Myrtle is an 87-year-old female with hypertension, urinary urgency and a mild dementia syndrome. She lives with her daughter and manages with her support. She is taking hydrochlorothiazide, amlodipine, ASA, tolterodine LA, and mirtazapine for sleep. Myrtle recently slipped on the stairs and twisted her back. Because of the pain, she started taking acetaminophen/methocarbamol. Her daughter brings her in because she has become confused.
Issue: Why is Myrtle now confused?
Bottom Line: Anticholinergic effects are seen with many classes of medications. Members of a class may vary in their level of anticholinergic activity but recognition of the cumulative effect of anticholinergic activity is important in successful medication management.
Evidence: Acetylcholine is a key neurotransmitter, both centrally and peripherally. Activation of the cholinergic system by acetylcholine increases gastric acid secretion and transit through the gastro-intestinal tract; slows the heart rate and reduces cardiac output; leads to bronchoconstriction, bladder smooth muscle contraction and tear secretion; and is postulated to have a role in memory and attention. Agonists are drugs that bind to receptors and lead to a degree of activation, from partial to full. Antagonists block receptors and may or may not have some activation of the receptor effect. The degree of antagonist activity of any particular drug determines its anticholinergic effect.
Anticholinergic drugs are used for their positive clinical benefits including their effects on urinary urgency and incontinence and for bronchodilation when they are inhaled. There are also numerous negative effects. Peripheral effects include drying of the mouth and eyes, decreasing sweating, constipation and tachycardia. Central effects may include drowsiness, memory impairment, hallucinations, delirium, excitement and/or restlessness.[i]
With aging, a decrease in central cholinergic activity is seen. There is also an increase in blood-brain permeability and, frequently, medical comorbidities. Potential impacts of the use of drugs with anticholinergic activity can include worsening of existing health conditions such as ischemic heart disease/angina, benign prostatic hyperplasia, congestive heart failure, and cognitive decline. In addition, aging may be associated with a risk for adverse effects of drugs being mis-ascribed to aging, or to age-related diseases.
Anticholinergics fall into two different categories. Those that have a recognized and known anticholinergic effect are generally identified by the Beers Criteria as drugs to avoid.[ii] The second group are those that have an unrecognized, or less well-known, anticholinergic effect. For these, the majority are unlikely to have a major impact when used on their own, but have an additive impact when used with other agents that also have an anticholinergic effect. The higher the total anticholinergic load, the higher the risk for adverse effects.
The gold standard for determination of anticholinergic effect of any drug is serum anticholinergic activity. This is not, however, practically useful. Alternative mechanisms to identify anticholinergic effect have been developed and, in general, rely on rating scales. At least three rating scales have been developed.
The Anticholinergic Drug Scale (ADS) was developed based on serum anticholinergic activity. It identifies the potential anticholinergic effect of any particular agent, using a 0-3 (none to high) scale. There may be some utility in terms of identifying peripheral anticholinergic effects however the clinical utility of this approach has not been established.[iii]
The Anticholinergic Risk Scale (ARS) is based on a combination of evidence and opinion, and ranks medications on a 1-3 (low to high) scale. It sums the ratings from each medication being taken to determine a score reflective of total anticholinergic load. It has been prospectively validated in a primary care cohort. The utility relates to identifying target drugs and reducing the exposure to them.[iv]
The Anticholinergic Burden Scale (ABS) was developed through a Medline search for studies associating anticholinergic activity and cognitive function. Drugs were then reviewed and rated by an expert panel and a 1-3 point was developed for each drug. One (1) represents a potential for anticholinergic effect whereas three (3) has demonstrated blood-brain permeability and an association with delirium. The list generated was then compared to both the ARS and the ADS for validation.[v]
The Pharmacist’s Letter published an additional useful reference list in December 2011, though this requires a subscription for access.[vi]
Both the ARS and the ABS produced published lists of drugs that have the potential to contribute to anticholinergic burden, along with an estimate of the extent to which they may do so. It is important to note that the scales are a guide and do not address individual aging changes that may increase the risk for an anticholinergic adverse event.
The most common drug classes with anticholinergic effects include the tricyclic antidepressants, the generally more sedating antihistamines, antipsychotics including both typical and atypical agents, skeletal muscle relaxants and anti-muscarinics used for management of incontinence.
Less commonly recognized drugs include antidepressants such as bupropion, paroxetine and trazodone; analgesics including codeine, fentanyl and morphine; and certain antihypertensives such as atenolol, metoprolol, nifedipine and digoxin.
Myrtle, who has a mild dementia syndrome, was taking nifedipine, which has a low anticholinergic effect, along with tolterodine for the anticholinergic effect that it produces. In spite of her cognition, she was managing until she added methocarbamol. The total anticholinergic burden then became too great for her, leading to an adverse effect of confusion.
It is important to have a high index of suspicion for the potential for an anticholinergic effect from any medication. As a rule of thumb, having access to a list that identifies anticholinergic potential will assist in addressing the situation and, potentially, prevent it from occurring.
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[i] Feinberg M. The Problems of Anticholinergic Adverse Effects in Older Patients. Drugs & Aging 1993; 3(4):335-348
[ii] Beers Criteria 2012 Update JAGS – DOI: 10.1111/j.1532-5415.2012.03923.x
[iii] Carnahan R et al. The Anticholinergic Drug Scale as a Measure of Drug-Related Anticholinergic Burden: Associations with Serum Anticholinergic Activity. J Clin Pharm 2006;46:1481-86
[iv] Rudolph J et al. The Anticholinergic Risk Scale and Anticholinergic Adverse Effects in Older Persons Arch Int Med 2008;168(5): 508-13
[v] Boustani M et al. Impact of anticholinergics on the aging brain: a review and practical application. Aging Health 2008;4(3): 311