Anticholinergic effects of medication in elderly patients

Anticholinergic Effects of Medication in the Elderly Anticholinergic Effects of Medication in Elderly Patients
Larry E. Tune, M.D.
Anticholinergic toxicity is a common problem in the elderly. It has many effects ranging from dry Copyright 2001 Physicians Postgraduate Press, Inc.
mouth, constipation, and visual impairments to confusion, delirium, and severe cognitive decline. Thetoxicity is often the result of the cumulative anticholinergic burden of multiple prescription medica-tions and metabolites rather than of a single compound. The management of elderly patients, particu-larly those suffering from dementia, should therefore aim to reduce the use of medications with anti-cholinergic effects.
(J Clin Psychiatry 2001;62[suppl 21]:11–14) n frail, elderly patients, particularly those with demen- tia, anticholinergic toxicity can result in excess morbid- ity and mortality, behavioral symptoms (including agita- Delirium and confusional states are common in elderly tion), and delirium. The problem is not new—it is dis- patients with dementia. They are an important contributor cussed in the writings of Hippocrates and Celsus—but it to behavioral symptoms and give rise to significant levels is becoming more widely recognized. This increased rec- of morbidity and mortality. Delirium has an associated ognition is mainly a result of the aging population and the mortality rate of up to 40% and is present in 10% to 25% concomitant dramatic increase in the number of medica- tions that patients are prescribed. In the United States, for In the Commonwealth-Harvard study, Levkoff et al.2 in- example, the average 85-year-old patient may take an av- vestigated all geriatric (age > 65 years) admissions to the erage of 8 to 10 prescription medicines. In addition, they Beth Israel Hospital, Massachusetts, from either the com- may be taking nonprescription substances, such as St.
munity or nursing homes. They found that, during 1 year, 24% of admissions who had been living in the community In most instances, it is this accumulation of medicines were delirious compared with 64% of patients admitted that gives rise to anticholinergic toxicity. The problem from the extended-care rehabilitation facility. Rovner et does not occur because patients are overdosing on indi- al.3 examined 454 new admissions to nursing home facili- vidual drugs, such as benztropine or biperiden, but rather ties in the Baltimore, Maryland, area. They found that 17% because the different drugs, both psychiatric and non- had significant behavioral problems. The 3 leading causes psychiatric, taken by the patient produce a significant anti- were delirium, delusions, and depression.
In a separate study, Lerner et al.4 examined 199 well- Several published studies have found significant corre- defined cases of Alzheimer’s disease (AD). They found lations between peripheral serum anticholinergic levels that 17% of these patients had experienced delirium in the and functional disability, agitation in dementia, and de- previous 3 years. The primary causes were found to be uri- lirium. In this article, data from a number of these clinical nary tract infection, stress, surgery, medical illness, and investigations are reviewed. Specific recommendations to medications. Importantly, delirious demented patients had avoid or replace medications with anticholinergic effects more hallucinations and more paranoid delusions for the remainder of their illness than did nondelirious patients;only 19% recovered to baseline levels.
The risk factors for and possible causes of delirium are From the Division of Geriatric Psychiatry, Wesley Woods Center on Aging, Emory University School of Medicine,Atlanta, Ga. Presented at the symposium “Restoring Harmony—Adding Life to Years,” which was held June 16–17, 2000, in Seville, Spain, and supported by an unrestricted educational grantby Janssen Cilag and Organon. Financial disclosure: Dr. Tune is a consultant for Pfizer, Why focus on acetylcholine? Acetylcholine is important Abbott, Eisai, Janssen, and AstraZeneca; has received grant/research support from Janssen, Eisai, Pfizer, Lilly, and Bristol- since it decreases with patient age and is reduced in patients Myers; and has received honoraria from and is on the speakers with AD and other dementias. Cholinergic disturbance is bureau for Janssen, AstraZeneca, Pfizer, Eisai, and Abbott. Reprint requests to: Larry E. Tune, M.D., Wesley Woods also postulated as the central lesion in delirium. There are Geriatric Center, 1821 Clifton Rd., Atlanta, GA 30329. over 600 known anticholinergic medications, and a dispro- Table 1. Risk Factors for and Possible Causes of Deliriuma
Table 2. Systems Affected by Cholinergic Impairment and
Patient Outcomesa
Copyright 2001 Physicians Postgraduate Press, Inc.
Chronic obstructive pulmonary disease causing hypoxia Reprinted, with permission, from Feinberg.8 cause agitation because of the associated discomfort.
