Are You Prescribing Loco Weed?

Abstract & Commentary

By Allan J. Wilke, MD, Residency Program Director, Associate Professor of Family Medicine, University of Alabama at Birmingham School of Medicine—Huntsville Regional Medical Campus. Dr. Wilke reports no financial relationship to this field of study.

Synopsis: Use of anticholinergic drugs is associated with mild cognitive impairment.

Source: Ancelin ML, et al. Non-degenerative mild cognitive impairment in elderly people and use of anticholinergic drugs: longitudinal cohort study. BMJ. 2006;332:455-459.

Mild cognitive impairment (mci) lies in that no-man's land between normal (no cognitive deficits) and dementia (cognitive deficits in more than one sphere). MCI comes in 2 flavors: amnestic-type or multiple cognitive deficits-type (or mixed-type). Risk factors for the transition from normal to MCI include age, presence of at least one apolipoprotein 4 allele, and at most 12 years of education. Cognitive leisure time activities (reading, writing, crossword puzzles, board or card games, group discussions, or playing music), but not physical activities (tennis, golf, swimming, bicycling, dancing, group exercises, team games, walking, climbing more than two flights of stairs, and babysitting), are associated with a lower risk of developing amnestic MCI. People with MCI are at greater risk for developing dementia. Donepezil (Aricept®) is associated with a slowing of the progression of MCI to Alzheimer's dementia for up to 3 years.

The Eugeria project is a longitudinal study of elderly patients from the south of France. Subjects were recruited from the offices of general practitioners in rural and urban areas. At the beginning of the study, the 372 subjects had no senile dementia. They were evaluated at baseline and again at year 1 and year 2 with a general health interview, focusing on current and past illnesses (including depression) and on prescription and over-the-counter drug use. Because the evaluations were conducted in the subjects' usual place of residence, the interviewers asked to see the actual medications. The subjects also had a computerized neuropsychometric evaluation and an examination by a neurologist who was blinded to the results of the cognitive testing. The neuropsychometric exam focused on reaction time, reasoning, attention, memory, visuospatial ability, and language. At year 8, surviving subjects underwent a second neurological assessment, looking closely for dementia. For the purposes of this study, MCI was defined as performance greater than 1.5 standard deviations below the mean score for the entire group at baseline, adjusted for age and level of education.

The medications were evaluated for their potential anticholinergic effects by combining information regarding their ability to block muscarinic receptors with their average estimated clinical effects. This combination determined the individual subject's "anticholinergic burden," which was graded on a 0 (no anticholinergic drugs used) to 3 (drugs used with high effect) scale.

The 372 elders were divided into 3 groups: those who had used at least one anticholinergic drug at baseline and during year 1 ("consistent users", n = 30), those who had used at baseline or during year 1, but not both (n = 45), and those who had not taken any anticholinergic (consistent non-users, n = 297). No one was taking a cholinesterase inhibitor (eg, donepezil or rivastigmine). Consistent users were 77% female. Compared to consistent non-users, they were older (80.9 vs 74.8 years) and less educated. On the neuropsychometric exam, they had slower reaction times and decreased attention. Their visuospatial memory was impaired, as were their narrative recall and their verbal fluency. The differences were adjusted by age, gender, and education and were all statistically significant. MCI was diagnosed in 105 of 297 (35%; 95% confidence interval 30-41%) consistent non-users and 24 of 30 (80%, 66-94%) consistent users.

A logistic regression model designed to predict MCI at Year 1 that incorporated anticholinergic drug use, age, gender, education, untreated depression, and treated hypertension, identified only age (OR, 1.09, 1.06-1.13) and anticholinergic drug use (OR, 5.12, 1.94-13.51) as highly significant predictors. At Year 8, the rates of diagnosis of dementia were similar between the two groups (16% for users and 14% for non-users).

Commentary

Jimson weed (a/k/a "loco weed," Datura stramonium) contains atropine, hyoscyamine, and scopolamine, the archetypical anticholinergic drugs. Jimson is a corruption of Jamestown, where the symptoms from ingestion were first recorded in 1676. Ingestion manifests as classical atropine poisoning with dry mouth, thirst, difficulty swallowing and speaking, blurred vision, and urinary retention. Central nervous system symptoms can include confusion, agitation, combative behavior, hallucinations, seizures, and coma. Is it not surprising, then, that anticholinergic medications might be associated with MCI? Study design (longitudinal cohort) prevents making a causal connection; maybe elders take anticholinergic drugs because they have incipient MCI. Table 1 in the article lists the 27 anticholinergic drugs taken by the study' participants. Some are prescribed for mental illness (for instance, phenothiazines, tricyclic antidepressants, and benzodiazepines), but most aren't the kinds of drugs one might prescribe for a cognitive problem (oxybutynin, codeine, colchicine, digoxin, furosemide, and theophylline).

The issue of prescribing anticholinergic drugs to the elderly is not new. Certainly, in some situations treating a life-threatening disease or one that causes significant reduction in quality of life might trump causing cognitive impairment. I suspect, though, that, if given a choice, our patients might express an interest in maintaining their mental agility at the expense of not treating another ailment aggressively. As physicians we need to look at our patient as a whole, rather than an assemblage of parts. We need to ask ourselves, "Is there an alternative treatment that does not involve use of an anticholinergic drug?"