3 Clinical psychopharmacology3.3 Pharmacodynamics
3.3.2.7 Cognitive enhancers
2 min read2 figures
Written by Resident Doctor Committee · Published
Principles
Cholinesterase inhibitors raise synaptic acetylcholine by reversibly blocking acetylcholinesterase, the enzyme that hydrolyses it, so released acetylcholine acts longer at muscarinic and nicotinic receptors.
The rationale is basal forebrain cholinergic loss, so benefit depends partly on surviving cholinergic terminals.
Cholinesterase inhibitors and memantine are symptomatic treatments. They help cognition, global function, daily living and behaviour, but they do not modify the underlying neuropathology.
No drug is recommended to prevent or delay progression from mild cognitive impairment to dementia. This includes cholinesterase inhibitors, memantine, nootropics, supplements and anti-inflammatories.
Individual cholinesterase inhibitors
Drug | Binding | Enzymes inhibited | Clearance | Other points |
|---|---|---|---|---|
Donepezil | Piperidine; reversible | Acetylcholinesterase, highly selective over butyrylcholinesterase | Hepatic cytochrome P450 | Half-life about 70 hours, so once daily; morning dosing often settles cholinergic dreaming |
Galantamine | Competitive, reversible | Acetylcholinesterase | Hepatic cytochrome P450 | Also allosterically potentiates nicotinic acetylcholine receptors |
Rivastigmine | Carbamate; slowly reversible, non-competitive | Acetylcholinesterase and butyrylcholinesterase | Esterase hydrolysis, largely by the cholinesterases it inhibits | Oral form licensed in the UK for mild to moderate Parkinson's disease dementia |
Rivastigmine alone inhibits butyrylcholinesterase, which sits mainly in glia and rises as Alzheimer's disease advances.
Donepezil is avoided in confirmed pseudocholinesterase (butyrylcholinesterase) deficiency, because it exaggerates the suxamethonium-type neuromuscular block that the deficiency already prolongs.
Adverse effects of cholinesterase inhibitors
These effects follow raised peripheral cholinergic tone. Slow titration improves tolerability.
Nausea is the most common adverse effect, very common with rivastigmine, and is more frequent than bradycardia. It comes from acetylcholine acting on gut muscarinic receptors.
Donepezil's very common adverse effects are headache, nausea and diarrhoea.
The bowel moves towards diarrhoea and the bladder towards urgency and incontinence, not constipation or retention, which are antimuscarinic effects.
Vagotonic bradycardia and heart block can occur, and memantine does not share them.
Memantine
Memantine is an N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, a different mechanism from cholinesterase inhibitors, which act on acetylcholine.
It is a low-affinity, uncompetitive, use-dependent blocker of the open NMDA channel near the magnesium site, so it binds only after the channel has opened.
Fast dissociation lets it damp sustained glutamate excess while sparing brief physiological signals.
By limiting sustained glutamate stimulation and calcium influx, it may protect neurons from excitotoxic injury in Alzheimer's disease.
It is used in moderate to severe Alzheimer's disease.
It is renally excreted.
Anti-amyloid antibodies
Lecanemab and donanemab are anti-amyloid monoclonal antibodies that aim to slow progression in selected early Alzheimer's disease.
They cause amyloid-related imaging abnormalities (ARIA), which is why patients have scheduled magnetic resonance imaging (MRI) during treatment.
Type | Changes |
|---|---|
ARIA-E | Vasogenic oedema and sulcal effusion |
ARIA-H | Microhaemorrhages and superficial siderosis |