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Cognition enhancers for the treatment of dementia Naveed Malek and John Greene Scott Med J published online 27 November 2014 DOI: 10.1177/0036933014561948 The online version of this article can be found at: http://scm.sagepub.com/content/early/2014/11/27/0036933014561948
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Scott Med J OnlineFirst, published on November 27, 2014 as doi:10.1177/0036933014561948
Educational Article
Cognition enhancers for the treatment of dementia
Scottish Medical Journal 0(0) 1–6 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933014561948 scm.sagepub.com
Naveed Malek and John Greene
Abstract Dementia is a broad term used to describe several chronic progressive neurological disorders that adversely affect higher mental functions including memory, language, behaviour, abstract thinking, comprehension, calculation, learning capacity and judgement. Alzheimer’s disease is the most common form of dementia but other neurological conditions such as Parkinson’s disease, cerebrovascular disease and chronic infections such as syphilis can also lead to the clinical syndrome of dementia. Initial investigations should always focus on finding any treatable cause for dementia such as HIV, structural lesions such as subdural haematomas or specific nutritional deficiency states such as that due to vitamin B12 and treated appropriately. Where no treatable or reversible aetiology is found, a referral to a specialist should be considered who may initiate further investigations including magnetic resonance imaging or perfusion single-photon emission computerised tomography scans of the brain, and sometimes cerebrospinal fluid examination or an electroencephalogram.
Keywords Acetylcholinesterases, Alzheimer’s disease
Introduction Alzheimer’s disease, the most common neurodegenerative disorder affecting the elderly, accounts for the greatest proportion of cases of dementia in the western world, therefore, research into treatments for dementia has largely been focussed on finding drugs that can help people with this condition. The deficiency in cholinergic neurotransmission in Alzheimer’s disease led to trials of oral acetylcholinesterase inhibitors (AChEI) for this condition and in the last two decades have emerged as the first-line treatment for symptoms of this disease. Cholinesterase containing axons (and in some cases cells) are severely depleted in the cerebral cortex of patients with Alzheimer’s disease. Although the cerebral cortex of these patients continues to display abundant cholinesterase activity, the location of this enzyme is largely shifted to the neuritic plaques and neurofibrillary tangles. In patients with Alzheimer’s disease, AChEI would therefore appear to have a major and widespread effect directly upon the enzymatic activity within plaques and tangles. As a corollary, the clinical effects of AChEI in Alzheimer’s disease may be based on mechanisms that are different from those that apply to the normal brain.1 The clinical benefits of these
agents include improvement or stabilisation of the inevitable decline in cognition, function and behaviour that is characteristic of this condition.2 There have also been trials of the use of AChEI in other forms of dementia such as Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB) and vascular dementia (VaD).
What are (acetyl)cholinesterase inhibitors? As early as the 1950s, physostigmine and tacrine were recognised as potent inhibitors of acetylcholinesterase and their potential in treating Alzheimer’s disease was recognised, however, the first licensed AChEI for treatments of Alzheimer’s disease appeared in the market four decades later.3 Cholinesterases are a family of enzymes that catalyse the hydrolysis of the neurotransmitter acetylcholine Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK Corresponding author: Naveed Malek, Institute of Neurological Sciences, Southern General Hospital, Glasgow, G51 4TF, UK. Email: [email protected]
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into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.4 The common mechanism of action underlying this class of agents is an increase in available acetylcholine at central nervous synapses through inhibition of the enzyme, acetylcholinesterase, which breaks down this neurotransmitter. Tacrine was the first of the AChEIs licensed for the treatment of Alzheimer’s disease in 1993, but its use has been abandoned because of a high incidence of side effects including hepatotoxicity.5 Medications currently approved by regulatory agencies in the United States and Europe to treat the cognitive manifestations of Alzheimer’s disease and improve life quality of these patients are the reversible AChEIs: donepezil, rivastigmine and galantamine. Memantine is another medication licensed for the treatment of Alzheimer’s disease but does not work as an AChEI. It acts as a non-competitive N-methylD-aspartate (NMDA) receptor antagonist at the cellular level.
