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Continuing Education Activity

Donepezil hydrochloride is an acetylcholinesterase inhibitor most commonly used for the treatment of Alzheimer disease. Donepezil is FDA approved for use in mild, moderate, and severe Alzheimer disease. No evidence exists that donepezil alters the progression of the disease. It can, however, ameliorate some symptoms by improving cognition and/or behavior. It also has other off-label indications. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of donepezil, pertinent for members of the interprofessional team in the treatment of patients with Alzheimer dementia.


  • Identify the approved and off-label indications for donepezil.
  • Review the therapeutic mechanism of action of donepezil.
  • Summarize the adverse effects and potential drug interactions of donepezil.
  • Outline interprofessional team strategies for improving care coordination and communication to advance diabetes management and improve outcomes when using donepezil therapy.
Access free multiple choice questions on this topic.


Donepezil hydrochloride is an acetylcholinesterase inhibitor most commonly used for the treatment of Alzheimer disease.

FDA-approved Indications [1] [2]

  • Alzheimer disease: Donepezil is FDA approved for the treatment of dementia in mild, moderate, and severe Alzheimer disease. There is no evidence that donepezil alters the progression of the disease. It can, however, lessen some symptoms by improving cognition and/or behavior.

Off-label (Not FDA approved) Uses [3] [4] [5] [6]

  • Lewy body dementia: Some studies have shown the benefits of donepezil for the treatment of cognitive and behavioral symptoms in Lewy body dementia.
  • Traumatic brain injury: Some research suggests an improvement in memory dysfunction in patients with traumatic brain injury with donepezil use.
  • Vascular dementia: Studies have shown that donepezil may improve cognition in patients with vascular dementia but not overall global functioning.
  • Dementia associated with Parkinson disease: Some evidence suggests that donepezil can improve cognition, executive function, and global status in Parkinson disease dementia.

Researchers have also studied donepezil in patients with schizophrenia, mild cognitive impairment, ADHD, multiple sclerosis-related cognitive impairments, post-CABG cognitive impairment, Down syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL syndrome), with no proven significant benefits.[7] Small studies suggest donepezil may reduce sedation related to the analgesic use of opioids, but more extensive studies are needed to confirm this.[6][8][9]

Mechanism of Action

Donepezil hydrochloride is a piperidine derivative and a centrally acting, rapid, reversible acetylcholinesterase inhibitor. Acetylcholinesterase is an enzyme that degrades acetylcholine after release from the presynapse. Donepezil binds reversibly to acetylcholinesterase and inhibits the hydrolysis of acetylcholine, thus increasing the availability of acetylcholine at the synapses, enhancing cholinergic transmission. Some in vitro data has suggested that the anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain. It is structurally unrelated to other anticholinesterase agents like tacrine and physostigmine.[1]

Some noncholinergic mechanisms have also been proposed. Donepezil upregulates the nicotinic receptors in the cortical neurons, adding to neuroprotective property. It inhibits voltage-activated sodium currents reversibly and delays rectifier potassium currents and fast transient potassium currents, although this action is unlikely to contribute to clinical effects.[1][9]


Donepezil hydrochloride is available as an oral film-coated tablet in 5 mg, 10 mg, and 23 mg strength. It is also available as an orally disintegrating tablet in 5 mg and 10 mg strength.

  • For mild to moderate dementia, the initial dose is 5 mg/day; it can be increased to 10 mg/day slowly over four to six weeks.
  • For moderate to severe dementia, the dose can increase gradually up to 23 mg/day after the patient has been on a 10 mg/day dose for at least three months. The 23 mg tablet should be swallowed as a whole, not crushed, chewed, or split, as that may increase its rate of absorption. It is given a once-daily dose. Absorption is not affected by food or the timing of administration.

Pharmacokinetics/Pharmacodynamics [1] [9] [10] [11]

  • Donepezil absorbs well, with a relative oral bioavailability of 100%. The drug reaches peak plasma concentration in 3 to 4 hours. It has linear pharmacokinetics over a dose range of 1 mg to 10 mg, given once daily. The rate and extent of absorption are not affected by food or time of administration.
  • Steady-state is reached after multiple-dose administrations, about 15 days. The steady-state volume of distribution is 12 L/kg. It is approximately 96% bound to plasma proteins, mainly albumin (about 75%) and alpha1-acid glycoprotein (21%). It crosses the blood-brain barrier easily. 
  • It is metabolized by the liver (via CYP2D6, CYP3A4, and glucuronidation) into four major metabolites, two of which are active and several minor metabolites. It has a long half-life of about 70 hours.
  • Donepezil and its metabolites are excreted mainly by the kidneys. Two of those metabolites are known to be active. Around 17% is excreted unchanged in the urine.  About 15% to 20% is excreted in feces.

Specific Population 

Patient with Hepatic Impairment: No dosage adjustment is needed for compensated liver cirrhosis.

Patient with Renal Impairment: No dosage adjustment is needed for moderate or severe renal impairment.

Pregnant Women: Donepezil is a pregnancy category C drug. There are no sufficient data available for the use of donepezil hydrochloride in pregnant women and the risk associated with the developmental abnormalities.

