PharmacologyTier 1Medical Sciences concept

Cholinesterase inhibitor pharmacology and adverse effects

Core concept

Cholinergic deficit in Alzheimer disease from loss of basal forebrain neurons (nucleus basalis of Meynert)
ChEIs inhibit acetylcholinesterase in the synaptic cleft -> inc ACh availability
- Purely symptomatic - no effect on amyloid, tau or neuronal loss
- Modest benefit: ~2-3 points on ADAS-cog, delays functional decline by months; does not halt or reverse the disease
Effect is not selective for the CNS - every peripheral muscarinic and nicotinic synapse is also potentiated, which is where the adverse effects come from

	Donepezil	Rivastigmine	Galantamine
Target	AChE, reversible	AChE + butyrylcholinesterase, pseudo-irreversible	AChE + allosteric nicotinic modulation
Half-life	~70 h - once daily	~1-2 h (long tissue effect)	~7 h
Route	Oral	Oral or patch	Oral
Metabolism	CYP2D6/3A4	Non-hepatic esterase - fewest interactions	CYP2D6/3A4

Adverse effects - all predictable from cholinergic excess
- GI commonest: nausea, vomiting, diarrhoea, anorexia, weight loss
- Cardiac: bradycardia, AV block, syncope - a recognised and reversible cause of falls and of pacemaker insertion in older people
- Muscle cramps, vivid dreams and insomnia (give donepezil in the morning), urinary frequency, inc secretions
- Caution in asthma/COPD, peptic ulcer, sick sinus syndrome
Do a baseline ECG and check the pulse before and after starting - bradycardia is the important one
Prescribing a ChEI and an anticholinergic (oxybutynin, solifenacin, amitriptyline) together is pharmacological self-cancellation - a very common and very examinable error
Memantine is not a ChEI - an uncompetitive NMDA antagonist for moderate-severe disease; can be combined
Rivastigmine patch reduces GI effects but causes local reactions; butyrylcholinesterase inhibition may explain its use in Lewy body and Parkinson disease dementia

Indications: mild-to-moderate Alzheimer disease, dementia with Lewy bodies and Parkinson disease dementia (best evidence, especially rivastigmine)
- Not effective in vascular dementia or frontotemporal dementia - FTD may worsen
PBS in Australia requires a baseline MMSE and documented response for continuation
Assess for benefit at 3-6 months; stop if no benefit or intolerable adverse effects, and taper (abrupt cessation -> acute decline)
ChEI-induced bradycardia mimics and unmasks conduction disease - think of the drug before implanting a pacemaker
Same pharmacology, different setting: pyridostigmine in myasthenia gravis, neostigmine for reversal of non-depolarising blockade and for pseudo-obstruction, physostigmine (crosses the BBB) for anticholinergic delirium
Organophosphates are irreversible cholinesterase inhibitors - the toxidrome is the same mechanism taken to extreme

Dementia syndromes - Alzheimer, Lewy body, vascular, frontotemporal
Comparative anticholinergic potency of drugs; anticholinergic burden in the elderly
Toxidrome recognition - cholinergic
Neuromuscular junction physiology; myasthenia gravis
Anti-amyloid monoclonal antibodies as a separate, disease-modifying class

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