<p>Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review</p>

Sirasa Ruangritchankul; Prawat Chantharit; Sahaphume Srisuma; Leonard C Gray

doi:10.2147/TCRM.S323387

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Review

Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review

Authors Ruangritchankul S , Chantharit P , Srisuma S , Gray LC

Received 5 June 2021

Accepted for publication 16 August 2021

Published 4 September 2021 Volume 2021:17 Pages 927—949

DOI https://doi.org/10.2147/TCRM.S323387

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Professor Garry Walsh

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Sirasa Ruangritchankul,¹ Prawat Chantharit,² Sahaphume Srisuma,³ Leonard C Gray⁴

¹Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; ²Division of Infectious Diseases, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; ³Ramathibodi Poison Center and Division of Clinical Pharmacology and Toxicology, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; ⁴Centre for Health Services Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

Correspondence: Sirasa Ruangritchankul
Division of Geriatric Medicine, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Ratchathewi, Bangkok, 10400, Thailand
Tel +66 816404373
Fax +66 22012588
Email [email protected]

Abstract: The rising of global geriatric population has contributed to increased prevalence of dementia. Dementia is a neurodegenerative disease, which is characterized by progressive deterioration of cognitive functions, such as judgment, language, memory, attention and visuospatial ability. Dementia not only has profoundly devastating physical and psychological health outcomes, but it also poses a considerable healthcare expenditure and burdens. Acetylcholinesterase inhibitors (AChEIs), or so-called anti-dementia medications, have been developed to delay the progression of neurocognitive disorders and to decrease healthcare needs. AChEIs have been widely prescribed in clinical practice for the treatment of Alzheimer’s disease, which account for 70% of dementia. The rising use of AChEIs results in increased adverse drug reactions (ADRs) such as cardiovascular and gastrointestinal adverse effects, resulting from overstimulation of peripheral cholinergic activity and muscarinic receptor activation. Changes in pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PGx), and occurrence of drug interactions are said to be major risk factors of ADRs of AChEIs in this population. To date, comprehensive reviews in ADRs of AChEIs have so far been scarcely studied. Therefore, we aimed to recapitulate and update the diverse aspects of AChEIs, including the mechanisms of action, characteristics and risk factors of ADRs, and preventive strategies of their ADRs. The collation of this knowledge is essential to facilitate efforts to reduce ADRs of AChEIs.

Keywords: older adults, dementia, acetylcholinesterase inhibitors, adverse drug reactions, drug–drug interactions

Introduction

Globally, the number of older population aged 60 years or over was 962 million in 2017 and will almost double to reach 2.1 billion by 2050.^1,2 The rising geriatric population results in an exponential increase in incidence of neurodegenerative disorders such as dementia.^3,4 Worldwide, the population of people living with dementia was estimated at 50 million in 2017 and is predicted to increase to 131.5 million by 2050.^5,6 Dementia is described as symptoms related to a cluster of major neurocognitive disorders or conditions which are usually manifested as slowly progressive decline of multiple cortical functions including orientation, comprehension, memory, language, learning skills and problem-solving ability.⁷ The most common type of dementia is AD (50–75%), followed by vascular dementia (20%), dementia with Lewy bodies (5%) and finally frontotemporal lobar dementia (5%).^8–10 In AD, the progressive loss of cholinergic neurons in the basal forebrain leads to a decrease in acetylcholine (ACh) which is essential in cognition and neuroprotection.¹¹ Dementia has a devastating impact on healthcare infrastructures in economic and medical aspects. This neurodegenerative disease is one of the leading causes of death and contributors to premature disability and dependency burdens.^5,12,13 With increased disability, dementia could be overwhelming for caregivers and families, leading to increased healthcare needs.^3,12,14–17 Appropriate management, including non-pharmacological and pharmacological therapies, are necessary to delay worsening of symptoms and to reduce healthcare burdens.¹⁸ Anti-dementia medications are being used worldwide, especially in Alzheimer’s disease (AD), which is the most common type of dementia.¹⁹ One-fourth of older people with dementia are prescribed anti-dementia medications which are classified into two classes: Acetylcholinesterase inhibitors (AChEIs) and N-Methyl-D-aspartate (NMDA) receptor antagonists.^20,21 AChEIs were the first pharmacological treatment approved by the US Food and Drug Administration (FDA) for AD and have been reported to be used in 10–20% of dementia patients.^22–25

The aging population usually have multiple other chronic diseases as well as behavioral and psychological symptoms of dementia (BPSD),^{12,22,26–35} resulting in the concurrent use of five or more medications or polypharmacy.²⁶ The exposure of 82–98% of people with dementia to polypharmacy was reported in previous studies.^36–38 This can lead to a greater risk of undesirable or harmful reactions to medications or adverse drug reactions (ADRs).^39–41 The alterations in pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenetics (PGx) of AChEIs also result in higher risk of AChEIs’ ADR.^42–47 Over the last decades, there has been an increase in the reports of AChEI-induced ADRs with 70% being severe and up to 2.3% being fatal ADRs.^48–50

Therefore, the significance of the paper is to facilitate effort to address the issue of AChEI-induced ADRs among older patients with dementia. We aim to review and update the diverse aspects of AChEIs such as the mechanisms of action, characteristics and risk factors of ADRs, and preventive strategies of their ADRs.

Search Strategy

PubMed, Scopus and Web of Science databases were searched for relevant articles published in English from January 1, 1976 until March 31, 2021. The search terms were “donepezil”, “galantamine”, “rivastigmine”, “acetylcholinesterase inhibitors”, “dementia”, “Alzheimer’s disease”, “older adults”, “mechanism”, “pharmacokinetics”, “pharmacodynamics”, “pharmacogenetics”, “adverse drug reactions”, “drug-drug interactions”, “prevention”. Google Scholar was searched using main keywords for any additional studies.

