Donepezil

Article Author:
Anil Kumar
Article Editor:
Sandeep Sharma
Updated:
10/27/2018 12:31:32 PM
PubMed Link:
Donepezil

Indications

Donepezil hydrochloride, marketed under the trade name Aricept, is an acetylcholinesterase inhibitor most commonly used for the treatment of Alzheimer disease.

Indications

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

 Other off-label (Not FDA approved) uses include:

  • Lewy body dementia: Some studies have shown benefits of donepezil for the treatment of cognitive and behavioral symptoms in Lewy body dementia.
  • Traumatic brain injury: Some research suggests 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.

Donepezil has also been studied 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. Small studies suggest donepezil may reduce sedation related to the analgesic use of opioids, but larger studies are needed to confirm this.

Mechanism of Action

Donepezil hydrochloride is a piperidine derivative and a centrally acting, rapid, reversible inhibitor of acetylcholinesterase. Acetylcholinesterase is an enzyme that degrades acetylcholine after it is released 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 anticholinesterase activity of donepezil is relatively specific for acetylcholinesterase in the brain. It is structurally unrelated to other anticholinesterase agents like tacrine and physostigmine.

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. 

Administration

Donepezil is available either as an oral disintegrating tablet or an oral film-coated tablet. For mild to moderate dementia, the initial dose is 5 mg/day; it can be increased to 10 mg/day slowly over a period of 4 weeks. For moderate to severe dementia, the dose can be increased slowly up to 23 mg/day, after the patient has been on 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 a once daily dose. Absorption is not affected by food or timing of administration.

Pharmacodynamics/Kinetics

Donepezil absorbs well, with a relative oral bioavailability of 100%. Peak plasma concentration is reached 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 to 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 active, and several minor metabolites. Donepezil and its metabolites are excreted mostly by the kidneys. Around 17% is excreted unchanged in the urine. About 15% to 20%. Two of those metabolites are known to be active. Donepezil and its metabolites are excreted mostly by the kidneys. Around 17% is excreted unchanged in the urine. About 15% to 20% is excreted in feces. It has a long half-life of about 70 hours. 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.

No dosage adjustment is needed for compensated liver cirrhosis and moderate to severe renal impairment.

Donepezil is a pregnancy category C drug. It is not known if donepezil is excreted in breast milk. Safety and effectiveness in children is not established. 

Adverse Effects

Adverse effects of donepezil include:

  • 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 3 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. Syncopal episodes have been reported with 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.
  • Donepezil, like other cholinesterase inhibitors, can cause nightmares due to enhanced activation of visual association cortex during REM sleep. Dosing donepezil in the morning can reduce the frequency of nightmares.
  • Cases of neuroleptic malignant syndrome have rarely been reported with donepezil.
  • Rhabdomyolysis has rarely been reported with the use of donepezil.

Warnings/Precautions

  • Donepezil can cause QT interval prolongation and should be used with caution in patients at risk of prolonged cardiac repolarization. It can also cause bradycardia and/or heart blocks and should be used with caution in patients with symptomatic bradycardia, sick sinus syndrome, and cardiac conduction abnormalities.
  • Cholinesterase inhibitors can increase gastric acid secretion. Caution should be used in patients at risk of ulcer disease, and symptoms of GI bleeding should be monitored.
  • Donepezil and other cholinomimetic agents can trigger seizures and should be used with caution in patients with a history of seizure disorder.
  • Cholinomimetic agents like donepezil can cause or worsen bladder outflow obstruction and should be used with 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.

 Drug interactions

  • 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.

Contraindications

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

Monitoring

Some data suggest that therapeutic drug monitoring may be used to enhance the effectiveness of donepezil treatment. However, routine monitoring of donepezil drug levels is not indicated.

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

Toxicity

In the case of donepezil overdose, general supportive measures should be utilized. Poison control should be consulted. 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. Increasing muscle weakness can occur and can cause death if respiratory muscles are involved. Hepatotoxicity has been reported in a few cases with overdose. Like in 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 can be removed by dialysis.