Pros and Cons of Neuraminidase Inhibitors for Flu

Neuraminidase inhibitors are important tools when influenza strikes and epidemics develop.

Studies of the 2009 H1N1 pandemic found that adults who were hospitalized with the flu and given neuraminidase inhibitors within 48 hours were 25% less likely to die than those who did not receive neuraminidase inhibitors.

Two neuraminidase inhibitors approved for the treatment of influenza infection in the United States are oseltamivir and zanamivir.

Neuraminidase inhibitors may cause serious neuropsychiatric changes that can lead to sudden and accidental death on rare occasions, with children appearing to be at elevated risk. These neuropsychiatric changes can occur suddenly within 1 to 24 hours after the first dose and are usually fleeting unless respiratory or cardiac arrest occurs simultaneously.

The symptoms can relapse if the drugs are continued. Delayed symptoms typically appear after a few days of use and can continue for months to years.

Japanese providers consider oseltamivir contraindicated for patients younger than 20 years. Oseltamivir increases the risk of nausea, vomiting, headache, psychiatric, renal, torsades de pointes, and diabetic/hyperglycemic events, as well as pain in limbs.

Now, an article published ahead-of-print in journal

Infectious Diseases

reviews the biology of delayed-type adverse reactions to oseltamivir.

Neuraminidase inhibitors appear to relieve flu symptoms by inhibiting the influenza virus’s neuraminidase. In humans, oseltamivir acts at N-methyl-D-aspartate receptors to induce delayed schizophrenic reactions and limb pain. Oseltamivir directly causes neuroexcitability via the acetylcholine receptor blockade and MAO-A inhibition.

Oseltamivir suppresses pro-inflammatory cytokines (IL-6, TNF-alpha, and IFN-gamma) by decreasing GM1 ganglioside expression of CD8-positive T-cells. Elevated oseltamivir carboxylate serum concentration is directly related to the extent of QT prolongation.

Oseltamivir carboxylate activity on hepatic plasma membrane-associated sialidases leads to prolonged neuropsychiatric reactions, hyperglycemia, renal and hepatic impairment, pneumonia, infection exacerbation, and gastrointestinal tract hemorrhage.

Endogenous neuraminidase inhibition may drive oseltamivir’s delayed-type adverse reactions, including neuropsychiatric changes. Acetylcholine and MAO-A inhibition is a second mechanism for the neuropsychiatric adverse reactions, specifically.

Finding the cause of adverse effects may help predict when they may occur or identify ways to prevent them.