Acetylcholinesterase Inhibitors

Mechanism of Acetylcholinesterase Inhibitors

ACh is mostly hydrolyzed by acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).⁵¹ Both enzymes are responsible for rapid hydrolysis of ACh in synaptic clefts, producing the products: Choline and acetate. AChE predominates in the human brain whereas BuChE is widely distributed in peripheral nervous system (PNS) and other organs such as intestine, heart and liver.^52–54 In the brain, AChE levels are usually high in synapses while BuChE is distributed in glial cells.⁵³ In AD patients, BuChE has progressively increased activity in particular part of the brain such as hippocampal area and has raised accumulation of Aβ-aggregation and neurofibrillary tangles, resulting in the reduction of ACh.^52,55–61 Therefore, a class of AChEIs is developed to block both AChE and BuChE in the synaptic clefts to reduce the degradation of Ach.¹⁹ Furthermore, one AChEI has a pharmacological property for modulation of muscarinic or nicotinic receptors, contributing to enhancement of cholinergic activity.⁶² AChEIs increase cholinergic activities to improve and sustain cognitive functions and ADLs as well as to make better psycho-behavioral symptoms in dementia patients.²² However, AChEIs also inhibit rapid hydrolysis of ACh in PNS including sympathetic autonomic nervous system, and parasympathetic and preganglionic sympathetic neurons. This leads to peripheral adverse outcomes, such as diarrhea, nausea and vomiting, dizziness, and muscle cramping.⁶³

The first-generation of AChEIs such as tacrine, velnacrine, and physostigmine were removed from the market because of high incidence rates of potential drug interactions and serious side effects.⁶⁴ Three second-generation AChEIs were rapidly developed to replace the first-generation AChEIs. Donepezil, galantamine and rivastigmine have been approved by the FDA for the treatment of AD. Donepezil (58.4%) is the most frequently prescribed AChEIs, followed by rivastigmine (13.6%) and galantamine (12.4%).^22,65–67 Donepezil in oral form and rivastigmine transdermal patches have received regulatory approval for the treatment of all stages of AD ranging from mild to severe.^{19,22,68–80} There is no significant difference between the efficacy of these AChEIs in terms of improving psychometric and cognitive scales.⁸¹ However, three AChEIs differ in both PK and PD properties,^82–84 as shown in Supplementary Table 1.

Donepezil

Donepezil was the first AChEI approved by the FDA for AD treatment in 1996. It is a piperidine-based reversible inhibitor of AChE.^82,85 Donepezil is 500-fold selective for AChE inhibition in comparison with BuChE.^86,87 The oral bioavailability is 100% and time to peak plasma concentration (T_max) approximates 3–5 hours following a single-dose administration.^88,89 Plasma albumin binding is 75% and volume of distribution (Vd) is 12 L/kg.^88–90 Donepezil readily transports across the blood brain barrier (BBB), resulting in 7-fold higher concentration in the brain compared with plasma. Cytochrome P450 2D6 (CYP2D6) is accounted for the major Phase I metabolism (90%) and the rest by Cytochrome P450 3A4 (CYP3A4).^89,91 6-O-desmethyl donepezil (6DD) is the end product of Phase II metabolism which is excreted via kidney route.^88,92 The average apparent plasma clearance is approximately 0.13–0.19 L/h/kg. According to its elimination half-life (70 hours), it takes around 15 days to reach the steady state. Then, it is conveniently administered as once daily.^88,89 Both 5 mg and 10 mg once daily administration for 24 weeks could improve cognitive and quality of life scales in mild to moderate AD patients.^93–95 The initial dose should be administered initially with 5 mg/day, followed by slow-dose titration every 4–6 weeks along with the clinical status monitoring until reaching the maximum dose of 10 mg for mild to moderate AD.^64,95 For severe AD, the maximum daily dose of donepezil is 23 mg once daily.⁷⁶

Rivastigmine

Rivastigmine was approved by the FDA to be marketed in 1997. Rivastigmine is classified as a carbamate substance.^81,82,85 Its mechanism of action is a slow reversible or pseudo-irreversible inhibition of both AChE and BuChE.^85,96,97 The oral bioavailability is poor, approximate 40% with T_max ranging from 0.5 to 2 hours following oral single-dose administration.^88,98 Plasma protein binding is 40% and Vd is 1.8–2.7 L/kg.^88,99,100 Rivastigmine easily passes through the BBB to exert activity in the brain.^101,102 Intestinal esterase is the major enzyme responsible for first pass metabolism and the rest is minimally metabolized by liver cytochrome P450.⁸⁸ The main metabolite is NAP 226–90 which is rapidly excreted by renal system.⁸⁸ The plasma clearance of rivastigmine is estimated to be 1.5 L/h/kg. Its half-life is short, nearly 1.5 hours. Therefore, twice-daily dosing is recommended in clinical practice.^88,100 Several double-blind controlled studies showed significant improvement in cognitive and global functions with 6 month-treatment.^103,104 Clinical studies pointed out the effective doses of rivastigmine to be 6 to 12 mg per day.^64,105 Rivastigmine is recommended to start at the dose of 1.5 mg twice-daily as capsules or liquid formulations and slowly titrate up to 6 mg twice-daily at intervals of every 2 to 4 weeks.^81,103 In terms of other efficacy of rivastigmine, the improvement of peripheral insulin resistance has not been reported.¹⁰⁶ Transdermal patch is another preparation which delivers rivastigmine constantly into the blood circulation without level fluctuation.^71,97,107 The therapeutic dose of transdermal patch delivering rivastigmine is 4.6 mg per 24 hours to 13.3 mg per 24 hours in clinical practice.^107,108 Rivastigmine patch is suggested to be started at 4.6 mg per 24 hours for at least for 4 weeks and then to be increased to 9.5 mg per 24 hours. After a minimum of 6 months a dose of 9.5 mg per 24 hours, 13.3 mg per 24 hours is recommended for well-tolerated patients with progressive cognitive decline.¹⁰⁹

