Drug Therapies For Influenza

Influenza is a common infection in humans, birds, dogs, livestock, and whales.

The virus infects and hijacks our cells, causing them to churn out more viruses rather than the perform the normal metabolic activities the cell was intended to perform. 

Most of us that fall ill from influenza will recover within a few days. For some, however, the infection can lead to much more serious complications like pneumonia and death. 

Every once in a while, we experience more severe influenza outbreaks, with some of the more significant ones in the past having killed off about 6% of the worlds entire population and infecting as much as a third. \

This was the Spanish flu of 1918.

Another outbreak made the rounds in 2009, killing about 575 000 people across the world. 

The risk of another catastrophic influenza outbreak is high, and treatment options are limited. As far as drug therapies are concerned, there are 3 go-to drugs that doctors and hospitals have available, all of which are becoming less effective as time goes on.

The reason being that as a virus mutates, it can become resistant to the drugs we have available. This, combined with the lack of new drug development places the possibility of catastrophic viral disaster at a high risk. 

here we discuss the mechanisms of action behind the drug therapies most commonly used by health professionals to treat influenza, what their strengths and weaknesses are, and how they are best used to prevent a significant outbreak in the future. 

An Introduction To Influenza

Influenza comes in three main types, A, B, and C.

For the most part, influenza A and B are the main concern for human health. The virus works by using special protein complexes on the outside of the viral envelope to enter the cell and release special RNA segments into the nucleus of our cells.

From here, the RNA segments hiijack our DNA telling the cell to produce viral proteins instead of doing the normal function it was meant to do. 

Stopping this process with drugs needs to be done early, before the virus has infected too many of our cells. These drugs will usually work by inhibiting one of these protein complexes, preventing new viruses from leaving the cells that produced them. 

First Line Of Defence

The best treatment for anything is prevention.

This is achieved by physically blocking the viral particles from entering the body. Medical professionals achieve this with thorough and frequent hand-washing, and physical barriers placed on both the patient and the practitioner. 

N-95 Respiratory Masks

First Line Of Defence Against Influenza (make sure you are sized correctly)

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Face masks are a common form of prevention when in contact with infected individuals, but it's important to note that not all masks are the same.

Dust masks offer little protection from the infected, but do work in isolating viral particles in those already infected.

These masks don't filter the air for those wearing them, and airborne particles such as influenza can still enter the lungs of those wearing them. The better option is mask that actually filters the air entering the lungs such as the iconic N95 respirator masks. These masks need to be fitted to get the best results, but offers the best protection to those not yet infected. 

For those who are already infected, a common dust mask is often used because despite not filtering the exhaled air directly, they are effective in containing the spread of water droplets infected with the virus. 

Drug Therapy Options For Influenza

Fortunatly, we have a few different drugs that we can use to treat influenza if caught early. These medications mainly work by inhibiting a specific viral protein which thus prevents it from functioning properly. 

There are 3 main antiviral treatments for influenza

1. Zanamivir (Relenza®) (Inhalation)

2. Oseltamivir (Tamiflu®) (Oral)

3. Peramivir (Rapivab®) (IV)

Older, more outdated medicines include:

1. Amantadine

2. Rimantadine

The Strengths And Weaknesses Of These Drugs

These drugs are useful, and if prescribed within 48 hours of infection have a high success rate.

The problem is not in the effectiveness of these drugs, or even the side effects (aside from the older generation of drugs such as amantadine).

Rather, the problem lies in the rate at which viral strains have been achieving drug resistance, and the significant lack of development going into new drugs across the globe. 

Influenza Drug Resistance

Source: Hayden, F. (2009). Developing new antiviral agents for influenza treatment: what does the future hold?. Clinical Infectious Diseases, 48(Supplement_1), S3-S13.

Over the past decade, drug resistance to all of our most useful anti-influenza medications have been increasing exponentially.

