Donepezil

  • (RS )-1- benzyl-4- [(5,6 - dimethoxyindan - 1-on- 2-yl ) methyl ] piperidine
  • DL- 1-benzyl -4- [(5,6 - dimethoxyindan - 1-on- 2-yl ) methyl ] piperidine
  • (±)- E- 2020

N06DA02

Anti-dementia drugs

Reversible inhibition of acetylcholinesterase

211-212 ° C ( hydrochloride)

Template: Infobox chemical / molecular formula search available

Donepezil is a drug which is used in the treatment of certain forms of mild to moderate forgetfulness ( dementia). He engages in the neural conduction in the brain and to improve the memory and thinking skills.

  • 2.1 pharmacodynamics ( mechanism of action )
  • 3.1 stereochemistry

Clinical information

Areas of application (indications )

Donepezil is approved for the symptomatic treatment of mild to moderately severe dementia of the Alzheimer type. It can relieve the symptoms of dementia and halt the progression of symptoms for some time. The effect was statistically significant, although proven in scientific clinical trials with different measurement methods, but is very low. In severe Alzheimer's dementia, it is outside the regulatory drug approval in the form of a so-called off -label use as second choice. Also without regulatory drug approval donepezil is also occasionally used in vascular dementia and applies this as a drug of first choice. Its efficacy in the treatment of mild cognitive impairment, often harbingers or the first signs of dementia, is considered minimal and poorly documented.

Contraindications ( contraindications)

Donepezil is at a known hypersensitivity to this drug or other piperidine derivatives, such as domperidone, contraindicated. In patients with stomach ulcers, heart rhythm problems (sick sinus syndrome, supraventricular cardiac conduction disorders ), syncope, seizures, obstructive lung disease (eg, asthma, chronic obstructive pulmonary disease ), bladder obstruction, or regular use of nonsteroidal anti-inflammatory drugs, such as aspirin or naproxen, precautions and apply use of donepezil is subject to a risk-benefit assessment.

Monitoring

Since donepezil may be ineffective for individuals and should be discontinued in this case, after 15 to 20 weeks, the possible improvement of cognitive performance must be monitored. In addition, patients should ( which may indicate stomach ulcers or gastrointestinal bleeding ) also with regard to possible gastrointestinal complaints and ( can show the newly occurring cardiac arrhythmia ) in terms of their ECGs are observed. Therefore, a comparison should be derived ECG before starting treatment.

Interactions

Thanks to its effect on the acetylcholine metabolism of donepezil may show pharmacokinetic interactions with other drugs having effects on the acetylcholine system. These include, in particular, muscle relaxants, such as succinylcholine, acetylcholine agonists and anticholinergics. Pharmacodynamic interactions with beta-blockers are also possible.

Since donepezil is metabolized via the cytochrome P450 enzyme system, is at least the theoretical possibility of an interaction with substances which can inhibit or induce this enzyme system. Thus, experimentally CYP3A4 inhibitors, such as ketoconazole and erythromycin, and CYP2D6 inhibitors such as fluoxetine, inhibit the degradation of donepezil and thus lead to an increase in blood plasma levels of the drug. On the other hand, can accelerate the degradation of donepezil and so reduce its plasma levels enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol. The extent of these interactions and their clinical relevance is, however, not been adequately studied.

Side effects

Among the more common adverse effects that have been observed with the use of donepezil, diarrhea, nausea and headache include (> 10 %). Common ( 1-10 %) also occurred infections, loss of appetite, hallucinations, agitation, anxiety, syncope, dizziness, insomnia, fatigue, pain, injury, gastrointestinal symptoms including vomiting, rash, itching, muscle cramps, and urinary incontinence.

Infrequently, also had neuroleptic malignant syndrome (NMS ), a potentially life-threatening psychiatric complication, which is why the BfArM also plans in previously incompetent data able to take an appropriate warning in the product information.

Pharmacology

Pharmacodynamics ( mechanism of action )

Donepezil belongs to the group of reversible cholinesterase inhibitors. It mediates its effect therefore on the reversible blockade of the active site of the enzyme acetylcholinesterase. Through the inhibition of this enzyme slows the donepezil hydrolytic cleavage of the neurotransmitter acetylcholine into choline and acetate. Thus, the acetylcholine concentration in the synaptic cleft and acetylcholine receptors increases can be more active. Drugs with a similar mode of action include Galantamine, rivastigmine and tacrine. Even the insecticide parathion ( E605 ) affects the acetylcholinesterase, but it irreversibly inhibits.

Donepezil has a particularly strong binding affinity to the isoforms of acetylcholinesterase, which occur in the CNS, which reduces the side effects and should make the drug more tolerant than other cholinesterase inhibitors.

Chemistry

Stereochemistry

Donepezil is a drug with a chiral stereocenter. Therapeutically is the racemate, the 1:1 mixture of the (S ) - and (R)- isomers used, although it is known that the enantiomers in vivo and vitro have different effect on acetylcholinesterase. Therefore, several analytical methods for the enantioselective analysis of (S ) were - and (R ) - isomers of donepezil developed.

Commercial preparations

Aricept (D, A, CH, and other countries ), Yasnal (D), Memac (IT)

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