How well do they work in dementia? Evidence from clinical trials has led to the emergence of donepezil, galantamine, rivastigmine (cholinesterase inhibitors), as the first-line pharmacotherapy for mild to moderate Alzheimer’s disease and memantine (NMDA receptor antagonist) for moderate to severe Alzheimer’s disease.6–9 There is a substantial body of evidence that suggests these cholinesterase inhibitors decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer’s disease, increase the availability of acetylcholine at synaptic junctions and there is a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement.2 Memantine, a moderate-affinity, NMDA receptor antagonist, is currently the only agent approved for moderately severe to severe Alzheimer disease in Europe and for moderate to severe Alzheimer disease in the United States. In clinical trials involving Alzheimer’s disease patients, memantine has demonstrated a reduced rate of deterioration on global, cognitive, functional and behavioural measures.10 The combination of AChEIs and memantine has been investigated and found to be effective in patients with Alzheimer’s disease, particularly in slowing cognitive impairment and preventing the onset of agitation and aggression in elderly Alzheimer’s disease patients.11 PDD and DLB exist on a spectrum of Lewy body disorders and share common pathogenic mechanisms as well as clinical features. Patients with both conditions have severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using AChEIs could theoretically lead to
clinical improvements analogous to Alzheimer’s disease patients.12 A Cochrane database systematic review of six trials in which a total of 1236 participants were randomised provided supportive evidence for the use of AChEIs in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remained unclear.12 Memantine has been reported to produce substantial improvements on cognitive tests of attention and episodic recognition memory in DLB or PDD cases in randomised controlled trials.13,14 There is some evidence of benefit of rivastigmine and donepezil in vascular cognitive impairment (VCI) from clinical trials, however, neither rivastigmine nor donepezil have gained regulatory approval for the treatment of VCI (this includes VaD).15–19
Should these be prescribed to those with mild cognitive impairment? A recent systematic review and meta-analysis of cognition enhancers suggested that these drugs did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms.20 This includes patients with mild cognitive impairment (MCI) in PD.12
How safe are cholinesterase inhibitors and what are the precautions? Nausea, vomiting, anorexia, diarrhoea, fatigue, insomnia, headache and dizziness are the common side effects with all these drugs, but these are usually tolerable. There have, however, been reports of serious system side effects such as gastrointestinal bleeding,21 but these are not common.
System-specific side effects Gastrointestinal side effects. Dyspepsia, anorexia and weight loss have been reported. Two clinical trials have reported higher rates of GI bleeding in individuals taking donepezil than in those given placebo,22,23 although population-based studies have failed to demonstrate significant association between AChEI use and upper GI bleeding in elderly adults.24 Cardiovascular side effects. Palpitations, arrhythmias, first-degree AV block, hypotension and flushing have all been reported. Population-based studies have shown that the prescription of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia,
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pacemaker insertion and hip fracture in older adults with dementia.25 Pulmonary side effects. Although AChEIs may theoretically worsen airflow obstruction because of their procholinergic properties, however, population-based studies of elderly individuals with COPD and dementia have failed to demonstrate an increased risk for adverse pulmonary outcomes in AChEI users compared to those who were not receiving AChEIs.26
well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women where benefit can be demonstrated to outweigh the risks. This decision can be difficult when patients do not retain the capacity to give an informed consent.
Breast feeding These drugs are not indicated for use in nursing mothers.
Drug metabolism
Cautions
The bioavailability of the current crop of AChEIs (rivastigmine, galantamine and donepezil) ranges between 40% and 100%. The elimination half-life is considerably longer for donepezil (70 to 80 h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12 h). Donepezil is therefore administered once daily in comparison to rivastigmine and galantamine which are administered twice daily but modified release preparations are available (Table 2). Donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Donepezil is metabolised by hepatic cytochrome CYP3A4 and galantamine by CYP2D6. Rivastigmine is not metabolised via CYP enzymes but via esterases and sulfate conjugation to be excreted in the urine.27 Rivastigmine inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapses.28
Concomitant antipsychotic medication prescription with donepezil can increase risk of neuroleptic malignant syndrome. Galantamine can cause worsening of Parkinsonian symptoms and seizures. Rivastigmine can lead to anorexia and weight loss. All AChEIs due to their cholinergic effects can cause bradycardia and therefore are best avoided in those with a sick sinus syndrome or heart block. Memantine should be avoided in those with a history of epilepsy and dose reduction is required in those with renal impairment.
Drug interactions AChEIs are parasympathomimetic drugs and theoretically their effects can be antagonised by medications with antimuscarinic properties. Donepezil and rivastigmine could antagonise effects of non-depoloarising muscle relaxants and enhance the effects of the depolarising muscle relaxant suxamethonium. The plasma concentration of galantamine is increased by erythromycin and paroxetine. There is an increased risk of CNS toxicity when memantine is given with amantadine, dextromethorphan and ketamine (manufacturer of memantine advises to avoid concomitant use).
