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J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E Anticholinergic side-effects of drugs in elderly peopleJacobo Mintzer MD Old age is accompanied by an increased likelihood of illness, Peters5 identi®ed 22 categories with signi®cant anti- and old people take a disproportionate amount of self- cholinergic activity, including those with an anticholinergic administered and prescribed medications. In the USA, Box 1 Drugs with anticholinergic adverse effects used in the elderly people over 65 consume 30% of prescriptions and 40% of over-the-counter remedies, despite making up only 13% of the population1. In the UK, elderly people comprise only 18% of the population but use 45% of all prescription drugs, some of which are prescribed inappropriately and without proper attention to side-effects2. Elderly people living in nursing homes are even more likely to receive medications and to experience side-effects3. Thus, in one year, 97% of elderly nursing home residents received a prescription drug, compared with 71% of patients living in procyclidine, trihexyphenidyl,ethopropazine the community4. Failure to identify side-effects can lead to use of other drugs to treat the symptoms, rather than adjustment of the dose of the drug responsible.
Why do side-effects go unnoticed in elderly people? Older people often have low health expectations and are less likely to complain. Patients with cognitive impairment have dif®culties in communicating their discomfort; those living in nursing homes may rely on care staff to alert the physician to possible side-effects. Some side-effects can be mistaken for the effects of old age and age-related illness.
This is particularly the case for anticholinergic side-effects, which are among the most common drug-related effects experienced by elderly people living in nursing and residential homes5,6. This review highlights the need for better understanding, assessment and management of anticholinergic side-effects in elderly people.
Blazer et al.4 reported that, during one year, nearly 60% of dexchlorpheniramine,hydroxine, mepyramine nursing home residents had received drugs with anti- cholinergic (antimuscarinic) activity, compared with 23% of elderly people living in the community. The most frequently prescribed of these drugs were thioridazine, chlorpromazine and diphenoxylate/atropine. Several types of drug can cause anticholinergic side-effects (Box 1).
nortriptyline, protriptyline,amoxapine, maprotiline,clomipramine Medical University of South Carolina, Department of Psychiatry (PH-141), 67 President Street, PO Box 250861, Charleston, South Carolina, 29425, USA; 1School of Psychiatry and Behavioural Sciences, University Hospital of South Correspondence to: Professor Jacobo Mintzer J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E Table 1 In-vitro anticholinergic activity (at 10 nmol/L) of the does not always predict clinical effects; alternatively, the 25medications most commonly prescribed to elderly people activity reported by Tune et al., though insuf®cient to cause obvious side-effects with cimetidine monotherapy in young adults, might be troublesome in those already receiving anticholinergic medications or otherwise vulnerable. High doses of cimetidine in elderly patients have occasionally been associated with reversible confusional states (confu- sion, delirium, slurred speech, hallucinations, coma8).
Symptoms which may be caused by drugs with anti- . Dry or sticky lips; dif®culty beginning to speak (need to . Urinary disorders, necessitating use of catheter . Insecure movement; falls without obvious reason, . Increased anxiety, with rapid, shallow breathing, mode of action (e.g. drugs for parkinsonism, irritable bowel syndrome, urinary incontinence) and others with unwanted Anticholinergic actions affect multiple systems, causing a anticholinergic effects. Tune et al.7 looked for in-vitro range of peripheral and central side-effects and symptoms anticholinergic activity in the 25 drugs most commonly (Table 2). Central anticholinergic effects include memory prescribed for elderly people and found such activity in 14 de®cits, confusion and disorientation, agitation, hallucina- (Table 1). Often, elderly patients receive several such drugs tions and delirium4,6. In the extreme, anticholinergic toxicity depresses brain function, with coma and circulatory Many non-prescription drugs have anticholinergic potential; this is true of the antihistamines in cold/¯u and hayfever treatmentsÐe.g. diphenhydramine (Benylin Four Flu); triprolidine (Actifed); chlorpheniramine (Piriton/ Why should old people be at increased risk of anti- Contact 400); and promethazine (Night Nurse/Phenergan).
cholinergic side-effects4,9? Part of the reason may lie in Skin creams and lotions also contain antihistaminesÐe.g.
