Episode 102: Anticholinergic Burden
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Article Authors: Karl Wallenkampf, MA, Kyle Logan, BS, Adriana Alvarez, BS, Ryan Holas, BS, David Puder, MD
There are no conflicts of interest for this episode.
Medications that Worsen Mild Cognitive Impairment, Sundowning, and Delirium
Clinical issue
You are consulted for an “altered” patient whose dysfunctioning cognition and behavior are complicating the patient’s clinical care. Or, perhaps you are an outpatient therapist who notices that your patient’s attention is waxing and waning, and is drowsy during your interaction. This cognitive impairment could be your patient’s new baseline. It could be the progression of dementia but with some decrease in function later in the day due to sundowning. Or, it could be an aggressive derangement of sensorium known as delirium. Today, we consider these three issues. Finally, we discuss a way to approach the medication list and offer a resource we created to improve your treatment of “altered” patients, especially those with delirium precipitated by medications.
A spectrum of sensorium disruptions: from sundown to sunup
Our podcast covered sensorium in a previous series, but to review, we can consider sensorium as referring to “global brain function,” including heterogeneous issues that present with a spectrum of severity, such as: sundowning, mild cognitive impairment, dementia, and delirium. Sundowning is a diurnal phenomenon usually experienced in the evenings (“sundown”) found in patients with dementia. These patients may experience a group of symptoms including decreased attention, confusion, anxiety, disorientation, and even hallucinations. It can be influenced by pharmacologic, physiologic, and environmental factors (Canevelli et al., 2016). We will be focusing on pharmacologic factors in this podcast.
Sundowning usually occurs within dementia but we all have decreased sensorium mid-day. Dementia is defined as the constellation of symptoms characterized by progressive cognitive decline that interferes with the ability to function independently (activities of daily living) (Duong et al., 2017). Similar, but of lesser degree, is mild cognitive impairment, where patients may have cognitive symptoms and decline, but retain their ability to perform activities of daily living, and will score 18-25 on the Montreal Cognitive Assessment (Langa & Levine, 2015).
Diving deeper: delirium
Mild cognitive impairment and dementia may predispose patients to delirium. Delirium, a dangerous derangement of sensorium, has been described by the American Geriatrics Society/National Institute on Aging as “acute brain failure” (2015), analogous to acute heart failure in that there are multiple mechanisms leading to a final common pathway (Marcantonio, 2017). Delirium presents a unique challenge to clinicians, especially those in mental health, given the varied presentation, multitude of etiologies, and substantial morbidity and mortality.
Delirium is common, affecting 30% of patients over 70 years of age admitted to the hospital, and half of that 30% had already become delirious before presentation to the hospital (Marcantonio, 2011). It is the most common postoperative complication in the elderly, affecting as much as 50% of postoperative courses, depending on the severity of the surgery (Marcantonio, 2012). Delirium is also associated with substantial morbidity--and even mortality--in the hospital, with 10 times the risk of death and up to five times the risk for other complications (Marcantonio, 2011). The one-year mortality rate in patients diagnosed with delirium may range from 35-40% (Inouye, 2006).
The high morbidity and mortality may be in part due to how often delirium is missed, or misdiagnosed, in both the inpatient and outpatient. This is largely due to the difficulty of even noticing the symptoms in elderly patients. Patients often have an acute shift--which may have already occurred prior to the hospital stay--toward disturbed attention and awareness, with fluctuations throughout the day. While these changes necessarily must not be explained by a different neurocognitive disorder and are not a part of coma (per the DSM-V), these patients may have dementia as a predisposing factor.
Interestingly, about 50% of all delirium is the hypoactive subtype, about 30% is the mixed subtype and about 20% is the hyperactive subtype (Hosker & Ward, 2017). Hypoactive delirium is characterized by low attention, decreased verbal abilities, and drowsiness to the point of falling asleep during the interview. Hypoactive delirium is more subtle in its presentation compared to hyperactive delirium and can easily be missed. Collecting the patient’s change from baseline could manifest as predominantly drowsy and inactive, and collateral from caregivers and family is very important in teasing out hypoactive delirium, as it can easily be mistaken for depression. A study of 710 hospital admissions found that 75% of the admissions with delirium were not appreciated by the admitting team (Collins et al., 2010).
In distinguishing hypoactive delirium from depression, remember that depression does not present with reductions in consciousness, pronounced poor focus, or abrupt onset (e.g. depressed patients will be able to spell “world” backwards and draw a clock). An observational study on 60+ year-old inpatients found that 42% of the 67 patients referred for evaluation of a depressive episode were found to be delirious (Farrell, 1995). If you see someone who seems depressed in a medical hospital, consider first and foremost you might be seeing someone with hypoactive delirium.
