Amantadine

Absorption

Amantadine is well absorbed orally from the gastrointestinal tract.

Toxicity

Deaths have been reported from overdose with amantadine. The lowest reported acute lethal dose was 2 grams. Drug overdose has resulted in cardiac, respiratory, renal or central nervous system toxicity. Cardiac dysfunction includes arrhythmia, tachycardia and hypertension. Pulmonary edema and respiratory distress (including ARDS) have been reported. Renal dysfunction including increased BUN, decreased creatinine clearance and renal insufficiency can occur. Central nervous system effects that have been reported include insomnia, anxiety, aggressive behavior, hypertonia, hyperkinesia, tremor, confusion, disorientation, depersonalization, fear, delirium, hallucination, psychotic reactions, lethargy, somnolence and coma. Seizures may be exacerbated in patients with prior history of seizure disorders. Hyperthermia has also been observed in cases where a drug overdose has occurred.

Description

Amantadine is an agent that raises the concentration of dopamine in the synaptic cleft by releasing it from neurons and suppressing the process of reuptake.

Chemical properties

White to cream powder

The Uses of Amantadine

Amantadine is a primary amine derivative of adamantane. It has an effect on mycoviruses, which are RNA-containing viruses. It has a very narrow spectrum of action and is used only for treating and preventing influenza A. It is also used for treating Parkinsonism. The exact mechanism of antiviral action of amantadine is not completely understood. It is believed that it is an ion channel blocker. It has also been suggested that amantadine inhibits absorption of viral particles into the host cell, which is expressed in the breakdown of diffusion of the virus into the cell, or inhibition of the “stripping process” of the virus. The main use is for the prevention of type A2 influenza. Synonyms of this drug are simmetrel, viregit, mantadan, and others.

The Uses of Amantadine

Building block for an L-piperidinamide catalyst used in an enantioselective Strecker reaction of phosphinoyl imines.1

The Uses of Amantadine

Amantadine is an antiviral drug. The properties in amantadine, which relieve symptoms of Parkinsonism were discovered by accident. Treatment of Parkinsonism with a combination of levodopa, anticholinergic drugs, and amantadine gives better results than using any of these drugs individually.

Background

An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake.

Indications

For the chemoprophylaxis, prophylaxis, and treatment of signs and symptoms of infection caused by various strains of influenza A virus. Also for the treatment of parkinsonism and drug-induced extrapyramidal reactions.

Definition

ChEBI: A member of the class of adamantanes that is used as an antiviral and antiparkinson drug.

brand name

Symadine (Solvay Pharmaceuticals); Symmetrel (Endo).

Biological Functions

Amantadine was originally introduced as an antiviral compound, but it is modestly effective in treating symptoms of parkinsonism. It is useful in the early stages of parkinsonism or as an adjunct to levodopa therapy. Its mechanism of action in parkinsonism is not clear, but amantadine may affect dopamine release and reuptake. Additional sites of action may include antagonism at muscarinic and N-methyl-Daspartate (NMDA) receptors. Adverse effects include nausea, dizziness, insomnia, confusion, hallucinations, ankle edema, and livedo reticularis. Amantadine and the anticholinergics may exert additive effects on mental functioning

Synthesis Reference(s)

Journal of the American Chemical Society, 91, p. 6457, 1969 DOI: 10.1021/ja01051a047
Synthesis, p. 457, 1976

Antimicrobial activity

It inhibits influenza A virus replication at concentrations of 0.2– 0.6 mg/L, but has little or no activity against influenza B or C.

Acquired resistance

Resistance is the consequence of mutations in amino acid positions 27, 30 and 31 in the M2 transmembrane sequence. Cross-resistance between amantadine and rimantadine is universal. Influenza H3N2 strains worldwide are now resistant, but seasonal H1N1 strains remain susceptible. Postexposure family prophylaxis results in the prompt emergence of drug resistance after onset of treatment.

