CPAPtalk.com

Anticholinergic Agents
This class includes drugs with known anticholinergic properties such as the first-generation, sedating antihistamines (eg, diphenhydramine, hydroxyzine, chlorpheniramine, meclizine), antispasmodics (eg, belladonna, diphenoxylate, clinidium, dicyclomine, hyoscyamine), oxybutynin, trazodone, ipratropium bromide, tricyclic antidepressants (which are discussed separately under antidepressants), phenothiazines (eg, thioridazine, prochlorperazine, promethazine, chlorpromazine, fluphenazine), muscle relaxants (cyclobenzaprine, orphenadrine), mydriatics (atropine, homatropine, tropicamide), diphenoxylate/atropine, antiparkinsonian agents (eg, benztropine, trihexyphenidyl), and antiarrhythmics (eg, disopyramide, quinidine, procainamide). Further, other drugs which may have possible anticholinergic effects include codeine, colchicine, warfarin, digoxin, furosemide, haloperidol, isosorbide dinitrate, meperidine, nifedipine, cimetidine, ranitidine, prednisolone, quinidine, and theophylline.[10,35-37] Many drug classes starting with the prefix "anti" have anticholinergic properties (eg, antihistamines, antidepressants, antipsychotics, antispasmodics, antiparkinsonian drugs, and some antihypertensives) and may help alert the practitioner to drugs that may be a source of confusion in their patients.[38]

Anticholinergic agents have been causally linked to the development of memory impairment in healthy subjects. Memory impairment may be associated with basal forebrain cholinergic pathways, whereas changes in consciousness seen in delirium may be attributable to alterations in pontine cholinergic pathways projecting into the frontal cortex and brain stem. Acetylcholine is also involved with attention, the sleep-wake cycle, and other aspects of cognitive functioning.[8,13]

In a study that was published in 1983, approximately 60% of nursing home residents and 23% of ambulatory patients were receiving drugs with anticholinergic properties. In some cases, patients may have received 3 or more anticholinergic medications concurrently.[39]

Tune and others[36] examined the anticholinergic effects of drugs commonly prescribed for the elderly as a potential means for assessing risk of delirium (Table 4). Using a standard concentration of 10-8 M of 25 compounds and an anticholinergic radioreceptor assay, they assessed these substances against an internal standard of atropine. Atropine equivalents represented in nanograms per milliliter of equivalent amounts of atropine were compared to the test drug. Of the 25 drugs tested, 14 produced detectable anticholinergic effects with 10 of these 14 medications, resulting in anticholinergic levels that have been associated with significant deficits in memory and attention in normal elderly.

Medications that were not associated with anticholinergic effects in this study included hydrochlorothiazide, propranolol, salicylic acid, nitroglycerin, insulin, methyldopa, ibuprofen, diltiazem, atenolol, metoprolol, and timolol.[36]

In an earlier paper, Tune and colleagues[40] had found that postoperative cardiac surgery patients who had experienced delirium had high serum levels of anticholinergic drugs and that impairment in cortical function was related to this elevated level. This group later examined the cumulative anticholinergic effects of drug regimens among surgical intensive care unit patients.[41] They have since expanded their work to examine the anticholinergic effects of 48 commonly prescribed medications.[42]

Flacker and colleagues[35] analyzed the association of serum anticholinergic activity with delirium in medical patients aged 75 or older. Delirium was associated with a higher serum anticholinergic activity quintile. The number of symptoms of delirium were also associated with higher serum anticholinergic activity. Mach and colleagues[43] demonstrated the resolution of delirium in an elderly population upon discontinuation of medications, which resulted in a reduction of serum anticholinergic levels. Only 5 of 17 medications discontinued were known to have in vitro anticholinergic activity. Even topically administered anticholinergic ophthalmic preparations have been associated with the development of delirium.[44,45] Other investigators have reported the presence of high serum anticholinergic levels among patients who have not received a drug that blocks acetylcholine, which raises the possibility of an endogenous source of anticholinergic activity that may possibly increase during times of stress.[35,46] Among elderly nursing home residents, serum anticholinergic activity seems to increase during illness and declines upon recovery, regardless of medication changes.[47]

In the presence of central anticholinergic toxicity, the use of physostigmine (a 1- to 2-mg test dose) may rapidly improve mental status. However, this drug has many severe side effects, including increased secretions, bronchospasm, vomiting, aspiration, and bradycardia, so its routine use cannot be advocated in the elderly.[10] The value of acetylcholinesterase inhibitors such as donepezil in this setting is unclear. Often, removing the causative agent and offering supportive care may be sufficient.

In summary, the likelihood of developing delirium following ingestion of an anticholinergic is unpredictable and may depend on other concomitant medications that exert anticholinergic effects, baseline cognitive status, pharmacokinetic or pharmacodynamic effects, specific agent used, and the total anticholinergic burden.[18]

It should also be stated that despite all of this evidence, the association between anticholinergic drugs and the development of delirium is not universally accepted. Francis and coworkers [4] and Schor and colleagues[48] failed to demonstrate causality between the use of these agents and the development of delirium in elderly medical inpatient populations. Yet others have felt that the lack of association between delirium and anticholinergic drugs in epidemiologic studies is one of misclassification of drug effects rather than the inability of the anticholinergic effects of drugs not to produce delirium.[14]