Memantine

You know, being a human is not about having a good jump shot. It is about having a good mind. Don't ever waste it.

- Physician to one of the authors, more than 35 years ago on the night shift at a state hospital.

Since the headline-making release of tacrine a little more than a decade ago and the disappointing aftertaste of news "too good to be true," families, professionals working with patients suffering from Alzheimer's dis ease (AD), and individuals worried about their own cognitive future have greeted the advent of each new AD product with hopeful restraint. Although research continues to explore several different fronts of this battle, the medications most often prescribed have been those with a very particular approach to restoring mental function-drugs that block the breakdown of acetylcholine.

Each succeeding generation of these acetylcholine-enhancing agents has added something to the drug molecule to give it a unique mechanism of action, yet all, at the core, increased levels of intrasynaptic acetylcholine (e.g., tacrine [Cognex], donepezil [Aricept], rivastigmine [Exelon], and galantamine [Reminyl]). The newest drug for AD breaks out of the acetylcholine-enhancing mode and focuses on a different receptor complex. Memantine (Namenda), was approved for the U.S. market in October 2003 and has been used in Europe for more than 20 years.

AD is the most common type of dementia and the fourth leading cause of death for those over the age of 65. It is thought that 4 million people in the United States suffer from AD, and that number is expected to grow both in real numbers and in percentage of the population. The estimated cost of caring for a single patient ranges from $18,000/year (mild form) to $36,000/year (severe form) (Alzheimer Research Forum, 2004).

Memantine approaches the treatment of this cruel disease from a different perspective from the aforementioned acetylcholine-boosting drugs. Further, while those drugs are marketed for patients suffering from mild to moderate levels of AD, memantine is marketed for patients at the moderate to severe stages of the disease. Memantine is an N-methyl-D-aspartate (NMDA) receptor antagonist. Specifically, it blocks abnormal (i.e., sustained) signaling from glutamate neurotransmitters but does not affect the normal binding of this endogenous ligand. Glutamate, the most abundant neurotransmitter in the brain, is involved in learning and memory pathways; however, overstimulation by this neurotransmitter has been linked to cognitive decline and neuronal death via mechanism referred to as excitotoxicity (Doraiswamy, 2002). Abnormal glutamate activity is reduced by memantine, and it is thought that the drug may slow the deteriorating course of the illness. The manufacturer of Namenda, however, clearly states that there has not been confirmation that memantine prevents or slows the neurodegenerative process.

It should be noted that the NMDA receptor has been a receptor of interest for years. For instance, significant antagonism by the street drug PCP causes psychotic (often violent) behavior similar to that of paranoid schizophrenia disorder, whereas significant agonist stimulation causes the aforementioned excitotoxicity. Chemotherapeutic targeting of this receptor, therefore, suffers from inherent risks in both directions.

Pharmacokinetics

Memantine is 100% absorbed after oral dosing, demonstrates 45% protein binding, undergoes only slight metabolism, is eliminated primarily unchanged (-75%), and has a half-life of 60 to 80 hours (Forest Laboratories, 2003). Since it is not cytochrome P-450 dependent for metabolism, memantine/CYP-450 system interactions are not expected, nor are interactions arising from co-administered agents with high protein-binding characteristics. Because memantine is weakly basic in nature, alkalizination (~pH 8) of the urine can cause a reduction in elimination.

Side Effects

The most common side effects in preclinical studies included hypertension (4%), coughing (4%), constipation (5%), headache (6%), somnolence (6%), and dizziness (7%). Individuals with moderate to severe AD exhibit these same symptoms at a near similar rate.

Efficacy

Reisberg et al. (2003) studied 252 patients with moderate to severe AD treated with 20 mg of memantine or placebo. Memantine-treated patients experienced significant reduction in clinical deterioration compared to the placebo group. Tariot et al. (2004) studied 404 patients who were already receiving donepezil. The donepezil + memantine group showed significantly better outcomes on targeted symptoms (i.e., cognition, global improvement, activities of daily living) than did the donepezil + placebo group.

Dosing

The target dose for memantine is 20 mg per day given in two doses. It is started at 5 mg per day and titrated in 5 mg increments until the ideal dose is achieved.

Conclusion

AD patients, older individuals in general, families, and healthcare providers all continue to hope for a medication that will halt and even reverse the vicious consequences of this disease. The initial proclamations of the efficacy of tacrine and the subsequent retractions perhaps did us the service of lowering expectations. Certainly with the recent passing of one of our most beloved presidents, a nation's eyes have been refocused on the all-consuming nature of AD. To the United Negro College Fund's slogan, "A mind is a terrible thing to waste" we add, "It is also a terrible thing to lose." One of the major benefits of memantine may be its shifting of focus away from acetylcholine-enhancing agents to a wider array of chemical and biological targets. The authors are in awe of those who dedicate careers to developing treatments to improve the lives of those individuals who are losing the essence of life itself.

References

Alzheimer Research Forum. (2004, March). Memantine: Implications for treating Ahheimer's. Retrieved May 2004 from www.alzforum.org/ res /for/journal / dekosky / defalt.asp

Doraiswamy, P. (2002). Memantine: An update. The Caregiver, 21(2), 7-8.

Forest Laboratories, Inc. (2003). Memantine HCL briefing document. Retrieved May 2004 from www.fda.gov/ohrms/dockets/ac /03/briefing/3979Bl_01 jOrestLabs-Memantine.PDF

Reisberg, B., Doody, R., Stoffler, A., Schmitt, F., Ferris, S., & Mobius, HJ. (2003). Memantine in moderate-to-severe Alzheimer's disease. New England Journal of Mediane, 348,1333-1341.

Tariot, P.N., Farlow, M.R., Grossberg, G.T., Graham, S.M., McDonald, S., & Gergel, I. (2004). Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil. JAMA, 291, 317-324.

Norman L. Keltner, EdD, RN, and Beth Williams, SN

Norman L. Keltner, EdD, RN

Professor of Nursing

University of Alabama at Birmingham

Beth Williams, SN

is a student at the University of Alabama at Birmingham

School of Nursing

Author contact: KELTNERN@son.uab.edu, with a copy to the Editor: mary@artwindows.com

Search terms: Alzheimer's disease, memantine, tacrine

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