Donepezil in Alzheimer’s Disease

This report discusses the mechanism, pharmacokinetics, pharmacodynamics, and therapeutic use of Donepezil in Alzheimer’s Disease. It also highlights the adverse effects and proper dosage. Donepezil is a cholinesterase inhibitor that helps in improving memory, ability of working and the awareness of the patient. The drug is administered orally and has a half-life of 70 hours. The drug is effective in treating Alzheimer’s Disease, but it should be administered in an effective dose. The report also discusses the risk factors related to this drug use.

Running head: DONEPEZIL IN ALZHEIMER’S DISEASE
Donepezil in Alzheimer’s Disease
Name of the Student
Name of the University
Author Note

1DONEPEZIL IN ALZHEIMER’S DISEASE
Executive summary
The Alzheimer’s disease is one of the major neurological disorder throughout whole world.
Donepezil is one of the important drug to treat this disease. In this report, the mechanism of
donepezil is briefly discussed. Along with this the pharmacodynamics and pharmacokinetics of
this drug is also discussed. The adverse effect of donepezil while using this drug during several
physiological problems is also highlighted.

2DONEPEZIL IN ALZHEIMER’S DISEASE
Table of Contents
Introduction......................................................................................................................................3
Pharmacodynamics..........................................................................................................................3
Pharmacokinetics.............................................................................................................................4
Therapeutics.....................................................................................................................................5
Conclusion.......................................................................................................................................6

3DONEPEZIL IN ALZHEIMER’S DISEASE
Introduction
In this report the pharmacokinetics, pharmacodynamics, therapeutic use of Donepezil
drug is discussed. Donepezil is an oral medicine that is mainly used for the treatment of
Alzheimer’s disease (AD). The drug itself is a cholinesterase inhibitor and mainly helps in
improving memory, ability of working and the awareness of the patient. In Alzheimer’s disease
the cognitive and the motor function is mainly affected. These functions are associated with the
cholinergic neurons of brain tissues. The release of acetylcholine helps in maintaining signal
transmission. The enzyme acetyl cholinesterase causes the destruction of acetylcholine (ACh).
Donepezil inhibits the release of acetyl cholinesterase (AChEI) and stops the breakdown of
acetylcholine (Kumar and Singh 2015). However, it is mainly associated with the lowering of
the progression of decline by maintaining the acetylcholine level as high as possible. Although
nerve cell damage and destruction process still continues but in a very slow rate (Tan et al.
2014).
Pharmacodynamics
The term pharmacodynamics refers to the study of the process by which a drug affect an
organism and as well as the study of the mechanism by which the drug affects the particular
system. The drug, donepezil is a noncompetitive, selective, potent and reversible inhibitor of the
acetyl cholinesterase ( AChEI) and mainly used in treating AD. Donepezil works mainly by
increasing the extracellular concentration of the ACh and it causes binding of the ACh in the
cholinergic receptor. In this case, mainly cholinergic muscarinic receptor is associated this
process. The cholinergic muscarinic receptor is coupled with the phospholipase A2 ( cPLA2)
activation and along with this arachidonic acid is released from the synaptic membrane

4DONEPEZIL IN ALZHEIMER’S DISEASE
phospholipid. When the ACh is released from the presynaptic neuron in to the synaptic cleft and
it then bind to the muscarinic cholinergic receptor (H Ferreira-Vieira et al. 2016). The
acetylcholine is degraded into Choline and acetate by the acetyl cholinesterase. The inhibitor
donepezil blocks the active site of the particular enzyme so that the actual substrate of this
enzyme that is ACh cannot bind with the enzyme. As a result the degradation process by the
enzyme is stopped. Ultimately, it will increase the extracellular level ACh in the neurons.
However, the memantine administration along with donepezil shows better result. The
memantine works via NMDA receptor. This is a NMDA receptor anatagonist and it works by
altering the activity of the glutamate. Glutamate plays an effective role in learning and memory
by increasing the calcium influx through the NMDA receptor. Excess of amount of glutamate
stimulates the NMDA receptor to allow more calcium ions entering into the nerve cell. The
increased calcium concentration helps to create an environment that helps in storage of
information. Donepezil administration ultimately increase the ACh level of the nerve cells and

5DONEPEZIL IN ALZHEIMER’S DISEASE
maintain the homeostasis of chemical environment (Parsons et al. 2013).
In the figure.1, it is seen that the acetylcholine released from the presynaptic membrane
and inhibit the breaking of the acetylcholine into acetate and choline. This inhibition ultimately
increases the concentration of ACh in the nerve tissues.
Pharmacokinetics
The term pharmacodynamics refers to the section of pharmacology in which the
movement of the drug within body is discussed. The term pharmacokinetics also concentrate on
the facts like drug administration, absorption, metabolism, distribution and lastly the excretion of
the drug. The drug donepezil is mainly administered through mouth that means it is an oral
administrative drug. The drug has a half-life of 70 hours and as a result, the drug can be
administered in daily basis (Prvulovic and Schneider 2014). It is available as immediate release

