Adverse effects of anticholinergics may be neurologic or non-neurologic. Non-neurologic symptoms and signs of anticholinergic effect include dry mouth, sore throat due to decreased mucous production and cessation of perspiration leading to increased body temperature as well as tachycardia, urinary retention, constipation, and increased intraocular pressure, which may be dangerous for people with narrow-angle glaucoma. Globus pharyngeus is a feeling of lump in the throat and has been linked to salivary hypofunction. In a cross-sectional study, globus pharyngeus experienced by patients was due to a drying effect on salivation secondary to anticholinergic medication use (17).
Neurologic manifestations of chronic low-dose anticholinergic drug use may be subtle. Anticholinergic medications predispose elderly persons to falls. A retrospective study of elderly patients with mild cognitive impairment or dementia and two or more additional chronic conditions showed that the greatest increase in risk of falls or fall-related injuries occurred when level 2 and level 3 drugs were used in combination with a score of 5 on the anticholinergic cognitive burden scale (16). Other neurologic adverse effects include the following.
Cognitive impairment. A retrospective cohort study conducted over a period of two years showed that taking two or more anticholinergic medications significantly increases the risk of hospitalization for confusion or dementia (21). An association has been shown between anticholinergic drug use and cognitive decline in elderly patients with Parkinson disease. A cross-sectional survey has shown that higher anticholinergic burden is associated with cognitive impairment and freezing of gait, even in younger patients with Parkinson disease (33).
Use of anticholinergic drugs by elderly persons increases the risk for cognitive decline and dementia, whereas discontinuation of these drugs decreases the risk (05). Use of anticholinergics increases the risk of cognitive impairment if they are carriers of the epsilon4 allele of the APOE gene (27). Anticholinergic drugs are a potential risk factor for psychosis in Alzheimer disease (04). The dose of anticholinergic medicines in patients with Alzheimer disease should be reduced prior to start of therapy with cholinesterase inhibitors as the concomitant use of both increases anticholinergic load and can lead to aggravation of cognitive impairment (01). A double-blind, placebo-controlled, randomized, parallel-group study has shown that anticholinergic antidepressant amitriptyline can profoundly suppress REM sleep and can impair procedural memory consolidation in healthy subjects, whereas selective serotonin reuptake inhibitors do not show this effect (14). A systematic review of randomized controlled trials has revealed that drugs with anticholinergic effects are associated with risks of cognitive impairment in the elderly (34). Particularly, olanzapine and trazodone increased the risk of falls, whereas amitriptyline, paroxetine, and risperidone did not. In a retrospective cohort study on persons 65 years or older, increasing use of strong anticholinergics calculated by total standard daily dose increased the odds of transition from normal cognition to mild cognitive impairment (03). Results of this study suggest that interventions, which involve discontinuation of drugs, in older adults with normal cognition should test anticholinergics as potentially modifiable risk factors for cognitive impairment. In a retrospective study, one third of elderly patients who were consulted for loss of memory were taking anticholinergic drugs, and there was a greater tendency to cognitive impairment among those exposed to these drugs (22).
A case control study has shown that exposure to several types of strong anticholinergic drugs is associated with an increased risk of dementia and the attributable fraction associated with total anticholinergic drug exposure during the one to 11 years before diagnosis was 10.3% (09). Associations in this study were stronger in cases diagnosed before the age of 80 years and in those with vascular dementia rather than Alzheimer disease.
Acute anticholinergic syndrome. Neurologic signs of anticholinergic toxicity include ataxia, pupil dilation with blurred vision, and diplopia. Effects in the central nervous system resemble those associated with delirium. Although anticholinergic drugs may contribute to delirium due to the cumulative effect of multiple medications with modest antimuscarinic activity, multivariable logistic regression analysis, after adjustment for dementia and malnutrition, fails to prove a causative role in delirium (30). Further studies are needed to clarify this association.
Anticholinergic toxicity of antispasmodics, anticholinergic drugs, and plant alkaloids such as belladonna are common causes of hyperthermia. Neurotoxicity of anticholinergics is termed “acute anticholinergic syndrome,” and other manifestations besides those resembling delirium include cognitive impairment and visual, auditory, and sensory hallucinations. Seizures, coma, and death may occur rarely.
Two scales have been used to assess risk of adverse effects of anticholinergic drugs: (1) the Anticholinergic Drug Scale, which is based on serum anticholinergic values, and (2) the Anticholinergic Risk Scale, which is a ranked list of commonly prescribed medications with anticholinergic potential. Both anticholinergic scales can help detect an increased risk of appearance of peripheral anticholinergic signs, but not the central signs such as delirium (15). Anticholinergic syndrome is more likely to be caused by drugs with central anticholinergic effects that cross the blood-brain barrier and block muscarinic cholinergic receptors. There are over 600 medications that have some degree of serum anticholinergic activity. Some of the drugs reported to be associated with anticholinergic syndrome are listed in Table 1.
