Donepezil: Anesthetic Considerations

Introduction

• Donepezil (Aricept®) is a reversible acetylcholinesterase inhibitor.
• Donepezil is indicated for mild to severe Alzheimer’s disease symptoms due to the loss of central cholinergic processes.
• Donepezil was developed by Eisai Co. in the 1980s and released in the United States in 1997 after FDA approval in 1996.
  • Phase I and Phase II clinical trials showed donepezil’s safety in patients with renal or hepatic impairment and demonstrated its long half-life.¹
  • Phase III trials were double-blind and showed significant improvements in cognition and function in mild to moderately severe Alzheimer’s patients when treated with 5 or 10 mg/day of donepezil compared to placebo.¹
  • Adverse effects in phase II and III trials were mild and mainly cholinergic responses that quickly resided.¹

Chemistry

• Donepezil is a highly lipophilic piperidone-based compound, a structural property that enables rapid crossing of the blood-brain barrier and selective action on central cholinergic pathways while still producing peripheral muscarinic effects.
• Donepezil is rapidly absorbed, reaches peak levels within 3-4 hours, and exhibits 96% plasma protein binding, contributing to stable plasma levels and slow elimination.¹
• Donepezil has a half-life of approximately 70 hours: therefore, even if withheld the day before surgery, significant pharmacologic activity persists throughout the perioperative period.
• Donepezil is metabolized via CYP2D6, CYP3A4, and glucuronidation.²
• Donepezil is excreted through the kidneys and feces (15%-20%).¹
• Donepezil-mediated improvement of cognitive function in Alzheimer’s patients is associated with spontaneous brain activity in the right gyrus rectus, right precentral gyrus, and left superior temporal gyrus, as assessed using the regional homogeneity method in a resting-state functional magnetic resonance imaging study.³
• Additionally, significantly decreased Alzheimer’s Disease Assessment Scale-Cognitive Subscale and increased Mini-Mental State Examination scores are seen in Alzheimer’s patients taking donepezil.
• Because of its extended half-life and persistent cholinergic stimulation, donepezil meaningfully interacts with anesthetic agents, affecting autonomic tone, secretions, airway reactivity, heart rate, and neuromuscular transmission, making it highly relevant to anesthesiology.
• It is metabolized to two pharmacologically active metabolites and two inactive metabolites.¹

Pharmacodynamics

• Donepezil increases synaptic acetylcholine levels by reversibly inhibiting acetylcholinesterase, enhancing cholinergic neurotransmission in regions critical for learning, memory, and executive functioning, particularly within the hippocampus, cerebral cortex, and basal forebrain.
• The medication does not reverse neuronal loss or restore memories that have already been lost; instead, it maximizes function in surviving cholinergic neurons and slows the progressive decline characteristic of Alzheimer’s disease.
• Patients often exhibit improved attention, orientation, language skills, and activities of daily living, along with improved behavioral symptoms such as apathy, irritability, and disorientation.
• Off-label uses of donepezil include treatment for Lewy body dementia, vascular cognitive impairment, traumatic injury-associated cognitive deficits, and Parkinson’s dementia.⁴
• Donepezil enhances cholinergic neurotransmission primarily in the basal forebrain cholinergic system, specifically the nucleus basalis of Meynert, which is responsible for widespread cortical cholinergic projections involved in attention, learning, and memory
• Donepezil increases acetylcholine levels in the hippocampus, particularly in the CA1 pyramidal layer, in mouse models, a region that plays a central role in memory encoding, consolidation, and spatial orientation.⁵
• Oral donepezil for mild to moderate Alzheimer’s in adults should not exceed 10mg/ day, usually starting at 5mg taken at bedtime.
• Oral donepezil for moderate to severe Alzheimer’s in adults should not exceed 23mg/ day, usually starting at 10mg taken at bedtime.
• Transdermal donepezil is applied once weekly for mild, moderate, and severe Alzheimer’s, available in 5mg/day and 10mg/day strengths.