6DONEPEZIL IN ALZHEIMER’S DISEASE
and as well as in oral tablets. The oral tablets have the dose of 5, 10 and 23 mg. As donepezil is
noncompetitive and reversible inhibitor of AChE, it is more selective to bind with AChE than
butyrylcholinesterase ( BChE). The drug is administered quickly and the permeability is very
low through the blood brain barrier. In a 14-C labelled drug has shown less absorption than the
unlabeled drug. Along with this, the brain level of the radioactivity is declined almost in the
same manner with the plasma level of unaltered donepezil. In brain, no heterogeneous
localization of radioactivity is not present. The mean apparent plasma clearance of this drug is
0.13-0.19 L/hr/kg. The multiple dose of donepezil causes accumulation of this drug in the plasma
by 4-7 fold and the steady state is reached within the 15 days of administration. Donezepil is
almost 96% attached with the plasma protein of human body and the proteins are a mainly
albumins (almost 75% attachment) and another one is alpha 1- acid glycoprotein (about 21%).
The urine mainly excretes the drug and it is metabolized into four major components. Among
them, two are active in nature and other metabolites are not identified fully. Donepezil is
metabolized by CYP 450 isozymes named 2D6 and 3A4 and enters into glucuronidation cycle.
After administration of C-14 labelled donepezil, the plasma concentration of intact donepezil
was found to be 53% of total administration and along with this 6% of 6-O-desmethyl donepezil
was also found (Zemek et al. 2014). This concentration of the drug has the capability of
inhibiting AChE. The excretion of this drug is through feces and it is seen that almost 15% of
radioactivity is present in the feces after the radioactive labelled drug administration, whereas
urine showed 57% of radioactivity. During a 10 days period of drug administration, almost 17%
unchanged drug was recovered in the urine.

7DONEPEZIL IN ALZHEIMER’S DISEASE
Radioactivity in feces Radioactivity in urine ff ective percenatgeE
0
10
20
30
40
50
60
15
57
28
Bar diagram of radioactive labelled
Donepezil
Therapeutics
The donepezil can be given in a dose range of 1-10 mg and it should be given once per
day. However, the administration is not affected by consumption of any kind of food. After the
oral dosing of this drug in an Alzheimer’s patient, the peak plasma concentration of the drug is
achieved by the dose of 23 mg dose in approximately 8 hours period. The effect is almost double
in comparison to the administration of 10mg tablet. The clearance of drug is decreased by
increasing age. The 23 mg dose should be used in case of moderate to severe AD (Deardorff,
Feen and Grossberg 2015). This drug should not be used in patients with severe heart disease as
the drug can cause vagotonic effect on the Sino atrial and atrioventriclar nodes and ultimately
results in heart block. Patients with ulcers are not supposed to administer this drug as it can cause
GI bleeding. It is not also safe to use donepezil for the asthma patient. The administration of
donepezil can cause weight lose so the use of the drug should be closely monitored (Deardorff,
Feen and Grossberg 2015). According to FDA guideline, donepezil can be used in pregnant
Fig:2- The excretion of radio -active labelled donepezil by feces and urine.
Source: image created by the author.

8DONEPEZIL IN ALZHEIMER’S DISEASE
woman only if the benefit is more than that of the potential risk to the fetus. In a study in mice it
is seen that there is no teratogenic effect during the period of organogenesis at the doses up to
16/mg/kg/day and it is almost 6 times the maximum prescribed dose of human( 23 mg/day/ on a
mg/m2 basis). Oral administration of the drug (1,3,10 mg/kg/day) to rats during the late gestation
and also during the lactation causes increased mortality rate in the newborn through postpartum
(day 4) and this effect is seen in only in the mice who have administered the highest dose of the
drug. Although, it is not clearly known that, whether the drug is excreted through the human
milk or not. It is recommended to a nursing a mother that she should not administer the drug
donepezil in breast feeding period (Katzung and Trevor 2015).
Conclusion
Lastly, it can be concluded that the donepezil is very effective for the treatment of AD.
However, it is also important to administer the drug in an effective dose. The mechanism of
action of this drug is also discussed in this report. Along with this the pharmacodynamics of the
drug, the proper dose for various condition and the risk factors related to this drug use also
discussed in this report.
References
Deardorff, W.J., Feen, E. and Grossberg, G.T., 2015. The use of cholinesterase inhibitors across
all stages of Alzheimer’s disease. Drugs & aging, 32(7), pp.537-547.
H Ferreira-Vieira, T., M Guimaraes, I., R Silva, F. and M Ribeiro, F., 2016. Alzheimer's disease:
targeting the cholinergic system. Current neuropharmacology, 14(1), pp.101-115.
Katzung, B.G. and Trevor, A.J. eds., 2015. Basic & clinical pharmacology (pp. 753-756). New
York, NY: McGraw-Hill.
Kumar, A. and Singh, A., 2015. A review on Alzheimer's disease pathophysiology and its
management: an update. Pharmacological Reports, 67(2), pp.195-203.

9DONEPEZIL IN ALZHEIMER’S DISEASE
Moghul, S. and Wilkinson, D., 2001. Use of acetylcholinesterase inhibitors in Alzheimer’s
disease. Expert review of neurotherapeutics, 1(1), pp.61-69.
Parsons, C.G., Danysz, W., Dekundy, A. and Pulte, I., 2013. Memantine and cholinesterase
inhibitors: complementary mechanisms in the treatment of Alzheimer’s disease. Neurotoxicity
research, 24(3), pp.358-369.
Prvulovic, D. and Schneider, B., 2014. Pharmacokinetic and pharmacodynamic evaluation of
donepezil for the treatment of Alzheimer's disease. Expert opinion on drug metabolism &
toxicology, 10(7), pp.1039-1050.
Tan, Chen-Chen, Jin-Tai Yu, Hui-Fu Wang, Meng-Shan Tan, Xiang-Fei Meng, Chong Wang,
Teng Jiang, Xi-Chen Zhu, and Lan Tan. "Efficacy and safety of donepezil, galantamine,
rivastigmine, and memantine for the treatment of Alzheimer's disease: a systematic review and
meta-analysis." Journal of Alzheimer's Disease 41, no. 2 (2014): 615-631.
Zemek, F., Drtinova, L., Nepovimova, E., Sepsova, V., Korabecny, J., Klimes, J. and Kuca, K.,
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memantine. Expert opinion on drug safety, 13(6), pp.759-774.