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Chapter: Basic & Clinical Pharmacology : Antiviral Agents

Anti Influenza Agents

Influenza virus strains are classified by their core proteins (ie, A, B, or C), species of origin (eg, avian, swine), and geographic site of isolation.


Influenza virus strains are classified by their core proteins (ie, A, B, or C), species of origin (eg, avian, swine), and geographic site of isolation. Influenza A, the only strain that causes pandemics, is classified into 16 H (hemagglutinin) and 9 N (neuraminidase) known subtypes based on surface proteins. Although influenza B viruses usually infect only people, influenza A viruses can infect a variety of animal hosts. Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2. Fifteen subtypes are known to infect birds, providing an extensive reservoir. Although avian influenza subtypes aretypically highly species-specific, they have on rare occasions crossed the species barrier to infect humans and cats. Viruses of the H5 and H7 subtypes (eg, H5N1, H7N7, and H7N3) may rapidly mutate within poultry flocks from a low to high patho-genic form and have recently expanded their host range to cause both avian and human disease. Of particular concern is the avian H5N1 virus, which first caused human infection (including severe disease and death) in 1997 and has become endemic in Southeast Asian poultry since 2003. To date, the spread of H5N1 virus from person to person has been rare, limited, and unsustained. However, the emergence of the 2009 H1N1 influenza virus (pre-viously called “swine flu”) in 2009–2010 caused the first influenza pandemic (ie, global outbreak of disease caused by a new flu virus) in more than 40 years.

Although antiviral drugs available for influenza have activity against influenza A, many or most of the circulating strains of avian H5N1, as well as H1 and H3 strains causing seasonal influenza in the United States, are resistant to amantadine and rimantadine. Resistance to oseltamivir has also increased dramatically.


The neuraminidase inhibitors oseltamivir and zanamivir, analogs of sialic acid, interfere with release of progeny influenza virus from infected host cells, thus halting the spread of infection within the respiratory tract. These agents competitively and reversibly interact with the active enzyme site to inhibit viral neuraminidase activity at low nanomolar concentrations. Inhibition of viral neuraminidase results in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Unlike amantadine and rimantadine, oseltami-vir and zanamivir have activity against both influenza A and influenza B viruses. Early administration is crucial because repli-cation of influenza virus peaks at 24–72 hours after the onset of illness. When a 5-day course of therapy is initiated within 36–48 hours after the onset of symptoms, the duration of illness is decreased by 1–2 days compared with those on placebo, severity is diminished, and the incidence of secondary complications in children and adults decreases. Once-daily prophylaxis is 70–90% effective in preventing disease after exposure. Oseltamivir is approved by the Food and Drug Administration (FDA) for patients 1 year and older, whereas zanamivir is approved in patients 7 years or older.

Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body. The dosage is 75 mg twice daily for 5 days for treatment and 75 mg once daily for prevention; dosage must be modified in patients with renal insufficiency. Oral bioavailability is approximately 80%, plasma protein binding is low, and concentrations in the middle ear and sinus fluid are similar to those in plasma. The half-life of oseltamivir is 6–10 hours, and excretion is by glomerular filtration and tubular secretion in the urine. Probenecid reduces renal clearance of oseltamivir by 50%. Serum concentrations of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function; therefore, dosage should be adjusted in such patients. Potential adverse effects include nausea, vomiting, and abdominal pain, which occur in 5–10% of patients early in therapy but tend to resolve spontaneously. Taking oselta-mivir with food does not interfere with absorption and may decrease nausea and vomiting. Headache, fatigue, and diarrhea have also been reported and appear to be more common with prophylactic use. Rash is rare. Transient neuropsychiatric events (self-injury or delirium) have been reported, particularly in adoles-cents and adults living in Japan.

