Antiviral

Question 1

Describe viral replication

Answer 1

• Viruses bind to a cell surface receptor (in the case of influenza neuraminic or sialic acid) and gain entry to the cell by endocytosis
• ATP driven entry of protons into the endosome allows the viral membrane to fuse with the endosomal membrane & the virus uncoats
• Protons enter the virus itself via the M2 ion channel – the resulting low pH results in breakdown of the viral coat allowing viral RNA to move into the host cell cytoplasm
• Viral RNA is transcribed, new viruses are produced

Question 2

What are the main classes of influenza?

Answer 2

• A is the most serious – it has multiple host species & exhibits antigenic shift and drift
• B has lower mortality, no animal reservoir
• C is like the common cold

Question 3

What are M2 ion channel blockers? Examples?

Answer 3

M2 ion channel blockers (Amantadine and Rimantadine) are used to treat influenza A. Their use might be limited by mutations in H5N1

They prevent the entry of protons into the virus and breakdown of the viral nucleocapsid, which prevents release of RNA into the host cell cytoplasm.

Question 4

What are ADRs of M2 ion channel blockers? Excretion?

Answer 4

• Dizziness
• GI disturbance
• Hypotension
• Confusion
• Insomnia

Renal excretion

Question 5

What are neuraminidase inhibitors? MOA? Used to treat?

Answer 5

oseltamivir and zanamivir

They work by blocking release of virions (baby viruses) from the host cell in which they’ve been replicating (neuramidase is a transmembrane protein which allows them to escape by stopping them from getting stuck to glycoprotein residues on the cell surface)

They can be used to treat type A and type B influenza.

Zanamivir is given as an aerosol, low bioavailability, only used for treatment. Oseltamivir (Tamiflu) is a prodrug, which is well absorbed with 80% bioavailability, which means it can be given orally and used for both treatment and prophylaxis.

Question 6

ADRs of neuraminidase inhibitors

Answer 6

• GI disturbance
• Headache
• Nosebleed
• Respiratory depression
• Bronchospasm (both rare)

Question 7

How should neuraminidase inhibitors be dosed?

Answer 7

• The earlier treatment is started the better the outcome (up to 48 hours after onset after which there is little benefit)
• There seems to be a reduction in mortality, even when dosing was delayed until 64 hours after the onset of symptoms
• It is also effective in reducing the incidence of flu in the frail and elderly