How cost-effective are cholinesterase inhibitors? There is no evidence that treatment with an AChEI is not cost-effective as per a Cochrane database systematic review.29 Economic modelling for the NHS England and Wales demonstrates that AChEIs are probably cost saving and more cost-effective than best supportive care for mild-moderate Alzheimer’s disease. In people with mild to moderate AD, one probabilistic sensitivity analysis suggested that donepezil is the most cost-effective AChEI, per quality adjusted life year (QALY).30 Treatment with any of the three AChEIs or memantine seems to be reasonable in terms of clinical effects and a cost-effective strategy or even a cost-saving strategy.31
Who can prescribe cholinesterase inhibitors? Only specialists in the care of patients with dementia (that is, psychiatrists including those specialising in learning disability, neurologists and physicians specialising in the care of older people) should initiate treatment based on NICE guidance (March 2011).
Pregnancy
Who should we prescribe it to?
These medications are in the United States Food and Drug Administration (FDA) drug class C, which means animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and
Most cognition enhancers discussed here are licensed for Alzheimer’s dementia, the only drug that is licensed for PDD is rivastigmine. No drug is licensed for VaD.
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When to prescribe cholinesterase inhibitors? These drugs are generally indicated for patients with mild to moderate stage of AD except memantine which is indicated for moderate to severe stage of AD. Dementia is a clinical syndrome characterised by global cognitive impairment, which represents a decline from previous level of functioning, and is associated with impairment in functional abilities and, in many cases, behavioural and psychiatric disturbances.32 Using arbitrary cut-off scores on memory scales such as Addenbrooke’s cognitive examination revised (ACE-R) scale33 or cognitive screening instruments such as mini mental state examination (MMSE)34 or Montreal cognitive assessment (MOCA) test35 that are commonly used in hospital wards and clinics in the United Kingdom to define mild, moderate and severe stages of dementia may not be appropriate. Ability to perform functional activities of daily living are not taken into consideration in these scales and these are important to determine the severity of dementia. Information provided by carers can be vital about determining the effect of the cognitive decline on the performance of functional activities of daily living. One such scale that incorporates this information and should be used alongside a clinical scale such as the ACE-R or MMSE is the Functional Assessment Staging of Alzheimer’s Disease (FAST)36 (Table 1).
What are the standard doses? The starting doses and maximum allowed doses of AChEIs and memantine along with available formulations are shown in Table 2.
How to prescribe cognition enhancers? Most cognition enhancers are prescribed at the smallest therapeutic dose initially and gradually titrated upward over weeks towards a target dose based on clinical response and tolerance. (Table 2). For those unable to swallow tablets, orodispersible preparations that dissolve on the tongue (donepezil) and oral solutions are available (Table 2). If nausea and gastrointestinal side effects are troublesome or in the peri-operative setting, transdermal administration of rivastigmine as a patch may be considered. When switching from oral to transdermal rivastigmine therapy, patients taking 3–6 mg by mouth daily should switch to 4.6 mg/24 h patch, patients taking 9–12 mg by mouth daily should switch to 9.5 mg/24 h patch.
What monitoring is required? Patients who continue on treatment should be reviewed regularly using cognitive, global, functional and behavioural assessment questionnaires, instruments and scales to get an objective idea of cognitive function and functioning in daily life. Treatment should be reviewed by an appropriate specialist team, this is usually based at memory clinics in the community in the UK, unless there are locally agreed protocols for shared care.
How long to prescribe cholinesterase inhibitors? Treatment should continue as long as it is considered to have a worthwhile effect on cognitive, global, functional or behavioural symptoms by the treating clinician or general practitioner on his/her patient.
Table 1. Functional assessment staging of Alzheimer’s disease scale (FAST).36 Stage 1 Normal adult
No functional decline
Stage 2 Normal older adult
Personal awareness of some functional decline
Stage 3 Early Alzheimer’s disease Stage 4 Mild Alzheimer’s disease
Noticeable deficits in demanding job situations Requires assistance in complicated tasks such as handling finances, planning parties, etc
Table 2. Standard doses of licensed cognition enhancers for treating dementia patients. Acetylcholinesterase inhibitors Formulation
Maximum dose
Donepezil
Tablets, orodis5 mg nocte persible tablets
10 mg od
Galantamine
Tablets, MR capsules, oral solution Capsules, oral solution Patches
4 mg bd
12 mg bd
1.5 mg bd
6 mg bd
4.6 mg/24 h
13.3 mg/24 h
5mg od
20 mg od
Stage 5 Moderate Alzheimer’s Requires assistance in choosing disease proper attire. Stage 6 Moderately severe Requires assistance dressing, bathing Alzheimer’s disease and toileting. Experiences urinary and fecal incontinence.
