The Anticholinergic Cognitive Burden

Drugs with anticholingeric properties have been linked with clouded cognition and even increased mortality.

With the impending allergy season once again threatening to ruin spring, patients and health care providers share the common goal of containing the well-known allergic symptoms that appear to bloom right along with many of the offending flowering plants. Systemic antihistamines represent a major pharmacotherapy component in the management of seasonal allergies, so a discussion of recent renewed concerns over the anticholinergic effects of various medication classes—most relevantly antihistamine products—appears timely.

Alarming Evidence

A recent editorial published in The New York Times forewarned consumers and physicians about the underestimated ability of common “drug store staples”— including analgesics, antihistamines, and various psychotropic agents—to adversely affect brain function via interference with acetylcholine. ¹ Several research endeavors were cited, one of which examined whether use of agents with “possible” or “definite” anticholinergic activity (determined according to the anticholinergic cognitive burden [ACB] scale) increased the risk of cognitive impairment and mortality in older people. ²

Among the drugs listed on the ACB scale as having definite anticholinergic effects are various first-generation antihistamines (eg, diphenhydramine, brompheniramine, chlorpheniramine) that are still widely used as either stand-alone products or as components in multi-ingredient cold and allergy preparations. Although the classic prototype antihistamine diphenhydramine remains widely used for extensive allergic symptoms (particularly at night), these latest findings may be viewed as yet another incentive to reserve potent first-generation antihistamines for more severe allergic symptoms, and for more occasional, rather than regular, use. Patients (especially the elderly) seeking these products should be questioned more closely regarding patterns of use and, when possible, offered second-generation oral antihistamines (eg, loratadine, cetirizine) and/or topical (eg, intranasal, ocular) products for the regular treatment of allergic symptoms.

In the highlighted study, researchers followed approximately 13,000 British men and women 65 years or older (with normal or mildly impaired cognition) for 2 years. They found that those taking more than 1 anticholinergic drug scored lower on tests of cognitive function (Mini-Mental State Examination [MMSE]), and that heavy users had a 68% higher risk of mortality during the course of the study. ² Although the literature documenting the association between the use of anticholinergic medications and acute cognitive impairment is abundant, sufficient studies examining the long-term, cumulative cognitive effects—particularly a dose-response effect for anticholinergic load—have been largely lacking up to this point.

In this study, researchers specifically observed a dose-response relationship between greater total ACB score and lower MMSE scores, with patients scoring greater than or equal to 4 on the ACB having a mean MMSE score 0.34 points lower than those not taking anticholinergics. The greatest effect on cognitive decline was seen in the group with baseline MMSE scores of 26 to 30. In this group, taking any definite anticholinergic medication was associated with a decline of an additional 0.52 points on the MMSE. Based on these findings, older patients who already have some degree of cognitive impairment would be considered most vulnerable to anticholinergic agents. ²

In advanced age, the central nervous system is very sensitive to adverse anticholinergic effects due to the significant decrease in cholinergic neurons or receptors in the brain, the reduction in hepatic metabolism and renal excretion of medications, and the increase in blood—brain barrier permeability. ³ In contemplating the nature of anticholinergic-induced cognitive impairment, researchers surmise that the adverse effect may not arise exclusively from an individual agent with strong anticholinergic effects, but rather as an accumulation of multiple medications with varying degrees of anticholinergic effects. ⁴ Therefore, clinicians would need to look for cumulative anticholinergic burden in patients presenting with cognitive impairment.

Understanding the Risk

In the currently discussed study, 48% of patients were identified as using various anticholinergic medications, with the list extending well beyond diphenhydramine. The most frequently reported anticholinergic agents included furosemide, dextropropoxyphene, atenolol, and nifedipine, with each rated as having possible anticholinergic properties (ACB = 1). The most frequently reported medication with moderate anticholinergic activity was carbamazepine (ACB = 2), and the most frequently reported medication with severe activity was amitriptyline (ACB = 3). ²

One unique and rather unanticipated aspect of the study is the link between mortality and anticholinergic burden. As with cognitive impairment, the association between the use of anticholinergic medication and death at 2 years was an observed dose-response effect involving the ACB score. Twenty percent of those with an ACB score greater than or equal to 4 and 7% of those not taking anticholinergics died during the 2-year follow-up period. Alarmingly, for every additional point scored on the ACB, the odds of death increased by 26%. Moreover, the effect was present for the use of definite as well as possible anticholinergics, and results did not vary according to baseline MMSE scores. ²

In speculating on the reasons for the substantial increased risk of death observed among anticholinergic users, researchers appeared dissuaded from the idea that the studied population might have just been older or sicker at baseline. Data were adjusted for age, sex, baseline MMSE score, education, social class, number of nonanticholinergic medications, and number of health conditions. Although the lead author implicated the toll of anticholinergic agents on the cardiovascular and other major organ systems as a suspected reason for the increased risk of death, a cause-and-effect relationship has not been established. In fact, researchers remain uncertain about the validity of the findings because medications with possible anticholinergic effects are used for many diseases (eg, hypertension, congestive heart failure); therefore, the results may, after all, reflect the prevalence of anticholinergic prescribing in disease states with significant morbidity.

