Donepezil

Donepezil is a drug used to treat dementia associated with all stages of Alzheimer Disease (AD). It works by inhibiting an enzyme in the brain known as acetylcholinesterase that is responsible for breaking down the neurotransmitter acetylcholine. By increasing the amount of acetylcholine, it improves mental functioning and may improve the ability to think and remember, and may slow the loss of these abilities in people who have AD.

Other Names

Donepezil is marketed as Aricept by Eisai and Pfizer.

Uses

Donepezil is used to increase the amount of acetylcholine in the brain in patients with mild to moderate AD. Although it helps control the symptoms of AD, it does not cure the disease.

Donepezil is sometimes used in combination with another drug, memantine. Nemantine works differently than donepezil, and some people with AD benefit more from their combined use than either drug alone.

How Donepezil Is Taken

Donepezil is taken by mouth once a day; the initial dose is 5 mg. After at least 4 weeks the dose can be increased to 10 mg once a day. It is usually taken at bedtime, with or without food.

How Donepezil Works

Since one of the key abnormalities in the brains of patients with AD is a decrease in the amount of neurons that use acetylcholine as a neurotransmitter, the cholinergic hypothesis was formed. The basis of this hypothesis is that since AD patients have a relative lack of acetylcholine, inhibiting the destruction of this neurotransmitter will improve some of their cognitive functions in a measurable way. The acetylcholinesterase and butylcholinesterase enzymes are responsible for removing acetylcholine.

Donepezil is a cholinesterase inhibitor that inhibits acetylcholinesterase. It does not prevent the death of neurons that occur in AD, but rather increases communication between the functional neurons that remain.

How the Body Affects Donepezil

Donepezil rapidly crosses from the blood into the brain, where it has a long half-life of about 70 hours. (A drug's half-life is the time it takes the body to clear 50% of the drug, either through metabolism or via the urine or stool). It is metabolized by enzymes in the liver in the cytochrome P450 family; the individual enzymes are known as CYP2D6 and CYP3A4.

Benefits

Donepezil significantly improves cognitive functioning in patients with AD.

Side Effects

Minor side effects of donepezil include the following:

• nausea
• vomiting
• diarrhea
• loss of appetite
• weight loss
• frequent urination
• muscle cramps
• joint pain, swelling, or stiffness
• pain
• excessive tiredness
• drowsiness
• headache
• dizziness
• nervousness
• depression
• confusion
• changes in behavior
• abnormal dreams
• difficulty falling asleep or staying asleep
• discoloration or bruising of the skin
• red, scaling, itchy skin

More serious side effects include the following:

• fainting
• slow heartbeat
• chest pain
• black or tarry stools
• red blood in stools
• bloody vomit (hematemesis)
• inability to control urination
• difficulty urinating or pain when urinating
• lower back pain
• fever
• seizures

Risks and Precautions

Because of its effect on the lungs, donepezil is used with caution in people with existing lung disease, such as asthma or chronic obstructive pulmonary disease.

Overdosage

Overdosage may bring on a cholinergic crisis with dangerously high levels of acetylcholine, which can cause several symptoms:

• slow heart rate
• low blood pressure, which can lead to fainting
• muscle weakness
• respiratory depression
• salivation
• sweating
• vomiting

Drug Interactions

Drugs that inhibit the activity of CYP3A4 could increase the blood concentrations of donepezil. Some strong CUYP3A4 inhibitors include the antifungals ketoconazole (Nizoral) and itraconazole (Sporanox), as well as some antibiotics such as erythromycin.

Drugs that increase the activity of CYP3A4 may reduce the blood concentrations of donepezil. Some of these drugs include phenytoin (Dilanitn), rifampacin, and carbamazepine (Tagamet).

Alternatives

The U.S. Food and Drug Administration has approved five drugs for dementia. Four of these (donepezil, galantamine (Reminyl), rivastigmine (Exelon), and tacrine (Cognex) inhibiting acetylcholinesterase, whereas the fifth, memantine, blocks receptors for the neurotransmitter glutamate.

Research

One of the pivotal trials in assessing the effectiveness of donepezil was a multicenter study of more than 450 patients with mild to moderate AD.^[1] Twelve weeks of donepezil improved scores on surveys of cognition and physician-assessed improvements more than did placebo. Donepezil improved scores of cognition by 2.5–3.1 points (depending on dose) over the scores seen in patients receiving placebo. The physician-assessed scores of symptoms had improved 0.3–0.4 points over those seen in placebo-treated patients.

References

1. ↑ Rogers SL, Doody RS, Mohs RC, Friedhoff LT. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med. 1998 May 11;158(9):1021-31. Abstract | Full Text | PDF