Galantamine

Galantamine was approved by the FDA in 2000 for the treatment of AD.¹¹⁰ This agent is a tertiary alkaloid-based compound that acts as both rapidly reversible-competitive inhibitor of AChE and a positive allosteric modulator of nicotinic acetylcholine receptors.^62,85,110 The oral bioavailability of galantamine ranges from 85 to 100% with rapid absorption.^88,111 The T_max is approximately 52 minutes following a single oral administration. Unlike donepezil, protein binding of galantamine is less than 50% and the mean Vd is 2.64 L/kg.^88,111 This medication is demethylated and oxidized by CYP2D6 and CYP3A4. The active metabolite of galantamine is sanguinine or O-desmethyl galantamine.^88,112 Galantamine goes through glucuronidation forming a water-soluble metabolite which is excreted via the renal route.^88,111,112 The total plasma clearance of galantamine is 0.34 L/h/kg.¹¹³ Due to its short half-life of 6–8 hours, twice-daily dosing is recommended.^88,111,113 The formulation of galantamine consists of both immediate-release tablets and extended-release capsules. The efficacy of both extended and immediate release tablets of galantamine was studied in a randomized, double-blind, placebo-controlled trails, using doses titrating up to 16 or 24 mg per day for 6 months duration of treatment in patients with mild to moderate AD.^104,114,115 These studies demonstrated a significant improvement in cognitive and neuropsychiatric scales.¹¹⁴ The recommended therapeutic dose of galantamine is 8 mg per day and gradually escalates every 4 weeks up to a maximum daily dose of 24 mg.¹¹⁶

Therefore, the safety and effectiveness of AChEIs should be evaluated in older population in whom adverse reactions may be serious.¹¹⁷ In terms of efficacy and effectiveness assessment of AChEIs, the common tools for cognitive evaluation includes Mini-Mental-State Examination (MMSE),¹¹⁸ Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog),¹¹⁹ and Severe Impairment Battery (SIB).¹²⁰ Other tests are used to measures functional status and psycho-behavioral symptoms are the Basic and Instrumental Activity of Daily Living^121–123 and Neuropsychiatric inventory (NPI),¹²⁴ respectively. According to previous clinical practice guideline based on systematic reviews,^104,125,126 AChEIs treatment for dementia contributed to marginally significant improvement of cognitive function, functional and global status, and psycho-behavioural symptoms.^117,125,127 In mild to moderate AD patients, meta-analyses on AChEIs have revealed the results with cognitive improvements on 1.5 points in MMSE and 2.5 points in ADAS-cog, comparing to the placebo.¹⁹ The Pooled data presented an improvement of 0.1 standard deviations of ADLs^104,125 and 2 of 144 points in NPI.¹²⁸ Besides cognitive and behavioural improvement, AChEIs have positive effects on balance and gait function without orthostatic hypotension.¹²⁹ However, there is limited evidence of AChEI efficacy and effectiveness in severe dementia, advanced age and long-term treatment.^19,130,131

Adverse Drug Reactions of Acetylcholinesterase Inhibitors

The prevalence of AChEI-induced ADRs tends upward significantly in older population with dementia.⁴⁸ In a 16-year period study, the number of AChEI-induced ADRs increased from 1924 ADRs in 1998 to 2961 ADRs in 2013.⁴⁸ Most reported cases are serious ADRs (50–70%) of which 2.3% are fatal ADRs.^48–50 AChEIs have a dose-related toxicity and a narrow therapeutic index. Therefore, the prevalence of ADRs has an upward trend with an increasing dose.⁴⁸ Most ADRs of AChEIs are described as type A reactions which are associated with dose and altered PK and PD. However, most type A reactions are potentially preventable In a recent study, preventable ADRs from prescription and administration errors were presented in 2.0% of all serious cases.⁴⁸ According to the mechanism of AChEI action, overstimulation of central and peripheral muscarinic and nicotinic receptors may contribute to diarrhea, nausea, vomiting, vagotonic effects (bradycardia, heart block, syncope), tremor, insomnia, urinary incontinence, and seizure.^63,132–135 Common ADRs induced by AChEIs are principally neuropsychiatric (17%), gastrointestinal (16.2%), and cardiovascular (11.2%) in nature⁴⁹ as a result of overstimulation of peripheral cholinergic activity and muscarinic receptor activation, as revealed in Supplementary Table 2.^{48,72,83,132,133}

Gastrointestinal Adverse Effects

Oral administration of AChEIs increases gastric acid secretion of hydrochloric acid and internal propulsion which lead to the increase of gastrointestinal adverse effects, namely gastrointestinal ulceration and bleeding, especially for the concomitant use of AChEI and NSAIDs.^136,137 Commonly reported gastrointestinal adverse effects are abdominal pain, nausea, vomiting, diarrhea, and poor appetite.^{72,133,138–141} The increase of gastrointestinal side effects is associated with the rapid escalation of AChEI dose.¹⁴²

Cardiovascular Adverse Effects

Both conduction and sinus node function gradually deteriorate with advanced age. Moreover, AChEI increases the availability of choline in the heart and vagotonic effects via muscarinic receptors.^143,144 Cardiovascular side effects are some of the most common peripheral adverse cholinergic effects. Therefore, older adults treated with AChEIs are at greater risk of life-threatening conduction dysfunction such as sinoatrial and atrioventricular block,^140,145,146 severe sinus bradycardia¹⁴⁷ and QT interval prolongation with torsades de pointes (TdP).^148–150 Wandering atrial pacemaker (WAP) is another uncommon cardiac side effect in patients treated with donepezil. This condition is an atrial arrhythmia which presents with at least three distinctly different P wave morphologies.¹⁵¹ Negative chronotropic effects contribute to detrimental health outcomes including syncope, pacemaker insertion, falls, fractures, hospitalization.^{147,152–154} However, there is controversy that AChEIs result in negative chronotropic effects.^155–158 Therefore, older people receiving AChEIs should be routinely asked regarding syncope histories and be evaluated for arrhythmia or bradycardia by physical examination and electrocardiogram.¹⁵⁹ Concomitant use of AChEIs and drug-induced QT prolongation such as beta-blockers, antiarrhythmic drugs and antipsychotics should be closely monitored by physicians and pharmacists.¹⁵⁹ In contrast, AChEIs treatment may be correlated with lower risk of cardiovascular events.¹⁵⁸

Neurological and Psychological Adverse Effects

Neurological side effects mainly result from excessive activation of nicotinic receptors. Common neurological adverse effects are dizziness, dyskinesia, convulsion, muscle cramps, insomnia, and vivid dream. The epileptic seizure is a very rare neurological adverse effects induced by AChEIs.^160,161 From previous report, patient with mild AD treated with 10 mg donepezil once daily for 3 weeks presented convulsions during the treatment.¹⁶⁰ Moreover, AChEI-induced seizures may result from nutritional and metabolic disorders such as hyponatremia.¹⁶¹ The vivid dream results from the disorder of brainstem cholinergic systems in processing rapid eye movement sleep. One characteristic of the vivid dream is extremely realistic. Vivid dreams usually appear in patients treated with donepezil in the evening owing to peak plasma concentration at night.^63,162 Psychiatric adverse outcomes in older adults treated with AChEIs may include worsening of hallucination, anxiety, aggression, and confusion.^163,164 Psychiatric problems are usually presented in dementia patients treated with high doses of AChEIs.