Assessing delirium
If suspected, clinicians can screen using the Confusion Assessment Method (CAM) (Inouye et al., 1990) or the 3-Minute Diagnostic Interview for Delirium Using the Confusion Assessment Method (3D-CAM) (Marcantonio et al., 2014). Both of these are brief assessments any clinician may use during their interview. Screening is key, even in the outpatient environment, as delirium may be the presentation of an acute and serious medical problem. Urgent attention should be given to the diverse etiologies that could cause it. A useful mnemonic which spells “Delirium:” “Drugs,” “Electrolyte disturbances,” “Lack of drugs,” “Infection,” “Reduced sensory input,” “Intracranial disorders,” “Urinary and fecal disorders,” and “Myocardial and pulmonary disorders” (Marcantonio, 2017). Prompt diagnostic steps should be taken, but our focus today will be on the actions mental health professionals should take, specifically a review of the medication list. Dr. Puder mentioned his favorite screening is watching patients draw a clock and having them spell “world” backward.
Moving into the med list - how we made our medication table
Numerous papers (Ancelin et al., 2006; Han et al., 2008; Sittironnarit et al., 2011; Ehrt et al., 2009; Rudolph, 2008; Chew et al., 2008; Carnahan et al., 2006; and Boustani et al., 2008, see below for discussion) describe the anticholinergic burdens and effects of different medications. A few systematic analyses and meta-analyses (e.g. Duran et al., 2013 and Salahudeen et al., 2015) have also compared studies, combining their data to create tables that score the burdens and allow some comparison among scales. While these tables were systematically formed, they were not as conducive for clinician review, so we prepared our own table based on their work.
Our table uses the basis of Duran et al. (2013) and subdivides the table into both cognitive impairment and anticholinergic-specific effects, based on the above papers. We also added Boustani et al. (2008) to the table, expanding on the work in Duran et al. (2013), and numerous further medications from the work of Carnahan et al. (2006). Then, we added conditional formatting (green for 0, yellow for 1, orange for 2, and red for 3), allowing ease of visual comparison. Each paper was hyperlinked through its DOI for reference, and brief methods were added for improved comparison to the patient population, with a short definition of what scoring system was used. Also, some common drug names, classes, and indications were inserted for improved searching.
Review of the included papers
First, we assessed a systematic review (Salahudeen et al., 2015) seeking to compare anticholinergic burden quantified through risk scales, and assess the adverse outcome associations in older populations (Salahudeen et al., 2015, para 3). This analysis included studies in English using an expert opinion anticholinergic burden quantitative scale, with a study population age of 65 or older. Their study identified seven scales (Ancelin et al., 2006; Han et al., 2008; Sittironnarit et al., 2011; Ehrt et al., 2009; Rudolph, 2008; Carnahan et al., 2006; and Boustani et al., 2008, see below for discussion) and used them to form their own table of low, medium, and high anticholinergic burden, which was the theoretical basis of our own.
We adapted the tables from Duran et al. (2013)., as noted above, and formed our table. This paper is a detailed, systematic review of anticholinergic burden, somewhat differently organized from Salahudeen et al. (2015) .
Anticholinergic Burden Classification (ABC)
Four-point scale (0-3)
Basis: serum anticholinergic activity and expert opinion
Outcomes:
Cognitive performance was measured by ECO (Examen Cognitif par Ordinateur, a computerized neuropsychometric examination)
Mild cognitive impairment was diagnosed according to the Stockholm consensus group (Winblad et al., 2004) criteria
Results: cognitive performance. Users of anticholinergics (n=297) scored lower than non-users (n=30) in the following facets of cognitive performance: reaction time, attention, delayed non-verbal memory, narrative recall, visuospatial construction, and language tasks. There was no statistical difference seen between the groups in reasoning, immediate and delayed recall of wordlists, and implicit memory. Mild cognitive impairment. MCI was found in 80% of users of anticholinergics, and 35% of non-users (odds ratio 5.12; P=0.001). Upon follow-up in 8 years, no difference in dementia development was found.
Clinician-rated Anticholinergic Score (CrAS)
Four-point scale (0-3)
Basis: pre-existing published anticholinergic scales (Han et al., 2001) and expert opinion
Outcomes: short term memory and executive function at baseline and during follow-up
Short-term memory was measured by the Hopkins Verbal Recall Test (HVRT)
Executive function was measured by the Instrumental Activity of Daily Living scale (IADLs)
Results: cumulative anticholinergic exposure over the last 12 months was associated with pooper performance in both memory and executive function. “On average, a 1-unit increase in the total anticholinergic burden per 3 months was associated with a 0.32-point and 0.10-point decrease on the HVRT and IADLs, respectively” (p. 1).
