Anti-Influenza Agents PDF

​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ANTI-INFLUENZA AGENTS ​ ​ ​ ​ ​ Influenza virus strains are classified by their core proteins (ie, A, B, or C), species...

​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 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 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, including birds, providing an extensive reservoir. Current influenza A subtypes that are circulating among worldwide populations include H1N1, H1N2, and H3N2. Although avian influenza subtypes are typically 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, H7N9) may rapidly mutate within poultry flocks from a low to high pathogenic form and have recently expanded their host range to cause both avian and human disease. However, person-to-person spread of these avian viruses to date has been rare, limited, and unsustained. ​ ​ ​ ​ ​ There are 5 anti-influenza drugs approved for use: 3 are neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir, IV peramivir) and 2 are adamantanes (amantadine, rimantadine). Treatment is recommended for individuals with severe infection or at high risk for complications. The neuraminidase inhibitors have activity against both influenza A and influenza B, and there is currently a low level of resistance. The adamantanes have activity against influenza A viruses only, and in recent past seasons there was a high level of resistance (>99%) among both influenza H3N2 and influenza A H1N1. ​ ​ ​ ​ ​ OSELTAMIVIR & ZANAMIVIR ​ ​ ​ ​ ​ The neuraminidase inhibitors oseltamivir and zanamivir, analogs of sialic acid, interfere with release of progeny influenza A and B virus from infected host cells, thus halting the spread of infec- tion within the respiratory tract. These agents competitively and reversibly interact with the active enzyme site to inhibit viral neuraminidase activity at low nanomolar concentrations, resulting in clumping of newly released influenza virions to each other and to the membrane of the infected cell. Early administration is crucial because replication of influenza virus peaks at 24–72 hours after the onset of illness. Initiation of a 5-day course of therapy within 48 hours after the onset of illness (75 mg twice daily) modestly decreases the duration of symptoms, as well as duration of viral shedding and viral titer; some studies have also shown a decrease in the incidence of complications. Once-daily prophylaxis (75 mg once daily) is 70–90% effective in preventing disease after exposure. ​ ​ ​ ​ ​ Oseltamivir is an orally administered prodrug that is activated by hepatic esterases and widely distributed throughout the body. Oral bioavailability is ~ 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. Pro- benecid reduces renal clearance by 50%. Serum concentrations ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 892 SECTION VIII Chemotherapeutic Drugs ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ of oseltamivir carboxylate, the active metabolite of oseltamivir, increase with declining renal function; therefore, dosage should be adjusted in patients with renal insufficiency. Potential adverse effects include nausea, vomiting, and headache. Taking oseltami- vir with food does not interfere with absorption and may decrease nausea and vomiting. Fatigue and diarrhea have also been reported and appear to be more common with prophylactic use. Rash is rare. Neuropsychiatric events (self-injury or delirium) have been reported, particularly in adolescents and adults living in Japan. ​ ​ ​ ​ ​ Zanamivir is administered directly to the respiratory tract via inhalation. Of the active compound, 10–20% reaches the lungs; 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. Of the total dose (10 mg twice daily for 5 days for treatment or 10 mg once daily for prevention), 5–15% is absorbed and excreted in the urine with minimal metabolism. Potential adverse effects include cough, bronchospasm (occasionally severe), reversible decrease in pulmonary function, and transient nasal and throat discomfort. Zanamivir administration is not recommended for patients with underlying airway disease. ​ ​ ​ ​ ​ Although resistance to oseltamivir and zanamivir may emerge during therapy and be transmissible, >98% of H1N1 and H3N2 strains as well as 100% of influenza B virus tested by the Centers for Disease Control in the 2014–2015 season retained susceptibility to both agents. ​ ​ ​ ​ ​ PERAMIVIR ​ ​ ​ ​ ​ The neuraminidase inhibitor peramivir, a cyclopentane analog, has activity against both influenza A and B viruses, and is approved as a single 600-mg IV dose for the treatment of acute uncomplicated influenza in adults. As with the other neuraminidase inhibitors, early treatment is optimal (ie, within 48 hours). ​ ​ ​ ​ ​ Less than 30% of peramivir is protein-bound. Peramivir is not significantly metabolized in humans and the major route of elimination is the kidney. Dose adjustment is required for renal insufficiency. The elimination half-life following IV administra- tion is ~20 hours. ​ ​ ​ ​ ​ The main potential side effect is diarrhea, although serious skin or hypersensitivity reactions (e.g., Stevens-Johnson syndrome, ery- thema multiforme) have been rarely reported. In addition, as with the other neuraminidase inhibitors, an increased risk of hallucinations, delirium, and abnormal behavior in patients with influenza receiving peramivir has been reported. ​ ​ ​ ​ ​ AMANTADINE & RIMANTADINE ​ ​ ​ ​ ​ 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 amantadine in vitro. Amantadine is well absorbed and 67% protein-bound, with a plasma half-life of 12–18 hours that varies by creatinine clearance. Rimantadine is about 40% protein-bound and has a half-life of 24–36 hours. Nasal mucus concentrations of rimantadine average 50% higher than those in plasma, and cere- brospinal fluid levels are 52–96% of those in the serum. Amantadine is excreted unchanged in the urine, whereas rimantadine undergoes 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 severe hepatic insufficiency. ​ ​ ​ ​ ​ In the absence of resistance, both amantadine and rimantadine are 70–90% protective in the prevention of clinical illness when initiated before exposure and limit the duration of clinical illness by 1–2 days when administered as treatment. However, due to high rates of resistance in both H1N1 and H3N2 viruses, these agents are no longer recommended for the prevention or treat- ment of influenza. ​ ​ ​ ​ ​ The most common adverse effects are gastrointestinal (nausea, anorexia) and central nervous system (nervousness, difficulty in concentrating, insomnia, light-headedness). More serious side effects (eg, marked behavioral changes, delirium, hallucinations, agitation, and seizures) may be due to alteration of dopamine neurotransmission (see Chapter 28); are less frequent with rimantadine 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, hydrochlorothiazide, and trimethoprim-sulfamethoxazole. Clini- cal 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. ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​