Abstract
Medicines with anticholinergic activity are widely prescribed for the older population aged ≥ 65 years for various medical conditions. A current estimate is that one-third to more than one-half of commonly prescribed medicines for older people have potential anticholinergic activity. Medicines with anticholinergic activity are known to increase the risk of functional and cognitive decline, morbidity, mortality, institutionalisation and length of hospital stay in older people. The cumulative effect of taking one or more medicine(s) with anticholinergic activity is termed anticholinergic burden. Studies have reported anticholinergic burden to be a strong predictor of cognitive and physical impairment in older people.
The overarching aim of this thesis was to examine and estimate anticholinergic burden in older people. This involved a series of investigations.
The evidence-based and pharmacoepidemiological-based examination of anticholinergic burden was explored through a systematic review that examined anticholinergic burden quantified by the expert-opinion based anticholinergic risk scales (n = 7) and associations with adverse outcomes in older people. A pharmacoepidemiological study (n = 537,387) was conducted to investigate whether anticholinergic burden scores from nine published anticholinergic scales were associated with adverse health outcomes – including hospital admissions, length of stay in hospital, and an increase in visits to general practitioners. A meta-analysis (n = 8) was conducted on studies that reported associations between serum anticholinergic activity and decline in cognitive performance and functional impairment. Lastly, a systematic review investigated the impact of a discontinuation of anticholinergic activity medicines on cognitive outcomes in older people. This review found two randomised control trials and two prospective cohort studies that met the inclusion criteria.
Over the past decade, several tools to quantify anticholinergic burden have been developed, but there is not one standardised and universally accepted tool for quantifying anticholinergic burden. These tools differ in terms of how medicines are classified as anticholinergic and how they are weighted. There have been criticisms that the current tools used to quantify anticholinergic burden do not account for drug dosage and its affinity for muscarinic receptor binding. To address these shortcomings and better understand muscarinic occupancy interactions when taking multiple anticholinergic medicines, pharmacodynamic types of models are warranted. This thesis addressed the gap and developed a model-based estimation of anticholinergic burden by examining the clinical characteristics in older people (n = 2248) that predict adverse anticholinergic-type events such as delirium, constipation and urinary retention. In addition, a model-based approach was developed that accounted for both drug dose and muscarinic receptor binding affinity, using the pharmacological principles of ligand binding to quantify anticholinergic burden.
The findings from this thesis strongly reinforce the clinical significance of reviewing anticholinergic medicines in older people. Medicines with anticholinergic activity are best avoided in the geriatric population, unless considered clinically essential. In addition, the existing gaps identified in the literature were addressed to some extent with the compiled research in this thesis. This thesis recommends clinicians use a Pocket Reference Card for anticholinergic medicines in clinical practice.
In conclusion, the results embedded in this thesis provide the impetus for future investigations on the quantification of anticholinergic burden. Further research with larger trials or cohort studies with adequate power and appropriate follow-up periods are required to confirm associations between anticholinergic burden and adverse outcomes.