Anticholinergic Cognitive Burden (ACB)
Four-point scale (0-3)
Basis: published data and expert opinion
Searched the Medline database from 1966 to 2007 for any study that both measured the anticholinergic activities of a drug, as well as evaluated the association between this anticholinergic activity and the cognitive function in older adults (including delirium, MCI, dementia or cognitive decline)
A multidisciplinary panel of geriatricians, geriatric pharmacists, geriatric nurses, and aging brain researchers categorized these medications into mild, moderate, and severe cognitive anticholinergic negative effects
Anticholinergic Loading Scale (ACL)
Four-point scale (0-3)
Basis: pre-existing published anticholinergic scales (Ancelin et al., 2006, Han et al., 2008, Chew et al., 2008, Rudolph, 2008)
Outcomes: psychomotor speed and executive function
Results: in the healthy control, the anticholinergic load was associated with slower response speeds for the Stroop color and incongruent trials. No other relationships were noted.
Basis/Methods: a cohort study of a community-based cohort of 235 patients with Parkinson’s Disease, which were cognitively assessed over 8 years. Additionally, anticholinergic activity in medication was assessed and classified according to a standardized scale of 0 to 4. The scores from every agent used by each patient were aggregated to calculate the total AA (anticholinergic activity) load for each assessment point. The duration of treatment was scored from 0 to 3.
Outcomes: the study described the relationship between cognitive decline and AA load and duration of treatment.
Results: the results showed associations between decline on MMSE and total AA load (B = 0.229, p= 0.04) as well as duration of AA drug use (B = 0.231, p = 0.032) (Ehrt et al., 2009).
Basis/methods: a cohort study that retrospectively reviewed medical records of 132 geriatric evaluation and management (GEM) patients looking for anticholinergic medications. They also prospectively enrolled 117 primary care patients 65 years or older and performed medication reconciliation, then asked about anticholinergic adverse effects.
Outcomes: they developed the Anticholinergic Risk Scale, or ARS, a ranked categorical list of the 500 most commonly prescribed medications with possible anticholinergic effects. The medications were ranked on a scale from 0 to 3 based on anticholinergic potential. The patient’s ARS score was then calculated using the sum of the ARS rankings assigned for each of the medications the patient was taking.
Results: higher ARS scores increased the risk of anticholinergic adverse effects in both the GEM (adjusted RR, 1.3; c statistic, 0.74) and the primary care cohorts (adjusted RR, 1.9; c statistic, 0.77) (Rudolph, 2008).
Basis/methods: this study measured the anticholinergic activity of 107 medications commonly used by older adults. They then measured the AA on rodent forebrain and striatum at six clinically relevant concentrations of each medication.
Results: psychotropic medications had higher AA and Nortriptyline is dose-dependent (Chew et al., 2008).
Basis/methods: this cross-sectional observational study of delirium attempted to replicate a pilot study that associated anticholinergic drug scale scores (ADS scores) with serum anticholinergic activity (SAA).
Outcomes: the anticholinergic action of each drug was rated on a scale of 0 to 3 using the Anticholinergic Drug Scale scores. Then, the total anticholinergic scores were calculated based on the sum of the scores of each medication the subject received.
Results: ADS scores were significantly associated with and predicted serum anticholinergic activity (SAA) (P < 0.0001 for each). However, the modifications did not appear useful in optimizing the ADS (Carnahan et al., 2006).
Example medications
Hydroxyzine (e.g., Vistaril, Atarax)
Hydroxyzine is an H1-histamine antagonist (1st gen) often used as an antiemetic, anxiolytic, antipruritic, or perioperative drug. The studies we reviewed noted that it has a score of 3/3 in decreasing cognitive performance, 3 on frequency of anticholinergic events (confusion, dizziness, falls), and 3 on serum anticholinergic activity. However, we believe this is in error, due to a study Orzechowski 2005, which showed it had in humans an affinity to the acetylcholine receptor (1/Ki) estimated as 1/800 to 1/6000 nM, which means it is only an antihistamine. In patients with dementia, Dr. Cummings said he would be hesitant to use, because of the potent affinity for H1 which could cause idiosyncratic agitation.
Amitriptyline (e.g., Elavil)
A tricyclic antidepressant with many off-label uses including chronic fatigue, fibromyalgia, tension headache, interstitial cystitis, neuropathic pain.
Tricyclic antidepressants cause serotonin and norepinephrine to build up in the synaptic cleft.
Amitriptyline’s side effects are much more commonly established, however its anticholinergic burden is notable, with every study we reviewed, all eight, giving it a 3/3 score for anticholinergic burden.
For this drug, alternatives are more difficult to assess.
