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Amantadine

Amantadine: A Versatile Drug in Neurology and Virology

Introduction

Amantadine is a pharmacologically intriguing compound originally developed as an antiviral medication but later found to have significant benefits in treating various neurological disorders. Over the decades, its role has evolved from combating influenza A to becoming an adjunct therapy for Parkinson’s disease, and more recently, being explored for off-label uses in neuroprotection, traumatic brain injury, and fatigue in multiple sclerosis.

Historical Overviews:

Amantadine was first synthesized in the 1960s and gained FDA approval for the prophylaxis and treatment of influenza A virus infections. Its unexpected benefit in improving symptoms of Parkinson’s disease (PD) was discovered serendipitously when patients reported improved motor function while on the drug for flu prevention. This opened up a new therapeutic avenue in neurology, particularly in movement disorders. Today, Amantadine is a dual-action drug—used both as an antiviral and a dopaminergic agent, with a growing list of off-label applications.

Chemical Profile:

  • IUPAC Name: 1-adamantylamine

  • Molecular Formula: C10H17N

  • Molecular Weight: 151.25 g/mol

  • Structure: Tricyclic amine with a rigid cage-like skeleton

  • Class: Antiviral agent, Dopaminergic agent, NMDA receptor antagonist

Mechanism of Action:

1. Antiviral Action

Amantadine exerts its antiviral activity by:

  • Blocking the M2 ion channel of the influenza A virus

  • Preventing uncoating of the viral RNA, which is necessary for replication

Note: It is ineffective against influenza B and most current strains of influenza A due to high levels of resistance.

2. Neurological Action

In neurological conditions, Amantadine:

  • Increases dopamine release and inhibits its reuptake in the CNS

  • Acts as a non-competitive NMDA receptor antagonist, reducing glutamate excitotoxicity

  • May also influence norepinephrine and serotonin pathways

This makes it beneficial in Parkinson’s disease, drug-induced extrapyramidal symptoms, and fatigue associated with MS.

Approved Indications:

1. Parkinson’s Disease

Used to treat:

  • Bradykinesia

  • Rigidity

  • Tremor

  • Drug-induced dyskinesia (especially from levodopa)

2. Influenza A (limited use)

  • Prophylaxis and treatment

  • No longer recommended due to resistance

3. Extrapyramidal Symptoms

  • Drug-induced EPS from antipsychotics (e.g., akathisia, dystonia)

Off-Label Uses:

Condition Rationale
Multiple sclerosis (MS) fatigue Increases alertness and energy
Traumatic brain injury (TBI) Enhances arousal and cognition
ADHD Dopaminergic effects
Depression augmentation NMDA antagonism has antidepressant-like effects
Restless legs syndrome Dopaminergic modulation

Formulations and Dosage:

Available Forms

  • Oral capsules: 100 mg

  • Syrup: 50 mg/5 mL

  • Extended-release tablets: 129 mg, 193 mg

Common Dosages

Indication Adult Dosage
Parkinson’s Disease 100 mg 1–2 times/day; max 400 mg/day
Influenza A 100 mg twice daily (rarely used now)
MS fatigue 100–200 mg/day
EPS 100–200 mg/day

Dose adjustments are needed in renal impairment due to renal elimination.

Pharmacokinetics:

Property Value
Absorption Rapid and complete orally
Bioavailability ~90%
Half-life 10–14 hours (up to 29 hrs in renal impairment)
Metabolism Minimal hepatic metabolism
Excretion Primarily renal (90% unchanged)

Side Effects:

While generally well tolerated, Amantadine may cause:

Common Side Effects

  • Nausea

  • Dizziness

  • Insomnia

  • Dry mouth

  • Anxiety

Serious Side Effects

  • Livedo reticularis (net-like skin discoloration)

  • Orthostatic hypotension

  • Peripheral edema

  • Hallucinations, confusion (especially in elderly)

  • Seizures (in overdose)

Abrupt discontinuation may cause Parkinsonian rebound or withdrawal symptoms.

