As America’s population ages, the need to find new treatments for Alzheimer’s disease (AD) is increasingly urgent. Agents that have reached the medical mainstream in recent years target the disease in its mild to moderate stages. Memantine recently gained FDA approval for treating moderate to severe AD.
HOW IT WORKS
Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptors mediate the effects of the excitatory amino acid glutamate, promote entry of calcium through ion channel pores, and are essential for normal learning and memory.1 Prolonged excessive glutamate stimulation, however, can lead to excitotoxicity and nerve cell death.
High-affinity NMDA receptor antagonists cause unacceptable side effects in humans and have not been well tolerated in clinical trials. By contrast, memantine—a moderate- to low-affinity NMDA receptor antagonist with rapid blocking/unblocking kinetics—has been well tolerated in clinical trials. The agent is readily displaced by presynaptic stimuli to allow normal channel function, but it reduces calcium influx from chronic low-amplitude glutamate stimulation.2
Memantine: Fast facts
|Drug brand name:|
NMDA receptor antagonist
Moderate to severe Alzheimer’s disease
Oct. 17, 2003
5 mg, 10 mg (“titration packets” containing 5-mg and 10-mg tablets are available)
Begin at 5 mg/d for 1 week; increase to 5 mg bid the second week, then to 10 mg in the morning and 5 mg in the evening for the third week; increase to 10 mg bid for continued dosing
Memantine’s voltage-dependent characteristics allow it to block low-level tonic pathologic activation of NMDA receptors caused by low glutamate concentrations. This property also allows physiologic activation of receptors after synaptic release of larger glutamate concentrations that produce membrane depolarization.2 Memantine has demonstrated neuroprotection of neurons exposed to glutamate in a variety of in-vitro preparations.3
In experimental models, memantine has been shown to prolong long-term potentiation, a neurophysiologic correlate of learning and memory. Rats treated with memantine show enhanced learning recovery following entorhinal cortex lesions.3
Memantine has been shown to protect cholinergic cells in both acute and chronic animal models. It also prevents pathologic changes in the hippocampus produced by direct injection of betaamyloid protein.3 These findings suggest that memantine may improve learning and memory and may have neuroprotective properties in AD.
Memantine is absorbed completely from the GI tract and reaches maximum serum concentration in 6 to 8 hours. It is widely distributed and passes the blood-brain barrier with CSF concentrations approximately one-half those of serum levels. Dosages between 5 and 30 mg/d result in serum levels of 0.025 to 0.529 mmol. Relatively little biotransformation occurs.
The agent’s half-life ranges between 75 and 100 hours.4 Memantine is 10% to 45% protein bound, and 80% of circulating memantine is present as the parent compound. These kinetics justify once-daily dosing, although memantine usually is given bid.
Three metabolites have been identified, none of which exhibit NMDA receptor antagonist activity. Memantine minimally inhibits cytochrome P-450 enzymes, so interactions with drugs metabolized by these enzymes are unlikely.5
Memantine may potentiate the effects of barbiturates, neuroleptics, anticholinergics, L-dopa, ketamine, amantadine, dextromethorphan, and dopaminergic agonists. Concomitant use of memantine and amantadine should be avoided because the compounds are chemically related and both are NMDA antagonists. Memantine may hinder the effects of dantrolene or baclofen, so doses of these agents may need to be adjusted upward.
Memantine is eliminated almost completely via renal cation transport proteins. Drugs that use the same transport system—such as cimetidine, ranitidine, procainamide, quinine, and nicotine—may interact with memantine, possibly leading to increased plasma levels of these agents.
Hydrochlorothiazide activity is reduced by 20% when memantine is co-administered. Sodium bicarbonate, carbonic anhydrous inhibitors, and other drugs that alkalinize the urine may reduce memantine clearance and increase its serum levels.4
In healthy elderly volunteers with normal and reduced renal function, researchers observed a significant correlation between creatine clearance and total renal clearance of memantine, suggesting that patients with renal disease may require lower dosages.5
In a preliminary, placebo-controlled study7 of patients with vascular- or Alzheimer’s-type dementia, memantine was associated with improved Clinical Global Impression of Change and Behavioral Rating Scale for Geriatric Patients scores. Mini-Mental State Examination (MMSE) scores for all patients entering the study were <10, indicating severe cognitive impairment. Global measures improved in 61 of 82 (73%) patients taking memantine, 10 mg/d, and in 38 of 84 (45%) patients taking placebo. Care dependence improved 3.1 points in the memantine group and 1.1 points in the placebo group.
Reisberg et al8 gave memantine, 20 mg/d, or placebo to 252 patients with AD across 28 weeks. The memantine group performed at significantly higher functional levels than the placebo group on the Alzheimer’s Disease Cooperative Study ADL Scale and the Severe Impairment Battery (SIB). The differences on the Clinical Interview-Based Impression of Change with caregiver input (CIBIC-plus) scale were nearly significant (p = 0.06). Patients entering the study had MMSE scores between 3 and 14. The magnitude of drug-placebo difference was modest (approximately 6 points on the SIB).