Pharmacology

Anticholinergic agents are classified into two categories according to the receptors that they act on:

	(1) Antimuscarinic agents constitute most of the anticholinergic drugs; they act on the muscarinic acetylcholine receptors.
	(2) Antinicotinic agents act on the nicotinic acetylcholine receptors. The majority of these are nondepolarizing skeletal muscle relaxants for anesthetic use.

Antimuscarinic agents. A classic example is atropine, which blocks acetylcholine receptor sites, opposes the actions of the vagus nerve, increases firing of the sinoatrial node and conduction through the atrioventricular node of the heart, and decreases bronchiole secretions. Overall effect of atropine is to lower the parasympathetic activity of all muscles and glands regulated by the parasympathetic nervous system because acetylcholine is the main neurotransmitter used by the parasympathetic nervous system. Therefore, it may cause swallowing difficulties and reduced secretions.

In addition to classical antimuscarinic agents, drugs from other categories may have antimuscarinic effect. Examples of such drugs are antihistamines, cimetidine, prednisolone, theophylline, and digoxin. These agents are listed in Table 1 as causative agents of anticholinergic syndrome.

The effects of scopolamine on the peripheral nervous system are like the effects of atropine. However, scopolamine is a central nervous system depressant and constitutes a highly effective treatment to prevent motion sickness although at high doses it causes excitement with side effects like those caused by high doses of atropine.

Most of the approved anticholinergic agents for the treatment of Parkinson disease are nonselective antimuscarinic receptor antagonists.

Antinicotinic agents. These anticholinergic agents are ganglionic blockers, which target nicotinic receptors in nerve cells of either sympathetic or parasympathetic systems. The most used ganglionic blockers are trimethaphan and mecamylamine, which is used to treat hypertension.

Neuromuscular anticholinergic agents act on motor nerve choline receptors. They prevent the transmission of signals from motor nerves to neuromuscular structures of the skeletal muscle. Neuromuscular blockers are very useful as muscle relaxants in several surgical procedures, either as an adjuvant to anesthesia or as a premedication for anesthesia. Their main therapeutic use is in surgical procedures. Examples of the first group are mivacurium, tubocurarine, metocurine, doxacurium, and atracurium; the second group consists of rocuronium, vecuronium, pipecuronium, and pancuronium.

Clinical trials

There are few trials of anticholinergic drugs for treatment of neurologic disorders. A randomized, double blind, placebo-controlled, crossover study of ipratropium bromide was conducted in subjects with Parkinson disease and bothersome drooling (36). Although it did not affect objective measures of saliva production, there was a mild effect on subjective measures of sialorrhea. The treatment was well tolerated.

A prospective, 12-week dose titration trial of controlled-release oxybutynin chloride evaluated the efficacy and tolerability of higher doses of the drug in patients with neurogenic bladder and multiple sclerosis, spinal cord injury, or Parkinson disease (02).

Functional MRI during a randomized placebo-controlled trial of tolterodine (an anticholinergic drug) on patients with urinary frequency showed that after treatment, two areas of the parietal cortex (precuneus and postcentral gyrus) showed significantly greater activity in patients treated with tolterodine versus placebo (31). The significance of this finding is not known.

Indications

Anticholinergic drugs are used for the following neurologic disorders:

Parkinson disease. Anticholinergics are used for symptomatic treatment of certain manifestations of Parkinson disease, such as sialorrhea, drug-induced dyskinesia, and urinary urgency or frequency.

Hyperactive bladder. The term hyperactive bladder, or overactive bladder, is applied to symptoms of urgency, frequency, incontinence, and nocturia. A systematic review of randomized controlled trials of treatment with anticholinergic drugs for overactive bladder or urinary urgency in adults, excluding patients with neurogenic bladder dysfunction, showed that there was more symptomatic improvement when anticholinergics were compared with bladder training (32). According to meta-analysis of randomized trials, use of anticholinergic drugs for adult neurogenic detrusor overactivity was associated with more symptomatic improvement than use of placebo as reported by patients and significant reduction of maximum detrusor pressure (24). Anticholinergics may be used for hyperactive bladder in neurologic disorders other than Parkinson disease, for example, oxybutynin in multiple sclerosis. However, a systematic review of clinical trials of anticholinergics versus other treatments showed no significant difference between the two treatments in any efficacy outcome measure, and the available evidence did not support the use of anticholinergics in multiple sclerosis (28).

Urinary incontinence is common in patients with dementia. Central cholinergic stimulation is the mainstay in the treatment of cognitive decline. The use of anticholinergic medications for detrusor overactivity in demented patients carries the risk of mental deterioration, and further studies are needed to define treatment regimens for elderly individuals with both dementia and urinary dysfunction (35). A randomized double-blind clinical trial has shown that flexible dose fesoterodine, an antimuscarinic agent, significantly improved urgency urinary incontinence episodes and other outcomes versus placebo in elderly patients, and it was generally well tolerated (11).

Anticholinergics have been used for the treatment of nocturnal enuresis in children. A retrospective evaluation found that a combination of anticholinergics and alarm treatment did not improve the functional bladder volume or cure rate of children with nocturnal enuresis (38).

