Term
| What are the two M2 channel blockers, and what are they used for? |
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Definition
Amantadine and rimantadine are anti-influenza A drugs.
Note: Amantadine also has some anti-Parkinson's effectivity |
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Term
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Definition
The class of drugs including M2 channel blockers amantadine and rimantadine, which combat influenza A. |
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Term
| What is the core structure of M2 channel blockers? |
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Definition
Symmetrel
Amantadine R-group = NH2 (pictured)
Rimantadine R-group = CHNH2CH3
[image]
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Term
| How do amantadine and rimantadine combat influenza A? |
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Definition
They are M2 channel inhibitors, preventing acidification of the virus. Virus cannot cross the plasma membrane (no conformational change in HA). Specifically, adamantanes bind to the M2 protein. |
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Term
| What are differences in amantadine and rimantadine metabolism? |
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Definition
Amantadine is not metabolized and t1/2 = 15hr.
Rimantadine is extensively metabolized and t1/2 = 30hr. |
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Term
| How are M2 channel blockers absorbed, distributed, and excreted? |
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Definition
Well-absorbed orally; >90% bioavailability.
Distributed widely - including CSF.
Excreted renally.
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Term
| What are mechanisms of resistance against amantadine and rimantadine? |
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Definition
Mutations in the M2 proteins prevent binding of adamantanes.
Note: 92% of typical flue viruses are resistant.
Note: Resistant viruses are still fully pathogenic, unlike bacteria which sacrifice fitness for resistance. |
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Term
| What are some adverse effects of M2 channel blockers? |
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Definition
CNS effects
-- insomnia, dizzyness
GI irritation |
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Term
| How do neuraminidase inhibitors work? |
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Definition
They are analogs of sialic acid that bind to the conserved sialic acid binding region of neuraminidase. |
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Term
| What are advantages of neuraminidase inhibitors over M2 channel blockers? |
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Definition
1. NA inhibitors are active against influenza A and B
2. There is widespread resistance to M2 channel blockers |
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Term
The most important mechanism of resistance to neuraminidase inhibitors is a neuraminidase mutation. What is an important structural difference between oseltamivir and zanamivir that is relevant to resistance? |
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Definition
A single amino acid mutation can confer resistance to oseltamivir, but not zanamivir.
Oseltamivir has a hydrophobic side chain such that upon binding, a glutamate residue on NA has to shift to accommodate the hydrophobicity. This is not the case with zanamivir.
If there is a mutation and the glutamate can no longer shift, the strain will become oseltamivir-resistant.
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Term
| How is zanamivir administered, distributed, metabolized, and excreted? |
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Definition
Inhalant.
78% distribution to oropharynx, 13% to lungs.
Excreted renally, unchanged.
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Term
| How is oseltamivir administered, distributed, metabolized, and excreted? |
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Definition
Orally administered.
Systemically distributed.
Cleaved to active carboxylate form by serum esterases.
Excreted renally as active form. |
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Term
| How does metabolism of oseltamivir and zanamivir differ? |
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Definition
Oseltamivir must be converted to its active form, oseltamivir carboxylate.
Note: Oseltamivir has a longer half-life (6-10hrs vs. 2-5 hrs for zanamivir) |
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Term
| What are adverse effects of neuraminidase inhibitors? |
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Definition
Related to route of administation.
Oseltamivir: GI disturbances.
Zanamivir: Bronchospasm or decline in lung function.
Note: Some compounds complexed with zanamivir to make it inhablable irritate the respiratory tract. This is one reason oseltamivir is more popular. |
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Term
| How are neuraminidase inhibitors employed clinically? |
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Definition
1. To shorten duration of influenza A or B.
2. Prevention of infection
-- reduces infection by 30-50%
-- reduces infection with fever by >80%
Note: Must be given within 2 days of onset. |
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