NMDA antagonists

One possible mechanism for the pathophysiology of Alzheimer's disease is the glutamate excitotoxicity hypothesis. In this situation the NMDA receptors are overstimulated by glutamate thereby leading to apoptosis. A NMDA receptor antagonist such as memantine, blocks this action by moderately binding to the NMDA receptors (whereas PCP has high affinity and blocks both physiologic and pathologic NMDA activity). Memantine was studied as monotherapy in patients with moderate to severe Alzheimer's (MMSE between 3 and 14), however, it may be effective in combination with the AChE inhibitors.



Memantine is given in 5 mg doses every morning for a week before increasing the dose to 5 mg twice daily for week two. During week three, the doses are increased to 10 mg every morning and 5 mg every evening. After four weeks, the patient can be maintained on 10mg twice daily thereafter.

If the patient has an estimated creatinine clearance of less than 50 ml/min, then the maximum daily dose should not exceed 10 mg per day. For information on how to estimate a creatinine clearance see: excretion in elderly.



Excessive stimulation of glutamate receptors (particularly the NMDA receptor) seems involved in the death of cortical cholinergic neurons. 


Use of memantine with other NMDA antagonists such as amantadine, or dextromethorphan would be expected to lead to: