Antiviral Drugs 173

M2 Ion Channel Inhibitors

Amantadine and rimantadine are tricyclic symmetric adamantanamines. In the 1960s it was discovered that they inhibited strains of influenza (Stephenson 2001). They are active only against influenza A virus (influenza B does not possess an M2 protein), have more side effects than neuraminidase inhibitors, and may select for readily transmissible drug-resistant viruses.

M2 inhibitors block an ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991) and is required for viral uncoating (for more details see the Drugs chapter). Both drugs are effective as treatment if started within 24 hours of illness onset, reducing fever and symptoms by 1–2 days (Wingfield 1969, Smorodintsev 1970, van Voris 1981).

Daily prophylaxis during an influenza season reduces infection rates by 50–90 % (Dawkins 1968, Dolin 1982, Clover 1986). Post-exposure prophylaxis of households seems problematic, though. In one study, rimantadine was ineffective in protecting household members from influenza A infection (Hayden 1989).

Gastrointestinal symptoms are the major side effects associated with amantadine and rimantadine. In addition, amantadine has a wide range of toxicity which may be in part attributable to the anticholinergic effects of the drug. In addition, minor reversible CNS side effects may occur during a 5-day treatment in up to one third of patients (van Voris 1981). The same frequency of side effects was found when the drug was tested in young healthy volunteers over a four-week period. Among 44 individuals, side effects (dizziness, nervousness, and insomnia) were well tolerated by most subjects, but 6 volunteers discontinued amantadine because of marked complaints. Cessation of side effects occurred in more than half of those continuing amantadine. 16 volunteers had decreased performance in sustained attention tasks (Bryson 1980). When studied in 450 volunteers during an outbreak of influenza A, the prophylactic effects of rimantadine and amantadine were comparable. Influ- enza-like illness occurred in 14 % of the rimantadine group and in 9 % of the amantadine group (Dolin 1982). Withdrawal from the study because of central nervous system side effects was more frequent in the amantadine (13 %) than in the rimantadine group (6 %).

The potential for drug interactions is greater for amantadine, especially when coadministered with central nervous system stimulants. Agents with anticholinergic properties may potentiate the anticholinergic-like side effects of amantadine. For more details see the chapter, “Drugs”.

Point mutations in the M gene lead to amino acid changes in the transmembrane region of the M2 protein and may confer high-level resistance to amantadine. The genetic basis for resistance appears to be single amino acid substitutions at positions 26, 27, 30, 31 or 34 in the transmembrane portion of the M2 ion channel (Hay 1985). The mutants are as virulent and transmissible as the wild-type virus. In an avian model, they were also genetically stable, showing no reversion to the wildtype after six passages in birds over a period of greater than 20 days (Bean 1989). Such strains may develop in up to one third of patients treated with amantadine or rimantadine; in immunocompromised individuals the percentage may even be higher (Englund 1998). Drug-resistant influenza A virus (H3N2) can be obtained from rimantadine-treated children and adults as early as 2 days after starting treatment (Hayden 1991). Some H5N1 strains which have been associated with human