de®cient drug metabolism and elimination, as well as age- diphenhydramine (Allereze cream) or mepyramine (Anthi- related de®cits in cholinergic neurotransmission6. For san)Ðand treatments for sleep disturbance include people living in nursing homes, with little to distract them, diphenhydramine (Nightcalm/Nytol) and promethazine side-effects can be particularly distressing and dif®cult to (Sominex/Phenergan). Some hayfever medications contain cope with. For example, dry mouth, while apparently theophylline (e.g. Chest-Eze), antidiarrhoeals include trivial, can cause speech dif®culties, dental decay or trouble extract of belladonna (Enterosan, Opazimes) and some with dentures. Chewing and swallowing may become treatments for irritable bowel syndrome contain hyoscine painful, and the patient may refuse solid food. The pain of dry mouth can be extremely distressing for older patients, The number of drugs with anticholinergic potential who may become frustrated and agitated by an inability to available without prescription is increasing6, so that the use of such medications is becoming more dif®cult to monitor.
Older people often have multiple illnesses. In the USA For example, histamine H2 antagonists can be had over the as many as ®ve chronic conditions in one person is not counter for indigestionÐcimetidine (Tagamet/Acid-eze); unusual10, and conditions such as angina, congestive heart ranitidine (Zantac); famotidine (Pepcid AC). Of those drugs failure, constipation, diabetes mellitus, glaucoma, urinary examined by Tune et al.7, cimetidine had the highest anti- dysfunction, sleep disturbance and dementia are all cholinergic activity in vitro, although side-effects attributed worsened by drugs with anticholinergic activity6. Pupillary to this activity do not feature in the labelling of cimetidine.
dilatation and the inability to accommodate will impair near 458 One interpretation is that in-vitro pharmacological activity vision, thus increasing the risk of accidents, including falls, J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E Table 2 Spectrum of anticholinergic side-effects (Adapted from Ref. 6) Impaired perception of taste and texture of food Mucosal damageDental decay, periodontal disease, denture mis®tMalnutritionRespiratory infection Increased risk of accidents and falls, leading to Exacerbation/precipitation of acute angle closure Faecal impaction (in patients with constipation) Reduced gastric secretions, gastric emptying Altered absorption of concomitant medications Urinary retention, urinary tract infection Conduction disturbances, supraventricular Exacerbation of anginaCongestive heart failure Profound restlessness and disorientation, Ataxia, muscle twitching, hyperre¯exia, seizuresExacerbation of cognitive impairment (in patients and may precipitate narrow-angle glaucoma in predisposed events6. Nevertheless, physicians often attribute anti- patients. In patients with constipation, anticholinergic cholinergic symptoms in elderly people to ageing or age- effects may lead to stomatitis, paralytic ileus or faecal related illness rather than the effects of drugs6. Even impaction. Drug-induced increases in heart rate may physicians and carers who appreciate that such symptoms worsen symptoms of angina, and inhibition of sweating can be drug-induced may regard them as inevitable, simply may cause life-threatening hyperthermia. Patients with urinary hesitancy may experience urinary retention and urinary tract infection, a common cause of delirium. Men with prostatism are at high risk of acute urinary retention as In their nursing home study, Blazer et al.4 calculated that Delirium can be caused by blockade of brain muscarinic between 21% and 32% of residents could have been taking receptors; drugs with anticholinergic activity are the most two or more drugs with anticholinergic activity (three or common cause of drug-induced delirium7,11. More than more drugs 10±17% of patients; ®ve or more drugs, up to one-®fth of elderly patients admitted to hospital develop 5%). The most common combinations were thioridazine/ delirium, particularly those with dementia and multiple benzhexol and thioridazine/chlorpromazine (benzhexol is illnesses. In patients with dementia, anticholinergic drugs now seldom used). However, combined use of thioridazine further inhibit cognitive performance and counteract the and amitriptyline (each with marked anticholinergic bene®cial effects of cholinergic enhancers used to treat activity) was also very common, demonstrating a lack of concern about combined anticholinergic effects.
