Cholinergic System and Anticholinergics

Acetylcholine is a neurotransmitter that produces a variety of effects in the body through its action on nicotinic and muscarinic receptors. In the periphery, the actions of acetylcholine are mediated via the muscarinic receptors, and cholinergic blocking agents produce a wide range of effects such as tachycardia, mydriasis, cycloplegia, bronchodilatation; as well as decrease of salivation, bronchial secretions, gastric secretions, intestinal motility, and bladder contractility. Centrally, blockade of muscarinic receptors results in drowsiness, confusion, delirium, and cognitive impairment.

Therapeutically these actions are useful in Parkinson’s disease; urinary urge incontinence; reduction of secretions during surgery or in palliative care; gastrointestinal, renal or biliary spasm; motion sickness; asthma and chronic obstructive pulmonary disease; and other conditions.

Some clinicians may not be aware that medicines used for completely unrelated indications also have anticholinergic effects, including tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) for depression, medicines for schizophrenia or mood disorders (e.g. chlorpromazine or olanzapine), medicines for hay fever (e.g. loratadine or cetirizine), and even those for congestive cardiac failure (e.g. metoprolol).

Elderly patients are most susceptible to anticholinergic drug effects, with studies suggesting certain age-related changes contribute to this sensitivity; such as decreased hepatic and renal drug clearance, decreased cholinergic sensitivity and cholinergic atrophy in the brain, and increased blood-brain barrier permeability; especially during acute illness.

Anticholinergic Drug Burden Scales: ADS, ARS, ACB

Anticholinergic drug burden refers to the potential additive effects of multiple anticholinergic medicines, whether intentional or not. Patients may suffer adverse outcomes due to accumulation of undesirable adverse effects such as cognitive impairment, constipation and falls.

There have been multiple studies that have sought to develop lists scaling drugs by their anticholinergic potential in order to quantify and objectively ‘score’ a patient’s anticholinergic burden. Examples of existing scales are the Anticholinergic Drug Scale (ADS) by Carnahan et al, in which the scoring associates closely with serum anticholinergic activity (SAA) tests; Anticholinergic Risk Scale (ARS) by Rudolph et al which scores drugs based on an attempt to estimate the risk of peripheral and central anticholinergic adverse effects; and the Anticholinergic Cognitive Burden (ACB) scale by Boustani et al, developed from a systematic literature review to identify and scale drugs based on clinically relevant anticholinergic cognitive effects.

Each scale varies with the drugs that are listed and their allocated weighting. Although the scores do not correlate well between scales, each scale may be applied differently to garner potentially useful information. For instance, an ACB score of four or more was found in a study by Fox et al to be associated with increased morbidity and mortality in a population of elderly community dwelling or institutionalised participants. Pasina and colleagues asserted there is a dose-response relationship between ACB scores and cognitive impairment.

In the same study lead by Pasina, ARS was suggested to be associated more strongly with severe cognitive or physical impairment, especially the ability to perform activities of daily life. Rudolph et al demonstrated the association of ARS and an increased risk of anticholinergic adverse events in older patients, a correlation which was supported by Lampela et al in a later study. Zimmerman et al found an increase in ARS score was associated with an increased risk of delirium by about 40% in palliative care patients.

Furthermore, a study by Lertxundi et al suggested the ADS may be a useful predictor of peripheral anticholinergic effects but not central effects.

Conclusion

With an aging population and increasing polypharmacy, it is important to have an understanding and awareness of unintentional drug interactions and the adverse effects of medications. The use of objective measures such as the ACB, ARS or ADS may be considered as another tool to optimise patient outcomes, especially in regards to modifiable risk factors such as anticholinergic drug burden.

References:

  1. Boustani MA, Campbell NL, Munger S, Maidment I, Fox GC. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health. 2008; 4:311-20.
  2. Carnahan RM, Lund BC, Perry PJ, Pollock BG, Culp KR. The anticholinergic drug scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006; 46(12):1481-6.
  3. Cholinergic Receptors In: Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia AS, McNamara JO, et al., editors. Neuroscience. 2nd ed. Sunderland: Sinauer Associates; 2001.
  4. Fox C, Richardson K, Maidment ID, Savva GM, Matthews FE, Smithard D, et al. Anticholinergic medication use and cognitive impairment in the older population: the medical research council cognitive function and ageing study. J Am Geriatr Soc. 2011; 59(8):1477-83.
  5. Lampela P, Lavikainen P, Garcia-Horsman JA, Bell JS, Huupponen R, Hartikainen S. Anticholinergic drug use, serum anticholinergic activity, and adverse drug events among older people: a population-based study. Drugs Aging. 2013;30(5):321-30.
  6. Lertxundi U, Domingo-Echaburu S, Hernandez R, Peral J, Medrano J. Expert-based drug lists to measure anticholinergic burden: similar names, different results. Psychogeriatrics 2013; 13(1):17-24.
  7. Pasina L, Djade CD, Lucca U, Nobili A, Tettamanti M, Franchi C, et al. Association of anticholinergic burden with cognitive and functional status in a cohort of hospitalized elderly: comparison of the anticholinergic cognitive burden scale and anticholinergic risk scale. Drugs Aging. 2013;30(2):103-12.
  8. Rossi S, editor. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd; 2014.
  9. Rudolph JL, Salow MJ, Angelini MC, McGlinchey RE. The anticholinergic risk scale and anticholinergic adverse effects in older persons. Arch Intern Med. 2008; 168(5):508-13.
  10. Schliebs R, Arendt T. The cholinergic system in aging and neuronal degeneration. Behav Brain Res. 2011; 221(2): 555-63.
  11. Zimmerman KM, Salow M, Skarf LM, Kostas T, Paquin A, Simone MJ, et al. Increasing anticholinergic burden and delirium in palliative care inpatients. Palliat Med. 2014;28(4):335-41.

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