Antivirals Flashcards
How do antiviral drugs get developed?
Look at expenses vs need vs resistance
Burden of disease and clinical need
Understanding virology: what too target
Drug development: Screening compounds or drug design
Clinical trials and impact: Adverse effects and monitoring of resistance.
What are the three types of influenza?
Influenza A - multiple host specifies, antigenic drift and shift
Influenza B - No animal reservoir, Lower mortality
Influenza C - Like the common cold
What are the influenza related complications?
Most complications occur in otherwise healthy persons
- Bronchitis
- Sinusitis
- Exacerbations of underlying disease
60-80% received antibiotics if they had complications
Antibiotics prescribed for 30-45% of patients presenting with influenza or ILI
What is the structure of influenza A virus?
RNA inside
Surrounded by lipid envelope and a protein envelope
Proteins (Haemagglutinin) on outside which sticks to resp cells
Neuraminidase also on outside
Describe the influenza virus life cycle
Bind to Salic acid receptor on resp cells (Usally upper) Engulfed into cell (endosome) embrace fusion RNA transfer into nucleus Protein synthesis Viral budding and protolytic cleavage
What are amatadines and rimantadine?
They are tricyclics primacy amine which block M2 channel to inhibit viral incoating.
Anti-Parkinsonism activity
Available since 1960’s
Active against influenza A
What are the problems with M2 inhibitors?
Infuenza A only.
CNS and renal side effects
Single point mutation in M2 gene: S31N.
High level, rapid emergence resistance
Transmissible viruses
How do yo design new drugs?
Gene sequencing of protein
X-Ray crystallography
Nuclear Magnetic Resonance
What is neuraminidase?
Neuraminidase is essential for virus replication
Surface of influenza highly variable but neuraminidase active site is conserved across subtypes. -Human and non-human influenza-A Influenza B M2 resistant viruses Avian strains including H5N1 Reconstructed 1918 pandemic H1N1
How does neuraminidase work?
NA cleaves HA binding
Binding of virus with NA inhibition
What is Zanamavir?
Low bioavailability Acid degrades Dry powder aerosol Remains detectable in sputum up to 24 hours post dosing Renal excreted
What is oseltamivir?
Tablet
Pro-drug
80% bio-availability
Active site changes shape
Oseltamivir studies. Does it work?
Earlier treatment - 36% reduction in symptoms.
Yes, you have a 2/3 reduction in likelihood of death.
- 5 times less likely to die if in nursing home.
- 1 times less likely to die if over 65
Does oseltamivir work as seasonable prophylaxis?
Yes, prevent flu!
What is the safety profile of oseltamivir?
Vomiting
Abdominal pain
Epistaxis
No drug related serious events
Low rate of discontinuation in studies
How is oseltamivir used in H5N1 (bird flu) infection?
Bird flu = 70% mortality
But, rarely moves from birds to people so many people infected (luckily).
People treated with oseltamivir are more likely to live.
Olsetamivor resistance
Does get resistance but little resistance.
But, a close to 1/3 of virus resistant (Potential to be resistant…)
H1N1 Pandemic
Swine flu
Pandemic
Replaced 2008 human H1N1 circulating viruses which had developed oseltamivir resistance
The ‘swine’ derived H1N1 viruses remain oseltamivir sensitive.
What are the guideline for use of oselsetamivir
NICE
Cochrane review …
What are human herpes viruses?
Large family 150 species DNA viruses Widespread across animal kingdom High rates of infection Generally mild primary infection Established latent infection Secondary infection / reactivation
How do you classify herpes viruses?
Biological properties
Appearance
Genetic analysis
What some common herpes viruses?
Herpes simplex 1
Herpes simplex 2
Viracella-Zoster
Cytomegalovirus
Epstein-Barr Virus
Kaposi Sarcoma Virus
Describe the structure of Herpes Viruses
Nucleocapsid
Regiment (space)
Lipid bilayer with glycoproteins spikes (peplomers)
Where about do soem for he herpes viruses remain latent?
HSV1/2: Neurones (trigeminal / sacral)
VZV: Donal root ganglia
EBV: B cells
Describe the oncogenic potential of some of the Herpes Viruses
HSV1 and 2 CMV carcinogenic in animals
HHV6 and Kaposi’s Sarcoma
EBV is linked to tumours in humans:
B cell lymphoma (aids)
Burketts lymphoma
Nasopharyngeal carcinoma
How can you treat herpes viruses?
Specific antiviral therapy
Supportive care - Bacterial complications
Nucleoside analogues inhibiting herpes viral DNA polymerase:
- Acyclovir and valacyclovir (HSVm VZV)
- Cidofovir (CMV, resistant HSV)
- Gancyclovir (CMV, EBV)