Williamson et al.9 examined the use of psychotropics Partly through legislation, there have been reductions in and antiparkinsonian drugs (both have marked anti- the use in US nursing homes of psychotropic drugs, many of cholinergic effects) in nearly 2000 patients admitted to which have marked anticholinergic activity12. The avail- geriatric units. More than a quarter were receiving one such ability of newer psychotropic drugs has also had an drug, and 13% of those patients had signi®cant adverse impact on prescribing by primary care physicians J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E treating patients in nursing homes13. With increasing use of dementia23±25, despite a lack of prospective placebo- newer psychotropics anticholinergic side-effects in elderly controlled studies on their use in these circumstances26.
people may be declining, but many different drugs have Substantial differences exist between conventional neuro- some anticholinergic activity and elderly patients receiving leptic drugs with respect to anticholinergic activity; multiple drugs are still at risk of `anticholinergic load'14. In chlorpromazine and thioridazine have the highest theory the physician can predict the anticholinergic load and activity27,28 with considerable side-effects29 (see Box 1).
the risk of side-effects associated with any combination of Haloperidol has lower muscarinic af®nity and the risk of drugs. In practice, the information available from the anticholinergic side-effects is lower, but extrapyramidal product label and from the published work focuses on side- symptoms are more troublesome29. Conventional neuro- effects of drugs used as monotherapy. The concept of leptic drugs can also cause other side-effects. Low doses anticholinergic load illustrates that side-effects can be have been recommended for elderly patients, although this caused by combinations of drugs, even if the individual may limit the ef®cacy of these agents26.
drugs do not cause obvious side-effects.
Novel antipsychotic drugs have been widely studied in younger patients (particularly those with schizophrenia), but for most drugs no controlled trials have been reported in elderly patients26. An exception is risperidone, which has These are among the most common medications taken by been compared with placebo in two trials in elderly nursing elderly people living in nursing homes (mainly anti- home patients with dementia30,31. Risperidone is the only psychotics, antidepressants and anxiolytics/sedatives).
novel antipsychotic so far registered for this indication in Spore et al.15 found that 43% of elderly patients in certain countries (though not in the UK). It has no residential care were receiving psychotropic drugs.
measurable anticholinergic activity28 and has not been Antidepressants and antipsychotics have been linked most reported to cause anticholinergic side-effects in elderly often with disorders due to anticholinergic activity.
patients30,31. By contrast, clozapine has marked anti- cholinergic activity and is associated with profound anticholinergic side-effects32±34. When clozapine (and other The use of antidepressants in elderly people requires antipsychotics with high anticholinergic activity) are with- particular care16,17. Tricyclic antidepressants (TCAs) have drawn, two types of withdrawal reaction are seenÐ been in use for over 30 years, and imipramine and `cholinergic rebound', with nausea, vomiting, loss of amitriptyline are the standard against which new drugs are appetite, malaise, diarrhoea, rhinorrhoea, sweating, evaluated. Old patients are more likely than young adults anxiety, agitation and insomnia35,36; and movement to experience side-effects with TCAs (see Box 1 for disorders such as dyskinesia, akathisia and parkinsonism37.
examples). Apart from the postural hypotension and When switching patients to a drug with low anticholinergic sedation associated with the TCAs, anticholinergic side- potential, physicians sometimes mistake withdrawal symp- effects such as constipation, urinary retention and toms for the side-effects of the new drug.
confusion are particular causes for concern. Some authorities have advised against the use of TCAs such as imipramine, amitriptyline and doxepin in the elderly because of their side-effects, not least their anticholinergic Physicians should be alert to the possibility that dry mouth, effects18±20. Nortriptyline, lofepramine and desipramine constipation and blurred vision may be caused by (the least anticholinergic of the TCAs) tend to be better medication. Changes in intellectual function should also be investigated, especially in patients who already have Some newer antidepressants may be useful alternatives cognitive impairment. For patients in whom side-effects can to TCAs in elderly people21. The selective serotonin have particularly unpleasant consequences (e.g. those with reuptake inhibitors such as ¯uoxetine and sertraline have gastrointestinal disease, bladder neck obstruction, glau- been recommended, partly because of their relative coma, cardiac disease or cognitive impairment), serious freedom from anticholinergic side-effects19,20. Nefazodone, consideration should be given to switching to a drug that bupropion, venlafaxine and mirtazapine also have less anticholinergic potential than the older drugs22.
