Trifluridine

ANTI-INFLUENZA AGENTS Amantadine and Rimantadine

CHEMISTRYAND ANTIVIRALACTIVITY Amantadine (1-adamantanamine hydrochloride) and its a-methyl derivative rimantadine (a-methyl-1-adamantane methylamine hydrochloride) are tricyclic amines.

Both agents specifically inhibit the replication of influenza A viruses. Rimantadine is 4-10 times more active than amantadine.

MECHANISMS OFACTION AND RESISTANCE Amantadine and rimantadine inhibit an early step in viral replication, probably viral uncoating; for some strains, they also have an effect on a late step in viral assembly probably mediated through altering hemagglutinin processing. The primary locus of action is the influenza A virus M2 protein, an integral membrane protein that functions as an ion channel.

Primary drug resistance is uncommon in field isolates but occurs in some avian and swine influenza viruses, including H5N1 human isolates. Resistance is selected readily by virus passage in the presence of drug and is seen in 30% or more of isolates recovered during treatment. Resistance with >100-fold increases in inhibitory concentrations has been associated with single-nucleotide changes leading to amino acid substitutions in the transmembrane region of M2. Amantadine and rimantadine share cross-susceptibility and resistance.

ABSORPTION, DISTRIBUTION, AND ELIMINATION

The pharmacokinetics of amantadine and rimantadine are listed in Table 49-3. The elderly require only one-half the weight-adjusted dose of amantadine to achieve equivalent drug levels.

Both drugs have very large volumes of distribution. Nasal secretion and salivary levels of amantadine approximate those found in the serum. Amantadine is excreted in breast milk. Rimantadine

Table 49-3

Pharmacological Characteristics of Antivirals for Influenza

Table 49-3

Pharmacological Characteristics of Antivirals for Influenza

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