Breastfeeding Women: It is unknown if donepezil or its metabolites are excreted in breast milk.

Pediatric Patients: It is not established whether donepezil treatment would be safe and effective in children.

Geriatric Patients: The elimination half-life in elderly patients is even longer (around 100 hours) due to an increased steady-state volume of distribution throughout the whole body. No dosage adjustment is needed in elderly patients as steady-state clearance is similar at all ages.

Adverse Effects

Adverse Effects [9] [12]

The most common side effects are gastrointestinal. These include nausea, diarrhea, and vomiting. Other common side effects include insomnia, muscle cramps, fatigue, and anorexia, which are more common with higher doses. These side effects are mild and transient in most patients, lasting up to three weeks and usually resolving even with continued use.

  • Donepezil can cause bradycardia and heart block in patients with or without known underlying cardiac conduction abnormalities because of its vagotonic properties. In addition, there are reports of syncopal episodes with the use of donepezil. 
  • Other less common cardiovascular side effects include hypertension, edema, EKG abnormalities, and hypotension.
  • Donepezil can cause weight loss in about 5% of patients. Incidence is higher with higher doses.
  • Like other cholinesterase inhibitors, donepezil can cause nightmares due to enhanced activation of the visual association cortex during REM sleep. However, dosing donepezil in the morning can reduce the frequency of nightmares.
  • There are rare reports of cases of neuroleptic malignant syndrome with donepezil.
  • Rhabdomyolysis is a rarely reported adverse event with the use of donepezil.

Drug interactions [13] [14] [15]

  • Donepezil has synergistic effects with other cholinesterase blocking agents like neostigmine and physostigmine. 
  • Donepezil may prolong the effects of depolarizing neuromuscular blocking agents like suxamethonium.
  • Donepezil may increase the risk of bradycardia with beta-blockers like carvedilol, metoprolol, atenolol, and propranolol.
  • CYP2D6 and CYP3A4 inducers like phenytoin, carbamazepine, phenobarbital, rifampin, and dexamethasone may reduce levels of donepezil by increasing its rate of elimination.
  • Theoretically, inhibitors of CYP3A4 and CYP2D6 like ketoconazole and quinidine can inhibit the metabolism of donepezil, but its clinical significance is unknown.


Donepezil is not recommended for patients with known hypersensitivity to donepezil hydrochloride or piperidine derivatives.

Warnings/Precautions [14]

  • Donepezil can cause QT interval prolongation, and its use requires caution in patients at risk of prolonged cardiac repolarization. It can also cause bradycardia and/or heart blocks, and using this agent merits caution in patients with symptomatic bradycardia, sick sinus syndrome, and cardiac conduction abnormalities.
  • Cholinesterase inhibitors can increase gastric acid secretion. Therefore, caution is necessary for patients at risk of ulcer disease, and symptoms of GI bleeding require monitoring.
  • Donepezil and other cholinomimetic agents can trigger seizures, and clinicians should exercise caution in patients with a history of seizure disorder.
  • Cholinomimetic agents like donepezil can cause or worsen bladder outflow obstruction, and their use requires caution in patients with a history of prostatic hyperplasia.
  • It can exaggerate succinylcholine-induced muscle relaxation during anesthesia.
  • Because of its cholinomimetic properties, it should be prescribed with caution to patients with a history of asthma or obstructive pulmonary disease.
  • Use donepezil with caution in patients at risk for rhabdomyolysis. Risk factors include a history of muscular disorders, uncontrolled hypothyroidism, and concomitant use of medications associated with rhabdomyolysis.


Some data suggest that therapeutic drug monitoring may help to enhance the effectiveness of donepezil treatment. However, routine monitoring of donepezil drug levels is not indicated.[16]

Detailed baseline dementia assessment should take place before initiating therapy. After starting treatment, all follow-up appointments should include assessments of cognition and behavior to assess treatment efficacy.


In the case of donepezil overdose, general supportive measures are necessary, and the clinician should contact poison control for a consult. An overdose of donepezil can cause a cholinergic crisis. Symptoms of overdose include severe nausea, vomiting, sweating, and salivation. It can also cause bradycardia, hypotension, respiratory depression, collapse, and seizures. Donepezil overdose may increase muscle weakness and cause death if respiratory muscles are involved. There have been reports of hepatotoxicity in a few cases with overdose. Like other anticholinesterase inhibitor toxicity, tertiary anticholinergics like atropine may be used as an antidote for donepezil overdose. The dose of IV atropine should be titrated based on clinical response. It is unknown if donepezil or its metabolites are removable by hemodialysis, peritoneal dialysis, or hemofiltration.[9][17][18][19]

