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Cholinesterase inhibitors


Cholinesterase inhibitors are a group of drugs prescribed to treat symptoms resulting from the early and middle stages of Alzheimer disease .


Cholinesterase inhibitors are drugs that block the activity of an enzyme in the brain called cholinesterase. Cholinesterase breaks apart the neurotransmitter acetylcholine, which is vital for the transmission of nerve impulses. Cholinesterase inhibitors are used to reduce the action of cholinesterase, thereby making more acetylcholine available to nerve cells in the brain.

For normal nerve-to-nerve communication to occur, the excess acetylcholine must be dissolved following the transmission of a nerve impulse. This is the normal function of cholinesterase. This enzyme dissolves acetylcholine into its component molecules; acetate and choline. These building blocks can then be recycled to form more acetylcholine for the next round of nerve signal transmission.

In disorders such as Alzheimer disease, Lewy body disease, and vascular dementia , the production of acetylcholine is decreased. As a result, nerve communication is less efficient, with consequent problems of memory and other brain and body functions. The use of cholinesterase inhibitors impedes the normal enzymatic breakdown of the little acetylcholine that is present. Although improved nerve function results with the use of cholinesterase inhibitors, the damage to brain cells caused in Alzheimer disease cannot be halted or reversed.


As of mid-2004, there are four types of cholinesterase inhibitors that are available. These include donepezil (Aricept®), rivastigmine (Exelon®), galantamine (Reminy®), and tacrine (Cognex®). Tacrine is not available for use in Canada.

Donepezil was approved for use in the United States by the U.S. Food and Drug Administration (USFDA) in 1996. It is marketed by Pfizer as Aricept®. Rivastigmine received USFDA approval in 2000 and is sold by Novartis Pharmaceuticals as Exelon®. Galatamine received its USFDA approval in 2001 and is marketed in the U.S. as Reminyl® by Jassen Pharmaceuticals and Ortho-McNeil. Pointing out the importance of the natural world in providing therapeutic compounds, galatamine is extracted from the bulbs of daffodils. Finally, the drug tacrine is the oldest of the cholinesterase inhibitors, having received USFDA approval in 1993. Its use has declined due to incidents of serious side effects that include reversible liver damage.

Cholinesterase inhibitors are typically used to treat the early and middle stage symptoms of diseases such as Alzheimer's. This is because the deterioration in the production of acetylcholine accelerates over time, as more and more brain cells become damaged. Thus, the best chance to achieve a benefit for a person lies at the beginning of the disease path.

The benefits of cholinesterase inhibitors are judged by three patterns of the symptoms. In the early stages of Alzheimer disease, cholinesterase inhibitors may improve a person's condition, resulting in improvement of symptoms. As the disease progresses, cholinesterase inhibitors may act to stabilize the symptoms. Finally, the symptoms continue to worsen, but at a rate that is slower than would occur if the drug(s) were not taken.

One symptom that benefits from the use of cholinesterase inhibitors is called cognition. Cognition encompasses memory, language, and orientation (knowing the date, time, and a proper sense of direction). By improving, or at least retarding the rate of loss of cognition, the drugs can improve a person's quality of life. The benefits bestowed by cholinesterase inhibitors last only as long as effective levels of the drugs are present. Discontinuing the drug leads the return of symptoms within weeks.

Studies that have charted the time course of cognitive changes after taking the various cholinesterase inhibitors have demonstrated that improvements tend to peak about three months after the particular drug is first taken. After that time, a person's mental condition slowly begins to decline back to their starting point over the next six to nine months. If the drug continues to be taken, the cognitive decline becomes slower than in people who do not take the medication.

Recommended dosage

The recommended dosage of cholinesterase inhibitors varies with the approving agency in a particular country. But, dosages tend not to vary appreciably. The maximum daily dose of donepezil is normally 510 milligram (mg). This dose is taken just once a day, either in the morning or in the evening. The maximum daily dose of rivastimine is 612 mg. The drug is taken twice a day with meals (typically breakfast and dinner). The maximum daily dose of galantamine is 1624 mg, and it is also taken twice a day with meals.


As with any prescription drug, the recommended daily dosage and schedule for the drugs should not be changed independent of a physician's notification. Neither should someone stop taking cholinesterase inhibitors without seeking advice from a physician.

Side effects

Cholinesterase inhibitors can cause side effects. These are usually relatively minor, and constitute problems in digesting food, loss of appetite, nausea, vomiting, abdominal pain , and diarrhea. Not everyone will experience each discomfort, and the severity of the side effects can vary from person to person, depending on their tolerance to the discomfort. The drugs can vary in the severity of side effects caused. For example, rivastigmine produces greater weight loss and degree of nausea that the other drugs.

Less commonly, cholinesterase inhibitors can slow the heartbeat, cause dizziness , fainting , insomnia, fatigue , and produce muscle cramps in the legs. In general, the side effects tend to be mild and lessen after a drug has been taken for a few weeks. A notable exception is tacrine, which can cause liver damage. Periodic blood testing in order to monitor enzymes that relate to liver function is usually part of therapy with tacrine.


Some cholinesterase inhibitors should be used with caution in persons with asthma or lung disease, as cholinesterase inhibitors may interact with theophylline, a drug commonly used to treat both conditions.



Bird, T. D. "Memory loss and dementia." In Harrison's Principles of Internal Medicine, 15th edition, A. S. Franci, E. Daunwald, and K. J. Isrelbacher, eds. New York: McGraw Hill, 2001.

Castleman, Michael, et. al. There's Still a Person in There: The Complete Guide to Treating and Coping with Alzheimer's. New York: Perigee Books, 2000.

Fillit, Howard M. Drug Discovery and Development for Alzheimer's Disease. New York: Springer, 2001.


Cummings, J. L. "Cholinesterase inhibitors: a new class of psychotropic compounds." American Journal of Psychiatry (January 2000): 414.

Masterman, D. "Cholinesterase inhibitors in the treatment of Alzheimer's disease and related dementias." Clinical and Geriatric Medicine (February 2004): 5968.


"Cholinesterase Inhibitors: Current Drug Treatments for Alzheimer Disease." Alzheimer Society of Canada. (May 6, 2004). <>.

National Institute of Neurological Disorders and Stroke. NINDS Alzheimer's Disease Information Page. (May 6, 2004). <>.


Alzheimer Society of Canada. 20 Eglinton Avenue W., Suite 1200, Toronto, ON M4R 1K8, CANADA. (416) 488-8772 or (800) 616-8816; Fax: (416) 488-3778. [email protected] <>.

Alzheimer's Association. 225 N. Michigan Avenue, Chicago, IL 60601. (312) 335-8700 or (800) 272-3900; Fax: (312) 335-1110. [email protected] <>.

Brian Douglas Hoyle, PhD

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cholinesterase (acetylcholinesterase) An enzyme that hydrolyses the neurotransmitter acetylcholine to choline and acetate. Cholinesterase is secreted by nerve cells at synapses and by muscle cells at neuromuscular junctions. Organophosphorus insecticides (see pesticide) act as anticholinesterases by inhibiting the action of cholinesterase.

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cholinesterase (koh-lin-est-er-ayz) n. an enzyme that breaks down a choline ester into its choline and acid components. The term usually refers to acetylcholinesterase, which breaks down the neurotransmitter acetylcholine into choline and acetic acid.