Donepezil: What Anti-Dementia Medicines Can Do — and What They Can’t

1. At a Glance: Technical Data Sheet

2. What donepezil can do — and what it can’t

We have deliberately put this section near the top, because this is where most of the disappointment comes from. Donepezil is a medicine that works on the symptoms. It does not tackle the cause of the disease, does not remove protein deposits in the brain and does not protect a single nerve cell from dying.^¹,²

• What is realistic: stabilising memory, attention and everyday abilities over a limited period. In studies, treated groups score better on average than untreated groups in cognitive tests and on scales of everyday functioning.^³
• How big the effect is: moderate on average. Some families describe their father holding conversations again or getting dressed on his own; others notice nothing at all for months. Both experiences are consistent with the evidence.
• What donepezil cannot do: cure dementia, bring back lost abilities or halt its course. The disease keeps progressing during treatment — according to current knowledge, just from a somewhat higher level.
• What it is not, either: a remedy for normal age-related forgetfulness or for concentration problems without a diagnosis of dementia. It is not licensed for these situations and has no proven benefit there.

This sober view is not a rejection of the medicine: the German S3 guideline on dementia explicitly recommends acetylcholinesterase inhibitors in mild to moderate Alzheimer’s dementia, precisely because there are few options and a moderate effect can make a real difference in everyday life.^² It is simply about setting the bar at the right height — if you expect an improvement, you will be disappointed; if you accept a slower decline as the goal, you can judge the benefit fairly.

3. How it works: more acetylcholine in the brain

Nerve cells communicate via messenger substances that are released into the gap between two cells — the synaptic cleft. One of these messengers is called acetylcholine. It is particularly important for attention, learning and memory.

In Alzheimer’s dementia, it is precisely the nerve cells that produce acetylcholine that die off early. So less and less of it is available. Donepezil does not act on production — that cannot be restored — but on breakdown: it inhibits the enzyme acetylcholinesterase, which normally breaks acetylcholine down in the synaptic cleft within milliseconds. When this breakdown is slowed, the acetylcholine that is there stays active for longer. The signal gets louder even though the transmitter has grown weaker.^¹

This picture explains several things at once:

• Why the effect is limited: donepezil gets more out of what is still there. The further the disease progresses, the less acetylcholine there is left to preserve — which is why the licence is restricted to the mild to moderate stage.
• Where the side effects come from: acetylcholine is not purely a brain messenger. It also controls bowel movement, stomach acid, saliva production, the bladder muscles and — via the vagus nerve — the heart rate. More acetylcholine means more activity everywhere: that is the common thread running through the whole side effect profile (sections 6 and 7).
• Why anticholinergic medicines are a problem: they do exactly the opposite. If someone takes both, the effects partly cancel each other out — the key practical point in section 9.

Within the same group there are two further acetylcholinesterase inhibitors, rivastigmine and galantamine. They differ in dosage form (rivastigmine is available as a patch) and in tolerability, but not fundamentally in how they work. Memantine takes a completely different route: it is only used from the moderate stage onwards and acts on the glutamate system.^⁴

4. Dosing: why the dose is increased slowly

The information below describes the usual approach set out in the SmPC. It is not a dosing instruction — the dose and how quickly it is increased are set by the treating practice.

• Starting dose: usually the lower strength once a day.
• Increase: to the higher strength after about a month at the earliest — not out of caution alone, but because, given the long half-life, the drug level only settles over about two to three weeks.
• Target dose: the aim is usually the highest tolerated dose, because the benefit depends on the dose. “Tolerated” is the key word here.
• Maximum dose: 10 mg daily according to the SmPC.^¹

5. Taking it: in the evening, sleep and vivid dreams

Donepezil is usually taken once a day in the evening, regardless of meals. There is a practical reason for the evening dose: nausea that occurs during sleep is noticed less than in broad daylight.

1. Choose a fixed time and stick to it. In dementia, routine matters more than optimisation. The tablet belongs at a fixed point in the evening routine — after brushing teeth, before the news.
2. With a glass of water, with or without food. A small snack can improve tolerability.
3. Orodispersible tablets for swallowing problems. They disintegrate on the tongue and need hardly any fluid. Whether a tablet may be split or crushed is covered in the guide Splitting tablets — the decision is made at the pharmacy.
4. Missed dose: a skipped tablet is usually not made up; instead, carry on as normal the next day — a double amount is not the answer. General rules are in the guide Missed a medication.
5. If sleep problems appear, question the timing. Don’t change it yourself, but raise it — see the box below.

6. Side effects and what helps against them

Almost all the typical side effects of donepezil can be derived from one sentence: there is more acetylcholine at work in the body — not just in the brain.

Common, mostly in the starting and step-up phase

• Nausea and vomiting — more stomach acid and more movement in the stomach. Small meals, no very fatty food in the evening, slow dose increases.
• Diarrhoea — the bowel works faster. Usually eases; make sure to drink enough, because a lack of fluid quickly leads to confusion in older people.
• Loss of appetite and weight loss — the most important point in practice in dementia, because many people with dementia already eat too little. Regular weighing is part of it; persistent weight loss is a reason to discuss the treatment.
• Muscle cramps, especially calf cramps — acetylcholine is also the messenger at the junction between nerve and muscle. Unpleasant, but usually harmless.

Rarer, but important to know about

• Slowed heartbeat (bradycardia) and fainting — see the separate section 7.
• Stomach and duodenal ulcers, bleeding — more stomach acid meets a sensitive stomach lining. Particularly relevant if you have had ulcers before or are also taking anti-inflammatory painkillers.
• Seizures and worsening of asthma and COPD symptoms — both rare, but part of weighing up benefits and risks.
• Trembling and other movement disorders — rare according to the SmPC (so-called extrapyramidal symptoms); if pronounced, have it assessed by a doctor.

What should be reported, and how, is explained in the guide Medication side effects. In dementia there is one particular point: the people affected often can no longer put their complaints into words. Family members and carers are therefore the real observers — changes in behaviour, eating or walking count as much here as a reported symptom.

7. Keeping an eye on the heart: bradycardia, fainting, falls

The vagus nerve slows the heart — and it works with acetylcholine. If the breakdown of acetylcholine is inhibited, the pulse can drop. In most cases this has no consequences. In older people with pre-existing conduction disorders, however, it can turn into clinically relevant bradycardia, in extreme cases with pauses in the heartbeat.^¹,²,⁵

• What to look out for: newly occurring dizziness, palpitations, unusual weakness, vision going black and, above all, fainting (syncope).
• What usually happens: the pulse is checked and an ECG recorded if needed; with higher-grade heart block, donepezil is usually not suitable.