Cholinesterase Inhibitors and Memantine

For a more detailed discussion of this topic, see Cholinesterase Inhibitors, Sec. 31.15, p. 3089, Comprehensive Textbook of Psychiatry, 9th Edition.

Donepezil (Aricept), rivastigmine (Exelon), and galantamine (Reminyl), are cholinesterase inhibitors used to treat mild to moderate cognitive impairment in dementia of the Alzheimers type. Tacrine (Cognex) is no longer used. They reduce the inactivation of the neurotransmitter acetylcholine and, thus, potentiate cholinergic neurotransmission, which in turn produces a modest improvement in memory and goal-directed thought. Memantine (Namenda) is not a cholinesterase inhibitor, producing its effects through blockade of N-methyl-D-aspartate (NMDA) receptors. Unlike the cholinesterase inhibitors, which are indicated for the mild to moderate stages of Alzheimer’s disease, memantine is indicated for the moderate to severe stages of the disease. Tacrine, the first cholinesterase inhibitor to be introduced, is no longer used because of its multiple daily dosing regimens, its potential for hepatotoxicity, and the consequent need for frequent laboratory monitoring. Routine clinical practice often combines a cholinesterase inhibitor with memantine, and recent studies have actually shown that this combination provides beneficial response compared with only cholinesterase inhibitor pharmacotherapy.

Pharmacologic Actions

Donepezil is absorbed completely from the gastrointestinal (GI) tract. Peak plasma concentrations are reached about 3 to 4 hours after oral dosing. The half-life of donepezil is 70 hours in elderly persons, and it is taken only once daily. Steady-state levels are achieved within about 2 weeks. The presence of stable alcoholic cirrhosis reduces clearance of donepezil by 20%. Rivastigmine (Exelon) is rapidly and completely absorbed from the GI tract and reaches peak plasma concentrations in 1 hour, but this is delayed by up to 90 minutes if rivastigmine is taken with food. The half-life of rivastigmine is 1 hour, but because it remains bound to cholinesterases, a single dose is therapeutically active for 10 hours, and it is taken twice daily. Galantamine (Reminyl) is an alkaloid similar to codeine and extracted from daffodils of the plant Galanthus nivialis. It is readily absorbed, with maximum concentrations reached after 30 minutes to 2 hours. Food decreases the maximum concentration by 25%. The elimination half-life of galantamine is approximately 6 hours.

Tacrine (Cognex) is absorbed rapidly from the GI tract. Peak plasma concentrations are reached about 90 minutes after oral dosing. The half-life of tacrine is about 2 to 4 hours, thereby necessitating four-times-daily dosing.

The primary mechanism of action of cholinesterase inhibitors is reversible, nonacylating inhibition of acetylcholinesterase and butyrylcholinesterase, the enzymes that catabolize acetylcholine in the central nervous system (CNS). The enzyme inhibition increases synaptic concentrations of acetylcholine, especially in the
hippocampus and cerebral cortex. Unlike tacrine, which is nonselective for all forms of acetylcholinesterase, donepezil appears to be selectively active within the CNS and to have little activity in the periphery. Donepezil’s favorable side effect profile appears to correlate with its lack of inhibition of cholinesterases in the GI tract. Rivastigmine appears to have somewhat more peripheral activity than donepezil and is thus more likely to cause GI adverse effects than is donepezil.

Therapeutic Indications

Cholinesterase inhibitors are effective for the treatment of mild to moderate cognitive impairment in dementia of the Alzheimer’s type. In long-term use, they slow the progression of memory loss and diminish apathy, depression, hallucinations, anxiety, euphoria, and purposeless motor behaviors. Functional autonomy is less well preserved. Some persons note immediate improvement in memory, mood, psychotic symptoms, and interpersonal skills. Others note little initial benefit but are able to retain their cognitive and adaptive faculties at a relatively stable level for many months. A practical benefit of cholinesterase inhibitor use is a delay or reduction of the need for nursing home placement.

Donepezil and rivastigmine may be beneficial for patients with Parkinson’s disease and Lewy body disease and for treatment of cognitive deficits caused by traumatic brain injury. Donepezil is under study for treatment of mild cognitive impairment that is less severe than that caused by Alzheimer’s disease. People with vascular dementia may respond to acetylcholinesterase inhibitors. Occasionally, cholinesterase inhibitors elicit an idiosyncratic catastrophic reaction, with signs of grief and agitation, which is self-limited after the drug is discontinued. Use of cholinesterase inhibitors to improve cognition by nondemented individuals should be discouraged.

Precautions and Adverse Reactions

Donepezil

Donepezil is generally well tolerated at recommended dosages. Fewer than 3% of persons taking donepezil experience nausea, diarrhea, and vomiting. These mild symptoms are more common with a 10-mg dose than with a 5-mg dose, and when present, they tend to resolve after 3 weeks of continued use. Donepezil may cause weight loss. Donepezil treatment has been infrequently associated with bradyarrhythmias, especially in persons with underlying cardiac disease. A small number of persons experience syncope.

Rivastigmine

Rivastigmine is generally well tolerated, but recommended dosages may need to be scaled back in the initial period of treatment to limit GI and CNS adverse effects.
These mild symptoms are more common at dosages above 6 mg a day, and when present, they tend to resolve after the dosage is lowered. The most common adverse effects associated with rivastigmine are nausea, vomiting, dizziness, headache, diarrhea, abdominal pain, anorexia, fatigue, and somnolence. Rivastigmine may cause weight loss, but it does not appear to cause hepatic, renal, hematologic, or electrolyte abnormalities.

Galantamine

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