Amantadine and Rimantadine
Amantadine (Symmetrel) is a synthetic tricyclic
amine, and rimantadine (Flumadine) is
its -methyl derivative. Both drugs inhibit the replication of the three
antigenic subtypes of influenza A (H1N1, H2N2 and H3N2) and have negligible
activity against influenza B.
Their mechanism of action involves inhibition of the viral M2
protein, an integral membrane protein that acts as a H+ channel. Blockade of the M2 protein
prevents the acid-mediated
dissociation of the ribonucleoprotein complex that occurs early in replication.
In certain strains, the pH changes that result from M2 inhibition alter the
conformation of hemagglutinin, hence inhibit viral assembly.
Viral resistance develops
rapidly in approximately 30% of individuals treated with amantadine or
rimanta-dine. Resistant viruses are associated with the failure of drug
prophylaxis in close contacts of infected individu-als who have been treated
with these antiviral agents. Mutation in the transmembrane domain of the M2
pro-tein is the most frequent cause of resistance to amanta-dine and
Amantadine is rapidly and
completely absorbed from the gastrointestinal tract, and peak blood levels are
achieved in 2 to 5 hours. The serum half-life of amanta-dine averages 17 hours
in young adults and 29 hours in the elderly. Most of the drug (90%) is
eliminated un-changed by glomerular filtration and tubular secretion.
Rimantadine is well absorbed
following oral admin-istration, with peak blood levels achieved in 5 to 7
hours. Its elimination half-life averages 25 hours in young adults and 32 hours
in the elderly. Less than 25% of the dose is excreted in the urine as unchanged
drug; the remainder is eliminated as hydroxylated or conju-gated metabolites.
Amantadine and rimantadine
are used for the treat-ment of diseases caused by influenza A strains. When
these agents are administered within 48 hours of the on-set of symptoms, they
reduce the duration of fever and systemic complaints by 1 to 2 days and may
decrease the duration of viral shedding. Evidence is insufficient to suggest
that treatment with these drugs will prevent the development of influenza A
virus pneumonitis or other complications in high-risk patients.
The Centers for Disease Control’s (CDC) Immuni-zation Practices
Advisory Committee recommends an-nual vaccination as the method of choice in
the preven-tion of influenza infection. However, when vaccination is contraindicated or early vaccination is not possible,
amantadine and rimantadine are effective prophylactic agents that have been
shown to protect approximately 70 to 90% of patients from influenza A
infection. Since these drugs do not prevent the host immune response to influenza A,
they may be used to prevent infection during the 2- to 4-week period required
to develop immunity following vaccination. An additional use of amantadine, unrelated to its antiviral activity, is
in the therapy of Parkinson’s disease .
The most frequently reported
side effects of amanta-dine and rimantadine are nausea, anorexia, dizziness,
and insomnia. These effects are dose-related and are more common with
amantadine than rimantadine. Depression, impaired coordination, confusion,
anxiety, light-headedness, urinary retention, and dry mouth are also more
frequent with amantadine. High doses of amantadine may produce cardiac
arrhythmias, delirium, hallucinations, and suicidal ideation; long-term
treat-ment may cause peripheral edema, orthostatic hypoten-sion, and rarely,
congestive heart failure. Abrupt with-drawal of amantadine may produce a
neuroleptic malignant syndrome. Both drugs can produce seizures or worsen
preexisting seizure disorders. Animal studies have shown that amantadine is
teratogenic and riman-tadine may be embryotoxic.
Neither drug should be given
during pregnancy and lactation. Individuals with congestive heart failure,
edema, orthostatic hypotension, seizure disorders, or uncontrolled psychosis
should be closely monitored during therapy with amantadine. The dosage of
riman-tadine must be decreased in cases of renal or hepatic impairment, whereas
amantadine requires dosage ad-justment only when renal impairment is present.
The elderly are more susceptible to the central nervous sys-tem (CNS) and
gastrointestinal effects of these drugs; rimantadine is generally better
tolerated in this popula-tion. Individuals over age 65 require half the dose of
ei-ther drug given to younger adults.
Several drug interactions
involving amantadine and rimantadine are clinically significant.
Anticholinergic drugs can potentiate the toxicity of amantadine. Thiazide–triamterene,
trimethoprim–sulfamethoxazole, quinine, and quinidine increase plasma
amantadine levels. Cimetidine decreases rimantadine clearance, and aspirin and
acetaminophen decrease rimantadine plasma levels.