Educational draft · awaiting clinical reviewThe full textbook explains uncertainty but does not replace live national or local guidance, specialist advice, or current prescribing information.
Cholinesterase inhibitors and memantine principles
Psychiatry · UK scope · Sources checked 27 Aug 2026 · Clinical review pending
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Collapse or toxicity requires urgent medicine review
Syncope, marked bradycardia, new conduction disturbance, severe vomiting or dehydration, gastrointestinal bleeding, seizure, severe confusion, repeated patch exposure or suspected overdose requires urgent physiological assessment and cessation advice from an appropriate prescriber or toxicology service.
Action: Assess ABCDE, pulse, blood pressure, glucose and ECG; identify every formulation, strength, dose and last administration; remove all rivastigmine patches if duplication is possible; correct immediate complications; and seek urgent medicines, poison-information or acute medical support. Do not restart or retitrate until the event and indication have been reviewed.
Purpose and principles
Match cognitive medicines to dementia subtype and stage, initiate and titrate using a safe supported regimen, measure benefit beyond a test score, and avoid inappropriate withholding, continuation or withdrawal.
Cognitive medicines are selected by the best-supported dementia subtype, stage, contraindications and the person's goals. Donepezil, galantamine and rivastigmine increase cholinergic signalling by inhibiting acetylcholinesterase. Memantine modulates pathological glutamatergic NMDA-receptor activity. They may support cognition, everyday function or global symptoms for some people, but response varies and progression continues. Explain a trial as an opportunity to preserve meaningful ability, not a promise of recovery or a test of whether the diagnosis is real.
NICE recommends donepezil, galantamine or rivastigmine as options for mild-to-moderate Alzheimer's disease. When it is appropriate to use an AChE inhibitor, treatment should usually start with the option with the lowest acquisition cost, but another can be selected for adverse-effect profile, expected adherence, medical comorbidity, drug interactions or dose profile. Treatment may begin on the advice of a clinician with the necessary knowledge and skills rather than being restricted to one professional title.
Practice
Two practice questions
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Question 1 of 2
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PsychiatryOriginal SBA
Severe Alzheimer progression
A person taking donepezil for Alzheimer's disease has gradually progressed from moderate to severe dementia but remains medically stable and may still derive functional benefit. Which principle follows NICE guidance?
Sources and review status5 sources · checked 27 Aug 2026 · clinical review pending+
Sources
Sources and review status
National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.
NICE NG97 dementia recommendationsSubtype- and stage-specific AChE-inhibitor and memantine indications, combination use, selection and continuation principles.
Donepezil 5 mg SmPCUK licensed indication, 5 mg initiation, one-month review, 10 mg maximum and medicine-specific safety information.
Memantine monotherapy is recommended for moderate Alzheimer's disease when AChE inhibitors are not tolerated or are contraindicated, and for severe Alzheimer's disease. For a person already taking an AChE inhibitor, NICE says to consider adding memantine in moderate disease and to offer addition in severe disease. Combination decisions therefore depend on current therapy and stage. Do not substitute one isolated cognitive score for clinical severity, function, adverse effects and informed preference.
Dementia with Lewy bodies has a separate pathway. Offer donepezil or rivastigmine for mild-to-moderate DLB and consider galantamine only when both are not tolerated. Donepezil or rivastigmine may also be considered in severe DLB. Consider memantine when AChE inhibitors are not tolerated or contraindicated. NICE identifies these DLB medicine uses as off-label. In vascular dementia, only consider an AChE inhibitor or memantine when comorbid Alzheimer's disease, Parkinson's disease dementia or DLB is suspected. Do not offer these classes for frontotemporal dementia.
Pre-treatment assessment documents diagnosis, medication indication and a baseline that can be revisited. Record concrete daily abilities, cognitive domains, behaviour, sleep and carer observations. Check pulse, blood pressure, weight and relevant ECG or cardiac history; ask about syncope, conduction disease, peptic ulcer, seizures, asthma or COPD and urinary obstruction. Review beta-blockers and other rate-limiting medicines, anticholinergics that oppose treatment, drugs that increase bleeding risk, and renal function before memantine.
Start low and titrate according to the specific product. Donepezil is commonly started at 5 mg orally once daily and held for at least one month before clinical review and possible increase to 10 mg once daily. Galantamine prolonged-release starts at 8 mg once daily for four weeks, then 16 mg once daily for at least four weeks; 24 mg once daily is considered only after individual benefit and tolerability assessment. Formulations are not interchangeable without checking instructions.
