A 68-year-old woman with Alzheimer's disease is started on donepezil for cognitive decline. At 6 weeks, the family reports new-onset syncope and dizziness. Vital signs show a heart rate of 42 bpm with normal blood pressure. An ECG is ordered. Which additional investigation is most appropriate to assess the mechanism of bradycardia and guide further management?

## Investigating Donepezil-Induced Bradycardia **Key Point:** Donepezil, an anticholinesterase, increases vagal tone at the sinoatrial node, causing bradycardia and conduction abnormalities. A 24-hour Holter monitor is the most appropriate investigation to characterize the rhythm disturbance and detect paroxysmal conduction blocks or sinus pauses. ### Pathophysiology of Anticholinesterase-Induced Bradycardia Donepezil inhibits acetylcholinesterase, increasing acetylcholine at muscarinic M~2~ receptors on the SA node: - Increased vagal parasympathetic tone - Slowed SA node automaticity - Delayed AV nodal conduction - Risk of sinus pause, AV block, or syncope **High-Yield:** Anticholinesterases (donepezil, rivastigmine, physostigmine) are **contraindicated in patients with:** - Sick sinus syndrome - AV block (2nd or 3rd degree) - Symptomatic bradycardia - Baseline heart rate < 50 bpm ### Why 24-Hour Holter Monitor is Optimal | Investigation | Why It Fits | Why It Doesn't Fit Alternatives | |---|---|---| | **24-hour Holter** | Captures intermittent bradycardia, sinus pauses, and conduction blocks over 24 hours; guides decision to continue or withdraw donepezil | **Atropine challenge:** Confirms parasympathomimetic effect but does not characterize the arrhythmia burden or guide long-term management | | | Detects paroxysmal events causing syncope | **EP study:** Invasive; reserved for symptomatic bradycardia refractory to medical management or when pacemaker is being considered | | | Non-invasive, safe, and repeatable | **Serum levels:** Donepezil levels are not routinely measured and do not correlate with bradycardia severity | **Clinical Pearl:** A single resting ECG may show only mild bradycardia; Holter monitoring reveals the frequency and duration of pauses, which determines whether the drug must be discontinued or the dose reduced. **Mnemonic:** **HOLTER = H**eart **O**ver **L**ong **T**ime **E**valuation **R**hythm