Continuing Education Activity

Memantine is an antagonist of the NMDA (N-Methyl-D-Aspartate)-receptor subtype of glutamate receptor. It is used to slow the neurotoxicity thought to be involved in Alzheimer disease and other neurodegenerative diseases.Memantine blocks the NMDA-receptor subtype of glutamate receptors preventing over-activation of glutamine receptors while allowing the normal activity. Its blocking effects antagonize an overactive glutaminergic system in the central nervous system (CNS) which is thought to be involved in the neurotoxicity seen in Alzheimer disease. This activity reviews the uses, indications, side effects and contraindications of memantine and highlights the role of the interprofessional team in the management of patients with dementia.

Objectives:

• Identify the mechanism of action of memantine.
• Describe the adverse effects of memantine.
• Recall the contraindications of memantine.
• Employ interprofessional team strategies for enhancing care coordination and communication to advance the safe use of memantine and improve patient outcomes.

Indications

Memantine is an antagonist of the NMDA (N-Methyl-D-Aspartate)-receptor subtype of glutamate receptor. It is used to slow the neurotoxicity thought to be involved in Alzheimer disease and other neurodegenerative diseases.[1] Memantine blocks the NMDA-receptor subtype of glutamate receptors preventing over-activation of glutamine receptors while allowing the normal activity. Its blocking effects antagonize an overactive glutaminergic system in the central nervous system (CNS) which is thought to be involved in the neurotoxicity seen in Alzheimer disease.[2][3]

Pharmacologic Class

• NMDA-receptor antagonist

Description

• Chemical name: 1-amino-3,5-dimethyladamantane hydrochloride
• Molecular formula: C12H21N•HCl
• Molecular weight: 215.76

Food and Drug Administration (FDA) Indication[4]

• Treatment of moderate to severe Alzheimer dementia

Other Uses (non-FDA approved)

• Mild to moderate Alzheimer dementia
• Mild to moderate vascular dementia
• Chronic pain
• Psychiatric disorders
• Mild cognitive impairment

Diagnosis of Alzheimer Disease

• The DSM-5 criteria for diagnosis include the following characteristics:

1. Evidence of significant cognitive decline from a previous level of performance in one or more cognitive domains: complex attention, executive function, learning, and memory, language, perceptual-motor or social cognition
2. The cognitive deficits interfere with independence in everyday activities
3. The cognitive deficits do not occur only in the context of delirium
4. Another mental disorder does not better explain the cognitive deficits
5. The onset is an insidious and gradual progression of impairment in at least 2 cognitive domains:

• Evidence of a causative Alzheimer disease genetic mutation from family history or genetic testing
• All 3 of the following: Clear evidence of a decline in memory and learning and one or more other domains; steadily progressive, gradual decline in cognition, without extended plateaus; and no evidence of mixed etiology due to other neurodegenerative disorders or cerebrovascular disease.

Role of Memantine in Alzheimer Dementia

Alzheimer disease is a neurodegenerative disorder characterized by the presence of extracellular amyloid-beta protein an intracellular neurofibrillary tangle composed of hyperphosphorylated protein in the brain. There is a decrease in acetylcholine synthesis and impaired cortical cholinergic function in patients with Alzheimer dementia. So cholinesterase inhibitors (like donepezil, rivastigmine, galantamine) in dementia provide symptomatic relief by inhibiting cholinesterase at synaptic cleft and increasing cholinergic transmission. However, the mechanism of action of memantine is distinct from those of cholinergic agents and is proposed to be neuroprotective. Glutamate is a major excitatory neurotransmitter in the brain. One of the receptors activated by glutamate is the NMDA receptor which is essential for processes like learning and memory. Excessive activation of NMDARs been shown to be associated with neuronal loss/damage contributing to various acute and chronic neurological disorders including dementia. However physiological NMDA-receptor activity is also needed for normal neuronal function. Any agents that block all NMDA-receptor activity will have unacceptable clinical side effects. Memantine, through its action as an uncompetitive, low-affinity, open-channel blocker (uncompetitive antagonist of extrasynaptic NMDAR), preferentially enters the receptor-associated ion channel when it is excessively open, and hence, does not interfere with normal synaptic transmission. By doing so, it prevents or protects against further damage from neuronal cell death induced by excitotoxicity. Therefore, memantine is used for the treatment of Alzheimer dementia in combination with acetylcholinesterase inhibitors.[2]

Mechanism of Action

Memantine is an uncompetitive antagonist of the NMDA subtype of glutamate receptors in the CNS. Alzheimer disease is believed to be caused by overstimulation of glutamate, the primary excitatory amino acid in the CNS, resulting in excitotoxicity and neuronal degeneration. The NMDA receptor is a voltage-gated cation channel that in the physiologic unstimulated state is blocked by magnesium ions. Stimulated magnesium is displaced allowing calcium influx and activation. In Alzheimer disease, there is pathologic overstimulation of the receptor causing it to be in a chronically active state. Memantine helps to counteract the excessive stimulation.[1]

Memantine also exhibits antagonist activity at the serotonergic type 3 (5-HT3) and nicotinic acetylcholine receptors. It has no activity at the gamma-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, or glycine receptors or for voltage-dependent calcium, sodium, or potassium channels.[1]

Administration

Starting Dosage

• 5 mg once daily

Target Dosage

• 20 mg once daily

Titration

• Dosage increased by 5 mg daily in weekly intervals as tolerated

Titration Schedule

• Week 1: 5 mg daily
• Week 2: 10 mg daily (5 mg twice daily)
• Week 3: 15 mg daily (5 mg one time and 10 mg one time daily)
• Week 4: 20 mg daily (10 mg twice daily) 

