Cholinesterase Inhibitors





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Cholinesterase Inhibitors





















Mechanism of action and cognitive benefit


  • Cholinesterase inhibitors increase the concentration of acetylcholine at the synapse and improve memory, attention, mood, and behavior.



  • Cholinesterase inhibitors are efficacious and well tolerated.

Indications and recommendations


  • For Alzheimer’s disease dementia in mild, moderate, and severe stages, we recommend using one of the following once-a-day cholinesterase inhibitor formulations:




    • Donepezil (generic & Aricept) pill or oral dissolving tablet



    • Galantamine (generic) extended-release (ER) pill



    • Rivastigmine (Exelon) patch.


Common side effects


  • Some common and important side effects are (listed in approximate order of prevalence):




    • Gastrointestinal: loss of appetite, nausea, vomiting, loose stools



    • Vivid dreams at night



    • Dehydration



    • Rash



    • Bradycardia



    • Peptic ulcer disease



    • Seizures



    • Other: weight loss, rhinorrhea, salivation, muscle cramps, fasciculations.




  • Cholinesterase inhibitors should not be used with some conditions and medications (see text).



  • To evaluate for risk of heart block we recommend obtaining an ECG in all patients started on cholinesterase inhibitors.

Judging efficacy


  • It is important to set appropriate expectations as to the magnitude of the average improvement observed with cholinesterase inhibitors:




    • Most patients improve equivalent to “turning the clock back” 6–12 months.




  • To determine whether the cholinesterase inhibitor is working, ask the patient, ask the family, and evaluate the patient’s cognition and function 2–3 months after starting the medication.

Off-label uses


  • We also recommend a trial of cholinesterase inhibitors in the following disorders:




    • Mild cognitive impairment due to Alzheimer’s disease



    • Dementia with Lewy bodies (Parkinson’s disease dementia) (FDA approved for the rivastigmine [Exelon] patch, off-label for other cholinesterase inhibitors)



    • Vascular dementia.






Cholinesterase Inhibitors in Alzheimer’s Disease


There are currently four cholinesterase inhibitors approved by the US Food and Drug Adminis­tration (FDA) for the treatment of Alzheimer’s disease dementia ( Table 16-1 ): tacrine (Cognex, no longer marketed), donepezil (generic and Aricept), rivastigmine (Exelon), and galantamine (generic, formerly marketed as Razadyne and Reminyl). These drugs all work in essentially the same way: they bind to and reversibly inhibit acetylcholinesterase, the enzyme responsible for metabolizing acetylcholine in the synapse ( Fig. 16-1 ). By doing this they increase the level of acetylcholine in the synapse. By increasing the level of acetylcholine in the synapse, the cholinesterase inhibitors are hypothesized to improve cognition. Although no one understands exactly how that happens, one hypothesis is as follows. In most regions of the brain, any individual neuron will receive input from tens or hundreds of other neurons. Because in Alzheimer’s disease neurons—particularly cholinergic neurons—are dying, there are fewer cholinergic neurons from which to receive input. The idea is that if the acetylcholine from the remaining cholinergic neurons can bind to the synaptic receptor more times before the acetylcholine is broken down, these remaining neurons will be able to compensate for those neurons which are damaged or dead. There are two basic decisions that a clinician must make regarding the cholinesterase inhibitors:



  • 1.

    Should I prescribe a cholinesterase inhibitor for my patient with Alzheimer’s disease or other dementia?


  • 2.

    If so, which one should I prescribe?



