Amantadine

Mechanism

Chemical and Commercial Profile

Common trade names: Amantadine, Mantadix.
Group: Antiparkinsonian, antiviral with a tricyclic structure (derived from adamantane).

Mechanism of Action

Amantadine acts through a dual complementary mechanism:

1. Dopaminergic Mechanism (Presynaptic Action): It directly stimulates the release of dopamine in the striatal presynaptic terminals and blocks its reuptake through weak inhibition of the DAT transporter, indirectly increasing dopaminergic tone in the indirect and direct pathway.
2. Antiglutamatergic Mechanism (Central Action): Acts as a **specific antagonist of the NMDA type glutamate receptor** (N-methyl-D-aspartate). By blocking the massive influx of calcium in response to glutamate, it depresses the state of neuronal excitability and directly modulates the severity of peak dose dyskinesias.

Pharmacokinetics

Pharmacokinetics

• Absorption: Rapid and almost complete after oral intake; bioavailability is 90%. The plasma peak is reached 2-4 hours after taking it on an empty stomach.
• Distribution: Very high binding to plasma proteins (90%). Large distribution volume of 4.5 L/kg. It quickly crosses the blood-brain barrier.
• Metabolism: Absent in the liver. It does not present interactions with the cytochrome system.
• Excretion: Renal predominantly by active tubular secretion and glomerular filtration (90%) as unchanged drug.
• Half-life (t_1/2): 15 hours in healthy adults; It is prolonged to >24 hours in the elderly due to the physiological decrease in renal clearance.

Indicators and dose

Indications

• Treatment of advanced Idiopathic Parkinson's Disease (as an adjuvant to reduce the severity of levodopa-induced peak-dose dyskinesias, and to improve rigidity and end-of-dose bradykinesia).
• Treatment and prophylaxis of influenza type A (historical, currently out of use due to massive strain resistance).

Dosage and Settings

• Initial Monotherapy (Oral): Start with 100 mg once a day; gradually increase after 7 days to 100 mg twice a day (maximum authorized dose of 200 mg/day).
• Analytical adjustment in Renal Failure:
  • Cl_Cr [30-50 ml/min]: Reduce the theoretical daily dose to 100 mg once a day.
  • Cl_Cr [15-30 ml/min]: Reduce the daily dose to 100 mg every other day.
  • Cl_Cr < 15 ml/min (Severe): Absolutely contraindicated.

Security

Contraindications

• Known decompensated congestive heart failure or dilated cardiomyopathy.
• Moderate to severe renal failure (Cl_Cr < 15 ml/min).
• History of previous seizures (amantadine temporarily depresses the epileptogenic threshold).

Adverse Effects (ADR)

Ophthalmic and Dermatological Safety Alert

Amantadine can cause two very characteristic vascular and dermatological adverse effects: livedo reticularis (a symmetrical mottled purple discoloration of the skin of the lower extremities due to vascular spasm secondary to the accumulation of tissue catecholamines), and severe irreversible corneal edema due to endothelial dysfunction. It requires adequate ophthalmic monitoring and discontinuing the drug immediately if persistent blurred vision is observed.

• CNS: Late-onset vivid visual hallucinations (common in the elderly), persecutory delirium, nightmares, mental confusion, insomnia, headache, postural dizziness.
• Gastrointestinal: Temporary nausea, dry mouth, moderate stomach pain of early onset.
• General: Symmetric orthostatic hypotension, bilateral malleolar edema, asthenia, unstable gait.

Clinical Interactions

• Anticholinergics: Amitriptyline or biperiden additively enhance the anticholinergic effects of amantadine, potentially triggering paralytic ileus or intestinal obstruction.
• CNS depressants: Pharmacodynamic synergy that multiplies the sedative effects with benzodiazepines, alcohol and opioids.

Pregnancy and Breastfeeding

FDA Category: C. Very limited human data; associates decreased embryonic growth in animals. Breastfeeding: Absolutely contraindicated. Like other dopaminergic drugs, it potently inhibits pituitary prolactin release reflexively, suppressing lactation, in addition to being excreted in breast milk.