Atypical Presentation of Acetylcholinesterase Inhibitor-Induced Diarrhea in Older Adults with Cognitive Decline: An Aspect not to be Underestimated

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Ann Geriatr Med Res. 2023;27(1):83-86
Publication date (electronic) : 2023 February 2
doi :
1Department of Geriatrics, Azienda Ospedaliera di Rilievo Nazionale Sant’Anna e San Sebastiano di Caserta, Caserta, Italy
2Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
3Department of Pharmacist, Azienda Ospedaliera dei Colli Cotugno, Napoli, Italy
4Department of Mental Health and Substance Dependence, ASL Caserta, Caserta, Italy
Corresponding Author Pagliuca Raffaele, MD Department of Geriatrics, Azienda Ospedaliera di Rilievo Nazionale Sant’Anna e San Sebastiano di Caserta, via Ferdinando Palasciano, 81100 Caserta, Italy E-mail:
Received 2022 October 13; Revised 2023 January 18; Accepted 2023 January 27.


The rivastigmine patch is the only existing transdermal delivery system used for the treatment of Alzheimer disease. Among the most common adverse events derived from its use are gastrointestinal events, particularly diarrhea. We report a clinical case of an 81-year-old patient admitted to our hospital under long-standing treatment with rivastigmine transdermal patch who presented with atypical watery diarrhea. Anamnesis showed that the patient presented with a likely infectious gastroenteric event, the diarrheal symptoms of which persisted upon resolution of the event and resolved only upon temporary discontinuation of acetylcholinesterase inhibitors. Failure to rapidly identify the causes of profuse diarrhea in older adults can have lethal consequences. When these symptoms occur, quickly recognizing the causes and providing proper management can be lifesaving.


The rivastigmine patch is the only existing transdermal delivery system used for the treatment of Alzheimer disease (AD). This drug has been reported to be effective for patients with difficulty using oral preparations owing to the risk of aspiration pneumonia.1) However, such treatment is not without side effects. Indeed, a greater number of adverse events, such as cardiovascular events, have been reported in patients treated with acetylcholinesterase inhibitors (AchE-I) compared to a placebo.2) Although many types of adverse events have been reported, nausea, vomiting, and diarrhea were significantly more frequent in those receiving AchE-I compared to those receiving placebo.3)

Rivastigmine causes adverse events that are generally expected to occur with AchE-Is. They are usually mild to moderate, short-lived, and respond to dose reduction. Unpublished data from 3,989 patients indicated that rivastigmine and placebo were associated with a similar incidence of serious adverse events and changes in laboratory parameters, electrocardiogram (ECG), and cardiorespiratory vital signs. The most common events affected the gastrointestinal, central, and peripheral nervous, and cardiovascular systems. However, compared to placebo, rivastigmine more frequently caused adverse events that resulted in treatment discontinuation. These events were more frequent in the gastrointestinal tract (particularly diarrhea) despite other body system and more common in women than men.4)

The impact of diarrhea can be more pronounced in older adults than in younger patients for several reasons, including structural and functional changes in the intestines related to age, concomitant diseases, polypharmacy, alterations of the senses of hunger and thirst, decreased nutritional intake and hydration, frequent hospital admissions, higher antibiotic administration, and subtler clinical presentation.5)

We report a peculiar clinical case of a patient undergoing long-standing treatment with a transdermal rivastigmine patch who was admitted to our hospital because of diarrhea.


An 81-year-old patient was admitted to our acute care geriatrics department from the Emergency Room (ER) with diarrhea of unspecified origin and electrolyte imbalance. In his past medical history, he reported dyslipidemia, bilateral carotid atheromasia under treatment with low-intensity statins, cognitive decline in chronic cerebral vasculopathy under treatment with rivastigmine (9.5 mg patch) and escitalopram (10 mg), hypertension under treatment with amlodipine and olmesartan medoxomil, bilateral presbycusis in a hearing aid wearer, and recent left purulent otitis media treated with tympanoplasty. The patient was vaccinated against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) using three shots of the vaccine. Rivastigmine was prescribed approximately 24 months before the geriatric outpatient visit, and the schedule of dose titration was a 9.5-mg patch renewed every 6 months.

Watery diarrhea presented approximately 20 days before hospitalization in association with relapsing-remittent fever (maximum temperature 37.5°C) and was treated with rifaximin (800 mg bid), loperamide, and metoclopramide.

Blood tests performed in the ER documented acute renal failure (serum creatinine 2.2 mg/dL), severe hypokalemia (2.1 mEq/L), mild reduction of cholinesterase (2,701 IU/L), and leukocytosis (12,980 mm3, 77% neutrophils). A nasopharyngeal swab tested negative for SARS-CoV-2. Plain abdominal radiography revealed hydroaeric levels in the right lumbar and iliac regions. Chest radiography revealed accentuation of the pulmonary pattern and other findings with no clinical significance. Full abdominal ultrasound showed no structural changes in the parenchymatous organs or fluid deposition in the explorable peritoneal recesses.

On admission, he presented with a fair clinical condition, alertness, and cooperation at examination despite his cognitive decline, lying in a neutral position. The vital parameters were within normal limits (temperature, 36.2°C; heart rate, 57 bpm; blood pressure, 100/60 mmHg; oxygen saturation, 99% on room air). Physical examination of the chest was unremarkable The abdomen was soft and non-tender, although with some signs of meteorism. The diarrhea was characterized by more than four abundant (>100 mL) episodes per day. The stools were liquid with a yellowish color but not smelly.