TABLE 16-1

FDA-Approved Medications for the Treatment of Alzheimer’s Disease (AD)












































































Drug Mechanism of Action Half-Life Metabolism/Elimination Dosing (Therapeutic Doses in Italics) Common Side Effects Comment FDA Approved Demonstrated Efficacy
Donepezil ( generic & Aricept ) Inhibits acetylcholinesterase 70–80 h liver; CYP450; 2D6; 3A4/urine and feces Once daily



  • 5 mg QD 4 weeks



  • 10 mg QD 3 months



  • 23 mg QD (for moderate to severe patients; see text prior to prescribing)

Nausea, vomiting, anorexia, diarrhea Generally well tolerated. Also comes in same strength oral dissolving tablet Alzheimer’s disease. 5 mg QD: mild to moderate; 10 mg QD: mild, moderate, and severe; 23 mg QD: moderate to severe Cognition (memory, attention), mood, behavior
Rivastigmine ( Exelon ) capsule Inhibits acetylcholinesterase (also inhibits butylcholinesterase) 2 h plasma; CYP450/urine 97%, feces 0.4% Twice daily



  • 1.5 mg BID 4 weeks



  • 3 mg BID 4 weeks



  • 4.5–6 mg BID

Nausea, vomiting, anorexia, diarrhea; side effects more frequent than with others Side effects less if taken with food and titrated slowly Mild, moderate Alzheimer’s disease Cognition (memory, attention) mood, behavior
Rivastigmine ( Exelon ) patch Inhibits acetylcholinesterase (also inhibits butylcholinesterase) 2 h but in continuous release patch plasma; CYP450/urine 97%, feces 0.4% Once daily



  • 4.6 mg/24 h QD patch 4 weeks



  • 9.5 mg/24 h QD patch



  • 13.3 mg/24 h QD patch

Nausea, vomiting, anorexia, diarrhea; these side effects equal to or less than others; also rash/skin irritation Well tolerated. Patch should be removed slowly and carefully to reduce skin irritation Mild, moderate, and severe Alzheimer’s disease and mild, moderate Parkinson’s disease dementia Cognition (memory, attention) mood, behavior
Galantamine (generic, formerly Razadyne and Reminyl) Inhibits acetylcholinesterase (also has allosteric nicotinic modulation) 5–7 h liver partially; CYP450; 2D6; 3A4/urine 95%, feces 5% Twice daily



  • 4 mg BID 4 wks



  • 8 mg BID 4 wks



  • 12 mg BID

Nausea, vomiting, anorexia, diarrhea; 12 mg dose side effects more frequent 12 mg dose highly efficacious; side effects less if taken with food Mild, moderate Alzheimer’s disease Cognition (memory, attention) mood, behavior
Galantamine (extended release) (generic, formerly Razadyne and Reminyl) Inhibits acetylcholinesterase (also has allosteric nicotinic modulation) 5–7 h, released immediately and 12 hours later (metabolism/elimination as galantamine) Once daily



  • 8 mg QD 4 wks



  • 16 mg QD 4 wks



  • 24 mg QD

Nausea, vomiting, anorexia, diarrhea 24 mg dose side effects more frequent 24 mg dose highly efficacious; side effects less if taken with food Mild, moderate Alzheimer’s disease Cognition (memory, attention) mood, behavior
Memantine ( generic ) Glutamate antagonist (also dopamine agonist) 60–80 h liver minimally; CYP450/urine Twice daily



  • 5 mg QAM 1 wk



  • 5 mg BID 1 wk



  • 10 mg QAM, 5 mg QPM 1 wk



  • 10 mg BID

Confusion, drowsiness Can be taken with acetylcholinesterase inhibitors Moderate, severe Alzheimer’s disease Cognition (attention, alertness) mood, behavior
Memantine XR ( Namenda XR ) Glutamate antagonist (also dopamine agonist) 60–80 h liver minimally; CYP450/urine Once daily



  • 7 mg QAM 1 wk



  • 14 mg QAM 1 wk



  • 21 mg QAM 1 wk



  • 28 mg QAM

Confusion, drowsiness Can be taken with acetylcholinesterase inhibitors. Capsule can be opened and sprinkled on food. Moderate, severe Alzheimer’s disease Cognition (attention, alertness) mood, behavior







FIGURE 16-1


Cholinesterase inhibitor mechanism of action.

