Background
Donepezil hydrochloride, marketed in the United States under the trade name Aricept, is a chemically distinct and specific acetylcholinesterase (AChE) inhibitor that has found wide clinical usage in the palliative treatment of dementia of the Alzheimer’s type (Reyes et al., 2004). The importance of donepezil HCL is underscored by the fact that it can improve cognition and behavior of individuals with Alzheimer’s disease, a condition that is projected to affect around 5-10% of the population over age 65 and as many as 50% of those exceeding 85 years of age in the US alone (Rogers et al., 2000). This paper looks into the pharmacology and mechanism of donepezil’s action, the behavioral and physiological effects of the drug, as well as its abuse potential, toxicity, and risk of relapse.
Drug Pharmacology and Mechanism of Action
Receptors
Donepezil, 1-benzyl-4-[(5,6-dimethoxy-1-indention)-2-yl]methylpiperidine hydrochloride is a centrally acting reversible acetylcholinesterase inhibitor that is administered to treat individuals with mild, moderate, and advanced Alzheimer’s disease by enhancing the action of acetylcholine and ensuring the receptors the drug interacts within the brain become more responsive. In the areas of the brain first affected by Alzheimer’s disease, research has found a shortage of acetylcholine chemical that assists to send messages between certain nerve cells and a loss of the nerve cells that use acetylcholine (Sugimoto et al., 2002). The indanone benzylpiperidine derivative is known to up-regulate nicotinic receptors in cortical neurons and also to promote non-amyloidogenic pathways of APP processing by stimulation of α-secretase mediated through protein kinase C (PKC), resulting in an enhancement in neuroprotection and subsequent reduction of symptoms associated with Alzheimer’s disease (Cacabelos, 2007).
According to available scientific scholarship, the drug improves the symptoms of Alzheimer’s disease not only by inhibiting acetylcholine degradation in the synaptic cleft (the structure that allows a neuron or nerve cell to pass an electrical or chemical signal to another neuron or nerve cell) but also through enhancing choline reuptake at the presynaptic level (Reyes et al., 2004). These actions are associated with an increase in acetylcholine synthesis in presynaptic terminals located in the brain and subsequent improvement in cognition and capability to undertake activities of daily living for people with Alzheimer’s disease. Donepezil is known to cause minimal membrane depolarization due to its highly selective nature in inhibiting neuronal cholinesterase enzyme and has protective effects against ischemic damage, glucose excitotoxicity, and Abeta toxicity; however, an accidental overdose or abuse of the drug may produce sinus bradycardia or ventricular arrhythmias (Akasofu, Kimura, Kosasa, Sawada, & Ogura, 2008; Lionte, Bologna, & Sorodoc, n.d.).
Neurotransmitters
The neurotransmitter involved in the administration of donepezil HCL is acetylcholine. Because Alzheimer’s disease is believed to result from a deficiency in chemicals (neurotransmitters) used by brain nerves to communicate with each other, the administration of donepezil inhibits acetylcholinesterase enzyme which is responsible for the destruction of the acetylcholine neurotransmitter in the brain (Reyes et al., 2004). Specifically, donepezil’s mechanism of action entails enhancing the cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase, which in turn maintains the functionality of the cholinergic neurons (Cacabelos, 2007). The inhibition of acetylcholinesterase leads to increased concentrations of acetylcholine in the brain, which in turn improves the symptoms of Alzheimer’s disease) by protecting acetylcholine from breaking down and ensuring that the naturally occurring neurotransmitter has a longer action (Sugimoto et al., 2002).
Reuptake
In terms of reuptake (the reabsorption of a secreted substance by the cell that originally produced and secreted it), acetylcholinesterase inhibitors (AChEIs) such as donepezil and other second-generation drugs have been proposed as “an option to inhibit acetylcholine degradation in the synaptic cleft and to increase choline reuptake at the presynaptic level to enhance acetylcholine synthesis in presynaptic terminals, this facilitating cholinergic neurotransmission” (Cacabelos, 2007, p. 306). It should be recalled that the acetylcholinesterase enzyme breaks down the neurotransmitter acetylcholine, hence affecting its availability at the synapse and reabsorption capacity. Because various CNS neurotransmitters act upon related neural pathways (e.g., acetylcholine on cholinergic pathways), donepezil helps to enhance the choline reuptake to reverse some of the symptoms prevalent in patients with Alzheimer’s disease such as memory loss and cognitive deterioration (Fromme, 2011).
