Rivastigmine (Exelon)

• All three acetylcholinesterase inhibitors have demonstrated efficacy for:
  • Mild to severe Alzheimer's Disease (AD), and Alzheimer's Disease (AD) with cerebrovascular disease.
    • Therefore most patients with AD should have a trial of an acetylcholinesterase inhibitor. There are small improvements in cognitive, functional, behavioural, and global measures.^[1]
• Donepezil and rivastigmine have particular evidence in Parkinsons's Disease Dementia (PDD) and Dementia with Lewy bodies
• There is an number needed to treat (NNT) = 12 for improved global impression, and an NNT = 7 for stabilization. There is a NNH = 12 for common adverse events (e.g., nausea, diarrhea, vomiting).

• Acetylcholinesterase inhibitors, including donepezil, rivastigmine, and galantamine all inhibit acetylcholinesterase and block the breakdown of acetylcholine.
• The break down of acetylcholine is prevented by the drug binding and reversibly inactivating cholinesterases.
  • This inhibits the hydrolysis of acetylcholine.
• As a result, acetylcholine levels increase in the brain, which may optimize function of remaining intact cholinergic neurons.
  • Acetylcholine deficits is a postulated mechanism of Alzheimer's dementia.
• This is thought to improve memory, cognitive function, and behaviours.
  • However, treatment does not alter the underlying course of the disease.
• The increase in acetylcholine also occurs in other organ systems innervated by cholinergic neurons, and leads to the side effects in this medication class as well.

• A baseline ECG (to rule out any conduction abnormalities such as heart block or QTc prolongation), heart rate (to detect bradycardia), weight, and blood pressure should be obtained prior to starting an acetylcholinesterase inhibitor.
  • If an individual already has a pacemaker implant, then this risk is mitigated.^[3]

• Weight loss
  • Lower-weight patients should be closely monitored for vomiting, diarrhea, and loss of appetite. This applies to especially frail, elderly women, who tend to be more frequently affected
• Upcoming surgeries
  • Acetylcholinesterase inhibitors can interact with muscle-relaxing anesthesias such as succinylcholine
• Anti-arrhythmic medications
  • Donepezil may increase the risk of bradycardia with concurrent use of beta-blockers such as carvedilol, metoprolol, atenolol, or propranolol
• History of gastric ulcers or regular NSAID (aspirin, ibuprofen, and naproxen)
  • Should be monitored for signs and symptoms of ulcers and gastrointestinal bleeding
• Alcohol or alcohol use disorder
  • Significant alcohol use can induce depressant effects, reduce the efficacy, and intensify the side effects of acetylcholinesterase inhibitors
• Anticholinergic medications
  • Cholinesterase inhibitors increase the amount of acetylcholine, while anticholinergics block acetylcholine and stop it from working! Thus, it is not advisable to use anticholinergics in a patient who is on cholinesterase inhibitors.^[4]
• Unexplained syncope

• Bradycardia (<50bpm), left bundle branch block (LBBB), AV block
• Sick sinus syndrome
• Severe asthma and COPD
  • Acetylcholine is the key neurotransmitter involved in autonomic regulation of the airways, and is responsible for bronchoconstriction, mucus secretion, and inflammation in diseases like asthma and COPD.
    • Inhaled anticholinergics (e.g. - ipratropium) are thus frequently used as bronchodilators in the management of asthma/COPD (i.e. - reducing acetylcholine activity reduces bronchoconstriction and inflammation).
  • Thus, those with a history of severe COPD also taking acetylcholinesterase inhibitors are at risk for worsening respiratory symptoms and exacerbation caused by the excess acetylcholine in the lungs.^[5]
  • Overall, the risk remains relatively low, and it is not contraindicated in mild to moderate COPD.^[6]
• Severe hepatic or renal failure
• Obstructive urinary disease
• Seizures

The most common side effects of cholinesterase inhibitors are procholinergic (opposite of anticholinergic) include:

• At lower doses: GI side effects (nausea, diarrhea, vomiting), weight loss, decreased appetite, insomnia, fatigue, muscle cramps, myalgia
  • These side effects will usually resolve on its own, starting low and going slow with dosing may help
• Can cause dizziness, drowsiness, or syncope, especially during initiation of therapy
• Discontinue if bradycardia develops or there is a significant conduction abnormality (i.e. - more than a first degree heart block)
• At higher doses: side effects include headaches, dizziness, drowsiness, blurred vision, urinary frequency and incontinence
• Can aggravate asthma and other breathing problems, and increase risk of seizures (decrease seizure threshold)
• Night-time administration of donepezil can cause night-time disturbances, including insomnia, nightmares, and vivid dreams.^[7]
  • Thus, daytime administration may be warranted if patients are experiencing night-time disturbances.^[8]

• Anticholinergic drugs (e.g. - atropine, benztropine) may be less effective when combined with an acetylcholinesterase inhibitor. The cholinergic action of acetylcholinesterase inhibitors (an agonist) opposes the anticholinergic action (antagonists) of these medications. Anticholinergic drugs can also decrease the cholinergic action of acetylcholinesterase inhibitor, reducing its efficacy.
• Beta-blockers (e.g. - propranolol, atenolol, timolol) combined with acetylcholinesterase inhibitors can increase the risk of bradycardia, heart block, and syncope.