Respiratory Adverse Effects

Bronchospasm was presented as a pulmonary side effect after AChEI administration.¹⁶⁵ Therefore, patients with a history of bronchoconstriction should be closely monitored during treatment.¹⁶⁵ Furthermore, nasal problems could be presented among patients treated with AChEI.¹⁶⁵ There is no report of respiratory failure from AChEIs for dementia treatment.

Genitourinary Adverse Effects

Urinary incontinence may occur after treatment with AChEIs, in particular for galantamine.¹⁶⁶ The mechanism is related to nicotinic Ach receptor stimulation at the neuromuscular junction, resulting in an increased peripheral ACh.

Dermatological Adverse Effects

Rivastigmine could be used in the form of a skin patch. The most common skin adverse reaction is irritant contact dermatitis as a local skin reaction which is not associated with an immunological process. Its manifestation is localized erythema and itching.^167,168 These symptoms usually resolve within 48 hours after patch removal. As a rare dermatological adverse reaction, allergic contact dermatitis is delayed type-IV immunologic reaction and manifests as erythema, vesicles and edema appearing more than 48 hours after rivastigmine patch removal. The life-threatening skin adverse reaction called Stevens-Johnson Syndrome (SJS) can occur in patients treated with oral or dermal administration and was reported in patients treated with galantamine.^{138,167–169}

Uncommon Adverse Effects

According to post-marketing surveillance, a rare dystonic reaction called Pisa syndrome has been reported in patients receiving AChEIs. This syndrome is described as tonic flexion of the head and trunk one side accompanied by slight axial rotation.¹⁷⁰ The pathophysiology of the syndrome results from dopaminergic-cholinergic imbalance. Pisa syndrome was reported in a patients receiving 9 mg per day rivastigmine for 2 years.^171,172 However, this abnormal syndrome disappeared when the drug dose was decreased.¹⁷¹ Rhabdomyolysis and neuroleptic malignant syndromes are uncommon side effects which have been reported in older adults receiving donepezil.^173–175 Furthermore, hemolytic anemia, syndrome of inappropriate antidiuretic hormone (SIADH),¹⁶¹ and severe hepatitis¹⁷⁶ also present as uncommon adverse effects in clinical practice.

AChEI-induced adverse effects may provide chance for prescribing cascades. AChEIs activate muscarinic receptors in urinary tract, leading to strong contraction of detrusor muscle and urinary incontinence. Therefore, bladder anticholinergic agents such as oxybutynin, tolterodine, trospium and solifenacin are usually used to relieve urge incontinence which called AChEI-induced urinary incontinence prescribing cascade.¹⁷⁷ Another common prescribing cascade is AChEI-induced rhinorrhea which is concomitant use of rhinorrhea medications to relieve side effects of AChEIs. The rhinorrhea medications consist of antihistamine, nasal anticholinergics and nasal glucocorticoids.¹⁷⁸ These co-medications may contribute to negative side effects. Therefore, physicians should consider dose reduction of AChEIs instead of adding other medications to treat adverse effects of AChEIs.¹⁷⁹

Factors Associated with Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older Adults with Dementia

In geriatric patients with dementia, changes in PK and PD are major risk factors of ADRs. In terms of PK, hepatic and renal functions usually decline in these patients, resulting in decreased drug elimination. Older patients are vulnerable to get an uneventful ADRs from these medications according to their sensitivity to the pharmacodynamic effects.¹⁸⁰ Additionally, patients with AD are prone to be sensitive to ADRs as a result of increased BBB permeability and decreased P-gp activity in the brain.^{43,101,102,181,182} Polypharmacy is common in aging populations and is an important risk factor for drug-related problems (DRPs) such as potentially inappropriate medications (PIMs), drug–drug interactions (DDIs), ADRs and poor compliance.^183,184 ADRs derived from DDIs, PIMs or poor compliance are often reported in older patients with dementia.^183,184 ADRs are major causes of hospitalization, morbidity and mortality in older people with dementia.^185,186

Changes in Pharmacokinetics

PK is what an individual’s body does to a medication after its administration, and refers to absorption, distribution, metabolism and excretion.^42–47 In geriatric population, the alteration of absorption does not lead to major adverse effects whereas changes in distribution, metabolism and excretion play important roles in clinical outcomes. The alterations of PK and PD of AChEIs among older people living with dementia were presented in Tables 1 and 2.

Table 1 The Changes in Pharmacokinetics of Acetylcholinesterase Inhibitors Among Older Adults Living with Dementia

Table 2 The Changes in Pharmacokinetics and Pharmacodynamics of Acetylcholinesterase Inhibitors Among Older Adults Living with Dementia

Absorption

Age-related gastrointestinal tract changes often affect the oral absorption. Hypochlorhydria in older adults alleviate the degree of absorption of weakly basic drugs. Furthermore, reduced splanchnic blood flow and gastrointestinal motility as well as delayed gastric emptying time result in longer staying of drug in the gastrointestinal tract and delaying absorption of the drug. Older adults treated with donepezil presented a significant increase in mean T_max but not in plasma level concentration contributing to slower donepezil’s absorption.^86,90 In contrast, the bioavailability and absorption of rivastigmine have no significant change with advancing age.¹⁸⁷ Concomitant administration of galantamine with food delays T_max by 1.5 hours and slows its absorption rate but does not affect the extent of absorption.⁷⁴ A moderate food effect was found in previous studies of rivastigmine.⁵⁴ Food slows the absorption of rivastigmine and reduces T_max by 30%.^54,188 Therefore, the coadministration of food and galantamine or rivastigmine is indicated to reduce cholinergic adverse effects such as nausea and vomiting. Conversely, food intake has no significant effect on the absorption of donepezil.^54,189

Rivastigmine could also be administered via a skin patch. Age-related changes in skin includes atrophy of epidermis and dermis and decreased blood perfusion, leading to reduced drug absorption via the skin.¹⁹⁰ Nevertheless, age-related changes to drug absorption have minimal effects on the pharmacotherapy of dermal medications.