Rivastigmine
Stage 7 Severe Alzheimer’s disease
Glutamate receptor antagonist Memantine Tablets, oral solution
Speech ability declines to about a half-dozen intelligible words. Progressive loss of abilities to walk, sit up, smile and hold head up.
Starting dose
MR: modified release preparation for once daily dosing.
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Table 3. Tips for hospital based clinicians treating dementia patients. 1. Alzheimer’s disease must be diagnosed and treatment initiated by a specialist with training in diagnosing and treating patients with dementia, i.e. a neurologist or psychiatrist. 2. Clinicians should not rely solely on scores on assessment scales to diagnose and determine the severity of dementia particularly when the patient has learning or other disabilities, or other communication difficulties. 3. The views of those caring for the person with dementia should be sought before and during treatment. 4. If prescribing an AChEI (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost to the health service.
Conclusion In conclusion, we summarise the clinically relevant advice for healthcare professionals looking after these vulnerable adults with dementia based on NICE guidance (March 2011) in Tables 3 and 4. Contribution of authors Both authors contributed equally to the paper
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of conflicting interests None declared. Table 4. Tips for general practitioners caring for dementia patients. 1. Treatment can be continued by general practitioners under a shared-care protocol with the specialist who diagnosed and initiated treatment. 2. Treatment should continue only if it is considered to have a worthwhile effect on cognitive, functional or behavioural symptoms, i.e. at end stage when person is bed-bound, these drugs may not have a substantial beneficial effect on quality of life. 3. All AChEIs (donepezil, galantamine and rivastigmine) due to their cholinergic effects can cause bradycardia and therefore are best avoided in those with a sick sinus syndrome or heart block. Memantine can be used in those with conduction abnormalities because of its different mechanism of action. 4. There is insufficient evidence to recommend the use of statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, either for the treatment or prevention of Alzheimer’s disease.
A decision to stop treatment may have to be made by the treating clinician in situations where the risks of treatment outweigh the benefits but carer input should be obtained before making this decision where the patient is cared for at home.
How do cholinesterase inhibitors compare to other therapeutic options? Despite the slight variations in the mode of action of the three cholinesterase inhibitors, there is no evidence of any differences between them with respect to efficacy. There appear to be less adverse effects associated with donepezil compared with rivastigmine.29 There is insufficient evidence from Cochrane database systematic reviews to recommend statins for the treatment or prevention of Alzheimer’s disease or other forms of dementia.37,38
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25. Gill SS, Anderson GM, Fischer HD, et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Int Med 2009; 169: 867–873. 26. Stephenson A, Seitz DP, Fischer HD, et al. Cholinesterase inhibitors and adverse pulmonary events in older people with chronic obstructive pulmonary disease and concomitant dementia: a population-based, cohort study. Drug Aging 2012; 29: 213–223. 27. Nordberg A and Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer’s disease: a comparison of tolerability and pharmacology. Drug Safety 1998; 19: 465–480. 28. Jann MW, Shirley KL and Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinetics 2002; 41: 719–739. 29. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev (Online) 2006; 1: CD005593. 30. Bond M, Rogers G, Peters J, et al. The effectiveness and cost-effectiveness of donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease (review of Technology Appraisal No. 111): a systematic review and economic model. Health Technol Assess 2012; 16: 1–470. 31. Pouryamout L, Dams J, Wasem J, et al. Economic evaluation of treatment options in patients with Alzheimer’s disease: a systematic review of cost-effectiveness analyses. Drugs 2012; 72: 789–802. 32. National Collaborating Centre for Mental Health. Dementia: A NICE-SCIE guideline on supporting people with dementia and their carers in health and social care. Leicester UK: The British Psychological Society & The Royal College of Psychiatrists, 2007. 33. Mioshi E, Dawson K, Mitchell J, et al. The Addenbrooke’s Cognitive Examination Revised (ACER): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 2006; 21: 1078–1085. 34. Folstein MF, Folstein SE and McHugh PR. ‘‘Minimental state’’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198. 35. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005; 53: 695–699. 36. Sclan SG and Reisberg B. Functional assessment staging (FAST) in Alzheimer’s disease: reliability, validity, and ordinality. Int Psychogeriatr 1992; 4(Suppl 1): 55–69. 37. McGuinness B, Craig D, Bullock R, et al. Statins for the prevention of dementia. Cochrane Database Syst Rev 2009; 2: CD003160. 38. McGuinness B, O’Hare J, Craig D, et al. Cochrane review on ‘Statins for the treatment of dementia’. Int J Geriatr Psychiatry 2013; 28: 119–126.