Physiological Effects

Cardiovascular System

• Donepezil reliably increases parasympathetic vagal tone, leading to bradycardia that may range from mild to profound, particularly in elderly patients or those with intrinsic conduction abnormalities.
• It increases the risk of atrioventricular block due to slowed nodal conduction, which can pose significant challenges during anesthesia when additional vagotonic agents are present.²
• Syncope can occur because donepezil can augment cardioinhibitory reflexes or exacerbate orthostatic hypotension.

Pulmonary System

• Donepezil increases bronchial secretions and enhances airway reactivity through muscarinic receptor stimulation, increasing the risk of bronchospasm during induction or emergence.
• These effects have direct anesthetic implications, especially during Stage II of anesthesia when airway reflexes are heightened.

Gastrointestinal System

• Enhanced muscarinic signaling leads to increased gastric acid secretion and accelerated intestinal motility, which may result in cramping, diarrhea, or nausea
• Increased gastrointestinal activity elevates the risk of perioperative reflux and aspiration, especially in older adults with impaired protective reflexes.

Central Nervous System

• Donepezil may cause dizziness, confusion, agitation, insomnia, and vivid dreams.

Genitourinary System

• Cholinergic stimulation of the detrusor muscle promotes urinary frequency, urgency, or incontinence, which may complicate perioperative bladder management.

Endocrine/Autonomic

• Increased sweating and flushing occur due to parasympathetic activation, which may alter patient comfort or temperature regulation.

Ocular and Musculoskeletal

• Miosis and blurred vision result from ciliary muscle contraction, while muscle cramps or fasciculations occur due to nicotinic receptor involvement at the neuromuscular junction.
• Donepezil decreases intraocular pressure. Glaucoma patients need to be cautious.

Effects on the Stages of Anesthesia

General Patient Considerations

• Most patients taking donepezil are 65 years or older, a population with decreased physiologic reserve and increased sensitivity to anesthetic-induced hemodynamic changes, airway compromise, and postoperative cognitive dysfunction.
• Withdrawal recommendations are inconsistent because withholding donepezil for its 70-hour half-life would require 2-3 weeks, during which cognitive decline or behavioral worsening may occur.⁶

Premedication

• Patients may require higher doses of antimuscarinic agents to offset increased secretions and vagal tone, though the effects are often incomplete due to persistent cholinesterase inhibition
• Elevated airway secretions increase the difficulty of inhalation induction and raise the risk of laryngospasm or bronchospasm.
• Behavioral symptoms, such as agitation or confusion, may alter sensitivity to benzodiazepines or other sedative premedications.

Cholinomimetic Interactions

• Smoking has minimal influence on donepezil metabolism, but nicotine withdrawal may destabilize autonomic tone.
• Concurrent use of other cholinergic agents may increase the risk of bradycardia or diarrhea.

Potential Effects on Spinal Anesthesia and Pain

• Spinal analgesia: Donepezil can exert analgesic effects by acting on muscarinic receptors in the spinal cord, which may be beneficial for pain management.
• Neuropathic pain: It has shown promise in preclinical models for treating neuropathic pain by increasing acetylcholine, which can lead to gamma-aminobutyric acid release in the spinal cord.
• An earlier study showed the potential of donepezil in pain management, including reducing hypersensitivity after nerve injury.⁷

Drug Interactions

Induction Agents

• Propofol may potentiate bradycardia due to its own vagotonic properties, requiring readiness to treat severe bradycardia.
• Etomidate is highly protein-bound, raising theoretical competition with donepezil but generally without significant clinical impact.
• Dexmedetomidine has strong sympatholytic and parasympathetic activity, producing a synergistic bradycardia that can be dangerous in combination with donepezil.
• Ketamine provides sympathetic stimulation that may offset donepezil-related bradycardia and be a beneficial induction agent in some patients.

Neuromuscular Blockers

• Succinylcholine is known to cause prolonged neuromuscular blockade when combined with donepezil.¹

Nondepolarizing Neuromuscular Blockers

• Rocuronium can lead to reduced sensitivity and a shorter paralysis duration, requiring larger doses, more frequent redosing, or adjustments to continuous infusion.
• Cisatracurium can require higher doses to achieve adequate paralysis despite its Hofmann elimination and predictable kinetics.