Treating the agitation with an antipsychotic that has anti-cholinergic properties will worsen the impaction and ag- gravate the agitation. Finally, visual impairments, such as Anticholinergic effects of many drugsRecent medication change mydriasis, may increase the risk of accidents and can pre- Need to rule out withdrawal syndrome (eg, from alcohol or cipitate narrow-angle glaucoma in patients predisposed aData on possible causes from Lipowski.5,6 Central anticholinergic effects range from sedation, confusion, and inability to concentrate to frank delirium,agitation, hallucinations, and severe cognitive decline.1,8 portionately large number of them (11%) are commonly Even mild central effects can reduce cognitive function and so increase dependency, resulting in greater caregiver The morbidity and management issues associated with burden, increased health care costs, reduced quality unwanted anticholinergic activity are underestimated and of life, and impaired activities of daily living.1,8 At the frequently overlooked.8 Anticholinergic side effects are other end of the spectrum, delirium, as mentioned above, common, but are often viewed as “unavoidable” or as a has serious consequences in terms of morbidity and mor- normal part of the aging or disease process. Table 2 pro- vides a summary of body systems affected by anticholiner- AD is the most common primary dementia in the el- gic side effects and the potential consequences of these ef- derly. A number of mechanisms have been suggested for the disease process, but a decrease in acetylcholine is a Peripheral anticholinergic effects include decreased se- change associated with the condition. It correlates closely cretions, slowed gastrointestinal motility, blurred vision, both with the characteristic neuropathologic changes and and increased heart rate. These may be uncomfortable for with the severity of the disease.11 The most successful a younger patient in relatively good health, but in older pa- strategy for the treatment of AD so far is to increase the tients they may be disastrous.8 The most common side ef- level of available acetylcholine by inhibiting the enzyme fect, dry mouth, may appear trivial at first sight, but can responsible for its metabolism. It is clear that adding a lead to an increased risk of serious respiratory infection, drug with anticholinergic effects is likely to worsen the dental or denture problems, impaired nutritional status, disease process, and this may account for the cognitive and a reduction in the ability to communicate.
decline seen in patients treated with certain agents.1,12–14 Other peripheral anticholinergic effects include con- Medications with anticholinergic effects, even mild stipation, causing pain, fecal compaction, and increased effects, are an important cause of acute and subacute de- use of laxatives,8,9 and urinary retention, resulting in dis- lirium in the elderly. One of the aims of treatment, there- comfort, urinary tract infections, and an increased need for fore, should be to reduce and limit the use of medications catheterization. Catterson et al.10 note the potential for a with anticholinergic effects. Some of the common anti- “vicious circle” of treatment and side effects. Fecal impac- cholinergic medicines are presented in Table 3. Notably, tion occurs frequently in patients with dementia and can while most psychiatrists would recognize the tricyclic an- Anticholinergic Effects of Medication in the Elderly Table 3. Commonly Used Medicines That Have
Figure 1. Relative Anticholinergic Potencies of 4 Atypical
Anticholinergic Effectsa
Antipsychotics in Comparison With Atropinea
Furosemide Copyright 2001 Physicians Postgraduate Press, Inc.
aReprinted, with permission, from Richelson.17 *Affinity = 10–7 × 1/K , where K = equilibrium dissociation constant Figure 2. Number of Anticholinergic Medications Taken by
Delirious and Nondelirious Patientsa
Total MedicationsTotal Anticholinergic Medications tidepressants as having anticholinergic properties, fewer would identify the antibiotics tobramycin and clindamycin as having significant anticholinergic effects. Some of theantipsychotics used for the treatment of behavioral and psychological symptoms of dementia also have anticho- linergic activity. These include thioridazine, chlorproma- aReprinted, with permission, from Tune and Egeli.18 zine, loxapine, clozapine, and, to an extent, olanzapine. In- *p < .007 vs. patients who were not delirious.
deed, a study by Richelson16 showed that olanzapine hasthe greatest M binding affinity of all atypical antipsy- chotics, and the U.S. package insert for olanzapine clearly lists possible adverse events related to anticholinergic ac- tivity. Risperidone, however, has no appreciable anticho-linergic properties. The relative anticholinergic potencies In a further study,7 34 residents of nursing homes were of 4 atypical antipsychotics, in comparison with atropine, assessed using psychometric tests, including the Saskatoon Delirium Checklist, the Wechsler Memory Scale (digits), Tune and Egeli18 examined 91 patients referred to the and the Mini-Mental State Examination (MMSE). All pa- Emory University Neurobehavioral Unit for “dementia tients had been receiving at least one “significant” anticho- with agitation.” Patients were classified as delirious or not linergic (commonly thioridazine) for more than 2 weeks.