Distribution

Many factors affect volume of distribution. Patients with dementia are more likely to experience malnutrition and frailty as a result of inability to feed by themselves, changes in feeding behaviours, and difficulty with swallowing.¹⁹¹ Changes in the body composition of older adults with dementia also occur including, 10–15% reduction in total body water, 25–30% reduction in muscle mass, and a 25–30% relative increase in body fat.^192,193 The aging and frailty processes in this group of patients also contributes to a 10–20% reduction in serum albumin concentration which plays a major role in plasma protein binding.^193–196 Medication that predominately binds albumin such as donepezil (75% bind to albumin), a reduction in albumin binding may contribute to the rising of unbound fraction being pharmacologically active, resulting in greater potency and toxicity.^88,90 Furthermore, donepezil may displace other high-protein binding medications such as warfarin, benzodiazepine and valproate, leading to an increased unbound form of these medications and serious adverse effects. Due to age-related changes, the Vd throughout the whole body of donepezil is substantially increased by approximately 40%, resulting in a prolonged half-life.^90,197

Metabolism

Liver CYP enzymes system plays a major role in drug metabolism and may be affected by increasing age. CYP2C19 functions are reduced with age while other isoenzymes show minimal reduction or no change.⁴⁵ In contrast, there is no significant change in phase II metabolism, especially conjugation in older adults. However, phase II metabolism and downregulation of the transporter pathway of AChEIs are decreased in frail older adults, leading to a greater risk of drug toxicity.^198–200 The decrease of drug metabolism in the geriatric population, especially in phase I metabolism, results from a 30% and 40% reduction in liver mass and in hepatic blood flow, respectively.^201–205 The reduction in drug metabolism may account for decreased hepatic clearance, prolonged half-life and increased dose-dependent ADRs. In terms of AChEIs, there are diverse pharmacological properties and differences of clinical outcomes. Data from clinical trials of geriatric patients with AD reveal that the steady-state concentrations of galantamine are 40% higher than those in a healthy younger population as a result of reduced galantamine’s metabolism.^{88,111,112,138} Based on a population pharmacokinetic analysis, the hepatic clearance of donepezil and of rivastigmine has a tendency to decrease with increasing age.^88,89,91,187 Apart from age-related changes in metabolism, most older adults with dementia have multiple chronic diseases including hepatic diseases or cirrhosis, which may lead to decreased hepatic function and drug metabolism. The clearance of both galantamine and rivastigmine was reduced by 25% and 65%, respectively in patients with moderate hepatic impairment (Child-Pugh score of 7–9).^88,111,121 Hence, dose adjustment is recommended for these populations. The use of galantamine for such patients should be initiated with a low dose (4 mg per day) and slowly titrated to a maximum daily dose (16 mg per day).^88,111,138 However, no data is available on the use of galantamine or rivastigmine in patients with severe hepatic impairment (Child-Pugh score of 10–15).^{88,111,112,138} Consequently, the use of galantamine or rivastigmine in patients with severe hepatic impairment is contraindicated in clinical practice.¹³⁸ A recent study showed a 20% reduction in the clearance of donepezil in dementia patients with cirrhosis.²⁰⁶ However, there is no clinically significant alteration in the PK of donepezil in AD patients with moderate or severe hepatic impairment.^206,207 This may explain why dose modification of donepezil is not required.

Excretion

After metabolism, most substances are transformed to products that are readily excreted via the kidneys. As a results of age-related physiological changes, the reduction in renal blood flow (50%), renal mass and size (20–30%), and number of nephrons (60%), lead to a decline in drug excretion and drug half-life prolongation.²⁰⁸ Apart from metabolism changes, dosage adjustment should be done based on renal function which is calculated from laboratory measurement (serum creatinine) by using a mathematical equation including the Cockcroft-Gault (CG) formula to ensure proper drug dose for older adults.^45,46,209 However, serum creatinine level in older frail individuals may not accurately present renal function because of decreased muscle mass.²⁰⁹ Older AD patients presented a 30% reduction in renal clearance of galantamine, compared with healthy individuals.²¹⁰ As a consequence of increasing age and frailty, the clearance rate of galantamine, rivastigmine and donepezil in older patients with AD is reduced, compared to healthy individuals.^138,210 The clearance of galantamine and rivastigmine is decreased by 25% and 64%, respectively in AD patients with moderate renal impairment.¹³⁸ This PK alteration may necessitate dose modification and close monitoring to avoid adverse outcomes.¹³⁸ A total daily dose of galantamine should not exceed 16 mg in patients with moderate renal decline or creatinine clearance 9–59 mL/min¹³⁸ whereas specific-dose adjustment of rivastigmine is not indicated.²¹¹ Nevertheless, the use of galantamine is not recommended given the insufficient data for patients with severe renal impairment or creatinine clearance less than 9 mL/min.¹³⁸ On the contrary, donepezil disposition is not affected by renal dysfunction. The renal clearance of donepezil in patients with moderate to severe renal impairment has no difference to sex- and age-matched healthy population despite donepezil and its metabolites are mostly excreted by kidneys. In a population pharmacokinetic study of AD patients with moderate to severe renal impairment, there is no clinically significant change of PK or PD parameters of donepezil, compared with healthy population. Therefore, dose adjustments are not necessary in AD patients with renal impairment.^64,207