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Cognition enhancers for the treatment of dementia Naveed Malek and John Greene Scott Med J published online 27 November 2014 DOI: 10.1177/0036933014561948 The online version of this article can be found at: http://scm.sagepub.com/content/early/2014/11/27/0036933014561948
Published by: http://www.sagepublications.com
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Scott Med J OnlineFirst, published on November 27, 2014 as doi:10.1177/0036933014561948
Educational Article
Cognition enhancers for the treatment of dementia
Scottish Medical Journal 0(0) 1–6 ! The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933014561948 scm.sagepub.com
Naveed Malek and John Greene
Abstract Dementia is a broad term used to describe several chronic progressive neurological disorders that adversely affect higher mental functions including memory, language, behaviour, abstract thinking, comprehension, calculation, learning capacity and judgement. Alzheimer’s disease is the most common form of dementia but other neurological conditions such as Parkinson’s disease, cerebrovascular disease and chronic infections such as syphilis can also lead to the clinical syndrome of dementia. Initial investigations should always focus on finding any treatable cause for dementia such as HIV, structural lesions such as subdural haematomas or specific nutritional deficiency states such as that due to vitamin B12 and treated appropriately. Where no treatable or reversible aetiology is found, a referral to a specialist should be considered who may initiate further investigations including magnetic resonance imaging or perfusion single-photon emission computerised tomography scans of the brain, and sometimes cerebrospinal fluid examination or an electroencephalogram.
Keywords Acetylcholinesterases, Alzheimer’s disease
Introduction Alzheimer’s disease, the most common neurodegenerative disorder affecting the elderly, accounts for the greatest proportion of cases of dementia in the western world, therefore, research into treatments for dementia has largely been focussed on finding drugs that can help people with this condition. The deficiency in cholinergic neurotransmission in Alzheimer’s disease led to trials of oral acetylcholinesterase inhibitors (AChEI) for this condition and in the last two decades have emerged as the first-line treatment for symptoms of this disease. Cholinesterase containing axons (and in some cases cells) are severely depleted in the cerebral cortex of patients with Alzheimer’s disease. Although the cerebral cortex of these patients continues to display abundant cholinesterase activity, the location of this enzyme is largely shifted to the neuritic plaques and neurofibrillary tangles. In patients with Alzheimer’s disease, AChEI would therefore appear to have a major and widespread effect directly upon the enzymatic activity within plaques and tangles. As a corollary, the clinical effects of AChEI in Alzheimer’s disease may be based on mechanisms that are different from those that apply to the normal brain.1 The clinical benefits of these
agents include improvement or stabilisation of the inevitable decline in cognition, function and behaviour that is characteristic of this condition.2 There have also been trials of the use of AChEI in other forms of dementia such as Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB) and vascular dementia (VaD).
What are (acetyl)cholinesterase inhibitors? As early as the 1950s, physostigmine and tacrine were recognised as potent inhibitors of acetylcholinesterase and their potential in treating Alzheimer’s disease was recognised, however, the first licensed AChEI for treatments of Alzheimer’s disease appeared in the market four decades later.3 Cholinesterases are a family of enzymes that catalyse the hydrolysis of the neurotransmitter acetylcholine Institute of Neurological Sciences, Southern General Hospital, Glasgow, UK Corresponding author: Naveed Malek, Institute of Neurological Sciences, Southern General Hospital, Glasgow, G51 4TF, UK. Email: [email protected]
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into choline and acetic acid, a reaction necessary to allow a cholinergic neuron to return to its resting state after activation.4 The common mechanism of action underlying this class of agents is an increase in available acetylcholine at central nervous synapses through inhibition of the enzyme, acetylcholinesterase, which breaks down this neurotransmitter. Tacrine was the first of the AChEIs licensed for the treatment of Alzheimer’s disease in 1993, but its use has been abandoned because of a high incidence of side effects including hepatotoxicity.5 Medications currently approved by regulatory agencies in the United States and Europe to treat the cognitive manifestations of Alzheimer’s disease and improve life quality of these patients are the reversible AChEIs: donepezil, rivastigmine and galantamine. Memantine is another medication licensed for the treatment of Alzheimer’s disease but does not work as an AChEI. It acts as a non-competitive N-methylD-aspartate (NMDA) receptor antagonist at the cellular level.