Other researchers conducting similar studies have also raised broad-scale concerns regarding the potential of anticholinergic drugs—specifically the widely used OTC “PM” preparations that contain diphenhydramine—to significantly increase the risk of delirium among older patients. ⁵ In one commonly cited metaanalysis, researchers examined 27 studies conducted between 1966 and 2008 and found an association between anticholinergic agents and either delirium, cognitive impairment, or dementia in all but 2 studies. ⁶

Throughout the studies evaluated in this review, investigators discovered minimal changes in global measures of cognitive function, but instead identified deficits in processing speed, psychomotor performance, concentration/attention, problem solving, recall ability, and language skills. Delirium was frequently identified by disorientation, altered consciousness, disorganized thinking, and fluctuating alertness. In applying the significance of these observations to the clinical setting, many practitioners rely on global measures to evaluate cognitive performance and, therefore, may not accurately identify a decline in cognitive function when evaluating exposure to anticholinergics. ⁶

In the consumer literature, some researchers have already started hinting at the potential increased risk of Alzheimer’s disease (AD) among those taking anticholinergics for specific time frames. ⁵ The authors of this meta-analysis cautioned, however, that the long-term effects of anticholinergics on cognition require further analysis, as few studies adequately quantified and correlated exposure to anticholinergics with the long-term risks of developing a neurodegenerative dementing disorder such as AD. ⁶

Final Thought

At least 20% of the 36 million Americans who are 65 years and older are being prescribed at least 1 anticholinergic medication, ⁷ either because treatment is essential (for conditions such as asthma, urinary incontinence, and psychiatric disorders) or simply due to prescriber unawareness of the long list of drugs linked to anticholinergic activity and their effects. As previously mentioned, first-generation antihistamines are more easily identified as anticholinergic offenders, but other agents with anticholinergic properties such as digoxin, warfarin, prednisone, and codeine are unlikely to set off alarms among prescribers, or perhaps even among pharmacists. Consumers may be better prepared to assess their own risk, given articles in the lay press, including the editorial in The New York Times, that refer them to the ACB scale. ^1,8 With the growing prevalence of aging baby boomers and the increasing practice of polypharmacy, it appears that health care providers, particularly pharmacists, should become well familiarized with the growing list of drugs with expected—as well as unexpected—anticholinergic effects.

Table. ACB Scoring of Select Drugs^a

ACB Score 1 = Possible Anticholinergic Effects

ACB Score 2 = Definite Anticholinergic Effects

ACB Score 3 = Definite Anticholinergic Effects

Alprazolam

Atenolol

Captopril

Codeine

Diazepam

Digoxin

Furosemide

Prednisone

Nifedipine

Warfarin

Amantadine

Belladona

Cyclobenzaprine

Cyproheptadine

Carbamazepine

Loxapine

Meperidine

Molindone

Oxcarbazine

Pimozide

Amitriptylline

Brompheniramine

Chlorpheniramine

Clomipramine

Clozapine

Dimenhydrinate

Diphenhydramine

Hydroxyzine

Paroxetine

Promethazine

^aNot a complete list.

Adapted from reference 8.

Dr.Beyzarov is scientific director for the Pharmacy Times Office of Continuing Professional Education.

References

1.Rabin RC. Cocktail of popular drugs may cloud brain. http://well.blogs.nytimes.com/2012/02/27/cocktail-of-popular-drugs-may-cloud-brain/.Accessed February 29, 2012.

2.Fox C, Richardson K, Maidment ID, 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):1477-1483.

3.Tune LE. Anticholinergic effects of medications in elderly patients. J Clin Psychiatry.2001;62(21):11-14.

4.Carnahan RM, Lund BC, Perry PJ, et al. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006;46(12):1481-1486.

5.Reinber S. Some OTC sleep, cold meds could harm aging brain. www.mountauburnhospital.org/body.cfm?id=8&action=detail&ref=27643. Accessed March 6, 2012.

6.Campbell N, Boustani M, Limbil T. The cognitive impact of anticholinergics: a clinical review. Clin Interv Aging. 2009;4:225-233.

7.United States Census Bureau. Nation’s Population One-Third Minority. www.census.gov.ezproxy2.library.drexel.edu/Press-Release/www/releases/archives/population/006808.html.Published May 10, 2009. Accessed February 10, 2009.

8.The anticholinergic burden scale. www.indydiscoverynetwork.org/AnticholinergicCognitiveBurdenScale.html. Accessed March 6, 2012.