As a result of decreased elimination of rivastigmine, dose adjustments with close monitoring should be done. Nevertheless, no study has been reported for rivastigmine transdermal patches in AD patients with renal or hepatic impairment. Therefore, rivastigmine transdermal patches should be avoided in AD patients with severe renal or hepatic impairment.^107,108

Changes in the Blood-Brain Barrier

The BBB is a highly selective semipermeable layer of endothelial cells which limits the access of water-soluble and large molecules transporting from blood circulation into the brain parenchyma. Older adults with dementia have changes in the permeability and integrity of the BBB, as presented in Table 2. BBB mechanism includes reabsorption of CSF and efflux pumps for molecules such as p-glycoprotein (P-gp) which assists the maintenance of hemostasis in the brain and in the clearance of beta-amyloid.^43,101,102 P-gp is a phosphorylated protein encoded by multidrug resistance gene 1 (MDR1) and belongs to the family of ATP-binding cassette (ABC) membrane transporters.^102,212 It is located on the apical surface of endothelial cells and is involved in limiting the transfer of small molecules into the brain.^213,214 With aging process and dementia, levels and activity of P-gp have a tendency to decline.^{101,102,181,215} Furthermore, micro-disruption of the BBB is found in patients with dementia, contributing to increased allowance of some medications across BBB around the disruption areas.¹⁸¹ These changes may lead to increased permission of AChEIs to the brain as a predisposing factor of AChEI-induced ADRs in this population.⁴³

Changes in Pharmacodynamics

By definition, PD is described as what medication does to the body such as receptor binding and chemical interaction.^42–47 The changes of PD are difficult to predict and evaluate in individuals. In the aging process, the sensitive affinity of receptors for particular medications may change. Moreover, the number of receptor sites may alter and may impact on the efficacy of many medications. The geriatric population is more susceptible to certain central nervous system (CNS) adverse outcomes of AChEIs due to increased permeability of the BBB and decreased P-gp activity.^{101,102,181,182,215} Furthermore, high sensitivity to cholinergic receptors in the brain and the reduction in homeostasis are found in the older adult population.^45,46,216 These alterations result in an elevated responses to AChEIs and contribute to PNS and CNS cholinergic ADRs, as presented in Table 2. However, changes in the PD of AChEIs in older patients with dementia have not been extensively explored.

Changes in Pharmacogenetics

Pharmacogenetics is defined as genetic variations in individuals which contribute to different responses to medications. PGx plays a major role in ADRs and therapeutic failures (TFs). Polymorphism of CYP enzymes for AChEIs results in PK and PD difference.^84,217 In terms of AChEIs, PGx of encoded gene on P-gp, CYP2D6, and CYP3A4 plays an important role in PK of donepezil and galantamine.²¹⁸ Interesting studies presented genetic variations of single nucleotide polymorphisms (SNP) in cholinergic markers on AChE and BuChE which have effects on clinical responses to AChEIs as well.^82,219 Moreover, polymorphism in the gene encoding choline acetyltransferase (ChAT), acetylcholine biosynthetic enzyme, and a genetic variation of paraoxonase-1 (PON-1) 192Q/R (rs662) which influences the activity of this arylesterase, are involved as the prognostic indicators of response to AChEIs.^220,221 Pharmacogenetic considerations for AChEIs should be heeded because they could help predict drug toxicity and efficacy in individuals. In recent decades, genetic polymorphism on CYP2D6 genotype was increasingly studied in various populations.^222–225 CYP2D6 phenotypes are categorized into four types of metabolizers: Poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultra-rapid metabolizers (UMs). PMs have functional deficiency of CYP2D6 due to mutated allele of CYP2D6. EMs have normal functions of CYP2D6 while UMs have a very low concentration of AChEI owing to multiple copies of CYP2D6 gene. IMs metabolize medications with a rate between PMs and EMs.^222,223,225 According to PGx of CYP2D6 (PGX-CYP2D6), approximately 30% of older AD patients have poor metabolite of galantamine and donepezil.²²⁶ This situation can be explained by the phenotypic profile of CYP2D6 genotypes being associated with the presence of the APOE-4 allele.^227–229 Furthermore, the prevalence of each CYP2D6 polymorphism differs according to race and ethnicity.^84,230 In Caucasian populations, PMs, IMs, EMs and UMs account for approximately 5–10%, 10–17%, 70–80% and 3–5% of individuals, respectively.^231,232 Asians, Africans and African Americans have a greater percentage of reduced-function of CYP2D6 (50%), compared with Caucasians (26%).²³³ CYP3A4 polymorphism is not responsible for the variation in metabolism of donepezil and galantamine. The effect of genetic variation in ATP-binding cassette sub-family B member 1 (ABCB1) on membrane transporter P-gp plays an important role in donepezil transporters across the BBB and in the clearance of amyloid β (Aβ) peptide related to APOE, ABCB1 gene polymorphisms which have an impact on distribution, excretion, and absorption of donepezil.^{102,212,234,235}

Drug–Drug Interactions

DDI is defined as the pharmacological activities of one drug changed by the concomitant administration of another medication.²³⁶ Generally, drug interactions are responsible for 20% to 30% of ADRs. Over 30% of reported ADRs caused by AChEIs result from DDIs.²³⁷ The major risk factors for DDIs are polypharmacy and age-related PK and PD changes.^238,239 DDIs are classified into two types: PK and PD drug interactions. By definition, PK drug interaction involves one medication altering the absorption, distribution, transport, metabolism or excretion of another medication.²⁴⁰ PD drug interaction is defined as one medication changing the response to another medication.²⁴⁰ CYP enzymes-mediated and transporter-mediated PK drug interactions as well as synergistic or antagonistic PD drug interactions are common DDIs among dementia patients treated with AChEIs.^241–243 Inducers and inhibitors of CYP2D6 and CYP3A4 enzyme play important roles in the mechanism of PK drug interactions of donepezil and galantamine.^226,244 P-gp inducers and inhibitors are involved in transporter-mediated PK drug interactions of donepezil, which is considered a weak P-gp substrate.²⁴⁵