How well do they work in dementia? Evidence from clinical trials has led to the emergence of donepezil, galantamine, rivastigmine (cholinesterase inhibitors), as the first-line pharmacotherapy for mild to moderate Alzheimer’s disease and memantine (NMDA receptor antagonist) for moderate to severe Alzheimer’s disease.6–9 There is a substantial body of evidence that suggests these cholinesterase inhibitors decrease acetylcholinesterase activity in a number of brain regions in patients with Alzheimer’s disease, increase the availability of acetylcholine at synaptic junctions and there is a significant correlation between acetylcholinesterase inhibition and observed cognitive improvement.2 Memantine, a moderate-affinity, NMDA receptor antagonist, is currently the only agent approved for moderately severe to severe Alzheimer disease in Europe and for moderate to severe Alzheimer disease in the United States. In clinical trials involving Alzheimer’s disease patients, memantine has demonstrated a reduced rate of deterioration on global, cognitive, functional and behavioural measures.10 The combination of AChEIs and memantine has been investigated and found to be effective in patients with Alzheimer’s disease, particularly in slowing cognitive impairment and preventing the onset of agitation and aggression in elderly Alzheimer’s disease patients.11 PDD and DLB exist on a spectrum of Lewy body disorders and share common pathogenic mechanisms as well as clinical features. Patients with both conditions have severe deficits in cortical levels of the neurotransmitter acetylcholine. Therefore, blocking its breakdown using AChEIs could theoretically lead to
clinical improvements analogous to Alzheimer’s disease patients.12 A Cochrane database systematic review of six trials in which a total of 1236 participants were randomised provided supportive evidence for the use of AChEIs in patients with PDD, with a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living rating scales. The effect in DLB remained unclear.12 Memantine has been reported to produce substantial improvements on cognitive tests of attention and episodic recognition memory in DLB or PDD cases in randomised controlled trials.13,14 There is some evidence of benefit of rivastigmine and donepezil in vascular cognitive impairment (VCI) from clinical trials, however, neither rivastigmine nor donepezil have gained regulatory approval for the treatment of VCI (this includes VaD).15–19
Should these be prescribed to those with mild cognitive impairment? A recent systematic review and meta-analysis of cognition enhancers suggested that these drugs did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms.20 This includes patients with mild cognitive impairment (MCI) in PD.12
How safe are cholinesterase inhibitors and what are the precautions? Nausea, vomiting, anorexia, diarrhoea, fatigue, insomnia, headache and dizziness are the common side effects with all these drugs, but these are usually tolerable. There have, however, been reports of serious system side effects such as gastrointestinal bleeding,21 but these are not common.
System-specific side effects Gastrointestinal side effects. Dyspepsia, anorexia and weight loss have been reported. Two clinical trials have reported higher rates of GI bleeding in individuals taking donepezil than in those given placebo,22,23 although population-based studies have failed to demonstrate significant association between AChEI use and upper GI bleeding in elderly adults.24 Cardiovascular side effects. Palpitations, arrhythmias, first-degree AV block, hypotension and flushing have all been reported. Population-based studies have shown that the prescription of cholinesterase inhibitors is associated with increased rates of syncope, bradycardia,
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pacemaker insertion and hip fracture in older adults with dementia.25 Pulmonary side effects. Although AChEIs may theoretically worsen airflow obstruction because of their procholinergic properties, however, population-based studies of elderly individuals with COPD and dementia have failed to demonstrate an increased risk for adverse pulmonary outcomes in AChEI users compared to those who were not receiving AChEIs.26
well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women where benefit can be demonstrated to outweigh the risks. This decision can be difficult when patients do not retain the capacity to give an informed consent.
Breast feeding These drugs are not indicated for use in nursing mothers.