on the basis of the Confusion Assessment Method and Patients were randomly assigned to intervention or nonin- the Pittsburgh Agitation Scale.19 A total of 47 patients were tervention groups. The intervention was to reduce the anti- categorized as delirious, compared with 44 nondelirious cholinergic load by 25%. Following this intervention for (but agitated and demented) patients. When the patients’ 2 weeks, the psychometric tests were readministered. De- medications were compared, it was found that the patients lirium significantly improved in the intervention group with delirium were receiving significantly more anti- compared with the control patients, as did attention span cholinergic medications than the nondelirious patients (Wechsler). The MMSE also showed the predicted trend, even in this small group of patients, although the difference was not statistically significant. Thus, reducing anticholin- 3. Rovner BW, Steele CD, German P, et al. Psychiatric diagnosis and uncoop- ergic load is an effective intervention.
erative behavior in nursing homes. J Geriatr Psychiatry Neurol 1992;5:102–105 4. Lerner AJ, Hedera P, Koss E, et al. Delirium in Alzheimer disease. Alzhei- 5. Lipowski ZJ. Delirium (acute confusional states). JAMA 1987;258: Anticholinergic toxicity is an important cause of de- 6. Lipowski ZJ. Update on delirium. Psychiatr Clin North Am 1992;15: lirium and confusional states in demented, agitated patients.
Importantly, the toxicity arises not from individually pow- 7. Tollefson GD, Montague-Close J, Lancaster SP. The relationship of serum anticholinergic activity to mental status performance in an elderly nursing erful drugs, but from an accumulation of anticholinergic home population. J Neuropsychiatry Clin Neurosci 1991;3:314–319 Copyright 2001 Physicians Postgraduate Press, Inc.
burden from a number of different medications. To reduce 8. Feinberg M. The problems of anticholinergic adverse effects in older pa- the morbidity and mortality associated with the anticholin- 9. Monane M, Avorn J, Beers MH, et al. Anticholinergic drug use and bowel ergic burden, patients’ medications should be closely moni- function in nursing home patients. Arch Intern Med 1993;153:633–638 tored. Where possible, medicines with anticholinergic ef- 10. Catterson ML, Preskorn SH, Martin RL. Pharmacodynamic and pharmaco- fects should be avoided in elderly patients, particularly kinetic considerations in geriatric psychopharmacology. Psychiatr ClinNorth Am 1997;20:205–218 11. Levy R. Is there life in the neurotransmitter approach to the treatment of Alzheimer’s disease? In: Levy R, Howard R, Burns A, eds. Treatment andCare in Old Age Psychiatry. Petersfield, United Kingdom: Wrightson Bio- Drug names: alprazolam (Xanax and others), amitriptyline (Elavil and others), benztropine (Cogentin and others), biperiden (Akineton), chlor- 12. Chui HC, Lyness SA, Sobel E, et al. Extrapyramidal signs and psychiatric diazepoxide (Librium and others), cimetidine (Tagamet and others), clo- symptoms predict faster cognitive decline in Alzheimer’s disease. Arch zapine (Clozaril and others), desipramine (Norpramin and others), dexa- methasone (Decadron and others), diazepam (Valium and others), 13. Stern Y, Mayeux R, Sano M, et al. Predictors of disease course in patients with probable Alzheimer’s disease. Neurology 1987;37:1649–1653 hydramine (Benadryl and others), doxepin (Sinequan and others), fu- 14. McShane R, Keene J, Gedling K, et al. Do neuroleptic drugs hasten cogni- rosemide (Lasix and others), loxapine (Loxitane and others), methyl- tive decline in dementia? prospective study with necropsy follow-up. BMJ dopa (Aldomet and others), nifedipine (Adalat, Procardia), olanzapine (Zyprexa), oxazepam (Serax and others), phenelzine (Nardil), quetia- 15. Tune L, Carr S, Hoag E, et al. Anticholinergic effects of drugs commonly pine (Seroquel), ranitidine (Zantac), risperidone (Risperdal), warfarin prescribed for the elderly: potential means for assessing risk of delirium.
16. Richelson E. Preclinical pharmacology of neuroleptics: focus on new gen- eration compounds. J Clin Psychiatry 1996;57(suppl 11):4–11 17. Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999;60(suppl 10):5–14 1. Mach JR Jr, Dysken MW, Kuskowski M, et al. Serum anticholinergic activ- 18. Tune LE, Egeli S. Acetylcholine and delirium. Dement Geriatr Cogn ity in hospitalized older persons with delirium: a preliminary study. J Am 19. Rosen J, Burgio L, Kollar M, et al. The Pittsburgh Agitation Scale: a user- 2. Levkoff S, Cleary P, Liptzin B, et al. Epidemiology of delirium: an over- friendly instrument for rating agitation in dementia patients. Am J Geriatr view of research issues and findings. Int Psychogeriatr 1991;3:149–167

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