Potent CYP2D6 and CYP3A4 inhibitors such as antidepressants (paroxetine, fluoxetine), and antifungal drugs (ketoconazole) contribute to increased plasma concentration of donepezil and galantamine, as shown in Table 3.^{138,242,246–249} The adverse outcomes may be hypercholinergic effects of AChEIs, such as bradycardia, diarrhea and hypersalivation. However, there is no significant CYP2D6 and CYP3A4 inducers of donepezil and galantamine. In terms of transporter-mediated PK drug interactions, PK of donepezil is affected by P-gp inhibitors and inducers. Most medications, which are transported by P-gp, are also metabolized by CYP3A4.^214,245,250 Many P-gp inhibitors and inducers are also inhibitors and inducers of CYP3A4. Therefore, many DDIs are associated with inhibition or induction of both CYP3A4 and P-gp.²⁵⁰ The most common P-gp inhibitors in patients with dementia are antibiotics (azithromycin, clarithromycin, erythromycin), cardiovascular medications (carvedilol, verapamil) and antiplatelets (cilostazol, ticagrelor), resulting in the rising of donepezil plasma concentration.^250–252 There was the clinical report of cardiotoxicity owing to coadministration of donepezil and cilostazol.²⁵² Due to P-gp interaction with cilostazol, the concentration of donepezil in the heart tissue was increased, leading QT prolongation.²⁵² In the case of P-gp inducers, the plasma concentration of donepezil is decreased by carbamazepine, phenobarbital, phenytoin and rifampicin,^250–252 as presented in Table 4.

Table 3 Common CYP Enzymes-Mediated Pharmacokinetic Drug Interactions of Acetylcholinesterase Inhibitors in Older Adults Living with Dementia

Table 4 Common Transporter-Mediated Pharmacokinetic Drug Interactions of Acetylcholinesterase Inhibitors in Older Adults Living with Dementia

Pharmacoepidemiological studies in people with dementia have revealed that anticholinergics, antidepressants, antipsychotics, non-steroidal anti-inflammatory drugs (NSAIDs), and cardiovascular drugs are common co-medications with AChEIs, resulting in PD drug interactions.^{237,243,253,254} Synergistic PD drug interactions of AChEIs with cholinomimetics or cholinergic agonists have additional cholinergic effects such as hypersalivation, diarrhea, nausea, and vomiting, as presented in Table 5.^255–257 Many antagonistic PD drug interactions of AChEIs are related to changes in PD from advancing age and to dementia processes. In the aging process, a reduction in the number of cholinergic and dopaminergic neurons and dopamine D₂ receptors are reported. Therefore, the uses of anticholinergics and antipsychotics which affect cholinergic and dopaminergic neurotransmitters, potentially interfere with the activity of cholinesterase inhibitors and can cause adverse clinical outcomes.^{253,254,258,259} The clinical report described rigidity, parkinsonism and immobilization in AD patients treated with donepezil and risperidone which these adverse symptoms resolved after risperidone was discontinued.²⁶⁰ Furthermore, concomitant use of beta-blockers, calcium channel blockers or antiarrhythmics in older patients with dementia treated with AChEIs may result in adverse cardiovascular effects such as bradyarrhythmia, heart block, syncope and QT prolongation,^63,243,261 as presented in Table 5.

Table 5 Pharmacodynamic Interactions in Older Adults with Dementia

Principles for Prescribing Acetylcholinesterase Inhibitors

Recommendations for Prescribing Acetylcholinesterase Inhibitors

AChEI should be initiated at a low efficient dose and titrated slowly upward. The starting dose of donepezil is 5 mg once daily. Donepezil dosage should not be adjusted too quickly because the time to reach the steady state is within 15 days. Therefore, donepezil should be slowly titrated after the first dose is started over 4–6 weeks. Older adults with moderate to severe AD could slowly titrate the donepezil dose to 23 mg per day,²⁶² as presented in Supplementary Table 1. However, gastrointestinal complaints and poor appetite may be reported in patients receiving high donepezil doses.^{75,139,262,263} Among patients with mild to moderate hepatic insufficiency, a low dose (5 mg daily) consumption of donepezil is safe and the use of its doubling dose should be monitored.²⁶⁴ Galantamine is a daily oral medication ranging from 8 to 24 mg per day,¹¹⁶ as shown in Supplementary Table 1. Galantamine doses must be adjusted for people with moderate hepatic impairment. Furthermore, galantamine should not be recommended to patients with severe liver and kidney dysfunction. Rivastigmine may be a good choice for older demented patients exposed to polypharmacy to reduce the incidence of PK drug interactions related to CYP enzymes. Rivastigmine prescriptions start at 1.5 mg and could be gradually increased to 6 mg twice a day,^{64,81,103,105} as shown in Supplementary Table 1. Rivastigmine transdermal patches are usually recommended for dementia patients with severe gastrointestinal side effects from oral administration. Transdermal patches have a long half-life and are easily applied only once a day. The dose of rivastigmine in a patch can be titrated from 4.6 mg per 24 hours to 13.3 mg per 24 hours.^107–109 However, some patients treated with a transdermal patch may develop dermatological side effects such as pruritus or an allergic reaction. Therefore, patients should be examined for adverse skin reactions during treatment.¹⁰⁸

Contraindication and Caution in the Prescribing of Acetylcholinesterase Inhibitors

Allergic reaction to the medication itself and chemicals in the same structural group is an absolute contraindication. Donepezil is a piperidine-based compound.^81,82,85 Rivastigmine is derived from carbamate compound whereas galantamine is belonged to alkaloid substance.^62,81,82,85 Rivastigmine patches are contraindicated for patients with suggestive allergic contact dermatitis.^107–109 Galantamine is also contraindicated for patients with severe hepatic and renal dysfunction.²¹² Additionally, patients with sick sinus syndrome (SSS) and second or third heart block should avoid using AChEIs.^138,140,141 AChEIs should be used with cautions in people with severe hepatic impairment, severe obstructive pulmonary disease, active gastrointestinal ulcers or bleeding, seizure and significant conduction abnormalities such as supraventricular conduction problems, and arrhythmias.^138,140,141 However, older patients treated with AChEIs rarely develop cholinergic crisis in the clinical practice.