For most drugs with anticholinergic potential an alternative is available. Combinations of drugs with strong anticholinergic activity, such as thioridazine and amitripty- line, should obviously be avoided. The use of drugs with Conventional neuroleptic drugs are widely used in the minimal anticholinergic activity from the outset should 460 treatment of behavioural and psychological symptoms of avoid the need to switch medication (and the risk of J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E cholinergic rebound). If switching is necessary, the hazard 3 Furniss L, Burns A, Craig S, Cooke J, Scobie S. The effect of a of rebound can be lessened by slowly tapering the doses, pharmacist's intervention in nursing and residential homes. Br J with additional anticholinergic medication if necessary38.
4 Blazer DG, Federspiel CF, Ray WA, Schaffner W. The risk of For patients already receiving treatment, the current anticholinergic toxicity in the elderly: a study of prescribing practices anticholinergic load should always be considered before in two populations. J Gerontol 1983;38:31±5 another drug is introduced. If the current load is high, even 5 Peters NL. Snipping the thread of life. Antimuscarinic side effects of drugs with moderate or low anticholinergic activity may medications in the elderly. Arch Intern Med 1989;149:2414±20 precipitate side-effects. No drug should be introduced 6 Feinberg M. The problems of anticholinergic adverse effects in older without careful assessment of existing medications and 7 Tune L, Carr S, Hoag E, Cooper T. Anticholinergic effects of drugs symptoms. Often, there is little published information on commonly prescribed for the elderly: potential means for assessing risk the complex combinations of drugs used in elderly people.
of delirium. Am J Psychiatry 1992;149:1393±4 In-vitro activity can only be a broad predictor of clinical 8 Martindale the Extra Pharmacopeia. London: Pharmaceutical Press, 1989 effects, and information from clinical trials may likewise be 9 Williamson J, Chopin JM. Adverse reactions to prescribed drugs in the of limited value; for example, so far, trials of antipsychotic elderly: a multicentre investigation. Age Ageing 1980;9:73±9 drugs in elderly people have not speci®cally inquired about 10 OTA Project Staff, Solan G, Behney C, et al. Prescription Drugs and Elderly Americans:Ambulatory Use and Approaches for Coverage for Medicare.
anticholinergic side-effects but have relied on spontaneous Washington, DC: US Congress Of®ce of Technology Assessment, reporting by patients or carers. The range and severity of side-effects may therefore have been underestimated.
11 Jitapunkal S, Pillay I, Ebrahim S. Delirium in newly admitted elderly persons: a prospective study. Quart J Med 1992;83:307±14 12 Rovner BW, Edelman BA, Cox MP, et al. The impact of antipsychotic drug regulations on psychotropic prescribing practices in nursing Informing patients and carers about potential side-effects is 13 Lasser RA, Sunderland T. Neuropsychotropic medication use in of great importance. Dif®culties with side-effects are likely nursing home residents. J Am Geriatr Soc 1998;46:202±7 to result in poorer treatment outcomes and are a major 14 Seifert R, Jamieson J, Gardner R. Use of anticholinergics in the nursing cause of non-compliance. If patients and carers are home: an empirical study. Drug Intell Clin Pharmacy 1983;17:470±3 sensitively informed about unwanted effects, this will help 15 Spore D, Mor V, Larrat EP, Hiris J, Hawes C. Regulatory environment and psychotropic use in board-and-care facilities: to reduce the anxiety and distress that side-effects may results of a 10-state study. J Geront A Biol Sci Med Sci 1996; 16 Gerson SC, Plotkin DA, Jarvik LF. Antidepressant drug studies 1964 to 1986: empirical evidence for aging patients. J Clin Psychopharmacol When anticholinergic side-effects do occur and the drug 17 Alexopoulos GS. Treatment of depression. In: Salzman C, ed. Clinical Geriatric Psychopharmacology. Baltimore: Williams & Wilkins, 1992 cannot be stopped, some steps can be taken to reduce their 18 Meyers BS, Kalayam B. Update in geriatric psychopharmacology. In: impact on the patient. The discomfort of dry mouth can be Billig N, Rabind PV, eds. Issues in Geriatric Psychiatry. Basel: Karger, reduced by taking sips of water, or by chewing sugarless gum or soft sweets, while arti®cial tears are useful for dry 19 Preskorn SH. Recent pharmacologic advances in antidepressant therapy eyes. Pilocarpine solution has been used as a mouthwash for for the elderly. Am J Med 1993;94:2S±12S dry mouth or as eye drops for blurred vision39,40.