Switching from Immediate-Release (IR) to Extended-Release (ER)

• Start ER day after the last dosage of IR; IR 10 mg twice daily should be switched to ER 28 mg daily

Missed Dosage

• Single dose missed do not double up on next dose; if several dosages are missed, resume at a lower dose and titrate as tolerated

Special Population

• Renal impairment: A target dose of 5 mg twice daily is recommended in patients with severe renal impairment (creatinine clearance of 5 to 29 mL per minutes based on the Cockroft-Gault equation)
• Hepatic impairment: mild to moderate no dosage adjustment necessary; severe use with caution
• Pregnancy: FDA category B (No evidence of risk in studies; animal reproduction studies have shown adverse events); use with caution
• Breastfeeding: It is not known if memantine is excreted in breast milk; use with caution in nursing mother
• Pediatric use: safety and effectiveness have not been established

Dosage Forms[3]

• Capsule, extended-release, 24-hour, oral, as hydrochloride: Generic: 7 mg, 14 mg, 21 mg, 28 mg
• Solution, oral, as hydrochloride: Generic: 2 mg/mL (360 mL)
• Tablet, oral, as hydrochloride: Generic: 5 mg, 10 mg 

Administration

• Any formulation: With or without food; do not chew, crush, or divide
• Extended-release capsules: may be swallowed whole or entire contents of capsule sprinkled on food and swallowed immediately.
• Oral Solution: Do not mix with any other liquid; administer with provided dosing device supplied with the device consisting of a syringe, syringe adaptor cap, tubing and other needed supplies; slowly squirt into the corner of the mouth

Storage

• Room temperature between 20 C to 25 C (68 F to 77 F)

Adverse Effects

Most common in clinical trials: Dizziness, headache, confusion, diarrhea, and constipation[5]

Others: Fatigue, pain, hypertension, weight gain, hallucination, confusion, aggressive behavior, vomiting, abdominal pain, urinary incontinence

Uncommon (Post-marketing surveillance, clinical trials, or case reports): 

• Neurologic: Abnormal gait, Cerebral infarction, Cerebrovascular accident, Intracranial hemorrhage, Seizure, Somnolence, Tardive dyskinesia
• Cardiovascular: bradyarrhythmia, Heart failure, Myocardial infarction, peripheral edema, syncope, tachycardia
• Endocrine: weight change
• Gastrointestinal: Loss of appetite, nausea
• Hematologic: anemia
• Hepatic: Hepatitis, Liver failure
• Renal: Acute renal failure, Urinary tract infection
• Respiratory: Bronchitis, Pneumonia, Upper respiratory infection
• Dermatologic: Rash, Stevens-Johnson syndrome
• Musculoskeletal: Arthralgia
• Others: Falling injury, Influenza-like symptoms, Neuroleptic malignant syndrome

Contraindications

Patients with hypersensitivity to memantine hydrochloride or any agents used in the formulation.

Warning/Precautions[5]

• Genitourinary conditions: Conditions that raise urine pH may decrease the urinary elimination of memantine
• Cardiovascular disease: Increased incidence of cardiac failure, angina, and hypertension occurred in clinical trials 
• Hepatic impairment: Precaution use in severe hepatic impairment; effects of impairment on pharmacokinetics have not been established

Monitoring

No routine monitoring required for toxicity.

Monitoring Efficacy

• Activities of daily living and cognitive functioning improvements 
• Slowing in the progression of decline in cognitive function and memory impairment
• It may take months for any noticeable improvement

Toxicity

Pharmacokinetics

Onset

• Fourteen days (based on first improvements of Sandoz Clinical Assessment Geriatric [SCAG] scores compared to placebo)

Time to peak concentrations 

• Three to 7 hours for oral immediate-release
• Nine to 12 hours for oral extended-release 

Absorption

• 100% (oral administration) with 100% bioavailability
• Effects of food: immediate-release: no effect; extended-release: shown to decrease Tmax by 7 hours with no effect on AUC or Cmax 

Distribution

• Volume of Distribution: 9 to 11 L/kg
• Sites: 

1. Protein-bound: 45%
2. Brain: High concentration
3. Kidney: High concentration
4. Liver: Low concentration
5. Lung: High concentration

Metabolism

• Sites: Liver (partial): Hepatic CYP450 enzyme system does not play a significant role
• Metabolites: All have minimal NMDA-receptor antagonist activity- N-glucuronide conjugate, 6-hydroxy memantine, and 1-nitroso-deaminated memantine

Excretion

• Site: Renal 48% to 50% unchanged parent drug in urine involving active tubular secretion moderated by pH-dependent tubular reabsorption (reduced excretion by alkaline urine pH)

Time to Peak Concentrations

• Three to seven hours for immediate-release 
• Nine to twelve hours for extended-release

Terminal Elimination Half-Life

• Sixty to 80 hours 

Enhancing Healthcare Team Outcomes

There is no cure for Alzheimer's disease and the few drugs available are only for mild cognitive impairment. Prescribers of memantine should be aware that the drug can worsen the symptoms of dementia. Hence, these patients should be closely monitored by the pharmacist, mental health nurse, psychiatrist and the primary care provider reporting complications to the primary team leader. The response to memantine is mild and most patients do not show any real benefit.[6][7][8]