Recommendations for Discontinuation of Acetylcholinesterase Inhibitors

The continuous use of AChEIs should be often weighted the risks and the benefits. According to the Food and Drug Administration Adverse Event Reporting System database, serious ADRs related to AChEIs were reported, especially in long-term treatment.^{135,136,179,213,265,266} Advanced dementia patients may be offered unnecessary treatment that may not provide positive effects, resulting in increased adverse outcomes.²⁶⁷ Therefore, many studies offered recommendations to discontinue AChEI treatment in particular conditions to optimize medication prescribing.²⁶⁸ The common reason for deprescribing AChEIs were lack of response, significantly impaired functional status, severe cognitive impairment (MMSE score < 10), and side effects.²⁶⁸ Besides minimized medication prescribing, the benefits of AChEI discontinuation are improved medication non-adherence, and reduced DDI, medication management burden and cost of medications.²⁶⁹ The discontinuation of AChEIs should be slowly tapered the dose by halving the previous dose and stepping down to the lowest available dose.²⁶⁹ The abrupt cessation should be done in patients with experiencing ADRs. After discontinuation, physicians should closely monitor the withdrawal symptoms and the changes of cognitive function, psycho-behavioral symptoms and functional status.²⁶⁹

Strategies to Prevent Adverse Drug Reactions of Acetylcholinesterase Inhibitors

Many strategies have been developed and implemented to prevent ADRs in patients using AChEIs, as shown in Table 6. Minimizing effective dose is required to reduce the occurrence of adverse outcomes. The “start low go slow” strategy is widely recommended as the lowest initial dose, slow-dose titration and close monitoring.^270,271 The dose adjustment of AChEIs is recommended according to the alteration of PK or PD.^{47,270,272–275} Furthermore, older patients usually have comorbidities for which multiple medications are taken, resulting in DRPs including potential DDIs, drug–disease interactions, inappropriate medications and medication non-adherence.^{270,272–274,276} Thus, comprehensive medication reviews and optimizing medications prescribing are necessary to address DRPs.²⁷⁵ Another potential strategy could be using tools such as the Micromedex Drug Interaction Database²⁷⁷ and the 2019 American Geriatrics Society Beers criteria²⁷⁸ to evaluate DDIs and PIMs, respectively.^238,279 The discontinuation of AChEIs in older adults with particular circumstances including lack of treatment response, severe cognitive function, significantly impaired functional status, could have reduced DDIs and PIMs.²⁶⁸ Moreover, computerized alert systems for screening prescriptions and flagging DDIs and PIMs could also prevent ADRs.^275,280,281 Medication non-adherence is another major DRP in older adults, resulting from language barriers, complex regimens and physiological changes including cognitive impairment, visual and auditory problems and bone-joint deformities.^282–286 Many techniques could provide benefits to people with medication non-adherence; for example, readily openable containers, clearly written instructions in large print, the simple possible dosage regimens and supporting technology (alarm clock and drug calendar).^287,288

Table 6 Prevention Strategies for Adverse Drug Reactions of Acetylcholinesterase Inhibitors

Conclusions

AChEIs have been widely prescribed to delay worsening of cognitive functions and psycho-behavioral problems in older people living with dementia. In the aging population, age-related PK and PD changes, and multiple comorbidities lead to altered pharmacological responses and increased ADRs. Furthermore, geriatric people are more likely to be sensitive to pharmacological toxicity. The most common negative effects of AChEIs are adverse neuropsychiatric, gastrointestinal, and cardiovascular outcomes. Thus, prescribing of AChEIs for dementia treatment should carefully consider both risks and benefits. The discontinuation of AChEIs in older people with particular circumstances such as lack of treatment response, severe cognitive impairment and side effects, could reduce DRPs. Many strategies have been developed to prevent adverse effects. The “start low go slow” strategy as well as comprehensive medication review are highly recommended to address ADRs.

Abbreviation

ABCB1, ATP-binding cassette sub-family B member 1; Aβ, amyloid β; Ach, acetylcholine; AChE, acetylcholinesterase; AChEIs, acetylcholinesterase inhibitors; AD, Alzheimer’s disease; ADRs, adverse drug reactions; AGS Beers Criteria, American Geriatrics Society Beers Criteria; BBB, blood brain barrier; BPSD, behavioral and psychological symptoms; BuChE, butyrylcholinesterase; CG, Cockcroft-Gault; ChAT, choline acetyltransferase; CNS, central nervous system; CSF, cerebrospinal fluid; CYP, cytochrome P450; CYP2D6, cytochrome P450 2D6; CYP3A4, cytochrome P450 3A4; DDIs, drug–drug interactions; DRPs, Drug-related problems; Ems, extensive metabolisers; FDA, Food and Drug Administration; GI, gastrointestinal; IMs, intermediate metabolisers; MDR1, multidrug resistance gene 1; nAChRs, nicotinic acetylcholine receptors; NMDA, N-Methyl-D-aspartate; NSAIDs, non-steroidal anti-inflammatory drugs; PD, pharmacodynamics; P-gp, p-glycoprotein; PIMs, potentially inappropriate medications; PGx, pharmacogenetics; PGx-CYP2D6, pharmacogenetics of CYP2D6; PK, pharmacokinetics; PMs, poor metabolisers; PNS, peripheral nervous system; PON-1, paraoxonase-1; SIADH, syndrome of inappropriate antidiuretic hormone; SJS, Stevens-Johnson Syndrome; SNP, single nucleotide polymorphism; SSS, sick sinus syndrome; TdP, torsades de pointes; TFs, therapeutic failures; T_max, time to peak plasma concentration; Ums, ultra-rapid metabolisers; Vd, volume of distribution; WAP, wandering atrial pacemaker; 6DD, 6-O-desmethyl donepezil.

Acknowledgments

The authors would like to thank Leila Shafiee Hanjani, Centre for Health Services Research, Faculty of Medicine, The University of Queensland, for providing valuable advice and comments.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Funding

The authors received no financial support for the research.

Disclosure

The authors declare no potential conflicts of interest regarding this work.

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