At drug review, current antibiotic therapy with rifaximin, probiotics, and anti-diarrheal agents was discontinued. Fecal cultures, blood cultures, antigenic (glutamate dehydrogenase [GDH]) and molecular (nucleic acid amplification tests [NAAT]) Clostridium difficile tests, and parasitological examination performed during hospitalization were negative. Electrolyte solutions were administered to compensate for diarrheal losses. Because of persistent diarrhea, a second drug review was performed, and the rivastigmine patch was suspended, which resulted in diarrhea remission. Oral protein supplements were administered because of hypoalbuminemia without evidence of exacerbation of the diarrheal symptoms. Following gastroenterologic consultation and due to altered fecal calprotectin levels, the patient underwent thyroid blood tests, which revealed normal results. Ileocolonoscopy showed only internal hemorrhoids, and multi-level biopsies (ileum, right colon, transverse colon, and left colon) reported non-specific mild chronic inflammation.

The patient was discharged with activation of Home Care services to continue the rehabilitation program. The rivastigmine patch was reintroduced at discharge, first at starting dose of 4.6 mg/day and then, after 7 days, the pre-hospital dosage of 9.5 mg/day was reinstated. At the follow-up outpatient visit performed after 30 days, the patient and caregiver reported clinical stability and regression of diarrheal symptoms. The prescribed dose of a 9.5 mg/day rivastigmine patch was confirmed.

Informed consent for the processing of clinical data was obtained from the patient in the presence of the caregiver, in accordance with the best medical practice and ethics.


The present clinical case report describes a peculiar case of adverse drug reactions that resolved successfully after discontinuation of the rivastigmine patch. Diarrhea is among the most important side effects listed in the technical data sheet of the drug (up to all tablet formulations); this effect is mainly linked to inadequate drug titration.6) In this specific case, diarrhea occurred following a gastrointestinal event of a probable infectious nature and persisted despite the gastrointestinal infection because of increased cholinergic tone provided by the drug in use for 2 years, such that the diarrhea only resolved and reversed upon temporary discontinuation of the transcutaneous AchE-I.

Limited literature is available concerning this event. Cholinergic neurotransmission plays a key role in motility and secretory reflexes as well as in the intrinsic sensory and vascular reflexes of the intestine. Glial cells, which were not considered in the present investigation, could also be responsible for the observed influence of AchE-I on colonic motility as they detect acetylcholine through the M3 and M5 subtypes of muscarinic receptors.7) With drug dosing administered in murine models, an approximately 50% reduction in AchE-I activity in colon tissue preparations and an approximately 50% increase in propulsion time (e.g., for donepezil) was achieved. Stool consistency, in turn, is highly dependent on transit time because of the duration of water reabsorption. This aspect should be considered when comparing microbiomes derived from patients with AD treated with different drugs.5)

A multicenter clinical trial conducted in China to evaluate the efficacy and tolerability of the drug reported a 7.2% incidence of diarrhea in 222 drug-naïve patients with mild-to-moderate AD treated with rivastigmine capsules and followed for 16 weeks.8)

Another study in African Americans studied donepezil administration for 12 weeks and observed a significant incidence of diarrhea (5.6%) among the side effects.9)

In addition, the gastrointestinal side effects of AchE-I are more frequent during dose increase than during maintenance therapy.10) This finding supports the hypothesis that the infectious overlap initiated diarrhea in the present case. In older adults, intestinal infections of bacterial or viral etiology are common, particularly norovirus (9.0%), followed by diarrheal Escherichia coli (DEC) (5.5%), rotavirus (3.9%), non-typhoidal Salmonella (NTS) (2.9%), and Shigella spp. (2.5%).11) It is not always possible to isolate the pathogens involved, especially if testing is performed a distance from the acute event; in our case, a febrile event occurred several days before admission.12) Other immune defense mechanisms include small intestine motility and commensal colon bacteria that protect the host. Drug-induced hypomotility can result in bacterial overgrowth, bile salt deconjugation, and diarrhea. Less commonly, diarrhea may occur because of hypermotility due to cholinergic syndrome.13) Furthermore, age-related changes in gut microbiota with a shift towards a pro-inflammatory microbiome and higher local inflammation may make the guts of aged individuals more vulnerable to both infectious and non-infectious events.14,15)

All the above-mentioned studies mostly refer to oral AchE-I therapies; limited literature has described the different types of administration (oral or transdermal). However, Osada et al.1) reported a 4.2% occurrence of gastrointestinal complaints in patients using the rivastigmine patch.

In our case, the rivastigmine patch was probably responsible for the exacerbation of diarrhea. Possible confounders (e.g., other antibiotics) were ruled out, and an adequate wash-out was performed upon the patient's admission to the ward, without regression of the symptoms. It is assumed that similar physiopathogenetic mechanisms are common with both routes of drug administration (oral and transdermal), albeit less frequently with transdermal forms.

All caregivers and healthcare providers must be aware of the possible risks associated with polypharmacotherapy in older adults,16) particularly with the use of AchE-I drugs. Therefore, it is of paramount importance to take measures to appropriately prescribe these drugs if there are well-founded suspicions.

Failure to rapidly identify the cause of profuse diarrhea in older adults can have lethal consequences. When these symptoms occur, the ability to recognize their causes and provide proper management can be lifesaving.



The researchers claim no conflicts of interest.




Conceptualization, PR, MVP; Data curation, PMI, VFP; Funding acquisition. GV; Investigation, VFP; Methodology, VFP; Project administration, GV; Supervision, GV; Writing-original draft, PR; Writing-review & editing, PMI.


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