell to cell.
What types of influenza do Oseltamivir / Zanamavir work against?
Will it interact with the vaccine?
What can it be used for?
These are effective against both types of influenza A and B.
Do not interfere with immune response to influenza A vaccine.
Can be used for both prophylaxis and acute treatment.
What is the brand name for Oseltamivir?
Tamiflu
What is the spectrum of activity for Tamiflu?
3
Infuenza A and B in both children and adults,
avian influenza,
H5N1 disease
Tamiflu adverse effects?
NV, headache
Zanamivir (Relenza®) spectrum of activity?
2
MOA?
Dosage form?
Adverse effects?
Uncomplicated influenza A and B, some strains of avian influenza
Neuraminidase inhibitor
Given via inhalation
Adverse effects: nasal and throat discomfort, bronchospasm
Amantadine (Symmetrel®) Rimantadine (Flumadine®) MOA? Spectrum of activity? Adverse effects? 5
What do we really need to know about these??
NOT CURRENTLY RECCOMENDED IN THE US
MOA:
Prevents the release of viral nucleic acid into host cell
SPectrum of Activity: Influenza A, however resistance is frequent
Adverse effects: Seizures, anticholinergic, CNS, edema, blurry vision
Used for extrapyramidal sx and parkinsonism
Whats the difference b/w Amantadine (Symmetrel®) and
Rimantadine (Flumadine®)?
Amantadine cross extensively BBB whereas Rimantadine does not cross extensively.
MOA for Ribavirin?
Antiviral spectrum for ribavirin?
5
Purine nucleoside analog
Mechanism of action not fully understood
-Inhibition of RNA polymerase
Antiviral spectrum:
DNA and RNA viruses are susceptible,
including
influenza, HCV, parainfluenza viruses, RSV, Lassa virus
Ribavirin is the drug of choice for?
3
Ribavirin is an alternative drug for?
Dosage forms?
RSV bronchiolitis and pneumonia in hospitalized children (given by aerosol)
Lassa Fever
Influenza, parainfluenza, measles virus infection in immunocompromised patients
Used in combination with interferons for HCV
Available orally and via inhalation
Intravenous and available through the CDC
Ribavirin pregnancy cat?
Lactation?
Pregnancy Category: X (teratogenic/embryocidal effects in all animal species)
Lactation: Probably Unsafe
Adverse affects for ribavirin?
BBW-Hemolytic anemia!!
Hepititis is a general term that refers to swelling or inflammation of the liver in response to?
4
Drugs
Toxins
Excessive alcohol
Infections from bacteria or viruses
How do we treat Hep A?
Clears on its own with rest and adequate hydration
How do we treat Hep B?
3
- May clear on its own
2. Chronic cases may be treated with: Interferon Nucleoside Reverse Transcriptase Inhibitors (NRTI) such as: Emtricitabine Tenofovir Entacavir Lamivudine
- Some patients may need liver transplant
Standard treatment for Hepatitis C has long been what?
BUt what is the downside?
2
a synthetic, injectable version of interferon plus the antiviral drug ribavarin
Side effects are intolerable
Virus can become resistant to the meds
Hepatic Viral infections?
4
- Interferons
- Lamivudine – cytosine analog – HBV
- Entecavir – guanosine analog – HBV Lamivudine resistance strains
- Ribavirin – Hepatitis C (with interferons)
Researchers learned that to stop hepatitis C any effective drug had to do what?
2
What was the new medication that met this formula?
3
- incorporate itself in the virus’s genetic code so as to halt replication
- To avoid potentially debilitating side effects the medication needs to enter the liver quickly and directly, avoiding as many other organs as possible
sofosbuvir (Sovaldi)
Sofosbuvir paired with ledipasvir cured at least 94% of patients with genotype 1 disease
This combination mixed in a single daily pill (Harvoni) heralded a new curative treatment for patients with hepatitis C….consistent cure rates >90%
Flu A virus causes what disease?
What is our drug of choice?
What is our alternative drug?
- Influenza
- Oseltamivir and Zanamivir
- Amantidine and Rimantadine
RSV caues what diseases?
Drug of choice?
- Pneumonia and Bronchitis
2. Ribavirin (aerosol)
HSV can cause genitial herpes. What is the drug of choice and the alternative drugs?
Acyclovir
Valacyclovir and Famciclovir
HSV can cause Keratitis conjunctivitis. What is the drug of choice and the alternative drugs?
Trifluridine
Idoxuridine and Acyclovir
HSV can cause encephalitis. What is the drug of choice and the alternative drugs?
ONLY IV acyclovir
HSV can cause Neonatal HSV infection. What is the drug of choice and the alternative drugs?
ONLY IV acyclovir
WHat is the drug of choice and alternative drugs for HSV in an immunocomprimised host?
Acyclovir
Valacyclovir and Famciclovir
How do we treat VZV is a normal host?
How do we treat VZV in an immunocomprimised host, during pregnancy or shingles?
Alternative drugs?
No therapy
Acyclovir
Valacyclovir and Famciclovir
What disease does CMV cause?
What is our drug of choice?
What is the alternative drug?
Retinitis
Ganciclovir
IV Foscarnet
HBV and HCV cause what disease?
What drugs do we have to treat them?
7
Hep B and Hep C
Ribavirin Interferons Lamivudine Entecavir Sofosbuvir (Sovaldi) Simeprivir (Olysio) Ledipasvir-sofosbuvir (Harvoni)