|Mechanism of action and cognitive benefit|
|Indications and recommendations|
|Common side effects|
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:
Should I prescribe a cholinesterase inhibitor for my patient with Alzheimer’s disease or other dementia?
If so, which one should I prescribe?
|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 ||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 ||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 ||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 ||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 ||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 ||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 ||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|
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.
|Side Effect||Possible Management Technique|
|Loss of appetite||Take at night or reduce dose|
|Nausea||Take at night or 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|
|Rhinorrhea (runny nose)||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|
|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|