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. 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:
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. 
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. 
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.
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.
Adverse effects of donepezil include:
Donepezil is not recommended for patients with known hypersensitivity to donepezil hydrochloride or piperidine derivatives.
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. 
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. 
Donepezil is most commonly used for the treatment of Alzheimer's dementia and is FDA approved for use in mild, moderate, and severe Alzheimer disease. It is very important to educate the family and caregivers that donepezil does not alter the progression of Alzheimer's disease. However, it can ameliorate some symptoms by improving cognition and/or behavior. After starting treatment, all follow-up appointments should include assessments of cognition and behavior to assess the efficacy of treatment. Management of dementia needs a team approach including health care professionals such as doctors, nurse practitioners, physician assistants, nurses, family, and caregivers. 
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