Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: anti-parkinson drugs, ATC code: N04BB01
Amantadine has various pharmacological effects. The agent has an indirectly agonistic effect at the striatal dopamine receptor. Animal studies have shown that amantadine increases the extracellular dopamine concentration both by increased dopamine release and through blockade of re-uptake into the presynaptic neurones. At therapeutic concentrations, amantadine inhibits the release of acetylcholine mediated by NMDA receptors and can thus trigger anticholinergic effects. The agent has synergistic effects with L-dopa.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
Absorption:
Amantadine hydrochloride undergoes rapid and complete absorption from the gastrointestinal tract after oral administration.
Plasma concentration, elimination:
Peak plasma concentrations are reached approximately 2 and 8 hours (tmax) after administration of a single dose. The freely soluble amantadine hydrochloride gives higher peak plasma amantadine concentrations than the more sparingly soluble amantadine sulphate, for which the peak plasma concentration (Cmax) is reached later than that of the hydrochloride. After a single oral dose of 250 mg amantadine hydrochloride, a Cmax of 0.5 µg/ml is attained.
At a dosage of 200 mg/day steady state is reached after 4-7 days, with plasma concentrations of 400-900 ng/ml. After administration of 100 mg amantadine sulphate Cmax is 0.15 µg/ml.
The total amount of active substance absorbed (AUC) is the same for the two amantadine salts.
Plasma clearance was found to be identical to renal clearance, at 17.7 ± 10 L/h in healthy elderly volunteers. The apparent volume of distribution (4.2 ± 1.9 L/kg) is age-dependent; in the elderly it is 6.0 L/kg.

The elimination half-life is between 10 and 30 hours, with a mean of approximately 15 hours, and is largely dependent on the age of the patient. Elderly male patients (62-72 years) show an elimination half-life of 30 hours. In patients with renal insufficiency, the terminal plasma half-life may be substantially prolonged, to 68 ± 10 hours.
In vitro, amantadine is approximately 67% plasma-protein bound; approximately 33% is present in plasma in the unbound form. It overcomes the blood-brain barrier by virtue of a saturatable transporter system.
Amantadine is excreted in the urine almost completely unchanged (90% of a single dose), small amounts being excreted in the faeces.
The dialysability of amantadine hydrochloride is low, at some 5% for a single dialysis.
Metabolism:
Amantadine is not metabolised in humans.