Amitriptyline is heavily metabolized by CYP2D6.
Nortriptyline (e.g., Pamelor)
Nortriptyline is a tricyclic antidepressant.
Some studies found amitriptyline to have a higher anticholinergic burden at a given dose compared to nortriptyline (Chew et al., 2008).
Han 2008 - 3
Ehrt 2010 - 2
Rudolph 2008 - 2
Chew 2008 - 2
Carnahan 2006 - 3
Boustani 2008 - 3
Diphenhydramine (e.g., Benadryl)
H1-receptor antagonist
Allergy symptom relief, motion sickness, insomnia
Han 2008 - 3
Rudolph 2008 - 3
Chew 2008 - 2
Carnahan 2006 - 3
Boustani 2008 - 3
Promethazine (e.g., Phenergan)
H1-receptor antagonist, dopamine receptor antagonist
Motion sickness, nausea, vomiting
Sitironnarit 0
Rudolph 3
Carnahan 3
Bustani 3
Metoclopramide (e.g., Reglan)
D2 and 5-HT3 receptor antagonist
Nausea, vomiting, gastroparesis
Han 2008 - 3
Sittironnarit 2011 - 1
Ehrt 2010 - 0
Rudolph 2008 - 1
Carnahan 2006 - 0
Quetiapine/Olanzapine (e.g., Seroquel/Zyprexa)
Decreases delirium, but also has an anticholinergic effect. At least one article argues to use haloperidol for treating delirium, though quetiapine and olanzapine may be used
Quetiapine
Han 2
Ehrt 1
Rudolph 1
Chew 1
Carnahan 0
Boustani 3
Paroxetine (e.g., Paxil)
Selective serotonin reuptake inhibitor
Strong CYP2D6 inhibitor
Desipramine increased 360% due to paxil inhibition of CYP2D6. Other tricyclic antidepressants are also increased.
Han 2,
Sittironnarit 2
Ehrt 2
Rudolph 1
Chew 2
Carnahan 1
Boustani 3
Oxybutynin (e.g., Ditropan)
Smooth muscle muscarinic antagonist
Urinary urgency
Ancelin 2006 - 3
Sittironarrit 2008 - 2
Ehrt 2010 - 3
Cetirizine (e.g., Zyrtec)
H1-receptor antagonist
Allergic rhinitis, urticaria
Han 2008 - 2
Sittironnarit 2011 - 2
Rudolph 2008 - 2
Note that Chew 2008 and Carnahan 2006 noted scores of 0
Carbidopa (e.g., Lodosyn)
Peripheral decarboxylase inhibitor
Decreases peripheral conversion of levodopa to dopamine
Han 2008 - 1
Sittironnarit 2011 - 1
Rudolph 2008 - 1
Chew 2008 and Carnahan 2006 both 0
Furosemide (e.g., Lasix)
Loop diuretic
Ascites, edema
Ancelin 2006 - 3
Sittironnarit 2011 - 0
Ehrt 2010 - 1
Chew 2008 - 1
Carnahan 2006 - 1
Boustani - 1
Baclofen (e.g., Lioresal)
Muscle relaxer
Han 2008 -2
Rudolph 2008 - 2
Chew 2008 and Carnahan 2006 both 0
Switch to robaxin
Alprazolam (e.g., Xanax)
Anxiolytic
Ancelin 2006 - 3
Han 2008 - 1
Sittironnarit 2011 - 1
Chew 2008 - 0
Carnahan 2006 - 1
Boustani 2008 - 1
Step 3 - look for other causes
While to some extent the primary service should look for other causes, the psychiatric provider should also review the patient’s medical history, recent interventions and changes, and recommend (when appropriate) subtle changes in the patient’s environment that may bring increased calm and comfort, such as: cessation of overnight vitals, cessation or periodicity of early AM lab draws (e.g. every other day), and the possibility of lighting changes or other environmental factors. Also, though complicated by the current pandemic, efforts should be made to bring family visitors to bedside to possibly create connections that have been lost.
Where to go from here
It is advisable to review a patient’s medications on an ongoing basis. At times, patients may start a medication on an inpatient basis but continue as an outpatient due to absent or miscommunication between the inpatient and outpatient providers, psychiatric or otherwise. Changes made on an inpatient basis may be continued without review, so it may be helpful to assess patients’ medication lists on a regular basis, but also immediately after a hospital discharge.
Summary:
There are medications that worsen cognitive function and all mental health providers should be aware, and work on optimizing sensorium.
To download the excel sheet that goes with this episode, go here.
To learn more about Sensorium:
Episode 006: Sensorium Part 1: Total Brain Function Optimization
Episode 009: Diet Optimization for Cognitive Function and Brain Optimization
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