Drug-induced dyskinesias. Rabbit syndrome, a movement disorder generally associated with prolonged use of antipsychotics, responds favorably to anticholinergic drugs (07). Use of anticholinergic medications for treatment of extrapyramidal side effects associated with antipsychotics may cause several side effects, and anticholinergics can often be withdrawn during the maintenance phase of antipsychotic treatment without recurrence of extrapyramidal effects. A study on patients whose anticholinergic burden was reduced showed a significant improvement in side effects, memory, and quality of life (23).

Treatment of nerve agent poisoning. Atropine is recommended as the first-line treatment of sarin poisoning, and the dose should be titrated, with the goal of drying secretions and the resolution of bronchoconstriction. Atropine autoinjection is indicated as an initial treatment of the muscarinic symptoms of nerve agent poisonings. Each prefilled autoinjector provides a dose of the antidote atropine, an anticholinergic drug that reduces secretions in the mouth and respiratory passages, relieves the constriction and spasm of respiratory passages, and may reduce the paralysis of respiration, which results from actions of the toxic agent on the central nervous system. Physostigmine is also an effective treatment against sarin intoxication.

Diagnostic procedures in neurologic disorders. The pupillary light reflex test for Alzheimer disease involves tropicamide blockade of cholinergic oculomotor functions. Pupillary constriction amplitude correlates significantly with severity of dementia, and cholinesterase inhibitor therapy may partially normalize pupillary light reflex abnormalities in these patients.

Contraindications

Anticholinergic drugs are contraindicated in patients with urinary retention due to bladder neck obstruction, myasthenia gravis, severe decreased gastrointestinal motility conditions, and uncontrolled narrow angle glaucoma.

Goals and duration of treatment

Most anticholinergic therapies are short-term or intermittent. Chronic or long-term use is limited by neurotoxicity of many of these compounds. They mostly provide symptomatic relief and do not correct the underlying pathology of the disease. There is considerable variation among several anticholinergic risk scales that are available as a guide for selection of specific drugs, as well as for grading of anticholinergic potency. A screening software for anticholinergic burden lists 100 anticholinergic drugs (12). Several drug scales, such as the Anticholinergic Drug Scale, Anticholinergic Cognitive Burden Scale, and Anticholinergic Risk Scale, are available for estimation of the total anticholinergic burden of drugs in combination with measurement of serum anticholinergic activity using a competitive radioreceptor binding assay of muscarinic receptors (19).

Dosing

Numerous anticholinergic agents are in use. The Physicians’ Desk Reference should be consulted for doses of individual agents.

Special considerations

Pediatric. Anticholinergic drugs have been used in children, for example in the treatment of overactive bladder. Although some of the drugs are approved, few clinical trials have been conducted specifically in pediatric populations. There are no specific precautions in children, and contraindications are the same as in adults.

Geriatric. Decreased cholinergic reserve in older persons is a cause of susceptibility to the side effects of anticholinergic medications, which include cognitive decline, impaired homeostatic regulation, and delirium. They are also at a higher risk for developing an anticholinergic toxicity syndrome. Unlike retrospective studies, the findings of a prospective noninterventional study did not support a higher risk of hospital admission within 30 days for older people with high anticholinergic burden as assessed from their discharge prescriptions (06).

Dementia, renal function impairment, slowing of gastrointestinal motility, urinary obstruction due to prostatic hyperplasia, narrow angle glaucoma, diabetes mellitus, and cardiovascular disorders (arrhythmias, congestive heart failure) are more common in the elderly and require caution in the use of anticholinergic drugs.

Pregnancy. The effect of anticholinergic agents on pregnancy is not well documented due to the lack of animal experimental or human studies, and caution should be exercised for use during pregnancy. The administration of anticholinergics should be avoided in patients with severe preeclampsia. There are no available data on excretion in breast milk, but anticholinergics suppress lactation; use in breastfeeding mothers should be avoided.

Anesthesia. Anticholinergics have been used extensively as preanesthetic medications, for muscle relaxation and for postoperative complications such as nausea and vomiting. Anticholinergic syndrome has been reported following general anesthesia due to interaction with intravenous fentanyl, an opioid, given at an analgesic dose for postoperative pain control and required treatment with physostigmine (08).

Interactions

Patients with Alzheimer disease being treated with cholinesterase inhibitors have a greater decline in their mental status after taking concurrent anticholinergic drugs for prolonged periods. This combination should be avoided as anticholinergic drugs reduce the therapeutic efficacy of cholinesterase inhibitors. Moreover, anticholinergic drugs can interact with cholinesterase inhibitors to produce bradycardia.

Use of anticholinergic drugs for overactive bladder together with those prescribed for psychiatric or neurologic indications that also have anticholinergic properties can lead to pharmacodynamic drug interactions that might produce an anticholinergic toxicity (25).

Levels of the anticholinergic drugs can be increased to high levels by CYP3A4 inhibitors such as macrolide antibiotics (eg, erythromycin, anti-HIV agents, antidepressants, and calcium channel blockers). Therefore, this combination is contraindicated.

Adverse effects

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.