Memantine inhibitors

The ChE inhibitors all have the indication for the treatment of mild to moderate dementia of the Alzheimer s type. Guidelines for the treatment of AD were written before the approval of memantine and recommend the use of ChE inhibitors as a valuable treatment for AD.27-29 None of the ChE inhibitors have been compared in head-to-head studies, so the decision to use one over another is based on differences in mechanisms of action, adverse reactions, and titration schedules. 

Adverse reactions associated with memantine include constipation, confusion, dizziness, headache, coughing, and hypertension. These adverse effects are similar to those experienced with ChE inhibitors. Extra monitoring should be done if memantine is given concurrently with a ChE inhibitor. 

Alternatively, consider memantine or cholinesterase inhibitor therapy alone. Behavioral symptoms may require additional pharmacologic approaches. 

Memantine (Namenda) blocks glutamatergic neurotransmission by antagonizing N-methyl-D-aspartate receptors, which may prevent excitotoxic reactions. It is used as monotherapy, and data suggest that when it is combined with a cholinesterase inhibitor, there is improvement in cognition and activities of daily living. 

Cholinesterase inhibitors and memantine are first-line therapy in early management of behavioral symptoms. Modest improvement may be achieved. 

Alzheimer s Disease This disease is due to the accumulation of j8-amyloid protein in the brain. The protein is believed to trigger brain degeneration through cell death of the neurons. Alzheimer s disease is characterized by loss of memory and intellectual performance, and slowness in thought. In the United States, a class of drugs called cholinesterase inhibitors is approved to treat Alzheimer s disease. Both Europe and the United States have approved a drug called memantine for treatment of Alzheimer s disease. 

The side effects of memantine are generally mild and include headache, dizziness, and constipation. Memantine is started at an initial dose of 5 mg each morning and is increased to 5 mg twice daily after 1 week. The maximum dose of memantine is 10 mg taken twice daily. A recent study indicates that memantine works syner-gistically with cholinesterase inhibitors (see Section 10.5.5), and it has quickly become routine clinical practice to coadminister memantine with one of these agents. 

The key to successful brain protection for Alzheimer s disease is the newly introduced NMDA receptor antagonist, memantine. Family members should be advised that the protection provided by memantine will slow the progression of Alzheimer s disease, but it does not halt or reverse the course of the illness. Memantine is now commonly coadministered with a cholinesterase inhibitor. 

Memantine (Namenda) [Anti Alzheimer Agent/NMDA Receptor Antagonist] Uses Mod/ evere Alzheimer Dz Action N-methyl-D-aspartate recqjtor antagonist Dose Target 20 mg/d, start 5 mg/d, t 5 mg/d to 20 mg/d, wait >1 wk before t dose use doses if >5mg/d Caution [B, /-] Hqjatic/mild-mod renal impair Disp Tabs, sol SE Dizziness Interactions t Effects W amantadine, carbonic anhydrase inhibitors, dextromethorphan, ketamine, Na bicarbonate t effects W/ any drug, herb, food that alkalinizes urine EMS Use NaHCOs w/ caution OD May cause restlessness, hallucinations, drowsiness, and fainting symptomatic and supportive... 

Geriatric Considerations - Summary Memantine is modestly effective for treatment of cognitive decline associated with moderate-to-severe Alzheimer s disease. Furthermore, for persons with moderate-to-severe AlzheimeFs disease using cholinesterase inhibitors, there is some evidence that memantine confers some additional benefit. Memantine is expensive, and its cost-effectiveness has not been demonstrated. Persons using drugs to treat Alzheimer s should be monitored closely, and prescribers should have a low threshold for discontinuing these agents if no clinical benefit is observed. 

Clinicians often use each cholinesterase inhibitor in combination with memantine however, the best evidence to date for such combination treatment is the use of memantine in patients with moderate to severe Alzheimer s disease already taking donepezil (Tariot et al. 2004). 

Persistent excitatory glutamatergic stimulation of postsynaptic NMDA receptors, which may cause neuronal toxicity by allowing excessive calcium entry into neurons, has been implicated in the symptomatology of dementia of the Alzheimer s type (Farber et al. 1998). Memantine is a moderate-affinity, noncompetitive inhibitor of NMDA receptors (Danysz et al. 2000). 

Excitotoxic activation of glutamate transmission via NMDA receptors has been postulated to contribute to the pathophysiology of Alzheimer s disease. Memantine binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade. This drug appears to be better tolerated and less toxic than the cholinesterase inhibitors. Memantine is available as Namenda in 5 and 10 mg oral tablets. 

Q8 The drugs currently licensed for Alzheimer s disease in Britain are cholinesterase inhibitors, with one exception-memantine hydrochloride. This agent... 

Alzheimer s disease) and donepezil (79). These findings support the potential for combining memantine and cholinesterase inhibitors in patients with Alzheimer s disease. 

Alisky JM. Could cholinesterase inhibitors and memantine alleviate HIV dementia J Acquir Immune Defic Syndr 2004 38 1-3. 

Altematively, arnsider memantine or cholinesterase inhibitor therapy alone. 

CARBONIC ANHYDRASE INHIBITORS ANTIDEMENTIA DRUGS-MEMANTINE Possibly t memantine levels 1 renal excretion Watch for early features of memantine toxicity... 

Autopsy studies on Alzheimer-afflicted brains some 40 years later showed a similar huge drop in neurotransmitter levels, but this time it was acetylcholine (ACh) in the hippocampus —which is associated with memory. Choline-esterase inhibitors, which stop the breakdown of ACh, were introduced and are presently the only symptom treatment available (Aricept, Excelon, Reminyl, Cognex). Recently, in 2004, memantine was approved as the first treatment to slow progression of Alzheimer s in mild to moderate cases. Work is ongoing to define acetylcholine-like muscarinic M-1 agonists and M-2 agonists that act on acetylcholine receptors directly. 

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