M2 ion inhibition, which is the mechanism of action for the older generation of drugs like amantadine and rimantadine, has become virtually useless for treating various influenza strains as a result of drug resistance. (See chart to the right). [1-8]. 

New medications (Zanamivir, Oseltamivir, and Peramivir) work by inhibiting a viral protein known as neuraminidase, which is needed for newly formed viruses to exit the cell and infect other hosts. This has also seen significant increases in resistance by viral strains and continues to grow [9-17]. 

It is unknown how much longer these medications will be effective in treating influenza A, B, and C. 

Comparing Drug Therapies For Influenza

Drug Name	Mechanism of Action	Strengths	Weaknesses
Amantadine	M2 Inhibitor	Also used to treat Parkinson's disease.	Drug resistant influenza strains are common Not effective for Influenza B
Rimantadine	M2 Inhibitor	N/A	Drug resistance common Adverse reactions common
Peramivir	Neuraminidase inhibitor	Best bioavailability due to IV application	IV medication only, limiting its use to hospitals.
Oseltamivir	Neuraminidase inhibitor	Oral tablet allows for better compliance.	Drug resistance is becomming more common.
Zanamivir	Neuraminidase inhibitor	Inhalation delivers the drug directly to the respiratory tract. Low incidence of side effects.	Drug resistance is becomming more frequent.

1. Amantadine Hydrochloride

Amantadine is one of the older medications used in treating influenza.

It works by inhibiting the M2 ion channel in the influenza A virus.

This ion channel is used to pump ions into the viral envelope one inside the cell membrane in order to dump its RNA segments into the cell. By inhibiting this channel, viral RNA cannot make their way into the cell nucleus, thus inactivating the virus. 

Amantadine Hydrochloride

MOA:	Virion M2 ion inhibitor
Pharmacokinetics:	Absorbed well orally. Conjugation Pathway unknown Excreted in the urine unchanged (100%) Half-life: 17h Excreted in urine (50-90% unchanged);
Pharmacodynamics:	Inhibits M2 protein (ion channels) on influenza A virions NMDA receptor agonist Releases dopamine from synapses
Pregnancy:	Category C
Interactions:	Anticholinergic agents, levodopa, antipsychotics, combination diuretics.
Adverse Reactions:	Psychological disturbances, dilusions, hallucinations, death.
Contraindications:	Renal impairment can decrease excretion. Higher serum concentrations have an increased chance of developing adverse reactions. History of epilepsy
Strengths:	Also used as a Parkinson's medication.
Weaknesses:	Drug resistance is common. CNS side effects are common. Only relevant for influenza A infection. Deaths have been reported.

2. Zanamivir

This drug was invented in Australia around the same time as its competitor Oseltamivir (Tammiflu®). Both of these drugs work by inhibiting the viral envelope protein neuraminidase. By inhibiting this protein, the virus is not able to exit the cell to infect other hosts. 

Zanamivir differs from Oseltamivir in its application. It is inhaled as a powdered spray, which allows it to reach the site of infection (respiratory tract0 more effectively. this is beneficial in several ways: 

• Comes into direct contact with the infected tissue

• Reduces systemic side effects

• Bypasses the low oral bioavailability of the drug

Zanamivir (Relenza®)

MOA:	Selective neuraminidase inhibitor
Pharmacokinetics:	Poor bioavailability in the gut Not metabolised by CYP450 enzymes Excreted in the urine unchanged (100%) Half life is 2.5 - 5 hours
Pharmacodynamics:	A selective neuraminidase inhibitor. The exact binding site is not clear.
Pregnancy:	Category C
Interactions:	None noted.
Adverse Reactions:	Can worsen existing lung diseases, anaphylaxis, delerium, headaches, nausea, vomitting, diarrhea, fever, chills, joint pain.
Contraindications:	Young children (<5)
Strengths:	Drug interactions are not likely due to the selective nature, and lack of liver metabolism in this chemical.
Weaknesses:	Drug resistance has been noted in some influwnza strains. Only effective if taken in the first 48 hours of infection. Contraindicated in young children. Prescription only medication. Some mistake its use as a substitute for vaccination.