Table 1. Drugs That Can Produce Anticholinergic Syndrome
• Anesthesia, analgesia, and postoperative medications |
| - Atropine sulfate
- Benzodiazepines
- Codein
- Glycopyrrolate
- Halothane
- Hyoscine
- Enflurane
- Ketamine
- Opioids
- Oxycodone
- Transdermal scopolamine |
• Antiarrhythmics |
| - Propafenone
- Quinidine |
• Antiasthmatics |
| - Ipratropium bromide |
• Antiemetics |
| - Cyclizine
- Meclizine |
• Antibiotics |
- Ampicillin
- Clindamycin
- Gentamicin
- Piperacillin
- Vancomycin |
• Antihistaminics with anticholinergic activity |
| - Brompheniramine
- Carbinoxamine
- Chlorpheniramine
- Cyproheptadine
- Cyclizine
- Dimenhydrinate
- Diphenylhydramine
- Doxylamine
- Hydroxyzine
- Meclizine
- Promezathine |
• Anti-incontinence agents |
| - Flavoxate
- Oxybutynin
- Propantheline bromide |
• Antiparkinsonian medications |
| - Amantadine
- Benztropine
- Biperiden
- Ethopropazine
- Procyclidine
- Trihexyphenidyl |
• Antipsychotics |
| - Clozapine
- Chlorpromazine
- Chlorprothixene
- Olanzapine
- Quetiapine
- Thioridazine |
• Antispasmodics for the gastrointestinal tract |
| - Dicyclomine
- Hexocyclium
- Hyoscyamine
- Isopropamide
- Oxyphenonium
- Propantheline
- Tridihexethyl |
• Antiparkinsonian medications |
| - Amantadine
- Benztropine
- Biperiden
- Ethopropazine
- Procyclidine
- Trihexyphenidyl |
• Baclofen
• Cardiovascular medications
- Captopril
- Digoxin
- Diltiazem
- Furosemide
- Hydralazine
- Isosorbide mononitrate
- Nifedipine |
• Corticosteroids
- Corticosterone
- Dexamethasone
- Hydrocortisone
- Prednisone |
• Ophthalmic preparations |
| - Atropine 1% ophthalmic solution
- Cyclopentolate
- Eucatropine
- Tropicamide |
• Tricyclic antidepressants |
| - Amitriptyline
- Amoxapine
- Clomipramine
- Desipramine
- Doxepin
- Imipramine
- Nortriptyline |
• Drug interactions |
| - Desipramine and venlafaxine
- Venlafaxine-fluoxetine
- Paroxetine and clozapine |
• Herbal medications |
| - Datura species (eg, Angel's trumpet)
- Solanum erianthum (contains anticholinergic tropane alkaloids) |
Source: (20)
A pharmacovigilance study in France has shown an association between an atropinic drug and an anticholinesterase agent in one out of two Alzheimer disease patients, and a clinically significant atropine burden was seen in 10% to 20% these patients (26). This should be considered before prescribing anticholinergic drugs in patients who are already on anticholinesterase therapy (26). Anticholinergic burden, as measured by number, dose, and degree of anticholinergic activity of medicines, is a predictor of adverse effects and can be minimized by avoiding, reducing dose, and discontinuing medicines with anticholinergic activity where clinically possible (29).
Results of a study indicate that higher cumulative anticholinergic exposure using an anticholinergic agent or switching anticholinergic agents is associated with a cumulative increase in the risk of incident dementia in patients aged 50 years and older who suffer from lower urinary tract infections (37).
Management. Acute anticholinergic syndrome is completely reversible and subsides once the toxin has been excreted. Usually no specific treatment is indicated, but in severe cases, especially those that involve severe distortions of mental state, a reversible cholinergic agent such as physostigmine may be used as 1 mg intravenous dose. Continuous infusion of physostigmine is rarely used because of risk of cardiotoxicity, but physostigmine infusion with a total dose of 25.5 mg has been used successfully to reverse anticholinergic delirium in a child who accidently ingested olanzapine (18). Anticholinergic syndrome due to clozapine overdose is rare, and there are no standard guidelines for management. Most of the reported cases underwent detoxication measures, such as charcoal therapy or gastric lavage. There is a report of successful management of anticholinergic syndrome by intravenous physostigmine without detoxification in a 28-year-old man with clozapine intoxication due to overdose who presented with impaired vigilance, tachycardia, and hyperventilation (10). The patient recovered completely, and the authors advise against the use of artificial respiration in such cases.
