Different types of antivirals and their roles in curtailing the spread of influenza virus.
Written by: Kavya, Akshaya, Haritha
Antivirals are an important class of drugs that are necessary to keep viral infections at bay. With the current COVID-19 pandemic going on, several companies have been testing antivirals as a possible method to reduce the spread of the virus. Although COVID-19 is the newest virus on our minds, that doesn’t stop the regular flu virus from infecting us this flu season. Read on to find out about how exactly antivirals keep the influenza virus in check and the commonly used antivirals for influenza.
Influenza virus (1)
What are antivirals?
CDC estimates that around 29,000 to 60,000 people die each year of influenza-related illnesses in the United States (12). How do we treat influenza and other viral ailments? Antivirals are medications administered for viral infections. Antivirals help to lower the multiplication of the virus in our bodies (7). Virus replication is the primary mode of spread. Therefore, by interfering with viral replication, antivirals help combat the spread of the virus within our bodies. Antivirals may also target where the viral particles bind. Instead of letting the viral particle adhere to the cell membranes, the viral particle may have more affinity for the drug than the membrane (9). This will prevent the virus from entering the cell. However, antivirals are not the primary source of protection against viruses. Vaccines are more effective against viruses than antivirals (7). Antivirals in combination with vaccines are more effective than without. The way antivirals commonly inhibit the viral replication is through the drug’s interference with a specific enzyme called neuraminidase (8). We dive into the details of neuraminidase inhibitors below. Antivirals have to be prescribed and are not available over the counter. Antivirals are specific to the type of virus that they treat. Therefore, with the high mutation rates of viruses and more generally, the vast number of viruses that affect us, it is challenging and time-consuming to produce antivirals.
Influenza A and B
Influenza is one of the most common respiratory viruses. There are four types of influenza virus. Influenza A and B are the strains that cause seasonal flu outbreaks. Influenza A is found in humans, birds, and pigs (11). Therefore, Influenza A has a higher mutation rate and is more prevalent during the influenza season. Influenza A, also for the same reason, has the ability to cause pandemics (11). Influenza B is found only in humans (11).Influenza A can also be categorized into subtypes, H (Hemagglutinin) and N (Neuraminidase). These refer to the types of proteins on the viral surface (11). Influenza A is usually associated with more severe cases; however, both Influenza A and B are equally contagious. Influenza B cases also arise more frequently during the beginning of the flu season (11).
Although common cold and flu may present similar symptoms, flu symptoms usually last longer and may be more severe. At the first sign of symptoms, it is advised that you receive medical consultation so that the effects of the viral infection can be minimized. (2)
Neuraminidase inhibitors
Neuraminidase inhibitors are a newer class of antiviral drugs used to treat prophylaxis in the case of an influenza infection. They are effective against all types of influenza, and are as a result, useful in curtailing pandemics and epidemics (4). Neuraminidase inhibitors are usually used for the treatment of influenza in individuals that have been symptomatic for less than 48 hours (1). Other than being effective against Influenza A and Influenza B, these drugs have also been shown to be effective against the coronavirus strain that caused the 1918 pandemic as well as avian influenza A strains (1).
Different types of drugs in this category
The most common drugs in this category are zanamivir, oseltamivir and peramivir (4). Zanamivir is a dry powder that is inhaled whereas oseltamivir is administered orally and is absorbed through the gastrointestinal tract (4). Peramivir is given through an intravenous (IV) dose (1). Zanamivir has been approved for treatment in people 12 or older whereas oseltamivir has been approved for treatment in people 18 or older (10). These drugs are given only after the person has shown symptoms and are not approved to be used as prophylactics (to prevent the flu). However, studies in laboratory settings have shown that zanamivir and oseltamivir seem to be effective prophylactics. However, vaccination still remains the best prophylactic for influenza (10).
Chemical structures of common neuraminidase inhibitors. (3)
Mechanism of action
Neuraminidase inhibitors act on the replication cycle of the virus. They prevent the progeny of the influenza virus from being released from the host cell (4). It is necessary for these drugs to be administered at the replication stage of the cycle, which happens 24-48 hours after the onset of symptoms (4). As a result, these antivirals are administered within 1-2 days of infection for best results. Host cells contain carbohydrates on their surface. The carbohydrates contain sialic acid residues on them. Neuraminidase present on Influenza A and Influenza B cleaves the terminal sialic acid residue thereby causing the virus progeny to get released from the host cell. Neuraminidase inhibitors are analogues of sialic acid. They bind to neuraminidase on the virion and prevent neuraminidase from binding to sialic acid on the host cell. Hence, the terminal sialic acid on the host cells does not get cleaved. Viral hemagglutinin binds to the sialic acid instead (10). This prevents virus progeny from getting released from the host cell and reduces the amount of new viruses that can infect other cells (10).