Specific Brain Regions
Available literature demonstrates that donepezil HCL “works in the cerebral cortex blocking the degradation of acetylcholine” (Fromme, 2011, p. 205). The cholinergic hypothesis of Alzheimer’s disease holds that the memory dysfunction associated with the disease is a result of a cholinergic insufficiency in the brain of affected individuals in large part due to failure or loss of neurons in the basal forebrain. Donepezil HCL functions to increase acetylcholine concentration in the synaptic cleft of the hippocampus typically through AChE inhibition (Tsuno, 2009), with available scholarship demonstrating that the increased concentration of acetylcholine addresses the age-related decline in the number of neurons of the nucleus basalis of Maynert and the substantially abridged quantity of cholinergic synapses in cortical frontoparietal-temporal areas in the entorhinal cortex through the action of blocking the degradation of acetylcholine (Cacabelos, 2007).
Behavioral and Physiological Effects
Central Actions
The drug exerts its therapeutic effect in the central nervous system (CNS) by improving cholinergic function (increasing the concentration of the acetylcholine neurotransmitter) within the cerebral cortex and subcortical structures through reversible inhibition of acetylcholine hydrolysis by acetylcholinesterase (Reyes et al., 2004; Trovato, Slomine, Pidcock, & Christensen, 2006). Available literature shows that donepezil HCL “works on the central nervous system, but cholinesterase is present in large quantities in the heart too and it is believed that the effect of cholinesterase on the vagal nerve can have side effects such as bradycardia, atrioventricular block, and prolonged QT” (Igeta, Suzuki, Tajiri, & Someya, 2014, p. 292).
Peripheral Actions
Donepezil’s inhibition of AChE in red blood cells corresponds closely to its effect at synapses in the CNS, though the drug’s inhibition capacity of cholinesterase activity in the plasma, heart, small intestine, liver, and pectoral muscle is shown to be more tissue-selective and is greater in aged rats than in young rats (Kosasa, Kuriya, Matsui, & Yamanishi, 1999). This observation can perhaps explain why donepezil does not lead to unwanted peripheral cholinergic side effects such as gastrointestinal complications, slow heartbeat, and weak breathing, though it should not be administered to patients awaiting a general anesthetic operation as it may exaggerate muscle relaxation during anesthesia (Igeta et al., 2014; Sugimoto et al., 2002).
Abuse Potential, Toxicity, and Risk for Relapse
Abuse Liability
In vitro studies reported in the literature demonstrates that “donepezil has a high selectivity for AChE isolated from rat brain tissue, is without effect on cholinesterases isolated from cardiac muscle or intestinal smooth muscle, and has an only marginal effect on striatal muscle cholinesterase” (Rogers et al., 2000, p. 8). The drug is easily tolerated in the body and was found devoid of toxicity in 1-year studies with rats and dogs; however, caution needs to be exercised during oral administration of the drug to avoid possible abuse. Research has also found that donepezil HCL is not hepatotoxic. Abuse potential may arise from failure to follow the doctor’s instructions (e.g., dosage requirement, how to take the drug, and time of the day to take the drug) and may lead to complications such as liver damage, stomach, and duodenal ulcers, bleeding in the stomach or intestines, hallucinations, and muscle stiffness (Trovato et al., 2006). Clinical trials have demonstrated that the most common adverse events leading to the discontinuation of donepezil include nausea, diarrhea, vomiting, insomnia, muscle cramps, anorexia, fatigue, and headache; however, these symptoms are most profound during the initiation of donepezil or elevation of dosage (Fromme, 2011).
Dose-Response Curves
Donepezil HCL increases NMDAR/AMPAR ratios via Muscarine Receptor Activation and has a long elimination half-life (40-70 hrs), implying that it can be administered to patients in single doses daily (Ishibashi, Yamazaki, Miledi, & Sumikawa, 2014). The drug undergoes extensive first-pass metabolism following oral administration (metabolized principally by the liver), with available literature demonstrating that “the peak plasma concentration (Cmax) of donepezil following the administration of a single oral 5 mg dose of donepezil was increased by 37.5% in male patients with stable hepatic impairment compared with age- and weight-matched healthy controls” (Reyes et al., 2004, p. 10). Donepezil HCL is always administered as long-term therapy and high drug effectiveness (inhibition of AChE is around 64% with donepezil 5mg and 78% for doses under 10 mg in patients with Alzheimer’s disease) is achieved with continued daily administration for 29-35 days (Fromme, 2011; Tsuno, 2009).
Brain Changes Related to Drug Use
The most common brain change related to donepezil use is the inhibition of AChE to block the degradation of acetylcholine, resulting in improved cognitive function, activities of daily living, and behavior (Tsuno, 2009). According to this author, the brain may also experience increased cholinergic transmission to remedy the disruption of nerve transmission in the temporal and parietal neocortex and hippocampus.
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