Enhancing Healthcare Team Outcomes

Donepezil is most commonly used for the treatment of Alzheimer dementia and is FDA approved for use in mild, moderate, and severe Alzheimer disease. It is crucial to educate the family and caregivers that donepezil does not alter the progression of Alzheimer disease. However, it can alleviate some symptoms by improving cognition and/or behavior. Healthcare professionals, including clinicians, need to be aware of the benefits and limitations of donepezil when prescribing to older adults. After starting treatment, prescribers should follow up for cognition and behavior assessments to assess treatment efficacy, drug tolerance and check cholinergic excess symptoms. A pharmacist consult should include verifying dosing, performing medication reconciliation, looking for drug-drug interactions, and reporting to the prescriber if any issues. Nurses should monitor for adverse effects, evaluate medication compliance and therapeutic effectiveness. Management of dementia needs an interprofessional team approach, including health care professionals such as clinicians, nurse practitioners, physician assistants, nurses, pharmacists, family, and caregivers, all engaged in the collaborative activity and open communication to drive optimal patient outcomes.[1][2] [Level 5]

Review Questions


Seltzer B. Donepezil: a review. Expert Opin Drug Metab Toxicol. 2005 Oct;1(3):527-36. [PubMed: 16863459]
Kumar A, Sidhu J, Goyal A, Tsao JW. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Aug 11, 2021. Alzheimer Disease. [PubMed: 29763097]
Morey CE, Cilo M, Berry J, Cusick C. The effect of Aricept in persons with persistent memory disorder following traumatic brain injury: a pilot study. Brain Inj. 2003 Sep;17(9):809-15. [PubMed: 12850946]
Dubois B, Tolosa E, Katzenschlager R, Emre M, Lees AJ, Schumann G, Pourcher E, Gray J, Thomas G, Swartz J, Hsu T, Moline ML. Donepezil in Parkinson's disease dementia: a randomized, double-blind efficacy and safety study. Mov Disord. 2012 Sep 01;27(10):1230-8. [PubMed: 22915447]
Ballesteros J, Güemes I, Ibarra N, Quemada JI. The effectiveness of donepezil for cognitive rehabilitation after traumatic brain injury: a systematic review. J Head Trauma Rehabil. 2008 May-Jun;23(3):171-80. [PubMed: 18520431]
Szigeti K, Hafeez MU. Exploring the role of donepezil in dementia with Lewy bodies. Drugs Today (Barc). 2015 Oct;51(10):579-90. [PubMed: 26583300]
Kishnani PS, Sommer BR, Handen BL, Seltzer B, Capone GT, Spiridigliozzi GA, Heller JH, Richardson S, McRae T. The efficacy, safety, and tolerability of donepezil for the treatment of young adults with Down syndrome. Am J Med Genet A. 2009 Aug;149A(8):1641-54. [PubMed: 19606472]
O'Carroll CB, Woodruff BK, Locke DE, Hoffman-Snyder CR, Wellik KE, Thaera GM, Demaerschalk BM, Wingerchuk DM. Is donepezil effective for multiple sclerosis-related cognitive dysfunction? A critically appraised topic. Neurologist. 2012 Jan;18(1):51-4. [PubMed: 22217618]
Seltzer B. Donepezil: an update. Expert Opin Pharmacother. 2007 May;8(7):1011-23. [PubMed: 17472546]
Shigeta M, Homma A. Donepezil for Alzheimer's disease: pharmacodynamic, pharmacokinetic, and clinical profiles. CNS Drug Rev. 2001 Winter;7(4):353-68. [PMC free article: PMC6741644] [PubMed: 11830754]
Cacabelos R. Donepezil in Alzheimer's disease: From conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat. 2007 Jun;3(3):303-33. [PMC free article: PMC2654795] [PubMed: 19300564]
Bryson HM, Benfield P. Donepezil. Drugs Aging. 1997 Mar;10(3):234-9; discussion 240-1. [PubMed: 9108896]
Heath ML. Donepezil, Alzheimer's disease and suxamethonium. Anaesthesia. 1997 Oct;52(10):1018. [PubMed: 9370854]
Kho J, Ioannou A, Mandal AKJ, Cox A, Nasim A, Metaxa S, Missouris CG. Long term use of donepezil and QTc prolongation. Clin Toxicol (Phila). 2021 Mar;59(3):208-214. [PubMed: 32609550]
Levy RH, Collins C. Risk and predictability of drug interactions in the elderly. Int Rev Neurobiol. 2007;81:235-51. [PubMed: 17433928]
Hefner G, Brueckner A, Hiemke C, Fellgiebel A. Therapeutic drug monitoring for patients with Alzheimer dementia to improve treatment with donepezil. Ther Drug Monit. 2015 Jun;37(3):353-61. [PubMed: 25384119]
Greene YM, Noviasky J, Tariot PN. Donepezil overdose. J Clin Psychiatry. 1999 Jan;60(1):56-7. [PubMed: 10074883]
Pourmand A, Shay C, Redha W, Aalam A, Mazer-Amirshahi M. Cholinergic symptoms and QTc prolongation following donepezil overdose. Am J Emerg Med. 2017 Sep;35(9):1386.e1-1386.e3. [PubMed: 28668178]
Shepherd G, Klein-Schwartz W, Edwards R. Donepezil overdose: a tenfold dosing error. Ann Pharmacother. 1999 Jul-Aug;33(7-8):812-5. [PubMed: 10466911]
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Bookshelf ID: NBK513257PMID: 30020629


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