Mechanism of action of neuraminidase inhibitors. These inhibitors (black) bind to neuraminidase on the virion and prevent it from binding to sialic acid on the host cell. (4)
Side effects and drug resistance
Since zanamivir is inhaled, some patients notice side effects such as cough, bronchospasm (which causes difficulty in breathing) and reduced pulmonary function (4). Caution must be exercised while using this drug in people with asthma or chronic obstructive pulmonary disease (COPD) (10). Adverse effects of oseltamivir include nausea, vomiting and abdominal pain. However, these side effects occur only in 5-10% of patients (4). Although the development of resistance is very rare, some studies in children showed mutations in the viral neuraminidase protein. These mutant forms could bind to the neuraminidase inhibitor and cause the release of viral progeny. This is a concern since children are an important source of transmission of the flu in communities (4). Zanamivir and oseltamivir are more expensive than adamantanes such as amantadine and rimantadine, which are described below (10).
Adamantanes
Other than Influenza A, Adamantanes can be used to treat symptoms of Parkinson’s Disease and some other illnesses. In this post, we will mainly be discussing its effects on symptoms of Influenza, as well as for treatment of the respiratory infections caused by this viral infection. Adamantanes essentially work to stop the spread of Influenza A in the body by increasing dopamine levels (2). Since they don’t target the specific proteins of Influenza B, these medications are only useful in consumption for those with the Influenza A virus.
Chemical Structure of an Adamantane (5)
Different types of drugs in this category
There are two different types of Adamantanes, but the medications are not recommended in the United States because of the antiviral resistance surrounding Influenza A viruses. Amantadine is administered to individuals who are more than 1 year old, whereas Rimantadine is approved for treatment only in individuals 17 and older (3). To prevent (not treat) the A-strain viruses, it is FDA-approved for individuals above 1 year old. Amantadine has shown to result in more harmful effects in individuals, producing more symptoms of Adamantanes than Rimantadine. Although both drugs can impact the gastrointestinal region negatively, Amantadine can affect the nervous system as well (6).
A study examining the effects of Amantadine and Rimantadine, revealed that neither of these drugs would really be recommended in the prevention or treatment of Influenza A. Despite Amantadine being capable of preventing the virus, in order to do so for one case, it would have to be used for 14-18 weeks in 17 children (6). In regards to Rimantadine, although its use was able to reduce fever in the children within 3 days of consuming the drug, it doesn’t necessarily give enough reason to use it to treat everyone with Influenza A. Additionally, Rimantadine did not provide any benefit to the elderly in the study. Both drugs, when compared to the placebos, did not prove to have any drastic difference in prevention or treatment of the virus (6). Though this specific study did not have a high quality of evidence, multiple research studies also suggest that the use of Adamantanes would not help against Influenza A effectively, with strains of the virus which are susceptible to the drugs being present and spreading.
Mechanism of action
The way these two types of Adamantanes work to prevent and treat Influenza A is by blocking its M2 ion channels. These channels are employed in the uncoating of the viral particle which takes place during different stages of viral replication (5). Unfortunately, due to the dominance of resistance to these drugs which can be caused by a single substitution of residue of the M2 protein, it has not proved to be an effective medication for Influenza today. Adamantanes can help to reduce the length of time that one experiences symptoms and worsening of the virus if used within 48 hours after symptoms were present, but they can also cause side effects. Inside the body, the drug works to rid the viral infection by stopping the replication of the virus. As mentioned earlier, this process is done by restricting the viral RNA from being uncoated (5).
Adamantanes work to prevent Influenza A by restricting the “uncoating” process of the viral RNA by blocking the M2 protein ion channels. (6)
Side effects
Adamantanes can cause several side effects after consumption, including experiencing dry mouth, constipation, having a decreased appetite, being tired and having uncontrollable contraction (tightening) of muscles (2). Additionally, this drug can leave more detrimental, long-term effects, which include having hallucinations, depression, anxiety, shortness of breath, swelling, difficulty urinating, or experiencing suicidal thoughts. If there is an overdose of Adamantanes, it is possible the individual may experience lack of energy, confusion, difficulty breathing, irregular heart beating, seeing/hearing things that do not exist, or other serious health-related issues (2). Particularly with the case of Amantadine, symptoms are more common.
In this article, we have explored the most commonly used antiviral medications and how they work to inhibit the spread of the virus. Antivirals are specific to a particular virus and require lots of research and time before widespread use. Although antivirals play a huge role in combating viral infections, vaccines are the primary defense against viruses. When entire populations are vaccinated, viruses can be eradicated, saving many lives within a few years!
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