Influenza amantadine/rimantadine

Fleming DM. Managing influenza amantadine, rimantadine and beyond. Int J Clin Pract 2001 55(3) 189-95. 

Immunoprophylaxis with inactivated vaccine remains the principal means for reducing influenza-related morbidity and death. Although the vaccine provides the best protection against influenza, there are four antiviral agents that are used to prevent or treat influenza amantadine, rimantadine, zanamivir, and oseltamivir. To shorten the duration of influenza symptoms, all agents should be initiated within 2 days of onset of symptoms. 

Fig. 1.4 Hemagglutination assay results from the active fraction of the red alga Gigartina skottsbergii. a Red blood cells (RBCs) hemagglutinate in the presence of influenza virus top row) and with extract A4 -t- virus or extract A4 alone. The bottom two rows present the back titration of the virus used in this experiment, b In contrast to the other anti-influenza drugs (ribavirin, amantadine, rimantadine, and zanamivir) that do not induce hemagglutination of human as well as chicken RBCs, extract A4 does it in a dose-dependent manner...

Anti-influenza drugs Inhibitors of vital uncoating Amantadine Rimantadine... 

Amantadine hydrochloride [665-66-7] (1-adamantanamine hydrochloride, 41), C qH N HQ., (93) is a good example of a narrow-spectmm agent active only against influenza A vims. It became the first antiviral dmg available for systemic use in the United States when it was approved by the FDA in 1966 for use against Asian influenza. In 1976, FDA approval was extended to the use of amantadine for the reHef of symptoms of all influenza A strains. Amantadine is marketed by Du Pont de Nemours Co., Inc. A stmcturaHy related dmg, rimantadine hydrochloride [1501 -84-4] C 2H2 N HQ, (a-methyl-l-adamantanemethylamine hydrochloride, 42), is widely used in Russia to treat influenza A vims (94). 

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. 

In pharmacology, two adamantane derivatives. Amantadine (1-adamanta-neamine hydrochloride) and Rimantadine (a-methyl-1-adamantane methyla-mine hydrochloride) (see Fig. 24), have been well known because of their antiviral activity [129]. The main application of these drugs is prophylaxis (treatment to prevent the onset of a particular disease) and treatment of influenza-A viral infections. They are also used in the treatment of parkinsonism and inhibition of hepatitis-C virus. Memantine (1-amino-3,5-dimethyladaman-tane) (see Fig. 24) has been reported effective in slowing the progression of Alzheimer s disease [130]. 

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. 

During known epidemics involving the influenza A virus, amantadine or rimantadine may be effective in minimizing associated symptomatology if administered early in the course of the disease. 

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... 

Rimantadine (Flumadine) [Antiviral] Uses Prophylaxis Rx of influenza A viral Infxns but not for HlNl swine flu Action Antiviral Dose Adults Feds >9 y. 100 mg PO bid Feds 2-9 y. 5 mg/kg/d PO, 150 mg/d max daily w/ severe renal/hepatic impair elderly initiate w/in 48 h of Sx onset Caution [C, -] w/ cimetidine avoid w/ PRG, breast-feeding Contra Component amantadine allergy Disp Tabs SE Orthostatic X BP, edema, dizziness, GI upset, X Sz threshold Interactions T Effects W/ cimetidine i effects W/ acetaminophen, ASA EMS Concurrent EtOH usage may result in light-headedness, confusion, syncope, and hypotension OD May cause N/V, tremors, Szs, anticholinergic Sxs, ventricular arrhythmias give IV fluids... 

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. 

Amantadine Symmetrel) is a synthetic tricyclic amine, and rimantadine (Flumadine) is its a-methyl derivative. Both drugs inhibit the replication of the three antigenic subtypes of influenza A (HlNl, H2N2 and H3N2) and have negligible activity against influenza B. 

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). 

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. 

Both amantadine and rimantadine, in doses of 100 mg twice daily or 200 mg once daily, are approximately 70-90% protective in the prevention of clinical illness by influenza A. The effectiveness of postexposure prophylaxis is inconsistent. When begun within 1-2 days after the onset of clinical symptoms of influenza, both drugs reduce the duration of fever and systemic complaints by 1-2 days. 

In many viral infections the clinical symptoms appear late in the course of the disease at a time when most of the virus particles have replicated. [Note This contrasts with bacterial diseases in which the clinical symptoms are usually coincident with bacterial proliferation.] At this late, symptomatic stage of the viral infection, administration of drugs that block viral replication have limited effectiveness. However, some antiviral agents are useful as prophylactic agents. For example, amantadine [a MAN ta deen] and its congener, rimantadine [rih MAN ta deen] have been shown to be equally effective in preventing influenza A infections. [Note Amantadine is also effective in the treatment of some cases of Parkinson s disease (see p. 87).]... 

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. 

---