Drug metabolism
Cautions
The bioavailability of the current crop of AChEIs (rivastigmine, galantamine and donepezil) ranges between 40% and 100%. The elimination half-life is considerably longer for donepezil (70 to 80 h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12 h). Donepezil is therefore administered once daily in comparison to rivastigmine and galantamine which are administered twice daily but modified release preparations are available (Table 2). Donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Donepezil is metabolised by hepatic cytochrome CYP3A4 and galantamine by CYP2D6. Rivastigmine is not metabolised via CYP enzymes but via esterases and sulfate conjugation to be excreted in the urine.27 Rivastigmine inhibits both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) whereas donepezil and galantamine specifically inhibit AChE. Galantamine also modulates nicotine receptors, thereby enhancing acetylcholinergic activity at the synapses.28
Concomitant antipsychotic medication prescription with donepezil can increase risk of neuroleptic malignant syndrome. Galantamine can cause worsening of Parkinsonian symptoms and seizures. Rivastigmine can lead to anorexia and weight loss. All AChEIs due to their cholinergic effects can cause bradycardia and therefore are best avoided in those with a sick sinus syndrome or heart block. Memantine should be avoided in those with a history of epilepsy and dose reduction is required in those with renal impairment.
Drug interactions AChEIs are parasympathomimetic drugs and theoretically their effects can be antagonised by medications with antimuscarinic properties. Donepezil and rivastigmine could antagonise effects of non-depoloarising muscle relaxants and enhance the effects of the depolarising muscle relaxant suxamethonium. The plasma concentration of galantamine is increased by erythromycin and paroxetine. There is an increased risk of CNS toxicity when memantine is given with amantadine, dextromethorphan and ketamine (manufacturer of memantine advises to avoid concomitant use).
How cost-effective are cholinesterase inhibitors? There is no evidence that treatment with an AChEI is not cost-effective as per a Cochrane database systematic review.29 Economic modelling for the NHS England and Wales demonstrates that AChEIs are probably cost saving and more cost-effective than best supportive care for mild-moderate Alzheimer’s disease. In people with mild to moderate AD, one probabilistic sensitivity analysis suggested that donepezil is the most cost-effective AChEI, per quality adjusted life year (QALY).30 Treatment with any of the three AChEIs or memantine seems to be reasonable in terms of clinical effects and a cost-effective strategy or even a cost-saving strategy.31
Who can prescribe cholinesterase inhibitors? Only specialists in the care of patients with dementia (that is, psychiatrists including those specialising in learning disability, neurologists and physicians specialising in the care of older people) should initiate treatment based on NICE guidance (March 2011).
Pregnancy
Who should we prescribe it to?
These medications are in the United States Food and Drug Administration (FDA) drug class C, which means animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and
Most cognition enhancers discussed here are licensed for Alzheimer’s dementia, the only drug that is licensed for PDD is rivastigmine. No drug is licensed for VaD.
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When to prescribe cholinesterase inhibitors? These drugs are generally indicated for patients with mild to moderate stage of AD except memantine which is indicated for moderate to severe stage of AD. Dementia is a clinical syndrome characterised by global cognitive impairment, which represents a decline from previous level of functioning, and is associated with impairment in functional abilities and, in many cases, behavioural and psychiatric disturbances.32 Using arbitrary cut-off scores on memory scales such as Addenbrooke’s cognitive examination revised (ACE-R) scale33 or cognitive screening instruments such as mini mental state examination (MMSE)34 or Montreal cognitive assessment (MOCA) test35 that are commonly used in hospital wards and clinics in the United Kingdom to define mild, moderate and severe stages of dementia may not be appropriate. Ability to perform functional activities of daily living are not taken into consideration in these scales and these are important to determine the severity of dementia. Information provided by carers can be vital about determining the effect of the cognitive decline on the performance of functional activities of daily living. One such scale that incorporates this information and should be used alongside a clinical scale such as the ACE-R or MMSE is the Functional Assessment Staging of Alzheimer’s Disease (FAST)36 (Table 1).
What are the standard doses? The starting doses and maximum allowed doses of AChEIs and memantine along with available formulations are shown in Table 2.
How to prescribe cognition enhancers? Most cognition enhancers are prescribed at the smallest therapeutic dose initially and gradually titrated upward over weeks towards a target dose based on clinical response and tolerance. (Table 2). For those unable to swallow tablets, orodispersible preparations that dissolve on the tongue (donepezil) and oral solutions are available (Table 2). If nausea and gastrointestinal side effects are troublesome or in the peri-operative setting, transdermal administration of rivastigmine as a patch may be considered. When switching from oral to transdermal rivastigmine therapy, patients taking 3–6 mg by mouth daily should switch to 4.6 mg/24 h patch, patients taking 9–12 mg by mouth daily should switch to 9.5 mg/24 h patch.
