Donepezil

Donezepil is a psychotropic drug which, as a neuromodulator, influences the effectiveness of the endogenous neurotransmitter acetylcholine. Donezepil belongs to the substance group of cholinesterase inhibitors and increases acetylcholinesterase in the synaptic cleft of cholinergic neurons by selective and reversible inhibition of acetylcholinesterase in the brain.

As an anti-dementia drug, it is approved for symptomatic therapy to slow memory loss, cognitive impairment and loss of everyday abilities in mild to moderate Alzheimer's dementia.

Mechanism of action: Donepezil selectively and reversibly inhibits acetylcholinesterase, which catalyzes the breakdown of acetylcholine into acetate and choline, thereby increasing the concentration of acetylcholine in the synaptic cleft. This is intended to enhance the effect of acetylcholine at the acetylcholine receptors of the synapses, improve neuronal transmission and activity and support the associated cognitive functions.

Donepezil inhibits acetylcholinesterase in vitro about 1000 times more strongly than butyrylcholinesterase, the cholinesterase that occurs predominantly outside the central nervous system, and therefore acts largely selectively in the brain.

The rationale for the possible efficacy of donepezil is essentially based on the importance of the neurotransmitter acetylcholine for the cognitive abilities of the brain, and for its use in Alzheimer's disease on one of several hypotheses on the pathophysiology of Alzheimer's disease, that the destruction of cholinergic neurons and the reduction of acetylcholine could play a role in the development of the disease (acetylcholine hypothesis) (Bartus RT et al 1982; Hampel H et al 2018).

However, it is not to be expected that the effect of donepezil has an influence on the underlying neuropathological mechanisms and progression of Alzheimer's disease, which are presumably of multifactorial origin.

Therapy with donepezil is therefore at best a symptomatic treatment aimed at reducing or delaying the worsening of symptoms, such as the deterioration of cognitive and everyday abilities.

Approval studies: Clinical studies on Alzheimer's dementia: Dose of 5 mg or 10 mg once daily over a period of 6 mo or 12 mo (Rogers SL et al 1998, Rogers SL et. al. 1998, Winblad B et al 2001). Donepezil leads to a steady-state inhibition of the activity of acetylcholinesterase (measured after dose application in erythrocyte membranes) of 63.6 % and 77.3 % respectively.

Clinical efficacy criteria:
ADAS-cog (a measure of cognitive performance), CIBIC-plus (Clinician Interview Based Impression of Change with Caregiver Input - a measure of global function) and ADL (Activities of Daily Living Subscale of the Clinical Dementia Rating Scale - a measure of the ability to cope in society, at home, with hobbies and personal care).

A dose-dependent, statistically significant higher proportion of responders, i.e. patients with a positive response in terms of the following criteria: an improvement in the ADAS-cog by at least 4 points, no deterioration in the CIBIC, no deterioration in activities of daily living (ADL) based on the subscale of the Clinical Dementia Rating Scale, was shown after administration of donezepil compared to placebo.

Numerous other studies have been conducted on its use in severe Alzheimer's disease (Winblad B et al 2006), other forms of dementia e.g. vascular dementia or dementia in Parkinson's disease, cognitive impairment in multiple sclerosis, as well as on combination therapy (e.g. with memantine) and in some cases using other measurement instruments to assess cognitive abilities (Dichgans et al . 2008, Krupp LB et al 2011).

The results were inconsistent and showed at best low to moderate benefit with very early treatment, with not insignificant risks of sometimes serious side effects in this mostly elderly and multimorbid patient population, especially with a pre-existing cardiovascular risk.

The assessment of the practical clinical and economic benefits of the therapy and its long-term use also remained inconsistent. A minor short-term benefit of a few months delay in the worsening of symptoms is usually relativized over longer observation periods and is occasionally even outweighed by more hospital admissions due to adverse drug reactions (ADRs) (Courtney C et al 2004).

Critical aspects of the studies are the often highly pre-selected patient population due to the numerous exclusion criteria (bias for the occurrence of ADRs), the high drop-out rate, the difficulty of assessing and comparing the measured cognitive abilities and the practical and clinical relevance of the measured differences, as well as the often short study duration, which may overestimate short-term improvements.

Donepezil shows no efficacy for agitation, restlessness and aggression, which represent a heavy burden for caregivers and relatives alike and therefore have high clinical significance. Compared to drug treatment, non-drug measures, e.g. avoidance of stressors such as pain and noise, physical activity and music therapy as well as cognitive training were more effective (Howard RJ et al 2007). In addition, homeopathic substances such as ginkgo can also be used without a similarly high risk of serious ADRs as with donepezil (Bohlken J et al 2025).

Absorption and distribution:
C _max approx. 3 to 4 hours after oral administration. Plasma concentration and the area under the curve increase in proportion to the dose. Terminal half-life approx. 70 hours, with daily administration steady state is reached slowly over several days (approximate steady state after approx. 3 weeks).

Plasma protein binding of donezepil approx. 95 %; plasma protein binding of the active metabolite 6-O-desmethyl-donepezil not known; distribution of donepezil in various tissues of the body not investigated. In substance equilibrium studies, 28% of a labeled dose of 5 mg remained in the body after 10 days.