Rivastigmine transdermal treatment starts with a patch releasing 4.6 mg per 24 hours. If tolerated, increase after at least four weeks to 9.5 mg per 24 hours. Apply only one patch to clean, dry, hairless intact skin, remove the previous patch first and rotate sites. Interruption can require restarting at the lower strength: the product information states that after more than three days without a patch, restart at 4.6 mg per 24 hours and retitrate. Patch errors are preventable causes of serious toxicity.
Memantine is taken once daily and titrated by 5 mg weekly: 5 mg in week one, 10 mg in week two, 15 mg in week three and 20 mg from week four when tolerated. Renal impairment changes the ceiling: current SmPCs specify 10 mg daily for creatinine clearance 5 to 29 mL/min, and initially 10 mg daily for clearance 30 to 49 mL/min with possible increase to 20 mg after at least seven well-tolerated days. Check the current product because available tablet strengths and administration instructions vary.
AChE-inhibitor adverse effects include nausea, diarrhoea, vomiting, anorexia, weight loss, bradycardia, syncope, vivid dreams, sleep disturbance and muscle cramps. They can worsen conduction problems and increase gastric acid; pulmonary and seizure histories require care. Donepezil also has QT-prolongation cautions in current product information. Memantine can cause dizziness, somnolence, headache, constipation and hypertension; consider whether a new symptom instead reflects illness, another medicine or dementia progression.
Review after initiation and dose changes for adherence, administration errors, pulse, weight, gastrointestinal symptoms, falls, sleep, cognition, daily activities, behaviour and carer-observed change. Benefit can mean slower loss or maintenance, not only score improvement. NICE says not to stop AChE inhibitors solely because Alzheimer's disease has become severe. Conversely, an old prescription is not self-justifying: reconsider treatment when adverse effects, no continuing benefit, inability to administer safely or changed goals outweigh likely value.
Stopping should be planned, documented and followed. Clarify whether interruption is temporary, whether retitration is required and who will observe change. A marked deterioration after withdrawal may support reconsideration if restarting remains safe and consistent with goals, but acute decline needs assessment for delirium and illness. Ensure cognitive treatment never displaces personalised activity, occupational adaptation, communication support, vascular and sensory care, legal planning, caregiver support or palliative assessment when appropriate.
Key points
Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors; memantine is an NMDA-receptor antagonist with different indications and adverse effects.
NICE recommends any of the three AChE inhibitors as options for mild-to-moderate Alzheimer's disease, selecting by adverse effects, interactions, adherence and acquisition cost.
For Alzheimer's disease, offer memantine alone for moderate disease when AChE inhibitors are not tolerated or contraindicated, or for severe disease.
For a person already taking an AChE inhibitor, consider adding memantine in moderate Alzheimer's disease and offer addition in severe disease.
For mild-to-moderate dementia with Lewy bodies, offer donepezil or rivastigmine; consider galantamine only when both are not tolerated, and consider memantine when AChE inhibitors cannot be used. These DLB uses are off-label.
Only consider these medicines in vascular dementia when comorbid Alzheimer's, Parkinson's disease dementia or DLB is suspected; do not offer them for frontotemporal dementia.
Indications, selection and cautions
Cholinergic adverse effects
Nausea, diarrhoea, appetite loss, weight loss, cramps, vivid dreams, bradycardia and syncope can follow AChE-inhibitor initiation or titration.
Memantine intolerance
Dizziness, somnolence, headache, constipation or hypertension may emerge during weekly titration and require contextual benefit-harm review.
Meaningful stabilisation
Maintained conversation, dressing sequence, hobbies or orientation may represent benefit even without a large cognitive-score improvement.
Administration failure
Missed tablets, duplicated patches, swallowing difficulty and unsupervised dose changes can mimic treatment failure or create toxicity.
Disease progression
Gradual decline despite adherence does not automatically mean zero benefit, but should prompt stage, goals and ongoing value review.
Acute deterioration
Hours-to-days cognitive or functional worsening requires assessment for delirium and intercurrent illness before altering long-term cognitive treatment.
Red flags requiring action
Syncope, pulse slowing, new dizziness on standing or an ECG conduction abnormality may represent clinically important cholinergic cardiac toxicity.