The Future Of Drug Therapies For Influenza

With the increased rate of drug resistance amongst influenza viruses, and the catastrophic past of influenza infection, it is becoming ever more important to develop effective medications to treat them before another pandemic occurs. 

With the high level of antiviral activity in plants, including Elder (Sambucus nigra), it is likely that the next generation of antiviral medications for influenza will be derrived from these plant sources. 

Further Reading:

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N-95 Respiratory Masks

First Line Of Defence Against Influenza (make sure you are sized correctly)

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Virus: An Illustrated Guide

Marilyn J. Roossinck

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Influenza A and B Test Kit

By Sekisui Diagnostics

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Author:

Justin Cooke

The Sunlight Experiment

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References:

1. Hayden, F. (2009). Developing new antiviral agents for influenza treatment: what does the future hold?. Clinical Infectious Diseases, 48(Supplement_1), S3-S13.

2. Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay AJ, Pyke S. Recovery of drug-resistant influenza A virus during therapeutic use of rimantadine, Antimicrob Agents Chemother , 1991, vol. 35 (pg. 1741-7)

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4. Hall CB, Dolin R, Gala CL, et al. . Children with influenza A infection: treatment with rimantadine, Pediatrics , 1987, vol. 80 (pg. 275-82)

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6. Englund JA, Champlin RE, Wyde PR, et al. . Common emergence of amantadine- and rimantadine-resistant influenza A viruses in symptomatic immunocompromised adults, Clin Infect Dis , 1998, vol. 26 (pg. 1418-24)

7. Bright RA, Medina MJ, Xu X, et al. . Incidence of adamantane resistance among influenza A(H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern, Lancet , 2005, vol. 366 (pg. 1175-81)

8. Deyde VM, Xu X, Bright RA, et al. . Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide, J Infect Dis , 2007, vol. 196 (pg. 249-57)

9. Roberts NA. Treatment of influenza with neuraminidase inhibitors: virological implications, Philos Trans R Soc Lond B Biol Sci , 2001, vol. 356 (pg. 1895-7)

10. Whitley RJ, Hayden FG, Reisinger KS, et al. . Oral oseltamivir treatment of influenza in children, Pediatr Infect Dis J , 2001, vol. 20 (pg. 127-33) (erratum: Pediatr Infect Dis J 2001; 20:421)

11. Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) and its potential for use in the event of an influenza pandemic, J Antimicrob Chemother , 2005, vol. 55 Suppl 1(pg. i5-21)

12. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. . Resistant influenza A viruses in children treated with oseltamivir: descriptive study, Lancet , 2004, vol. 364 (pg. 759-65)

13. Ison MG, Gubareva LV, Atmar RL, Treanor J, Hayden FG. Recovery of drug-resistant influenza virus from immunocompromised patients: a case series, J Infect Dis , 2006, vol. 193 (pg. 760-4)

14. Whitley RJ, Monto AS. Prevention and treatment of influenza in high-risk groups: children, pregnant women, immunocompromised hosts, and nursing home residents, J Infect Dis , 2006, vol. 194 Suppl 2(pg. S133-8)

15. Neuraminidase Inhibitor Susceptibility Network. Use of influenza antivirals during 2003–2004 and monitoring of neuraminidase inhibitor resistance, Wkly Epidemiol Rec , 2005, vol. 80 pg. 156

16. Monitoring of neuraminidase inhibitor resistance among clinical influenza virus isolates in Japan during the 2003–2006 influenza seasons, Wkly Epidemiol Rec , 2007, vol. 82 (pg. 149-50)

17. Hatakeyama S, Sugaya N, Ito M, et al. . Emergence of influenza B viruses with reduced sensitivity to neuraminidase inhibitors, JAMA , 2007, vol. 297 (pg. 1435-42)

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