CLINICAL VIGNETTE

A Case of Complete Heart Block Associated with an Accidental
Overdose of Donepezil (Aricept)

Brandon Koretz, M. D.

Donepezil hydrochloride (Aricept) is indicated for the treatment of mild to moderate Alzheimer\'s Disease
(AD). It works by inhibiting acetylcholinesterase. The resulting increase in available acetylcholine is
responsible for both the therapeutic effects of this agent as well as its most common side effects. Health
care providers are familiar with the gastrointestinal effects of donepezil. However, relatively little is
written about its cardiovascular toxicity. This report describes an episode of complete heart block associ-ated
with an accidental overdose of donepezil.

Case Report

An 85-year-old woman had experienced a 5-year
history of gradual cognitive decline. Family members had reported periodic cooking accidents as well as
episodes of delirium accompanying urinary tract infection and surgical procedures. The patient would
occasionally drive for short trips and had not gotten any tickets or been in any traffic accidents recently.
She was evaluated by a neurologist who prescribed paroxitine 20 mg per day. She discontinued this
because it caused drowsiness. Subsequently, she took rivastigmine, which made her feel \"unwell.\" Neither
she nor her daughter could recall the dose. The patient had supervision 24 hours per day, as she was
unable to manage food preparation or her medica-tions.

Her past medical history was significant for colon cancer and osteoporosis. She had no history of
cardiovascular disease although she was hypertensive on occasion in the past. Her medications included
raloxifene 60 mg per day and donepezil 5 mg per day. On physical examination, her blood pressure was
elevated to 160/ 80 mm Hg. She scored 19/ 30 on the Mini-Mental Status Examination. The remainder of
her neurological examination was without deficit. Magnetic resonance imaging of her brain revealed
generalized atrophy. Laboratory evaluation including thyroid function, syphilis serology, and vitamin B 12
was unrevealing. An electrocardiogram (ECG) btained 8 months earlier showed normal sinus rhythm
without evidence of conduction abnormality.

She was given the diagnosis of probable AD and the donepezil dose was increased to 10 mg per day. For
two days, she experienced some nausea with this dose increase. On the third day, she inadvertently took 20
mg of donepezil.

A few hours later, she developed severe nausea and vomiting during a car trip. Shortly thereafter, she lost
consciousness. In a nearby emergency department, an ECG revealed complete heart block. A cardiologist
urgently placed a pacemaker and the patient has had no recurrence of the loss of consciousness. Her heart
block resolved spontaneously. She continues to take donepezil 10 mg per day without significant side
effect.

Discussion

Increasing age is the most important risk factor for the
development of AD. As the population matures, primary care practitioners will be seeing an increasing
number of patients with this disorder. Further, these practitioners will become more responsible for the
diagnosis and management of this condition.

At present, the initial diagnosis relies upon a detailed history and physical examination followed by
directed laboratory and anatomic imaging studies. Further evaluation with neuropsychological testing or
functional imaging can be helpful in some cases.

Pharmacologic treatment consists of vitamin E supplementation, acetylcholinesterase inhibitors
(AChEI), N-methyl-D-aspartate receptor antagonists, and herbal supplements. There are data to support the
use of each of these treatments. 1-4 In the United States, physicians have the most clinical experience
with the AChEIs as they were the initial class of agents to receive Food and Drug Administration
(FDA) approval for treatment of AD.

Donepezil is the only drug in its class with a half-life that permits once daily dosing. It is the second AChEI
to receive FDA approval for treatment of mild to moderate AD. By inhibiting the breakdown of acetyl-choline
in the neural synapses, it increases cholinergic activity. This mechanism of action enables donepezil
to improve mood, memory, behavior, and global functioning. 2,5 The increase in acetylcholine also causes the most common side effects: nausea, vomiting, and
diarrhea. Donepezil may also potentiate vagal tone in the sinoatrial node or the atrioventricular node.
Significant bradycardia requiring intravenous atropine has been described following inadvertent
ingestion of 50 mg of donepezil. 6 There are addi-tional reports of syncope and bradycardia with the use
of donepezil. 7,8

Acetylcholinesterase inhibitors should be used with some degree of caution in elderly patients due to their
potential cardiovascular affects. In patients with known conduction system disease, more caution may
be warranted.

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