What monitoring is required? Patients who continue on treatment should be reviewed regularly using cognitive, global, functional and behavioural assessment questionnaires, instruments and scales to get an objective idea of cognitive function and functioning in daily life. Treatment should be reviewed by an appropriate specialist team, this is usually based at memory clinics in the community in the UK, unless there are locally agreed protocols for shared care.
How long to prescribe cholinesterase inhibitors? Treatment should continue as long as it is considered to have a worthwhile effect on cognitive, global, functional or behavioural symptoms by the treating clinician or general practitioner on his/her patient.
Table 1. Functional assessment staging of Alzheimer’s disease scale (FAST).36 Stage 1 Normal adult
No functional decline
Stage 2 Normal older adult
Personal awareness of some functional decline
Stage 3 Early Alzheimer’s disease Stage 4 Mild Alzheimer’s disease
Noticeable deficits in demanding job situations Requires assistance in complicated tasks such as handling finances, planning parties, etc
Table 2. Standard doses of licensed cognition enhancers for treating dementia patients. Acetylcholinesterase inhibitors Formulation
Maximum dose
Donepezil
Tablets, orodis5 mg nocte persible tablets
10 mg od
Galantamine
Tablets, MR capsules, oral solution Capsules, oral solution Patches
4 mg bd
12 mg bd
1.5 mg bd
6 mg bd
4.6 mg/24 h
13.3 mg/24 h
5mg od
20 mg od
Stage 5 Moderate Alzheimer’s Requires assistance in choosing disease proper attire. Stage 6 Moderately severe Requires assistance dressing, bathing Alzheimer’s disease and toileting. Experiences urinary and fecal incontinence.
Rivastigmine
Stage 7 Severe Alzheimer’s disease
Glutamate receptor antagonist Memantine Tablets, oral solution
Speech ability declines to about a half-dozen intelligible words. Progressive loss of abilities to walk, sit up, smile and hold head up.
Starting dose
MR: modified release preparation for once daily dosing.
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Table 3. Tips for hospital based clinicians treating dementia patients. 1. Alzheimer’s disease must be diagnosed and treatment initiated by a specialist with training in diagnosing and treating patients with dementia, i.e. a neurologist or psychiatrist. 2. Clinicians should not rely solely on scores on assessment scales to diagnose and determine the severity of dementia particularly when the patient has learning or other disabilities, or other communication difficulties. 3. The views of those caring for the person with dementia should be sought before and during treatment. 4. If prescribing an AChEI (donepezil, galantamine or rivastigmine), treatment should normally be started with the drug with the lowest acquisition cost to the health service.
Conclusion In conclusion, we summarise the clinically relevant advice for healthcare professionals looking after these vulnerable adults with dementia based on NICE guidance (March 2011) in Tables 3 and 4. Contribution of authors Both authors contributed equally to the paper
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Declaration of conflicting interests None declared. Table 4. Tips for general practitioners caring for dementia patients. 1. Treatment can be continued by general practitioners under a shared-care protocol with the specialist who diagnosed and initiated treatment. 2. Treatment should continue only if it is considered to have a worthwhile effect on cognitive, functional or behavioural symptoms, i.e. at end stage when person is bed-bound, these drugs may not have a substantial beneficial effect on quality of life. 3. All AChEIs (donepezil, galantamine and rivastigmine) due to their cholinergic effects can cause bradycardia and therefore are best avoided in those with a sick sinus syndrome or heart block. Memantine can be used in those with conduction abnormalities because of its different mechanism of action. 4. There is insufficient evidence to recommend the use of statins, anti-inflammatory drugs, vitamin E and Ginkgo biloba, either for the treatment or prevention of Alzheimer’s disease.
A decision to stop treatment may have to be made by the treating clinician in situations where the risks of treatment outweigh the benefits but carer input should be obtained before making this decision where the patient is cared for at home.
How do cholinesterase inhibitors compare to other therapeutic options? Despite the slight variations in the mode of action of the three cholinesterase inhibitors, there is no evidence of any differences between them with respect to efficacy. There appear to be less adverse effects associated with donepezil compared with rivastigmine.29 There is insufficient evidence from Cochrane database systematic reviews to recommend statins for the treatment or prevention of Alzheimer’s disease or other forms of dementia.37,38
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