Anticholinergic Effects

Transmitter acetylcholine

The neurotransmission of acetylcholine is blocked by anticholinergic drugs, which typically bind to muscarinic receptors (subtypes M1-M5) that are distributed throughout the body. Acetylcholine plays an important role in numerous body functions. Among other things, the neurotransmitter in the CNS is relevantly involved in the control of attention, in learning processes and in the storage of memory content, it mediates the peripheral bladder contraction, controls the salivation, the intestinal motility and lowers the heart rate.

Symptoms and importance of anticholinergic side effects

The wide distribution of muscarinic receptors in the human body contributes to the fact that anticholinergic drugs can cause a multitude of undesirable effects (ADRs). The most common peripheral ADRs include dry mouth, pupillary dilatation with accommodation disorders, blurred vision and increased intraocular pressure, constipation, urinary retention and increased heart rate. Central ADRs are often drowsiness, dizziness, drowsiness, cognitive impairments and confusion. The more serious central ADRs include agitation, disorientation, ataxia, hallucinations and delirium Nishtala 2016 , Collamati 2016 , Ruxton 2015 , Lopez-Alvarez 2019 , Cardwell 2015.

More recent study results indicate that anticholinergic ADRs are associated not only with a reduced quality of life, but also with increased hospitalizations and increased mortality rates Ruxton 2015 , Salahudeen 2015 , Tune 1992 , Chwe 2008 . In addition, anticholinergic side effects are often misinterpreted as (new) diseases that arise in old age or are associated with the aging process. Collamati 2016 and lead to the prescription of additional drugs, which leads to so-called undesirable prescribing cascades Wawruch 2012.

Susceptibility in old age

Anticholinergic drugs are at higher risk of side effects, especially in the elderly. It is estimated that around 20-50% of the elderly are regularly exposed to drugs with potential anticholinergic effects, and 30-50% of the drugs prescribed to the elderly have potential anticholinergic activity Griebling 2012 , Nishtala 2016. Older people are more sensitive to anticholinergic side effects due to physiological changes typical of the aging process. Nishtala 2016. Because of the decreased metabolism and elimination in the elderly, drugs are eliminated more slowly. The cholinergic reserves and the cholinergic transmission are also reduced with age. Furthermore, the permeability of the blood-brain barrier increases, which means that larger and more polar molecules can enter the CNS and the concentrations of active substances in the CNS rise. The activity of the cerebral efflux protein P-glycoprotein also decreases with increasing age, so that substrates with anticholinergic properties (e.g. trospium chloride and darifenacin) can increase the risk of central anticholinergic toxicity Nishtala 2016 , Lopez-Alvarez 2019 , Bostock 2010. In addition, there are factors such as the frequent polypharmacy in old age, drug interactions and individual characteristics (for example diseases such as Alzheimer’s dementia), which can also promote anticholinergic side effects.

Previous classifications

To date, more than 20 different classifications, tools and scores have been published in the literature in order to identify drugs with anticholinergic properties and to be able to estimate the anticholinergic load for the patient Lavrador 2021 , Carnahan 2006 , Ancelin 2006 , Chew 2008 , Rudolph 2008 , Han 2008 , Honors 2010 , Sittironnarit 2011. However, the study setting and design, patient populations and outcome measurements are extremely heterogeneous, and the classification of drugs into anticholinergic risk categories is inconsistent. As a result, it is almost impossible for the doctor and pharmacist to decide which score can best be used to predict the risk for the individual patient. In addition, various characteristics of the patient and the drug have not yet been taken into account in the classifications, or only insufficiently, which, however, seem to be essential for reliable risk prediction.

Evaluation and further development

Our rating is currently based on the publications by Duran 2013 and Kiesel 2018. As a further development, the creation of a predictive model is planned that can predict cumulative (non-linear) anticholinergic ADRs on a patient-specific basis. Relevant patient characteristics that potentially have an influence on the anticholinergic load, such as underlying diseases, age, excretory capacity and associated pharmacokinetic changes and genetic characteristics, are taken into account. In addition, relevant substance characteristics are also included, such as CNS penetration in order to better differentiate the peripheral and CNS toxicity, binding affinity for the muscarinic receptor subtypes and dosages. The latter is also relevant, since for various substances in dose dependent toxicity profile was shown (for example, scopolamine results in low doses to xerostomia, in higher doses, the heart rate is also influenced Renner 2005.

The model is to be validated in a prospective clinical study and the relationship between anticholinergic exposure and clinical outcome evaluated. For this we are looking for scientific cooperation partners.