Anti-Influenza Virus Drugs

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Chapter: Essential pharmacology : Antiviral Drugs

Amantadine : Chemically, it is a tricyclic amine unrelated to any nucleic acid precursor, but inhibits replication of influenza A virus (a myxovirus). It appears to act at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication.


ANTI-INFLUENZA VIRUS DRUGS

 

Amantadine

 

Chemically, it is a tricyclic amine unrelated to any nucleic acid precursor, but inhibits replication of influenza A virus (a myxovirus). It appears to act at an early step (possibly uncoating) as well as at a late step (viral assembly) in viral replication. A protein designated ‘M2’ which acts as an ion channel has been identified as one of its targets of action. Resistance to amantadine develops by mutation causing amino acid substitutions in the M2 protein. Amantadine is well absorbed orally and excreted unchanged in urine over 2–3 days (t½ 16 hr).

 

Adverse effects Generally well tolerated; nausea, anorexia, insomnia, dizziness, nightmares, lack of mental concentration, rarely hallucinations have been reported. Ankle edema occurs due to local vasoconstriction.

 

Uses

 

1.   Prophylaxis of influenza A2 during an epidemic or seasonal, especially in high risk patients. It does not interfere with antibody response to influenza vaccination; both may be given together. If the vaccine is given, amantadine can be stopped after 2 weeks. It is quite virus specific: influenza B is unaffected.

 

2.   Treatment of influenzal (A2) illness: a modest therapeutic effect (reduction in fever, congestion and cough) occurs if the drug is given quickly after the symptoms appear. A 5 day treatment is advised.

 

3.   Parkinsonism (see Ch. No. 31)

 

Dose: 100 mg BD, elderly—half dose, children 5 mg/kg/ day; AMANTREL, NEAMAN 100 mg tab.

 

Contraindications: epilepsy and other CNS disease; gastric ulcer, pregnancy.

 

Rimantadine It is a more potent, long-acting (t½ 30 hr) and better tolerated congener of amantadine. Oral bioavailability is higher and it is largely metabolized. Dose and clinical application is similar to amantadine. Amantadine resistant virus is resistant to rimantadine as well.

 

Oseltamivir (TAMIFLU) This recently developed anti-influenza virus drug has a broader-spectrum activity covering influenza A (amantadine sensitive as well as resistant), influenza B and avian-influenza (bird flu) H5N1 and other strains. It is an ester prodrug that is rapidly and nearly completely hydrolysed during absorption in intestine and by liver to the active form oseltamivir carboxylate. The active metabolite is not further metabolized and is excreted by the kidney with a t½ of 6–10 hours. It acts by inhibiting influenza virus neuraminidase enzyme which is needed for release of progeny virions from the infected cell. Spread of the virus in the body is thus checked.

 

Oseltamivir is indicated both for prophylaxis as well as treatment of influenza A, B and bird flu. Started at the onset of symptoms, it reduces the severity and duration illness. However, considering the cost, and to preserve its efficacy, use should be restricted to high risk subjects. Dose: therapeutic 75 mg oral BD for 5 days; prophylactic 75 mg OD.

 

Side effects are nausea and abdominal pain due to gastric irritation (reduced by taking the drug with food), headache, diarrhoea, cough and insomnia. Skin reactions have been reported.

 

Zanamivir (RELENZA) Another influenza virus (A, B, avian strains) neuraminidase inhibitor that is administered by inhalation as a powder due to very low oral bioavailability. Small amount that is absorbed after inhalation is excreted by the kidney with a t½ of 2–5 hours. The mechanism of action, clinical utility and efficacy of zanamivir are similar to that of oseltamivir. Though viral resistance against both is not clinically significant, some variants resistant to oseltamivir remain sensitive to zanamivir and vice versa.

 

Dose: 10 mg through breath actuated inhaler, BD × 5 days for treatment, and OD for prophylaxis.

 

The inhaled powder can induce bronchospasm in some individuals. This may be severe in asthmatics; contraindicated in them. Headache, dizziness, nausea and rashes are mild and infrequent side effects.

 

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