Amantadine and Rimantadine

Amantadine and rimantadine are administered to individuals already infected with influenza A to lessen the extent of the illness associated with the virus. These drugs are also given prophylactically to individuals who may have been exposed to influenza A and to high-risk patients such as the elderly or those with cardiopulmonary and other diseases. Amantadine may also be somewhat effective in treating certain cases of hepatitis C infection.103 These drugs are typically administered orally, either in capsule form or in a syrup preparation. 

Mechanism of Action. Amantadine and rimantadine appear to inhibit one of the early steps in influenza A replication by blocking the uncoating of the virus and preventing the release of viral nucleic acid within the host cell.42 These drugs may also interfere with the assembly of viral components, thus inhibiting one of the final steps in the replication process42 This dual inhibitory effect on the early and late steps of viral replication accounts for these drugs antiviral effectiveness. 

Adverse Effects. These drugs may produce central nervous system (CNS) symptoms such as confusion, loss of concentration, mood changes, nervousness, dizziness, and light-headedness. These symptoms may be especially problematic in elderly patients. Excessive doses of amantadine and rimantadine may increase the 

Antiviral Efficacy and Clinical Use. Cidofovir (Vis-tide) is used primarily to treat CMV retinitis in people with AIDS.111 When used clinically, this drug is often combined with probenecid, an agent that inhibits renal excretion of cidofovir, thereby providing higher plasma levels of this antiviral agent.112 

Mechanism of Action. Cidofovir works like acyclovir and ganciclovir these drugs inhibit viral DNA replication by inhibiting DNA polymerase activity and by halting elongation of viral DNA chains.42 

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Two classes of inhibitors for influenza virus are currently available (Hayden 2006). The M2 proton channel inhibitors amantadine and rimantadine and the neuraminidase (NA) inhibitors oseltamivir carboxylate and zanamivir. Chapter 5 provides more details about the class of NA inhibitors. 

The site of action for Memantine is the central nervous system (CNS) and it has CNS affinity. Amantadine and Rimantadine can penetrate to the CNS and cause some adverse effects. 

Furthermore, because the half-life of Amantadine and Rimantadine in the bloodstream is long (12-18 hours for Amantadine and 24-36 hours for... 

The adamantanes, amantadine and rimantadine, are currently not recommended for prophylaxis or treatment in the United States because 92% of the circulating influenza A viruses are resistant to these agents. 

The two classes of antiviral drugs available for treatment of influenza are the same as those available for prophylaxis and include the adamantanes, amantadine and rimantadine, and the neuraminidase inhibitors, oseltamivir and zanamivir. Because of widespread resistance to the adamantanes among influenza A viruses in the United States, amantadine and rimantadine are not recommended for treatment of influenza until susceptibility can be reestablished. 

Hall M, Brown Michael D (2005) Evidence-based emergency medicine/systematic review abstract. Are amantadine and rimantadine effective in healthy adults with acute influenza Ann Emerg Med 46 292-293... 

Keyset LA, Karl M, Nafziger AN, Bertino JS Jr. (2000) Comparison of central nervous system adverse effects of amantadine and rimantadine used as sequential prophylaxis of influenza a in elderly nursing home patients. Arch Intern Med 160 1485-1488... 

Currently, two classes of drugs are available with antiviral activity against influenza viruses inhibitors of the ion channel activity of the M2 membrane protein, amantadine and rimantadine, and the neuraminidase inhibitors oseltamivir, and zanamivir. H5N1 viruses isolated from poultry and humans in Thailand and Viet Nam in 2004 invariably showed an amantadine-resistance indicating that amantadine treatment is not an option during the ongoing outb-treak in South-East Asia. 

Viral resistance develops rapidly in approximately 30% of individuals treated with amantadine or rimantadine. Resistant viruses are associated with the failure of drug prophylaxis in close contacts of infected individuals who have been treated with these antiviral agents. Mutation in the transmembrane domain of the M2 protein is the most frequent cause of resistance to amantadine and rimantadine. 