Biotransformation/elimination:

Donepezil is predominantly excreted in the urine (approx. 57% of which is unchanged, the remainder as metabolites) and is also metabolized by the cytochrome P450 system to several metabolites, not all of which have been identified. Approx. 14.5 % excretion in feces; no indication of enterohepatic circulation.

Donepezil is approved for the symptomatic treatment of mild to moderate Alzheimer's dementia.

Treatment should be started and monitored by a physician experienced in the diagnosis and treatment of Alzheimer's dementia.

The diagnosis should be made according to the recognized guidelines (e.g. DSM IV, ICD 10).

Potentially reversible causes of cognitive impairment or causes other than dementia, such as metabolic diseases, thyroid dysfunction, neuroinflammatory diseases or intracranial space-occupying lesions (e.g. subdural hematoma), etc. must be ruled out before treatment.

An individual risk-benefit assessment based on the situation of the individual patient isimportant, especially taking into account other underlying diseases and concomitant medication (no general prescription practice!).

A response to treatment with donepezil cannot be predicted in individual cases.

There is no approval for use in vascular dementia or other forms of dementia.

No use in pregnancy: animal studies show peri- and postnatal toxicity. No data are available in humans.

No use during lactation or while breastfeeding is not possible: Donepezil passes into breast milk in animal studies. No studies in humans.

Only start therapy with donepezil if regular drug intake and regular clinical assessment of the therapeutic benefit can be guaranteed.

Take orally as a tablet preferably in the evening before going to bed; if sleep disturbances and nightmares occur, also in the morning.

Start treatment with a dose of 5 mg/day for at least one month to achieve steady-state concentration and to allow assessment of the earliest clinical response to treatment.

Dose increase: according to clinical assessment of treatment, the dose may be increased to 10 mg/day if necessary.

Recommended maximum dose: 10 mg/day (doses above 10 mg/day have not been studied in clinical trials and should not be used due to possible occurrence of dose-related risks of serious ADRs).

Therapy monitoring: clinical benefit should be assessed regularly. Therapy should only be continued as long as a therapeutic benefit is demonstrable. As soon as a therapeutic effect is no longer detectable, therapy should be discontinued.

Renal impairment: No dose adjustment necessary as clearance is not impaired.

Hepatic impairment: in case of mild and moderate impairment, dose adjustment according to individual tolerance if necessary, as drug concentration may be increased; no data available in case of severe impairment.

5 mg donepezil hydrochloride, corresponding to 4.56 mg donepezil.

10 mg donepezil hydrochloride, corresponding to 9.12 mg donepezil.

There are no studies on the use in severe Alzheimer's dementia, other forms of dementia or other memory disorders (e.g. age-related cognitive decline).

Risk and warning information:

Anesthesia: the effect of succinylcholine-type muscle relaxants may be enhanced (cholinesterase inhibitors!).

Cardiovascular disorders: Cholinesterase inhibitors may exert vagotonic effects on the heart rate (e.g. bradycardia) especially in patients with sinus node syndrome (sick sinus syndrome) or other supraventricular conduction disorders of the heart, such as sinoatrial or atrioventricular block!

Seizures and syncope may occur, which may be caused by a block in conduction or a prolonged sinus pause!

Cases of QTc prolongation and torsade de pointes have been reported, therefore particular caution should be exercised in: pre-existing QTc prolongation; family history of QTc prolongation; patients being treated with drugs that affect the QTc interval; patients with relevant existing heart disease (e.g. uncompensated heart failure, recent myocardial infarction, bradyarrhythmias); electrolyte disturbances (hypokalemia, hypomagnesemia). Clinical monitoring (ECG) may be necessary!

Gastrointestinal system: There is an increased risk of gastric and intestinal ulcer formation, especially in patients with a history of ulcers or taking non-steroidal anti-inflammatory drugs (NSAIDs).

Genitourinary system: Cholinomimetics and cholinesterase inhibitors may lead to urination disorders.

CNS and nervous system: The seizure threshold may be decreased and there is an increased risk of generalized seizures.

Extrapyramidal symptoms may be increased or triggered.

In rare cases, malignant neuroleptic syndrome ( MNS ) may be triggered. MNS is a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, vegetative instability, changes in consciousness and elevation of creatine kinase (CK); in addition, myoglobinuria (rhabdomyolysis) and acute renal failure may occur.

The risk is increased , especially if antipsychotics are taken at the same time!

Treatment must be discontinuedif high fever and symptoms occur !

Mortality in vascular dementia: Increased deaths in vascular dementia according to NINDS-AIREN criteria in clinical trials were not clearly significant in frequency in small study populations compared to placebo and were evaluated in relation to the vascular problems of the patients.

Lung and respiratory tract: Use with caution in patients with a history of bronchial asthma and COPD and obstructive lung disease! Cholinomimetic effect intensifies the symptoms!

Important! The use of donepezil together with other acetylcholinesterase inhibitors, as well as with agonists or antagonists of the cholinergic system, and the simultaneous use of psychotropic drugs should always be avoided!

