What are the potential side effects of Donepezil (a cholinesterase inhibitor) in an elderly patient with Alzheimer's disease and potential co-morbidities, including cardiovascular disease?

Donepezil Side Effects

Donepezil causes primarily mild, transient gastrointestinal side effects (nausea, vomiting, diarrhea) and cardiovascular effects (bradycardia, heart block), with the 23 mg dose producing markedly higher rates of nausea (11.8%), vomiting (9.2%), and weight loss compared to lower doses. 1

Gastrointestinal Side Effects

Most Common Adverse Effects:

• Nausea, vomiting, and diarrhea are predictable consequences of donepezil's cholinergic mechanism 2, 1
• These effects are dose-dependent: more frequent with 10 mg/day than 5 mg/day, and substantially more frequent with 23 mg/day 1
• At 23 mg/day: nausea occurs in 11.8% (vs. 3.4% at 10 mg), vomiting in 9.2% (vs. 2.5% at 10 mg) 1
• Discontinuation due to vomiting: 2.9% at 23 mg vs. 0.4% at 10 mg 1
• Taking donepezil with food significantly reduces these gastrointestinal effects 2, 3
• Most gastrointestinal symptoms are transient, lasting 1-3 weeks, and resolve with continued use 1

Peptic Ulcer and GI Bleeding Risk:

• Increased gastric acid secretion occurs due to enhanced cholinergic activity 1
• At 5-10 mg/day: no increase in peptic ulcer disease or GI bleeding compared to placebo 1
• At 23 mg/day: increased incidence of peptic ulcer disease (0.4% vs. 0.2%) and GI bleeding (1.1% vs. 0.6%) 1
• Monitor closely in patients with ulcer history or concurrent NSAID use 1

Cardiovascular Side Effects

Bradycardia and Conduction Abnormalities:

• Donepezil produces vagotonic effects on sinoatrial and atrioventricular nodes due to its cholinesterase inhibitor mechanism 1
• Heart rate decreases significantly: from baseline 66 bpm to 62 bpm at 1,2, and 8 months of treatment (p=0.002) 4
• The 10 mg dose produces greater heart rate reduction than 5 mg at weeks 4,8, and 12 (p=0.041,0.026,0.008 respectively) 5
• PR interval increases significantly, particularly in patients not on other cardiac medications (155 ms to 163 ms at 8 months, p=0.02) 4
• Heart block and bradycardia can occur in patients both with and without underlying cardiac conduction abnormalities 1

Syncope:

• Syncopal episodes have been reported with donepezil use 1
• In hospitalized AD patients on donepezil who developed syncope, cardiovascular causes were identified in 69%: carotid sinus syndrome, complete AV block, sinus node dysfunction, severe orthostatic hypotension, and paroxysmal atrial fibrillation 6
• Importantly, cardiovascular evaluation should be performed before discontinuing donepezil in patients with unexplained syncope, as the syncope may be unrelated to the medication 6

Clinical Caveat for Cardiovascular Monitoring:

• Patients receiving donepezil should undergo regular cardiovascular monitoring, especially at higher doses 5
• The cardiovascular effects (decreased heart rate, increased PR interval) are most pronounced in patients NOT taking other negatively chronotropic or dromotropic drugs 4
• Patients already on beta-blockers, calcium channel blockers, or digoxin show less additional cardiovascular change from donepezil 4

Weight Loss

• Weight loss reported in 4.7% of patients on 23 mg/day vs. 2.5% on 10 mg/day 1
• Clinically significant weight loss (≥7% from baseline): 8.4% at 23 mg/day vs. 4.9% at 10 mg/day 1

Neuropsychiatric Effects

• Initial increase in agitation may occur in some patients but typically subsides after a few weeks 2
• Seizures are a theoretical risk with cholinomimetics, though seizures may also represent disease progression 1

Other Organ System Effects

Genitourinary:

• Bladder outflow obstruction is a theoretical risk but not observed in clinical trials 1

Pulmonary:

• Prescribe with caution in patients with asthma or obstructive pulmonary disease due to cholinomimetic effects 1

Hepatic:

• No hepatotoxicity occurs with donepezil, unlike tacrine 2, 7
• No clinically significant changes in liver function tests 8

Anesthesia Considerations

• Donepezil likely exaggerates succinylcholine-type muscle relaxation during anesthesia 1

Drug Interactions

• Conflicting evidence exists regarding interactions with cimetidine, theophylline, warfarin, and digoxin 2
• Despite 96% protein binding, donepezil has few clinically significant drug interactions 9

Dose-Specific Safety Profile

5 mg/day:

• Generally well-tolerated with mild, transient cholinergic side effects 8
• Can be given safely to patients with mild-to-moderate hepatic and renal disease 9

10 mg/day:

• Higher incidence of gastrointestinal effects and cardiovascular changes compared to 5 mg 1, 5
• Should only be administered after 4-6 weeks on 5 mg 1

23 mg/day:

• Markedly higher rates of nausea, vomiting, weight loss, peptic ulcer disease, and GI bleeding 1
• Should only be administered after at least 3 months on 10 mg 1
• The 23 mg tablet should not be split, crushed, or chewed 1