Contraindications and Precautions:

Condition Recommendation
Renal failure Reduce dose; risk of toxicity
History of seizures Use with caution
Heart failure May worsen peripheral edema
Pregnancy/lactation Category C; not recommended unless necessary
Elderly Monitor for cognitive effects and falls

Drug Interactions:

Amantadine may interact with:

  • CNS stimulants → additive effects

  • Anticholinergic drugs → enhanced side effects (e.g., dry mouth, confusion)

  • Levodopa → synergistic in Parkinson’s, but may worsen dyskinesias

  • Diuretics (triamterene) → may increase CNS toxicity

  • Alcohol → potentiates CNS depression

Amantadine in Parkinson’s Disease:

Amantadine is unique among anti-Parkinsonian drugs because:

  • It provides modest symptomatic benefit

  • It reduces levodopa-induced dyskinesias

  • It can be started early or added later in treatment

It is often prescribed when:

  • Motor complications arise

  • There is tolerance to dopamine agonists

  • Non-motor symptoms like fatigue or apathy need management

Gocovri® (Extended-Release)

This formulation is FDA-approved specifically for dyskinesia in Parkinson’s patients on levodopa. It maintains a steady plasma concentration, reducing fluctuations in efficacy.

Amantadine in Multiple Sclerosis:

Fatigue is one of the most disabling MS symptoms. Amantadine:

  • Improves wakefulness and energy

  • May enhance motor control and concentration

  • Is considered first-line pharmacologic therapy for MS fatigue by some guidelines

Dosing for MS Fatigue

  • 100 mg once or twice daily

  • Full effect seen in 2–4 weeks

Amantadine in Traumatic Brain Injury (TBI):

Amantadine is increasingly used in neurorehabilitation settings for TBI:

  • Promotes arousal in comatose or minimally conscious states

  • Improves cognitive recovery

  • Enhances executive function and motor initiation

Studies show benefit even when started weeks after injury, making it a cost-effective cognitive stimulant.

Amantadine Resistance in Influenza:

Widespread use of Amantadine in the past led to:

  • Rapid emergence of resistant influenza A strains

  • Reduced utility of the drug in viral epidemics

  • Current CDC guidelines no longer recommend Amantadine for influenza treatment or prophylaxis

Other antivirals like oseltamivir and zanamivir are now preferred.

Current Research and New Directions:

Recent research is exploring:

  • Amantadine analogs with better CNS selectivity

  • Role in long COVID-related fatigue

  • Combination with memantine or ketamine for depression

  • Use in L-dopa sparing strategies in Parkinson’s disease

Pharmacogenetic studies may soon guide personalized Amantadine use, especially in neuropsychiatric indications.

Patient Counseling Tips:

  • Take Amantadine in the morning to avoid insomnia.

  • Do not stop suddenly, especially in Parkinson’s disease.

  • Stay hydrated; report swelling or skin discoloration.

  • Watch for changes in mood or behavior.

  • Adjust dose carefully in elderly or renal impairment.

Conclusion:

Amantadine is a multifaceted and underappreciated drug that has proven valuable in both infectious diseases and neurology. Though its role in antiviral therapy has diminished, its impact on managing Parkinson’s disease, drug-induced movement disorders, and fatigue in neurological conditions remains significant. With emerging research supporting new indications, Amantadine continues to evolve as a neurotherapeutic agent with great potential. Proper patient selection, monitoring, and dose adjustments are key to maximizing its benefits while minimizing side effects.

References:

  1. LeWitt PA, et al. Amantadine for levodopa-induced dyskinesias in Parkinson's disease. Mov Disord.

  2. Giacino JT, Whyte J. Amantadine in the treatment of TBI. N Engl J Med.

  3. National Multiple Sclerosis Society Guidelines

  4. CDC Guidelines on Influenza Antiviral Resistance

  5. Drugs.com, FDA label on Gocovri and Osmolex ER

  6. UpToDate: Amantadine drug monograph.