Antiviral agents against influenza are most commonly used amongst the respiratory viruses. Currently two groups of drugs are available for influenza virus. These are M2 blockers and neuraminidase inhibitors.

M2 blockers: Amantadine and rimantadine are the two chemically related drugs of adamantine group. Rimantadine is the a-methyl derivative of amantadine.

Mechanism of action: Both act by inhibiting the M2 ion channel. M2 protein allows the entry of proton inside the virion during the uncoating process. This induces an acidic environment in the intracellular compartment, which helps in fusion of virus envelop with the plasma membrane of the host cell and release of the virus nucleic acid into the cytoplasm. Blocking of M2 protein inhibits the process of virus replication.

Uses:

• Acts against influenza A virus.

• Used as prophylactic agent against seasonal influenza A virus.

 • Decreases the severity and duration of illness when given within 48 hours of onset of clinical symptoms.

Resistance: Resistance to adamantine group of drugs occurs due to single point mutation in the M2 protein at positions 26, 27, 30, 31, 34, 38 amino acids of which mutation at position 31 is the commonest one. There occurs com plete cross-resistance between two drugs.

 • During the year 2003–2004, resistance to adamantines (amantadine, rimantadine) started appearing in influenza A H3N2 and by 2005, all most all H3N2 strains are considered as resistant. Because of this reason, adamantines are no more in use against seasonal influenza.

 • Influenza A H1N1 2009 pdm strains are inherently resistant to adamantines.

• Strains of H5N1 that emerged in 1997 were sensitive to amantadines. 2003 H5N1 strains contained mutations at Sr31Asn and leu27Ile and showed high level resistance.

Neuraminidase inhibitors (NI): This group of drug first came to market in 1999 and presently there are four NI compounds available: Oseltamivir (Tamiflu), zanamivir (Relenza), peramivir (Rapivab) and laninamivir (Inavir). These four drugs differ in their chemical structure, bioavailability and mode of administration. Amongst these only oseltamivir and zanamivir are the two approved drugs and oseltamivir is most widely used.

• Oseltamivir is approved for use in >1 year age patient and is available in oral form.

 • Zanamivir is approved for >7 years age patient. It has no oral bioavailability and available in dry powder form to be administered locally by oral inhalation.

• Peramivir is approved for intravenous use only during pandemic. Presently it is also approved in Japan, China and Republic of Korea.

 • Laninamivir is approved and used in Japan.

Mechanism of action: During the virus replication process, neuraminidase is synthesized and comes to the surface of the virus and destroys the receptor by removing the sialic acid. This helps the virus in getting out from the infected cell and thereby available to infect the adjacent cells and helps in spreading the infection. Neuraminidase inhibitor inhibits the spread of virus and reduces the severity of infection by inhibiting neuraminidase.

Uses: Used for treatment of seasonal influenza A H1N1, Inf A (H1N1) 09pdm, influenza A H3N2 and HPAI H5N1. The drug is better effective when given early phase of illness.

• Effective against both influenza A and B.

• To decrease the severity of infection.

• To shorten the duration of infection. The dose of NIs is given in Table 1.

Table1. Treatment and prophylaxis for influenza

Resistance: Common mutation sites responsible for H3N2 virus resistance are: R 292K, E119V and for Inf A (H1N1) pdm09 virus are: H275Y, I223R and I223V.

Oseltamivir resistant strains are generally resistant to peramivir but sensitive to zanamivir. This is due to the requirement of conformational change in oseltamivir for binding to the active site of neuraminidase which is not required in zanamivir.

NI resistant strains usually isolated in patients during or after treatment/prophylaxis with NI. However, resistant strains have also been reported without previous exposure to drug. More commonly resistance is observed in immunocompromised patients. This occurs because of delayed viral clearance in these patients which leads to prolong duration of treatment and selection of resistant strains.

The global status of neuraminidase inhibitor (NAI) susceptibility data by WHO is as follows:

• 2012–13: 0.5% of influenza virus is resistant (showed reduced inhibition or high reduced inhibition).

 • 2013–14: 1.9% of influenza virus is resistant (showed reduced inhibition or high reduced inhibition).

• 2014–15: 0.6% of influenza virus is resistant (showed reduced inhibition or high reduced inhibition).

This indicates >99% of all influenza strains (considering all circulating strains in human) are susceptible to neuraminidase inhibitors, thus these drugs are still the choice of treatment and prophylaxis for influenza virus infection.

However, clusters of NI resistant strains of influenza A (H1N1) 09pdm have been reported in various countries including USA, Japan and China.

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مواضيع ذات صلة

Agents Used to Treat Viral Infections

Entry and Integrase Inhibitors

Protease Inhibitors

Non-nucleoside Reverse Transcriptase Inhibitors

Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Introduction to Antiretroviral Drugs

Neuramidase Inhibitors

Anti-Cytomegalovirus Agents

Anti-Herpes Simplex Virus and Varicella-Zoster Virus Agents

Introduction to Antiviral Drugs