Amantadine, influenza

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. 

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). 

Both amantadiae and rknantadiae have been found to reduce the duration of influenza A-iaduced fever and malaise, and to lessen viral shedding. Prophylactic treatment has been recommended for high risk patients (95). It has been suggested that, ia the presence of amantadine, the influenza vims attaches normally to cells, but once iaside the ceU the vims fails to initiate repHcation. Thus amantadine appears to inhibit the initiation of transcription at an early stage between uncoating and viral-specific RNA synthesis (96). 

Amantadine is an antiviral agent that is active against influenza A infection and against some strains of H5NX avian flu. Draw a three-dimensional representation of amantadine showing the chair cyclohexane rings. 

AMANTADINE The nurse administers this drug for the prevention or treatment of respiratory tract illness caused by influenza A virus. Some patients are prescribed this drug to manage extrapyramidal effects caused by drugp used to treat Parkinsonism (See Chaps. 29 and 32). The nurse should protect the capsules from moisture to prevent deterioration. When the drug is administered for symptoms of influenza, it is important to start therapy within 24 to 48 hours after symptoms begin. 

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. 

Abed Y, Goyette N, Boivin G (2005) Generation and characterization of recombinant influenza A (HlNl) viruses harboring amantadine resistance mutations, Antimicrob Agents Chemother 49 556-559... 

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]. 

Amantadine hydrochloride (Fig. 5.21A) does not prevent adsorphon but inhibits viral penetration. It has a very narrow spectrum and is used prophylachcally against infechon with influenza A vims it has no piophylachc value with other types of influenza... 

The adamantane moiety is of medicinal chemical interest because of its inertness, compactness relative to lipid solubilizing character, and symmetry. Considerable interest, therefore, was engendered by the finding that amantadine (78) was active for the chemoprophylaxis of influenza A in man. There are not many useful chemotherapeutic agents available for the treatment of communicable viral infections, so this finding led to considerable molecular manipulation. The recent abrupt end of the National Influenza Immunization program of 1976 prompted a new look at the nonvaccine means for prophylaxis or treatment of respiratory tract infections due to influenza A, especially in that the well-known antigenic shift or drift of the virus obviates usefulness of the vaccine but not amantadine. 

Amantadine, a synthetic antiviral agent used prophylactically against influenza A2, is thought to act by... 

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. 

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...

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... 

Stange KC, Little DW, Blatnik B (1991) Adverse reactions to amantadine prophylaxis of influenza in a retirement home. J Am Geriatr Soc 39 700-705... 

Amantadine (C) specifically affects the replication of influenza A (RNA) viruses, the causative agent of true influenza. These viruses are endocytosed into the cell. Release of viral DNA requires protons from the acidic content of endosomes to penetrate the virus. Presumably, amantadine blocks a channel protein in the viral coat that permits influx of protons thus, uncoating is prevented. Moreover, amantadine inhibits viral maturation. The drug is also used prophylactically and, if possible, must be taken before the outoreak of symptoms. It also is an antiparkinsonian... 

Influenza A viral infection Amantadine is indicated for the prophylaxis and treatment... 

Prophylaxis - Start in anticipation of contact or as soon as possible after exposure. Use daily for at least 10 days following a known exposure. The infectious period extends from shortly before onset of symptoms to up to 1 week after. Because amantadine does not appear to suppress antibody response, it can be used in conjunction with inactivated influenza A virus vaccine until protective antibody responses develop administerfor 2 to 4 weeks after vaccine has been given. When the vaccine is unavailable or contraindicated, give amantadine for the duration of known influenza A in the community because of repeated and unknown exposure. 

Pharmacology Inhibits the replication of influenza A virus isolates from each of the subtypes. Amantadine s antiviral activity is not completely understood. Its mode of action appears to be the prevention of the release of infectious viral nucleic acid P.1044... 

Amantadine is 70% to 90% effective in preventing illnesses caused by type A influenza viruses. 

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... 

Amantadine (see Chapter 21, Section Ill.b.l) is a tricyclic symmetric adamantanamine. It inhibits the uncoating stage which takes place for binding of the virus to cells, of the influenza-A virus. It is used prophylactically for influenza-A infection, and when given within 24 hours of onset for active influenza-A. It shows good oral absorption and is excreted in the urine with an elimination half-life of about 12 hours. The adverse effects are mainly on the CNS and include insomnia, restlessness, nervousness and depression. 

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. 

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