Persistent vomiting, diarrhoea, anorexia or weight loss can cause dehydration and disproportionate frailty during cholinesterase-inhibitor treatment.
Assessment before treatment
01Subtype and stage reviewFirst step
Why
Confirm that the dementia formulation and current severity support the proposed medicine or combination.
Interpretation and limitations
Frontotemporal and uncomplicated vascular dementia generally lack an indication, while Alzheimer's and Lewy-body pathways differ.
02Functional and cognitive baseline
Why
Record meaningful daily abilities, symptom domains and supporter observations before treatment.
Interpretation and limitations
Later review can detect maintenance, improvement or decline without relying on one test score alone.
03Pulse, blood pressure and cardiac review
Why
Identify bradycardia, syncope, conduction disease, orthostasis and interacting rate-limiting medicines.
Interpretation and limitations
Symptoms or abnormal findings may require ECG, prescriber or cardiology input before an AChE inhibitor is used.
04Weight and gastrointestinal review
Why
Establish nutrition, appetite, ulcer, bleeding, vomiting and diarrhoea risk before cholinergic treatment.
Interpretation and limitations
Frailty, active symptoms or relevant interacting drugs change selection, monitoring and stop thresholds.
05Renal and hepatic function
Treatment approach
01Treatment selectionMatch medicine to subtype and stageFirst stepA confirmed dementia diagnosis prompts consideration of symptomatic cognitive treatment.+
1Confirm subtype, stage, current medicines, contraindications, administration support and the person's informed goals.
2Apply NICE Alzheimer's, Lewy-body, vascular or frontotemporal recommendations rather than treating all dementia identically.
3Choose formulation and agent using adverse effects, interactions, adherence, medical comorbidity, dose profile and acquisition cost.
02Initiation and titrationBuild safety into the regimenA cognitive medicine has a supported indication and treatment is accepted.+
1Document cognition, daily function, behaviour, weight, pulse, relevant investigations and who will support each dose.
2Start the product-specific low dose, titrate no faster than its authorised interval and check tolerability before every increase.
Regimens, contraindications and interactions
A licensed acetylcholinesterase-inhibitor option for mild-to-moderate Alzheimer's disease; NICE also supports defined off-label use in dementia-with-Lewy-bodies pathways.
Donepezil
Start 5 mg by mouth once daily and continue for at least one month; after clinical review, increase if appropriate to 10 mg once daily, which is the recommended maximum.
Review bradycardia, syncope, conduction disease, QT risk, ulcer or gastrointestinal bleeding, asthma or COPD, seizures, weight loss and interacting rate-limiting or anticholinergic medicines.
A licensed acetylcholinesterase-inhibitor option for mild-to-moderate Alzheimer's disease; NICE supports off-label use in mild-to-moderate DLB only when donepezil and rivastigmine are not tolerated.
Galantamine prolonged-release
Start 8 mg by mouth once daily for 4 weeks, then 16 mg once daily for at least 4 weeks; consider 24 mg once daily only after individual assessment of clinical benefit and tolerability.
Give with food and adequate fluids as product-directed; review renal and hepatic impairment, bradycardia, syncope, gastrointestinal symptoms, weight loss, ulcer risk and CYP-mediated interactions.
A licensed cholinesterase-inhibitor patch for mild-to-moderate Alzheimer's disease; NICE supports off-label rivastigmine use across defined DLB stages, with formulation chosen for the individual administration and tolerability profile.
Rivastigmine transdermal patch
Apply one 4.6 mg/24-hour patch daily; after at least 4 well-tolerated weeks increase to one 9.5 mg/24-hour patch daily; remove the previous patch and rotate the application site every day.
Complications, monitoring and follow-up
After starting or increasing an AChE inhibitor, review pulse, syncope, falls, weight, appetite, gastrointestinal symptoms, sleep and muscle effects.
During memantine titration review renal function context, dizziness, somnolence, headache, constipation, blood pressure and adherence each week when feasible.
Compare meaningful daily activities, communication, behaviour and supporter observations with baseline alongside any cognitive instrument.
Inspect rivastigmine patch sites and administration records, confirming that yesterday's patch is removed before today's patch is applied.
Reassess indication, interactions, goals, continuing benefit and tolerability after acute illness, care-setting transfer or major functional change.
Plan and observe withdrawal or interruption, distinguishing gradual loss of benefit from acute delirium or an unsafe restart at the prior dose.