20 Salzman C. Pharmacologic treatment of depression in the elderly. J Constipation can be reduced by high-®bre diets, ®bre 21 Katona CLE. New antidepressants in the elderly. In: Holmes, C, supplements, increased ¯uid intake or greater patient Howard R, eds. Advances in Old Age Psychiatry:Chromosomes to Community mobility (e.g. walking down the ward to meals). Oral Care. Peters®eld: Wrightson Biomedical Publishing, 1997;143±60 bethanechol, a cholinergic agonist, has been used to treat 22 Katona C, Livingston G, Manela M, et al. The symptomatology of anticholinergic effects but can itself cause tremor, diarrhoea depression in the elderly. Int J Psychopharmacol 1997;12(suppl 7):S19±23 and abdominal cramps39. Furthermore, treatment of drug 23 Yeager BF, Farnett LE, Ruzicka SA. Management of the behavioral manifestations of dementia. Arch Intern Med 1995;155:250±60 side-effects with another drug is not good practice; a much 24 Sunderland T. Treatment of the elderly suffering from psychosis and better strategy is to prescribe a medication relatively free dementia. J Clin Psychiatry 1996;57(suppl 9):53±6 25 Herrmann N, Lanctot KL, Naranjo CA. Behavioral disorders in demented elderly patients: current issues in pharmacotherapy. CNS 26 Stoppe G, Brandt CA, Staedt JH. Behavioural problems associated with dementia: the role of newer antipsychotics. Drugs Aging 1999;14:41±54 1 Salom IL, Davis K. Prescribing for older patients: how to avoid toxic 27 Bolden C, Cusack B, Richelson E. Antagonism by antimuscarinic and drug reactions. Geriatrics 1995;50:37±40 2 Royal College of Physicians. Medication for Elderly People. London: RCP, cholinergic receptors expressed in Chinese hamster ovary cells. J J O U R N A L O F T H E R O Y A L S O C I E T Y O F M E D I C I N E 28 Bymaster FP, Calligaro MS, Falcone JF, et al. Radioceptor binding 34 Chengappa KN, Baker RW, Kreinbrook SB, Adair D. Clozapine use in pro®le of the atypical antipsychotic olazapine. Neuropsychopharmacology female geriatric patients with psychoses. J Geriatr Psychiatr Neurol 1995; 29 Goff DC, Schader RI. Non-neurological side effects of antipsychotic 35 Staedt J, Stoppe G, Hajak G, Ruther E. Rebound insomnia after abrupt agents. In: Hirsch SR, Weinberger DR, eds. Schizophrenia. Oxford: clozapine withdrawal. Eur Arch Psychiatry Clin Neurosci 1996;246:79±82 36 Durst R, Teitelbaum A, Katz G, Knobler HY. Withdrawal from 30 Katz IR, Jeste DV, Mintzer JE, Clyde C, Napolitano J, Brecher M.
clozapine: the ``rebound phenomenon''. Isr J Psychiatry Relat Sci 1999; Comparison of risperidone and placebo for psychosis and behavioural disturbances associated with dementia: a randomized, double-blind 37 Ahmed S, Chengappa KN, Naidu VR, Baker RW, Parepally H, trial. Risperidone Study Group. J Clin Psychiatry 1999;60:107±15 Schooler NR. Clozapine withdrawal-emergent dystonias and 31 De Deyn PP, Rabberu K, Ramussen A, et al. A randomized trial of dyskinesias: a case series. J Clin Psychiatry 1998;59:472±7 risperidone, placebo, and haloperidol for behavioral symptoms of 38 Borison RL. Changing antipsychotic medication: guidelines on the transition to treatment with risperidone. The Consensus Study Group 32 Kumar V. Use of atypical antidepressants in geriatric patients: a on Risperidone Dosing. Clin Ther 1996;18:592±607 review. Int J Geriatr Psychopharmacol 1997;1:15±23 39 Ettinger RL. Xerostomia: a complication of ageing. Aust Dent J 1981; 33 Pitner JK, Mintzer JE, Pennypacker LC, Jackson CW. Ef®cacy and adverse effects of clozapine in four elderly psychotic patients. J Clin 40 Baker KA, Ettinger RL. Intra-oral effects of drugs in elderly persons.

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