The effects of acetylcholinesterase inhibitors on the heart

Acetylcholinesterase inhibitors (AchEI), like donepezil, galantamine and rivastigmine are the only drugs – together with memantine (glutamate receptor antagonist) – which obtained the indication for the symptomatic treatment of Alzheimer disease, but are also used for the treatment of other types of dementia.3,4
They act reversibly blocking the acetylcholinesterase activity, the enzyme which carries out the rapid hydrolysis of acetylcholine, increasing in this way the neurotransmitter central levels.
In Italy, the estimated average consumption of acetylcholinesterase inhibitors from 2008 to 2010 amounts to 0.974 DDDs (defined daily dose)/1,000 population/day  for donezepil; 0.448 DDDs/1,000 population/day for rivastigmine; 0.112 DDDs/1,000 population/day  for galantamine and 0.211 DDDs/1,000 population/day for memantine. Most reported adverse effects are: diarrhea, nausea, vomit and more rarely cardiovascular effects.2

Disregarded bradycardia

It has been clearly highlighted that initiating an acetylcholinesterase inhibitors therapy may double the risk for hospitalization due to bradycardia.5 Their cardiotoxicity is often disregarded to such a point that in the 50% of patients hospitalized for bradycardia the therapy is prescribed again.5  If these drugs are not identified as the causes for symptomatic bradycardia, the patient could incur in serious consequences, besides undergoing expensive investigations.6 A recent study did not reveal any correlation between the use of acetylcholinesterase inhibitors and the increment of chronotropic negative effects, hypotensive effects or arrhythmia in elderly patients with Alzheimer disease;7  on the other side, another study underlined a modest risk for bradycardia, but a high doses.4
It is opportune to consider that bradyarrhythmia can be transitory6 and could not be revealed by electrocardiographic screening. Besides, eligibility criteria in clinical studies often exclude the most fragile patients, i.e. the eldest ones with important comorbidity and polypharmacotherapy, and this could determine an important bias in the risks/benefit evaluation for a medicine in the target population.8
However, the percentage of brachycardia or syncope caused by acetylcholinesterase inhibitors in the daily clinical practice is not clear yet. It must be considered that patients affected by dementia have a high prevalence of neurovascular instability, which can show itself as bradyarrhythmia, vasovagal syndrome, carotid sinus syndrome, orthostatic hypotension and postprandial hypotension.9 In daily clinical practice, patients who assumes these drugs are on average older and have comorbities more important than patients enrolled for the clinical trials; besides the percentage of therapy suspension is higher for the patients not represented by the clinical studies, probably also for the greater incidence of adverse reactions induced by the drugs.10
According to some authors, the use of acetylcholinesterase inhibitors in elderly patients with dementia, in addition to bradycardia, would be associated to an increased incidence of syncope, pacemaker implant and femur fracture.6 It is opportune to highlight that patients with dementia who suffer a femur fracture have an elevate risk of ulterior functional decline, institutionalization and death.11

The hypothetical mechanism of action

Acetylcholinesterase inhibitors explicate their pharmacological effect, also at cardiac level, by amplifying and prolonging the cholinergic response. A possible explanation for their effect on the heart can be found when considering that muscarinic receptors, above all the subtype M2, are present in large numbers in the myocardial conduction tissue (at sinusatrial and atrioventricular node level) and are responsible for the cardiac cholinergic response, both chronotropic and dromotropic negative (prolonged PR interval on the ECG, till the development of atrioventricular block).12,13

In practice

The data discussed above underline the necessity – especially for patients affected by important cardiologic comorbidities – of carefully evaluating the risks/benefits ratio before starting (and also continuing)  an acetylcholinesterase inhibitors therapy, which must undergo a careful monitoring. In the event of syncope, as also advised by Beer’s criteria, it is important to suspend the acetylcholinesterase inhibitors therapy.14

Dementia numbers
The term dementia derives from the Latin dementia, without mind. The essential characteristic of dementia is the development of several cognitive deficits which include memory impairment and at least one of the following cognitive impairments: aphasia, apraxia, agnosia or an executive function disorder. These cognitive deficits must be sufficiently serious to cause a significant reduction in the capability of carrying out daily life activities and must represent a deterioration respect to previous function levels.
The Alzheimer disease is the most common form of dementia, representing from 50% to 70% of all cases, above all in the oldest age groups. Frontotemporal dementia explains about 2-25% of all dementia, vascular dementia about 10-20%, mixed dementia 10-30% and Lewy body dementia 5-10%.1
It is estimated that worldwide in 2010 there were 36.5 million of people affected by dementia, with 7.7 million of new cases every year and a new case of dementia every 4 seconds. Because of life prolongation, it is estimated that the number of people affected by dementia will double every 20 years, till 65.7 million in 2030 and 115.4 in 2050.2