Cholinesterase Inhibitors

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 the result of 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 h 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 19.2 ). 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.

A second common side effect is vivid dreams. These dreams are not nightmares; they are the dreams the patient normally has, just more vivid. These are brought about by the role of brainstem cholinergic systems in producing rapid-eye movement (REM) sleep (dream sleep). Vivid dreams are generally characterized by our patients as being extremely realistic and lifelike. In some instances, patients find these disturbing; in other cases, they are neutral about them; and occasionally, they even find them enjoyable. In cases where patients find these unpleasant, vivid dreams can usually be minimized or eliminated by moving the dosing of the medication to earlier in the day. This will cause the peak concentration of the medication to be during waking hours and the troughs at night.

Other less common side effects reported in the clinical trials of cholinesterase inhibitors are dizziness, insomnia, and headache. Other side effects of note in our clinical experience (and also reported in controlled studies) are rhinorrhea (runny nose), increased salivation, muscle cramping, fasciculations, rash, and rarely seizures or a slowing of the heart rate (one of our patients developed syncope and ultimately required a pacemaker). Because of this latter symptom of bradycardia that could be related to heart block, we recommend obtaining an electrocardiogram (ECG) on all patients prescribed cholinesterase inhibitors after they have been on the highest dose of the drug for several weeks, in addition to cautioning patients about the signs and symptoms of bradycardia. We recommend caution in prescribing cholinesterase inhibitors when patients have any of the conditions in Box 19.1 . Cholinesterase inhibitors may interact with many other medications. Although in our experience few of these interactions are clinically important, it is important to be aware of them. The most important interactions are related to the characteristics found in Box 19.2 . Please consult an up-to-date reference, website, or application when evaluating potential drug interactions in your patient.

Cholinesterase Inhibitors Are Efficacious

Comprehensive reviews of the efficacy of cholinesterase inhibitors generally conclude that the drugs have modest benefits in some, but not all, patients. For example, one comprehensive review carried out by the Cochrane Database of Systematic Reviews ( ) concluded that, in patients with mild, moderate, or severe dementia due to Alzheimer’s disease, those treated with cholinesterase inhibitors showed benefit in cognitive function, activities of daily living, and clinician-rated global clinical state. Additionally, clinicians who were blinded to the results of these objective cognitive tests judged patients on cholinesterase inhibitors to be doing better than patients on placebo.

This conclusion is certainly consistent with our clinical experience using these drugs in thousands of patients. We have found that in most, but not all, of our patients there is benefit in terms of both cognitive function and daily activities. When we talk to the caregivers, their most common description of the patient taking these medications is that not only do these medications improve memory but also that the patient is “more with it.” By this description they mean that the patient is more engaged in family activities, more likely to participate in day-to-day activities in the home such as setting the table or walking the dog, and more likely to engage in conversation in social situations. How much improvement should we and caregivers expect to see? Both studies (for review see ) and our experience suggest that for the majority of patients the response to cholinesterase inhibitors is equivalent to “turning back the clock” on their disease by 6 to 12 months. In other words, we expect that their memory and general level of functioning will return to where they were 6 to 12 months ago (see Fig. 18.1 ). For these reasons as well as the data from well-done research studies, we generally recommend a trial on one of these drugs to our patients with Alzheimer’s disease.

Thus it is clear from the preceding discussion that cholinesterase inhibitors are safe and effective in the majority of patients. But how do we know if a cholinesterase inhibitor is working in an individual patient?

Measuring Cognition

As discussed in Chapter 2 and in Appendix A , there are numerous brief measures of cognition that can be used to assess the efficacy of cholinesterase inhibitors. Probably the two that are most commonly used are the Mini-Mental State Examination (MMSE) ( ) and the Montreal Cognitive Assessment (MoCA) ( www.mocatest.org ) test. Each of these can be administered in about 10 minutes by office staff. In general, after successful treatment with cholinesterase inhibitors patients tend to improve two or three points on the MMSE and the MoCA.