Other Important Interactions

• Metoprolol is a selective β1-blocker. Donepezil, when combined with metoprolol, has been shown to increase myocardial salvage via anti-inflammatory mechanisms in rat models.⁸

Reversal and Pain Management

Reversal Agents

• Neostigmine is an acetylcholinesterase inhibitor that augments donepezil’s cholinergic effects and may precipitate severe bradycardia, bronchospasm, increased secretions, or cholinergic crisis-like symptoms.
• Sugammadex is preferable when using rocuronium or vecuronium because it bypasses cholinergic pathways entirely, avoiding the risk of compounding muscarinic side effects.
• Recovery from neuromuscular blockade can be highly unpredictable.

Pain Management

• Nonopioids
  • Acetaminophen is safe and unaffected by donepezil.
  • NSAIDs may produce increased gastrointestinal symptoms due to the donepezil-related cholinergic motility increase.
  • Tramadol metabolism (CYP2D6) may be unpredictable in the elderly and should be used cautiously.
• Opiates
  • Donepezil is valuable in treating opioid induced sedation increasing acetylcholine, and thus, cortical arousal, but could pose long-term safety concerns such as bradycardia, syncope, sleep disruption, and vivid dreams.⁹
• Antiemetics
  • Dexamethasone can reduce donepezil levels by increasing its elimination rate, as it is a CYP2D6 and CYP3A4 inducer.²
  • Ondansetron is a 5-HT3 receptor antagonist. In combination with donepezil, there may be beneficial symptomatic treatment of cognitive deficits in Alzheimer’s disease.¹⁰

Other Drug Interactions

Anticholinergics

• Anticholinergics counteract donepezil’s mechanism and increase the risk of delirium and autonomic instability, making cognitive and hemodynamic responses more unpredictable
• Donepezil’s central effects can be blunted when combined with anticholinergics.
• Patients taking donepezil often receive anticholinergics for an overactive bladder.

Beta-Blockers

• Beta-blockers amplify vagotonic effects of donepezil, significantly increasing the likelihood of severe bradycardia and conduction block.
• Donepezil can increase the risk of severe bradycardia, heart block, and syncope when taken with Beta-blockers.
• Patients taking donepezil often receive Beta-blockers for coronary artery disease.

General Anesthetic Agents

• Potentiation of donepezil’s effects:
  • General anesthetic agents can intensify the cardiovascular and airway effects of donepezil. This combination may increase the unpredictability of neuromuscular blockade, complicating anesthetic management.
  • Interaction with neuromuscular blockers:
  • Donepezil may cause resistance to non-depolarizing neuromuscular blockers, prolong the effects of succinylcholine, and increase airway secretions when combined with general anesthetics. These effects heighten the risk of bronchospasm and lead to unpredictable depth of paralysis during anesthesia.
• Perioperative vulnerabilities:
  • Patients taking donepezil who undergo general anesthesia are at increased risk for hemodynamic instability and postoperative cognitive dysfunction.
  • Effect of memantine co-therapy:
    • Memantine, an N-methyl-D-aspartate receptor antagonist often used alongside donepezil to reduce excitotoxicity, does not exacerbate the bradycardia or increased secretions caused by donepezil.

Antiarrhythmics

• Antiarrhythmics depress conduction and prolong the QT interval, raising the danger of bradyarrhythmia and torsades de pointes.¹
• Donepezil, with antiarrhythmics, can cause increased bradycardia and conduction delay.
• Patients taking donepezil and antiarrhythmics usually suffer from supraventricular tachycardias such as atrial fibrillation.

Antipsychotics

• Antipsychotics block dopamine and serotonin receptors, which can cause sedation and extrapyramidal symptoms. Centrally, they can modulate agitation, hallucination, and delusion.
• Donepezil’s effects can be lessened due to the anticholinergic effects of antipsychotics.
• Patients taking donepezil and antipsychotics most often suffer from behavioral and psychological symptoms of dementia.