(A) Normal cholinergic synapse with muscarinic receptor (M). Note the large number of acetylcholine (ACh) molecules. Acetylcholinesterase (AChE) breaks down acetylcholine into choline and acetic acid. (B) Cholinergic synapse in Alzheimer’s disease (AD). Because the neurons that produce acetylcholine in the nucleus basalis of Mynert are being damaged and destroyed by Alzheimer’s disease pathology, there are many fewer molecules of acetylcholine available. (C) The cholinesterase inhibitors tacrine, donepezil, rivastigmine, and galantamine reversibly inhibit acetylcholinesterase such that more molecules of acetylcholine are available in the synapse.




Should I Prescribe a Cholinesterase Inhibitor?


As with any medication, the decision to prescribe or not to prescribe is made on an individual basis for each patient and is based on a risk/benefit analysis. Let us consider the pros and cons of this class of medication.


Cholinesterase Inhibitors Are Well Tolerated


In our experience, supported by published clinical trials, cholinesterase inhibitors are tolerated by more than 90% of patients. The most common side effects, occurring in about 10% of patients, are gastrointestinal in nature including loss of appetite, upset stomach, mild nausea, and loose stools. These side effects are due to muscarinic cholinergic receptors in the gut. In the majority of cases, these gastrointestinal side effects subside in a few days and are not of any notable distress to the patients. In a small percentage of cases, the gastrointestinal side effects are more serious and include nausea and vomiting or loose stools. In these cases the patient should either stop taking the medication or reduce the dose. The gastrointestinal side effects will then fully resolve within a few days. It is next worth trying at least one other cholinesterase inhibitor, as some patients experience more side effects with one medication than with another. Lastly it is worth trying the rivastigmine (Exelon) patch, as some patients who cannot tolerate oral cholinesterase inhibitors do fine on the 4.6 or 9.5 mg/24 hour dose of the patch. Some clinicians may try to manage these side effects with antiemetic agents, but we have not found this to be a particularly helpful strategy ( Table 16-2 ). In general, we suggest that patients take the medication in the evening so that, if they experience mild gastrointestinal side effects during the peak concentrations (these generally occur within 2–6 hours after taking cholinesterase inhibitors), they can sleep through them.



Table 16-2

Selected Side Effects of Cholinesterase Inhibitors and Possible Management Techniques























































Side Effect Possible Management Technique
Loss of appetite Take at night or reduce dose
Nausea Take at night or reduce dose
Vomiting Reduce dose
Diarrhea/loose stools Can try over-the-counter Imodium A-D or the like, once or twice a week to reduce bowel movements to 1 or 2 per day. Or reduce dose
Vivid dreams Take in the morning or reduce dose
Dizziness Depends upon the cause; investigate swiftly whether this could be a sign of bradycardia (slowing of the heart rate)
Dehydration Determine cause, increase hydration, and/or reduce dose
Insomnia Take in the morning or reduce dose
Headache Reduce dose
Rhinorrhea (runny nose) Reduce dose
Salivation Reduce dose
Muscle cramps Increase water intake, increase electrolyte intake including eating bananas (for potassium) and taking over-the-counter magnesium oxide, or reduce dose
Fasciculations Reduce dose
Rash Discontinue immediately. Can later try another cholinesterase inhibitor
Bradycardia (slowing of the heart rate) Discontinue immediately, and immediately initiate an inpatient cardiac evaluation including continuous cardiac monitor
Seizure If single brief seizure, reduce dose and initiate seizure evaluation. If multiple or prolonged, discontinue immediately and initiate seizure evaluation

Note: This table contains some of the common and/or serious side effects that our patients have experienced and some strategies that we have found to be successful in dealing with these side effects. It is not meant to be an exhaustive list nor a substitute for clinical judgment. When in doubt regarding a serious side effect, discontinue the cholinesterase inhibitor and fully evaluate the patient.

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Sep 9, 2018 | Posted by in NEUROLOGY | Comments Off on Cholinesterase Inhibitors
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