Turning over the rocks

Addressing medication-related cognitive impairment

Both anticholinergic burden and benzodiazepine use are associated with cognitive decline, including lower Mini-Mental State Examination and Trail Making Test scores and diagnosis of dementia.^4–9 Increased blood-brain barrier permeability and age-related declines in cholinergic neurotransmission, as well as increased sensitivity to benzodiazepine medications with age are contributing factors. Discontinuing anticholinergics and benzodiazepines has been shown to decrease the risk of cognitive decline.^4,10

The fixed-combination medication chlordiazepoxideclidinium has been used for the short-term treatment of irritable bowel syndrome, but has limited benefit given the risks associated with long-term use.¹¹ The active metabolite of the benzodiazepine chlordiazepoxide has a half-life of up to 200 hours and, with clearance delayed in elderly patients, can result in prolonged duration of action and increased adverse effects. Resulting confusion, memory loss, dizziness, daytime sleepiness, falls and fractures, and depressed mood can lead to severe functional status impairment.¹² After the patient’s chlordiazepoxide-clidinium was stopped, there were substantial improvements in memory and cognitive function. Although long-term use of benzodiazepines is associated with adverse withdrawal symptoms, the long half-life of this agent likely was the reason that the patient tolerated an abrupt discontinuation. However, 2 months after discontinuation, the patient experienced a generalized tonic-clonic seizure and was started on 300 mg of phenytoin daily by an emergency department physician (eventually tapered to 200 mg daily at the GDH owing to symptoms of fatigue and dizziness, accompanied by a phenytoin level of 109 μmol/L). While seizures occur rarely following benzodiazepine withdrawal, the patient had a number of risk factors (meningioma, multiple CVAs) and it was unclear whether the chlordiazepoxide had been masking a seizure disorder or whether this was a single adverse drug withdrawal event. As the risks associated with long-term use of chlordiazepoxide (especially in terms of its contribution to her incorrect diagnosis of dementia) outweigh its ability to prevent seizures, a more appropriate anticonvulsant seemed warranted.

Anticholinergic medications are known to cause numerous side effects, notably constipation, dry mouth, urinary retention, dizziness, blurred vision, and confusion. The antispasmodic, clidinium, and tricyclic antidepressant, amitriptyline, both contributed substantially to anticholinergic load. While we were able to stop the chlordiazepoxide-clidinium with no substantial adverse withdrawal effects, stopping the amitriptyline was somewhat more difficult, as the patient’s depression had been severe and resistant to multiple other medications in the past. The patient’s geriatric psychiatrist recommended dose reduction to no lower than 150 mg at bedtime. With this dose reduction and eliminating the clidinium, the patient’s anticholinergic burden was meaningfully reduced.

Addressing medication-related falls

Benzodiazepines and anticholinergic medications cause central nervous system depression and increase the risk of falls in elderly patients.^13,14 These medications have an additive effect—similar to their effect on cognition—and the likelihood of falls increases when they are used in combination, especially when amplified by pre-existing medications. While the patient’s previous CVAs and related impairment were contributing to fall risk, the chlordiazepoxide-clidinium and amitriptyline, and some dizziness likely caused by other medications, were important to consider. In addition to stopping chlordiazepoxide-clidinium and reducing amitriptyline, the GDH physiotherapist facilitated lower extremity strength training and implemented a stretching and balance exercise program. The occupational therapist provided gait, balance, and transfer training and educated the patient about fall prevention techniques. An improvement in Berg Balance Scale score of 5 points indicates a true change in functional balance.¹⁵ This patient’s Berg Balance Scale score improved by 21 points. With strength, balance, and standing tolerance improved, the patient did not report any falls during the last 2 months of her GDH admission. The GDH recreation therapist assisted the patient in finding a community exercise program, which she readily agreed to attend.

Addressing other drug-related problems

While a number of medications used in the treatment of the patient’s bowel problems might have been contributing to dizziness and fall risk, the program admission period allowed for adjustments to her psyllium laxative and lactulose regimens with good effect. By discharge, bowel movements were regular, with 2 to 3 per week and no persistent symptoms of constipation or diarrhea; loperamide was no longer required. Improvement in constipation might also have been related to reduction in her anticholinergic load. The lansoprazole dosage was increased to twice daily for ongoing heartburn and this was effective in reducing symptoms. Her gastroenterologist was consulted regarding follow-up after GDH discharge.

Combined use of 2 β₂-agonists for relief of asthma symptoms can contribute to additive adverse effects and so the patient was advised of their similarity and asked to stop terbutaline. Using a salbutamol inhaler with a hand-grip adapter and an antistatic valved holding chamber, she was ultimately able to use the appropriate technique to improve effectiveness and minimize systemic absorption from breathing in too quickly. Calcium and vitamin D were added to the medication regimen. Codeine with acetaminophen was no longer required by the end of the admission, as her headaches had resolved. No changes to her ramipril dose were needed as her blood pressure during the second half of admission was usually below the target range.