Introduction
Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist approved for the treatment of moderate to severe Alzheimer's disease. It represents a distinct pharmacological approach from acetylcholinesterase inhibitors, targeting glutamatergic neurotransmission dysfunction associated with dementia. Originally developed in the 1960s and approved by the FDA in 2003, memantine has become a cornerstone in the management of Alzheimer's disease progression.
Mechanism of Action
Memantine exerts its therapeutic effects through non-competitive, voltage-dependent antagonism of NMDA receptors. In Alzheimer's disease, chronic glutamate excitotoxicity leads to neuronal damage. Memantine selectively blocks NMDA receptor channels during prolonged glutamate exposure while preserving physiological NMDA receptor activity required for normal synaptic transmission and learning. This modulation reduces calcium influx into neurons, thereby decreasing excitotoxic damage and potentially slowing neurodegenerative processes.
Indications
- Treatment of moderate to severe Alzheimer's disease (FDA-approved)
- May be used as monotherapy or in combination with acetylcholinesterase inhibitors
- Off-label uses include vascular dementia, mild cognitive impairment, and neuropathic pain (evidence varies)
Dosage and Administration
Standard titration regimen:- Week 1: 5 mg once daily
- Week 2: 5 mg twice daily
- Week 3: 10 mg morning, 5 mg evening
- Week 4 and maintenance: 10 mg twice daily
- Oral administration with or without food
- Available as immediate-release tablets, extended-release capsules, and oral solution
- Maximum recommended dose: 20 mg daily (10 mg twice daily for immediate-release, 28 mg once daily for extended-release)
- Renal impairment: Reduce dose in moderate to severe impairment (CrCl < 30 mL/min)
- Hepatic impairment: Use with caution in severe impairment
- Elderly: No dosage adjustment required based on age alone
Pharmacokinetics
Absorption: Well absorbed orally with absolute bioavailability of approximately 100% Distribution: Volume of distribution: 9-11 L/kg; 45% protein binding Metabolism: Partial hepatic metabolism via cytochrome P450 system (CYP2B6, CYP2C9, CYP2D6, CYP3A4) to three minor metabolites Elimination: Primarily renal excretion (57-82% unchanged); elimination half-life: 60-80 hours Steady-state: Reached in approximately 10 days with twice-daily dosingContraindications
- Hypersensitivity to memantine or any component of the formulation
- Severe renal impairment (CrCl < 30 mL/min) for extended-release formulation
- Concurrent use with other NMDA antagonists (amantadine, ketamine, dextromethorphan)
Warnings and Precautions
- Renal impairment: Dose adjustment required in moderate to severe impairment
- Seizure disorders: May lower seizure threshold
- Cardiac conditions: Use caution in recent MI, uncompensated CHF, or uncontrolled hypertension
- Psychiatric symptoms: May exacerbate psychosis or agitation in susceptible patients
- Urinary conditions: Use caution in patients with conditions that raise urine pH
- Pregnancy: Category B - use only if clearly needed
- Lactation: Not recommended during breastfeeding
Drug Interactions
Significant interactions:- NMDA antagonists: Increased risk of adverse effects (amantadine, ketamine, dextromethorphan)
- Urinary alkalinizers: Sodium bicarbonate, carbonic anhydrase inhibitors may decrease memantine elimination
- Cimetidine: May reduce renal clearance of memantine
- Hydrochlorothiazide: May increase memantine concentrations
- Cholinergic agents: Potential pharmacodynamic interaction with acetylcholinesterase inhibitors
Adverse Effects
Common (≥5%):- Dizziness (7%)
- Headache (6%)
- Constipation (5%)
- Confusion (6%)
- Fatigue, pain, hypertension, vomiting, anxiety, somnolence, hallucinations
- Back pain, dyspnea, coughing, peripheral edema
- Seizures
- Psychotic symptoms
- Stevens-Johnson syndrome
- Hepatitis
- Suicidal ideation
Monitoring Parameters
- Cognitive function: Regular assessment using standardized tools (MMSE, ADAS-cog)
- Functional status: Activities of daily living evaluation
- Behavioral symptoms: Monitoring for agitation, psychosis, or depression
- Renal function: Baseline and periodic serum creatinine assessment
- Adverse effects: Regular assessment for dizziness, confusion, constipation
- Clinical response: Evaluation of therapeutic benefit and tolerability
Patient Education
- Take medication exactly as prescribed; do not adjust dosage without medical supervision
- Extended-release capsules must be swallowed whole; do not crush, chew, or divide
- Report any new or worsening symptoms, especially dizziness, confusion, or mood changes
- Maintain adequate fluid intake to prevent constipation
- Inform all healthcare providers about memantine use, especially before new medications
- Do not stop medication abruptly without consulting healthcare provider
- Keep regularly scheduled follow-up appointments to monitor progress
- Caregivers should be educated about administration and monitoring
References
1. FDA Prescribing Information: Namenda (memantine hydrochloride) 2. McShane R, Westby MJ, Roberts E, et al. Memantine for dementia. Cochrane Database Syst Rev. 2019;3(3):CD003154 3. Kishi T, Matsunaga S, Oya K, et al. Memantine for Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimers Dis. 2017;60(2):401-425 4. Parsons CG, Danysz W, Dekundy A, et al. Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system. Neuropharmacology. 2017;124:1-23 5. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Alzheimer's Disease and Other Dementias. 3rd ed. 2021 6. Lexicomp Online, Lexi-Drugs. Memantine. Wolters Kluwer Clinical Drug Information, Inc. 2023