**5. Adverse effects of anticholinergics ("Alice in Wonderland")**

As mentioned previously, cholinergic receptors are found in various organ systems throughout the body. Blocking these receptors can have both therapeutic and toxic effects. The mnemonic "red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask" reflects the classic signs and symptoms of anticholinergic poisoning [23]. However, adverse events in older adults may be more subtle. These can include drowsiness, sedation, cognitive impairment, confusion, delirium, hallucinations, blurred vision, dizziness, falls/fractures, urinary retention, constipation, tachycardia, and xerostomia [3, 22].

Adverse CNS effects can be particularly burdensome among older adults. A recent study examining the effects of PIMs in patients with dementia found that almost one-quarter of adults aged ≥65 with cognitive impairment used drugs with clinically significant anticholinergic effects. This study measured anticholinergic burden using the ADS [11]. It found that the level 2 drugs that were most prescribed were ranitidine and cyclobenzaprine and the most commonly

prescribed level 3 drugs were meclizine, tolterodine and oxybutynin [24]. A systematic review examining drug-induced delirium found that ARS scores were consistently associated with delirium [25]. A recent retrospective analysis found that if older hospitalized adults scored 3 or higher on the ACBS, they had a 3–6 fold increased risk of developing delirium compared to those who score < 3 on this tool [26]. In older adults with mild to moderate Alzheimer's disease who were APOE-ε4 carriers, there was a positive correlation between greater progression of dementia severity and continued use of anticholinergic medications [27].

In addition to the CNS effects of anticholinergic agents in older adults, another concern is the risk of falls and fracture. After following women with a mean age of 55 years for approximately 24 months, the APOS (Aberdeen Prospective Osteoporosis Screening Study) found that those with a ACB of ≥2 had a 2.34-fold increased odds of having had recurrent falls in 'later life' with 'later life' referring to 12 months prior to follow-up; there was a 2-year follow-up period. They postulated that anticholinergic agents may contribute to falls by causing vision problems secondary to pupillary dilation, dizziness, slowed reflexes and/or cognitive impairment [28].

Death, the most significant anticholinergic adverse event, was observed in a systematic review of studies examining the association between anticholinergic burden and mortality in older adults. Of the 27 studies included in this systematic review, 63% of studies found a positive relationship between anticholinergic drug burden and mortality in older adults. When solely analyzing those studies that were deemed to be of the *highest quality*, the association between anticholinergic drug use and death rose to 80% in the elderly [29].