Amantadine and rimantadine are used for the treatment of diseases caused by influenza A strains. When these agents are administered within 48 hours of the onset 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 Centers for Disease Control s (CDC) Immunization Practices Advisory Committee recommends annual vaccination as the method of choice in the prevention 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 (see Chapter 31). 

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. 

In the absence of resistance, both amantadine and rimantadine, at 100 mg twice daily or 200 mg once daily, are 70-90% protective in the prevention of clinical illness when initiated before exposure. When begun within 1-2 days after the onset of illness, the duration of fever and systemic symptoms is reduced by 1-2 days. 

Mode of action The precise antiviral mechanism of amantadine and rimantadine remains to be established. Recent evidence points to a blockade of the viral membrane matrix protein, M2, which functions as an ion channel. This channel is required for the fusion of the viral membrane with the cell membrane that ultimately forms the endosome (created when the virus is internalized by endocytosis). [Note The acid environment of the endosome is required for viral uncoating.] These drugs may also interfere with the release of new virions. 

Resistance Influenza A resistance to amantadine and rimantadine is not a clinical problem as yet, although some viral isolates have shown a high incidence of resistance. Resistance has been shown to be due to a change in one amino acid of the M2 matrix protein. Cross-resistance occurs between the two drugs. 

Adverse effects Amantadine s side effects are mainly associated with the CNS. Minor neurologic symptoms include insomnia, dizziness, and ataxia. More serious side effects have been reported (for example, hallucinations, seizures). The drug should be employed cautiously in patients with psychiatric problems, cerebral atherosclerosis, renal impairment, or epilepsy. Rimantadine causes fewer CNS reactions since it does not efficiently cross the blood-brain barrier. Amantadine and rimantadine should be used with caution in pregnant and nursing mothers, because they have been found to be embryotoxic and teratogenic in rats. 

Therapies for typical human influenza viruses should work in treating avian influenza infection in humans however, influenza viruses can become resistant to drugs such as amantadine and rimantadine, decreasing their effectiveness. Currently no vaccine is available to protect humans against the H5N1 virus that causes... 

Heider H, Adamczyk B, Presber HW, Schroeder C, Feldblum R, Indulen MK. Occurrence of amantadine- and rimantadine-resistant influenza A virus strains during the 1980 epidemic. Acta Virol 1981 25(6) 395 00. 

Amantadine and rimantadine are tricyclic aliphatic primary amines, active only against influenza A virus Both agents are utilized for the treatment and prophy-... 

How do amantadine and rimantadine differ with regard to renal elimination and potential for CNS toxicity ... 

Amantadine and rimantadine are chemically related antiviral drugs active against influenza A but not influenza B viruses. Amantadine differs from rimantadine because it is primarily renally eliminated and is associated with more CNS side effects and can potentially lower the seizure threshold. 

Case Conclusion BB was started on oseltamivir since the neuraminidase inhibitors also have activity against influenza B, unlike amantadine and rimantadine. Also, with her seizure history, amantadine would not be an option because it may lower the seizure threshold. Her symptoms resolve 2 days sooner than her roommate s, and her finals go smoothly. 

D The most appropriate therapy would be a neuraminidase inhibitor such as oseltamivir since amantadine and rimantadine do not cover influenza B. Treatment of influenza must be initiated within 48 hours of symptoms for maximum efficacy. Influenza vaccination is only effective for the prevention of influenza and not for symptomatic therapy. If this were influenza A and amantadine was chosen to treat this patient, dose adjustments would be necessary due to her renal insufficiency. She would also be at increased risk of CNS toxicity due to her age and possible accumulation of the drug due to her renal insufficiency. 

Amantadine and rimantadine are approved in the United Sues I orpKvention and treatment of inlluen/a type A virus iticdimis.. Sco.sonal prophylaxis with either drug is about... 

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