Antivirals Flashcards
What are onsiderations for drug development
- Expense vs need vs resistance
- burden of disease and clinical need
- understanding virology: whar to target
- Drug development: screening compounds or drug design
- Clinical trials and impact: adverse effects and monitoring of resistance
What are 3 types of influenza virus
Three types Influenza A –Multiple host species e.g. birds
–Antigenic drift and shift: slowly changes coat from year to year. Sometimes a huge change can lead to a new virus which can cause a pandemic
Influenza B –No animal reservoir –Lower mortality
- outbreak every 3 or 4 years
Influenza C –Common cold like
What are influenza related complications
Most complications occur in otherwise healthy persons since it affects everyone everywhere every year
– Bronchitis, pneumonia
– Sinusitis
– Exacerbation of underlying disease e.g. DM, kidney disease, HF
What are the treatments for influenza related complications
|60%-80% of patients with complications receive antibiotics
Antibiotics prescribed for |30%-45% of patients presenting with influenza or ILI
Describe teh structure of influenza A virus
Flu - 7 rna segments . Protein envelope, capsid to protect. Around surfact another layer made out of fats and lipids to attach to human host cells. Proteins stic out - virulence factors - this is hemagglutinini in influenza a
Describe the life cycle of influenza virus
Glycoproteins receptor (hemaglutinign) on upper resp cells recognises Sialic acid on virus
- Virus sticks there.. once attached, then invades the host cell to replicate.
- Goes into cell in vesicle and breaks up Ito viral nucleic acid segments
- produces new parts of virus thru transcription and translation - - These are then excreted out of cell - goes on to produce ongoing infection.
If you block haemaglutinin , virus wont stick to cell
- Influenze vaccine contains hemagluttinin - antibody. Can target any point of virus life cycle . Eg at point when it leaves cell - neuraminidase inhibitor
What is the role of hte M2 channel in virus replication?
The M2 ion channel allows H+ into it. If the centre of the cell is acidic, viral capsid of a virus is removed, leading to the release of the viral genomic nucleic acid.
IF this channel can be blocked, then virus replication can be blocked.
What are Amantadanes?
Amantadine and rimantadine are active against influenza A. They are tricyclic primary animes which block the M2 channel to inhibit viral uncoating
Also has anti-parkinsonism activity
What are the limitations of M2 inhibitors?
- Work on influenza A only
- Have CNS and renal side effects
- A single point mutation in M2 gene S31N can stop the drug from working. 31N amino acid change alters the binding site: drug no longer binds and blocks channel function
How can m2 inhibitors be designed
The structure of a possible target, or binding of an existing compound can be used to evaluate and design new drugs
– Gene sequencing of protein
– X-ray crystallography
– Nuclear Magnetic Resonance Sits inpcket - ring binds
What is neuraminidase
Novel antiviral target: neuraminidase
Neuraminidase essential for virus replication Surface of influenza highly variable but NA 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
What is the role of neuraminidase in influenza?
NA cleaves haemagglutinin which releases the virus from the celll surface. If NA is inhibited tehn the virus is stuck
What is the role of a neuraminidase inhibitor
Can no longer releasedvirus from cell. Neuraminidase inhibitor - circus stuck there - not leaving the membrane - cant spread th infection . Stop them being releas
Gove some examples of neuraminidase inhibirots
Zanamavir
Oseltamivir
What are the actions of zanamavir and oseltamivir
Zanamavir:Prodrug that when activated, inhibits viral neuraminidase (glycoprotein enzymes on viral surface). By doing so, entry into uninfected cells and budding from infected cells is prevented. Hemagglutinin and sialic acid bond can’t be broken.
Oseltamivir: same as above but not a prodrug
What are the guidelemines for use of neuraminidase inhibirtos?
There was resisitance.
Cochrane review: concluded no value
PHE guidance UK Primary care: only when CMO letter confirms presence of circulating seasonal influenza – Healthy people: no Rx unless ptfelt to be at risk – At risk (inc preg): oseltamivir asap (no need for confirmation) – Severely immunosuppressed: oseltamivir
Primary care: only when CMO letter confirms presence of circulating seasonal influenza – Healthy people: no Rx unless ptfelt to be at risk – At risk (inc preg): oseltamivir asap (no need for confirmation) – Severely immunosuppressed: oseltamivir or inhaled zanamivir (espif H1N1) Secondary care: use oseltamivir in suspected or confirmed flu – If H1N1 (higher risk of oseltamivir resistance) circulating, consider zanamivirespecially in severely immunosuppressed: zanamivirinhaled ( nebuliser or IV if can’t take inhaler-but ?not licenced or available)
or inhaled zanamivir (espif H1N1) Secondary care: use oseltamivir in suspected or confirmed flu – If H1N1 (higher risk of oseltamivir resistance) circulating, consider zanamivirespecially in severely immunosuppressed: zanamivirinhaled ( nebuliser or IV if can’t take inhaler-but ?not licenced or available)
Every year 8 week period where flu active - surveillance program that detects starter flu program - when first isolate - then big peaks in influenza activity. When flue circulating in uk - if people pressing with influenza like symptoms, use neutominidase - just i they are at risk
What is human herpes virus?
Large family c150 species DNA viruses Widespread across animal kingdom High rates of infection in human population Generally mild primary infection Establish latent infection Secondary infection/reactivation
Describe the sturucture of herpes virus
ss
What is the treatment for HSV?
Specific antiviral therapy Supportive care
– Bacterial complications
Nucleoside analogues inhibiting herpes viral DNA polymerase
– Aciclovir and valaciclovir (HSV, VZV)
– Cidofovir (CMV, resistant HSV)
– Ganciclovir (CMV, EBV
Describe hsv-1 replicatuon
-
What is acyclovir used in
HSV-1 + HSV-2 infections
Chickenpox - topical use to reduce severity of skin lesions
Shingles - oral antivirals to reduce pain and accelerate healing of blisters
What is the moa of acyclovir?
Prodrug that is converted into a guanosine analogue (acyclovir triphosphate). Once incorporated, it inhibits viral DNA polymerase (acting as chain terminator).
What are valacyclovir and valgancyclovir
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