Donepezil

Donepezil Pharmacodynamics (Effect) Mechanism of action: Donezepil 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.The effect of donezepil inhibits acetylcholinesterase in vitro about 1000 times more stronglythan butyrylcholinesterase, the cholinesterase that occurs predominantly outside the central nervous system and therefore acts largely selectively in the brain.Clinical studies on Alzheimer's dementia: Dose of 5 mg or 10 mg once daily over a period of 6 mo or 12 mo. Donezepil leads to a steady-state inhibition of the activity of acetylcholinesterase (measured after dose application in erythrocyte membranes) of 63.6 % or 77.3 %.Measured inhibition correlates with changes in the ADAS-cog (scale that examines certain areas of perception) (industrial studies).An influence on possible underlying neuropathological mechanisms of Alzheimer's disease was not investigated and it can therefore not be assumed that the effect of Donezepil has an influence on underlying mechanisms or the progression of the disease. Donezepil therapy aims to reduce or delay the deterioration of symptoms such as cognitive and daily living skills.The rationale for a possible efficacy is essentially based on the importance of the neurotransmitter acetylcholine for cognitive abilities of the brain and for Alzheimer's dementia on one of several as yet unconfirmed 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).Efficacy was investigated in 2 studies over 6 months and 2 studies over 12 months.Efficacy criteria were: 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 ability to cope in society, at home, with hobbies and personal care).After administration of donezepil, there was a statistically significantly higher proportion of responders compared to placebo, i.e. patients with a positive response in the sense of an improvement in the ADAS-cog by at least 4 pointsNo deterioration in the CIBICNo deterioration in activities of daily living (ADL) based on the subscale of the Clinical Dementia Rating Scale.Further studies on its use in severe Alzheimer's disease, vascular dementia and combination therapy and in some cases other cognitive ability measurement instruments were also conducted. The results show at best little benefit with very early treatment and at the same time not insignificant risks of side effects in this mostly elderly and multimorbid patient population, especially with mostly pre-existing cardiovascular risk.Donezepil is not suitable for vascular dementia. Pharmacokinetics 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:DDonepezil 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. Indication Donepezil is indicated 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 recognized guidelines (e.g. DSM IV, ICD 10).Treatment should be initiated and monitored by a physician experienced in the diagnosis and treatment of Alzheimer's disease.A response to treatment with donepezil cannot be predicted in individual cases. Pregnancy/nursing period No use during pregnancy: animal studies show peri- and postnatal toxicity. No data are available in humans.No use during lactation or while breastfeeding is not possible: Donezepil passes into breast milk in animal studies. No studies in humans. Dosage and method of use Therapy with donepezil should only be started if regular drug intake and regular clinical assessment of therapeutic benefit can be ensured.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. Oral administration as a tablet preferably in the evening before going to bed; in case of sleep disturbances and nightmares also in the morning.Dose increase: after clinical assessment of the treatment, the dose may be increased to 10 mg/day. Recommended maximum dose: 10 mg/day (doses above 10 mg/day have not been studied in clinical trials ).Therapy monitoring: clinical benefit should be assessed regularly. Therapy should be continued as long as therapeutic benefit is demonstrated. Discontinuation of therapy should be considered as soon as a therapeutic effect is no longer demonstrable.After discontinuation of treatment, a slow fading of the beneficial effect is observed.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, 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. Undesirable effects 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 discontinued if 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 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 (Donezepil) 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: Interactions In vitro studies have shown that cytochrome P450isoenzymes 3A4 and - to a lesser extent - 2D6 are involved in the metabolism of donepezil. Ketoconazole and chi-nidine, inhibitors of CYP3A4 and 2D6, inhibit the metabolism of donepezil in vitro, i.e. possible enhancement of the effect of donezepil.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 medicinal products such as succinylcholine, other medicinal products with neuro-muscular blocking effects or cholinergic agonists and 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). Contraindication Hypersensitivity to donepezil hydrochloride, piperidine derivatives or any of the other ingredients.Drug contains lactose. Patients with the rare hereditary galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine. Preparations Aricept® original preparation (Eisai GmbH) 5mg; 10mgas well as several generics:Donepezil-HCl AbZ,Donepezil-HCl ratiopharm,Donepezil-HCl PfizerDonepezil-HCl Zentiva(active ingredient: donepezil hydrochloride)

Donepezil

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