Antiinfluenza Agents: Amantadine and Rimantadine

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 rimantadine.

Absorption, Metabolism, and Excretion

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.

Clinical Uses

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 .

Adverse Effects, Contraindications, and Drug Interactions

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.