No data are available on severe liver dysfunction.

Ability to drive: Since donepezil may cause dizziness, fatigue and drowsiness, the ability to drive and operate machinery may be impaired and should be assessed regularly by a doctor. In addition, the vagotonic effect can lead to an increased risk of syncope!

Frequency of side effects:

The most common adverse events are diarrhea, muscle cramps, fatigue, headache, loss of appetite, nausea, vomiting and insomnia.

Frequent: hallucinations, agitation, aggressive behavior, unusual dreams and nightmares (reversible after discontinuation); syncope (cardiac arrhythmia, e.g. consider heart block!), dizziness, urinary incontinence.

Occasionally: seizures, bradycardia. Gastrointestinal bleeding, gastric and duodenal ulcer, hypersalivation.

Rarely: Extrapyramidal symptoms, sinoatrial block, atrioventricular block, liver dysfunction including hepatitis (consider discontinuation!).

Very rare: Malignant neuroleptic syndrome (MNS), rhabdomyolysis (also independent of MNS when starting therapy and increasing the dose). In any case, discontinue immediately!

Frequency unknown: Polymorphic ventricular tachycardia, including torsade de pointes; prolonged QT interval on electrocardiogram. Pleurothotonus (Pisa syndrome) (form of dystonia). Increased libido, hypersexuality.

Overdosage/toxicology: estimated median lethal single oral dose in mice and rats: 45 and 32 mg/kg, respectively.

Toxic effects in animals: dose-related signs of cholinergic stimulation including: reduction of spontaneous movements, prone position, unsteady gait, lacrimation, clonic convulsions, respiratory depression, salivation, pupil constriction, fasciculations and decreased body temperature.

Overdose of cholinesterase inhibitors (donepezil) can lead to life-threatening cholinergic crisis characterized by: severe nausea, vomiting, salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and seizures. In addition, increasing muscle weakness is possible, which can lead to death if the respiratory muscles are involved.

Treatment measures:
General emergency medical measures.

Antidote: tertiary anticholinergics such as atropine; recommended intravenous atropine sulphate titrated to effect in an initial dose of 1.0 to 2.0 mg i.v. and subsequent doses based on the
clinical response. (Circulatory monitoring!)

Atypical blood pressure and heart rate responses have been observed with other cholinomimetics when used concomitantly with quaternary anticholinergics such as glycopyrrolate.

It is not known whether donepezil and/or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration).

There is increased pharmacovigilance. Please report suspected cases of side effects in connection with the intake to: nebenwirkungen.bund.de

In vitro studies: Cytochrome P450isoenzymes 3A4 and - to a lesser extent - 2D6 are involved in the metabolism of donepezil.

Ketoconazole and quinidine, inhibitors of CYP3A4 and 2D6, inhibit the metabolism of donepezil in vitro, i.e. possible enhancement of the effect of donepezil.

CYP3A4inhibitors, such as itraconazole and erythromycin, and CYP2D6 inhibitors, such as fluoxetine, may inhibit the metabolism of donepezil and thereby enhance its effect.

Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol could reduce the plasma levels of donepezil and thereby reduce its effect.

The extent of inhibition or induction is unknown. Therefore, use drug combinations with caution !
Donepezil can also influence the effect of other drugs with anticholinergic activity.
In addition, a synergistic effect may occur with concomitant treatment with drugs such as succinylcholine, other drugs with neuro-muscular blocking effects or cholinergic agonists, as well as beta-blockers, which have an effect on cardiac conduction.
Important: Cases of QTc interval prolongation and torsade de pointes have been reported in connection with donepezil. Caution should be exercised when donepezil is used in combination with other medicinal products known to prolong the QTc interval; clinical monitoring (ECG) may be required. E.g. with: Class IA antiarrhythmic drugs (e.g. quinidine) Class III antiarrhythmic drugs (e.g. amiodarone, sotalol)
Certain antidepressants (e.g. citalopram, escitalopram). Citalopram, escitalopram, amitriptyline)
Other antipsychotics (e.g. phenothiazinederivatives, sertindole, pimozide, ziprasidone)
Certain antibiotics (e.g. clarithromycin, erythromycin, levofloxacin, moxifloxacin).

Hypersensitivity to donepezil hydrochloride, piperidine derivatives or any of the other ingredients.

There are no studies on the use in severe Alzheimer's dementia, other forms of dementia or other memory disorders (e.g. age-related cognitive decline).

Do not use for causes of cognitive impairment that are not due to dementia.

In the case of pre-existing cardiac arrhythmia and cardiac conduction disorders or a family history, see the risk and warning information in the Adverse effects section. If in doubt, do not use!

See also section Interactions!

Drug contains lactose. Patients with the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

See specialist information for further information!

^Aricept® original preparation (Eisai GmbH) 5mg; 10mg

in addition several generics e.g:

Donepezil-HCl AbZ,

Donepezil-HCl ratiopharm,

Donepezil-HCl Pfizer

Donepezil-HCl Zentiva

(active ingredient: donepezil hydrochloride)