General Description

Amantadine has been used for years as a treatment for Parkinson disease. The adamantanamines have twomechanisms in common:they inhibit an early step in viralreplication, most likely viral uncoating,and in somestrains, they affect a later step that probably involves viral assembly,possibly by interfering with hemagglutinin processing.The main biochemical locus of action is the influenzatype A virus M2 protein, which is an integral membrane proteinthat functions as an ion channel. The M2 channel is a protontransport system. By interfering with the function of theM2 protein, the adamantanamines inhibit acid-mediated dissociationof the ribonucleoprotein complex early in replication.They also interfere with transmembrane proton pumping,maintaining a high intracellular proton concentrationrelative to the extracellular concentration and enhancingacidic pH-induced conformational changes in the hemagglutininduring its intracellular transport at a later stage. The conformationalchanges in hemagglutinin prevent transfer of thenascent virus particles to the cell membrane for exocytosis.

Flammability and Explosibility

Flammable

Pharmaceutical Applications

A symmetrical synthetic C-10 tricyclic amine with an unusual cage-like structure, supplied as the hydrochloride for oral administration.

Mechanism of action

Amantadine hydrochloride (1-adamantanamine hydrochloride) is a symmetric, tricyclic, primary amine that inhibits penetration of RNA viral particles into the host cell. It also inhibits the early stages of viral replication by blocking the uncoating of the viral genome and the transfer of nucleic acid into the host cell.

Pharmacokinetics

Amantadine is an antiviral drug which also acts as an antiparkinson agent, for which it is usually combined with L-DOPA when L-DOPA responses decline (probably due to tolerance). It is a derivate of adamantane, like a similar drug rimantadine. The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. It has been shown to cause an increase in dopamine release in the animal brain, and does not possess anticholinergic activity.

Pharmacokinetics

Oral absorption: >90%
C_max 200 mg oral per day: 0.4–0.9 mg/L after c. 4–6 h
Plasma half-life: 9.7–14.5 h
Volume of distribution: 10.4 L/kg
Plasma protein binding: 65%
Absorption and distribution
Absorption after oral administration is almost complete. Levels in secretions approach plasma concentrations.
Metabolism and excretion
About 56% of a single oral dose is excreted unchanged within 24 h by the kidney. Altogether 90% of an oral dose is excreted in the urine with a mean elimination half-life of 11.8 h in subjects with normal renal function. In elderly men, the half-life is 28.9 h and in patients with renal insufficiency half-lives of 18.5 h to 33.8 days have been observed. The renal clearance is around 398 mL/min (range 112–772 mL/min), indicating active secretion as well as glomerular filtration. Less than 5% of a dose is removed during hemodialysis and average half-lives of 8.3 and 13 days have been reported in patients on chronic hemodialysis. Extreme care must be taken to ensure that drug does not accumulate to toxic levels.

Clinical Use

Prevention and treatment of influenza A H1N1 infections

Clinical Use

Amantadine is used for the treatment of diseases caused by influenza A strains.

Side Effects

Embryotoxicity and teratogenicity have been observed in rats receiving 50 mg/kg per day, about 15 times the usual human dose. Neurological side effects include drowsiness, insomnia, light-headedness, difficulty in concentration, nervousness, dizziness and headache in up to 20% of individuals. Other side effects include anorexia, nausea, vomiting, dry mouth, constipation and urinary retention. All develop during the first 3–4 days of therapy and are reversible by discontinuing the drug. An exception to rapid onset of adverse reactions is livedo reticularis. Convulsions, hallucinations and confusion are dose related, usually occurring at levels in excess of 1.5 mg/L; convulsions may occur at a lower threshold in patients with a history of epilepsy and the drug is best avoided in such patients.

Safety Profile

Poison by intraperitoneal route.Moderately toxic by ingestion. Mutation data reported.When heated to decomposition it emits toxic fumes ofNOx. Used as an antiviral agent.

Synthesis

Amantadine, 1-adamantanamine (10.1.12), is synthesized from adamantane. It is directly brominated to 1-bromadamantane (10.1.10), which in Ritter reaction conditions when heated with a mixture of acetonitrile and concentrated sulfuric acid transforms into 1-acetylaminoadamantane (10.1.11). Hydrolysis of this product using alkali leads to the formation of amantadine (10.1.12) [16,17].

Metabolism

No appreciable metabolism, although negligible amounts of an acetyl metabolite have been identified.

Purification Methods

Dissolve the amine in Et2O, dry it over KOH, evaporate and sublime it in vacuo. [Stetter et al. Chem Ber 93 226 1960.]