Zanamivir is delivered directly to the respiratory tract via inhalation. Ten to twenty percent of the active compound reaches the lungs, and the remainder is deposited in the oropharynx. The concentration of the drug in the respiratory tract is estimated to be more than 1000 times the 50% inhibitory concentration for neuraminidase, and the pulmonary half-life is 2.8 hours. Five to fifteen percent of the total dose (10 mg twice daily for 5 days for treatment and 10 mg once daily for prevention) is absorbed and excreted in the urine with minimal metabolism. Potential adverse effects include cough, bronchospasm (occasionally severe), revers-ible decrease in pulmonary function, and transient nasal and throat discomfort. Zanamivir administration is not recommended for patients with underlying airway disease.

Resistance to oseltamivir may be associated with point muta-tions in the viral hemagglutinin or neuraminidase (eg, the H275Y mutation) genes. Rates of resistance to oseltamivir among seasonal H1N1 viruses have risen abruptly and dramatically worldwide, reaching 97.4% in tested strains in the United States from 2008 to 2009. Resistance to oseltamivir in pandemic H1N1 viruses and resistance to zanamivir in seasonal and pandemic H1N1 viruses are rare. All influenza A (H3N2) and influenza B viruses were susceptible to both oseltamivir and zanamivir. Swine-origin influenza A (H1N1) viruses are nearly always susceptible to both oseltamivir and zanamivir.


Amantadine (1-aminoadamantane hydrochloride) and its α-methyl derivative, rimantadine, are tricyclic amines of the adamantane family that block the M2 proton ion channel of the virus particle and inhibit uncoating of the viral RNA within infected host cells, thus preventing its replication. They are active against influenza A only. Rimantadine is four to ten times more active than amanta-dine in vitro. Amantadine is well absorbed and 67% protein-bound. Its plasma half-life is 12–18 hours and varies by creatinine clearance. Rimantadine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal secretion and salivary levels approximate those in the serum, and cerebrospinal fluid levels are 52–96% of those in the serum; nasal mucus concentrations of rimantadine average 50% higher than those in plasma. Amantadine is excreted unchanged in the urine, whereas rimantadine under-goes extensive metabolism by hydroxylation, conjugation, and glucuronidation before urinary excretion. Dose reductions are required for both agents in the elderly and in patients with renal insufficiency, and for rimantadine in patients with marked hepatic insufficiency.In the absence of resistance, both amantadine and rimantadine, at 100 mg twice daily or 200 mg once daily, are 70–90% protective in the prevention of clinical illness when initiated before exposure. When begun within 1–2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1–2 days.

The primary target for both agents is the M2 protein within the viral membrane, incurring both influenza A specificity and a mutation-prone site that results in the rapid development of resis-tance in up to 50% of treated individuals. Resistant isolates with single-point mutations are genetically stable, retain pathogenicity, can be transmitted to close contacts, and may be shed chronically by immunocompromised patients. The marked increase in the prevalence of resistance to both agents in clinical isolates over the last decade, in influenza A H1N1 as well as H3N2, has limited the usefulness of these agents for either the treatment or the pre-vention of influenza. Cross-resistance to zanamivir and oseltamivir does not occur.

The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness); side effects are dose-related and may diminish or disappear after the first week of treatment despite continued drug ingestion. More serious side effects (eg, marked behavioral changes, delirium, hallucinations, agitation, and seizures) may be due to alteration of dopamine neurotransmission ; are less frequent with riman-tadine than with amantadine; are associated with high plasma concentrations; may occur more frequently in patients with renal insufficiency, seizure disorders, or advanced age; and may increase with concomitant antihistamines, anticholinergic drugs, hydro-chlorothiazide, and trimethoprim-sulfamethoxazole. Clinical manifestations of anticholinergic activity tend to be present in acute amantadine overdose. Both agents are teratogenic and embryotoxic in rodents, and birth defects have been reported after exposure during pregnancy.


The neuraminidase inhibitor peramivir, a cyclopentane analog, has activity against both influenza A and B viruses. Peramivir received temporary emergency use authorization by FDA for intravenous administration in November 2009 due to the H1N1 pandemic. The drug is marketed in South Korea but has not yet been licensed in the United States. Clinical data on cross-resistance to oseltamivir and zanamivir are not yet available. Reported side effects include diarrhea, nausea, vomiting, and neutropenia.

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