Special situations
Maintenance may be benefit
A stable practical ability during progressive disease can matter even when a cognitive total does not visibly improve.
Subtype controls indication
The same memory symptom leads to different prescribing in Alzheimer's, Lewy-body, vascular and frontotemporal disease.
Patches need reconciliation
Visual inspection and a dated administration record prevent old and new rivastigmine patches being worn together during transfers.
Severity alone cannot stop
NICE specifically rejects stopping an AChE inhibitor solely because Alzheimer's disease has progressed to a severe stage.
Interruption changes dosing
Several products require a lower-dose restart after a gap, so admission and discharge reconciliation must include the last administered dose.
Common pitfalls
01
Starting a cognitive medicine from a vague dementia label without confirming subtype, stage, contraindications and administration support.
02
Offering donepezil or memantine for frontotemporal dementia or uncomplicated vascular dementia contrary to NICE recommendations.
03
Escalating a dose during acute delirium, non-adherence or medicine toxicity because cognition appears worse.
04
Judging benefit only by a screening total and ignoring maintained function, communication, behaviour and adverse effects.
05
Applying a new rivastigmine patch without removing the old one or restarting the prior strength after a prolonged interruption.
06
Failing to adjust memantine for renal impairment or to monitor bradycardia and weight loss with cholinesterase inhibitors.
07
Stopping an AChE inhibitor solely because Alzheimer's disease is severe, without reviewing benefit, harm and goals.
08
Presenting symptomatic treatment as disease reversal or allowing prescribing to replace non-drug support and future planning.
Do not stop an AChE inhibitor solely because Alzheimer's disease has become severe; review actual benefit, tolerability, goals and administration feasibility.
Before treatment document subtype, stage, cognition, function, behaviour, pulse, weight, comorbidity, interactions and who will support administration.
Titrate one change at a time and reassess adverse effects and meaningful function; apparent worsening may reflect delirium, non-adherence or an interrupted regimen.
Cognitive medicines are symptomatic, not curative; continue non-drug support, advance planning, sensory care, physical health treatment and carer support.
More than one rivastigmine patch applied at once can produce serious overdose; remove old patches before every new application.
Haematemesis, melaena or acute abdominal pain raises concern for gastrointestinal ulceration or bleeding, particularly with NSAIDs or prior ulcer disease.
New rigidity, hallucinations, acute inattention or reduced consciousness needs assessment for delirium, medicine effects and intercurrent illness rather than automatic dose escalation.
A rapid functional decline, seizure or focal neurology should reopen the diagnosis and trigger appropriate acute or specialist assessment.
Why
Select safe memantine dosing and identify altered exposure or tolerability for other agents.
Interpretation and limitations
Memantine maintenance is limited in important renal impairment; use current product-specific thresholds.
06Medication administration assessment
Why
Confirm formulation, swallowing, patch technique, adherence support, interactions and interruption history.
Interpretation and limitations
A safe plan needs one responsible administration system and explicit retitration instructions after interruptions.
3Give written missed-dose, patch-removal, interruption and urgent-adverse-effect instructions and communicate them across settings.
03Continuing reviewJudge benefit beyond severity labelsThe person is established on an AChE inhibitor, memantine or both.+
1Review meaningful function, cognition, behaviour, adherence, pulse, weight, falls and adverse effects with person and supporters.
2Do not stop an AChE inhibitor solely because Alzheimer's disease is now severe, but do not continue automatically without benefit-harm review.
3If stopping or interrupting, plan observation and product-specific retitration and investigate any acute deterioration medically.
Never apply multiple patches; inspect skin, weight and gastrointestinal tolerance; use caution below 50 kg, with conduction or ulcer risk, and restart at 4.6 mg/24 hours after more than three days interrupted.
A licensed NMDA-receptor antagonist for NICE-defined moderate or severe Alzheimer's pathways; NICE supports off-label use in DLB when acetylcholinesterase inhibitors are contraindicated or not tolerated.
Memantine
Give 5 mg by mouth once daily in week 1, 10 mg daily in week 2, 15 mg daily in week 3 and 20 mg daily from week 4 if tolerated; reduce according to creatinine clearance.
Check renal function: current SmPC dosing is 10 mg daily at creatinine clearance 5–29 mL/min and initially 10 mg at 30–49 mL/min; monitor dizziness, somnolence, constipation, hypertension, seizures and administration support.