Review

Drugs with anticholinergic

properties: a current perspective
on use and safety
1. Introduction Philip Gerretsen & Bruce G Pollock†
†
2. The cholinergic system University of Toronto, Faculty of Medicine, Department of Psychiatry, Toronto, Canada
3. Adverse effects of drugs with
Introduction: Many commonly used drugs have primary or secondary anticho-
anticholinergic effects
linergic effects contributing to adverse outcomes ranging from mild-to-severe
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14

4. Some common uses and

to potentially lethal. Anticholinergic adverse effects frequently occur with
adverse effects of
medications prescribed with other intended mechanisms of action, including
anticholinergic drugs
antihistamines, antidepressants, and antipsychotics. Anticholinergic drugs
5. Anticholinergic monitoring are also the principal treatments of clinical conditions, such as urinary incon-
6. Conclusion tinence, that tend to occur in the elderly. Older patients and those with men-
7. Expert opinion tal illness are particularly vulnerable to the adverse neuropsychiatric effects of
anticholinergics as they may already have cognitive impairment.
Areas covered: Medline and Pubmed literature searches (1966 -- the present)
were performed using ‘anticholinergic’ and ‘drug safety’. Abstracts were
assessed and references scanned for appropriate articles. Here, the authors
i) describe the neural pathways of the cholinergic system; ii) outline the
main clinical uses and adverse effects of anticholinergic agents with a focus
For personal use only.

on cognitive impairment; and iii) discuss anticholinergic safety monitoring.

Expert opinion: Prescribers need to be vigilant for adverse anticholinergic
effects, particularly in older patients. The symptoms may range from subtle
cognitive impairment to delirium and may be due to the cumulative effect
of multiple medications of modest antimuscarinic activity. The Anticholinergic
Drug Scale and tables listing drugs with known anticholinergic properties may
help in guiding clinical decision-making to reduce anticholinergic burden.

Keywords: anticholinergic adverse effects, anticholinergic drugs, anticholinergic safety

monitoring, anticholinergic toxicity, cholinergic neurotransmission, drug safety

Expert Opin. Drug Saf. (2011) 10(5):751-765

1. Introduction

It is estimated that one-third to more than one-half of the most commonly prescribed
drugs for elderly persons have anticholinergic properties [1,2]. The potent anticholin-
ergic drugs atropine and scopolamine are extracted from Atropa belladonna (deadly
nightshade) or other plants within the nightshade family. The Greek goddess Atropos,
who was one of the three Fates, was responsible for ‘severing the thread of life’. Her
ancient Roman name equivalent is ‘Morta’, which means death [3,4].
Many commonly used drugs have primary or secondary anticholinergic effects
that alleviate symptoms, but also contribute to adverse outcomes ranging from
mild-to-severe to lethal in overdose [5-7]. Anticholinergic drugs are commonly
used for the symptomatic management of a variety of conditions, including respira-
tory disorders, urge incontinence and Parkinson’s disease. Unintended or indirect
anticholinergic adverse effects frequently occur with medications prescribed with
other mechanisms of action in mind, such as antihistamines (e.g., diphenhydra-
mine), antidepressants (tricyclic antidepressants and some serotonin reuptake inhib-
itors) and antipsychotics [2]. Some agents may also have additional mechanisms that
can contribute to toxicity and death. For example, older generation antihistamines

10.1517/14740338.2011.579899 © 2011 Informa UK, Ltd. ISSN 1474-0338 751

All rights reserved: reproduction in whole or in part not permitted
 Drugs with anticholinergic properties: a current perspective on use and safety
Article highlights.
. Anticholinergic toxicity is associated with serious adverse
effects, including delirium, urinary retention,
hyperthermia and possibly death when in combination
with drugs with other mechanisms of action (e.g.,
tricyclic antidepressants or antihistamines, such
as diphenhydramine).
. Drugs with anticholinergic properties continue to be
commonly prescribed to the elderly and the mentally ill
who are susceptible to adverse effects even at
therapeutic doses.
. Anticholinergic activity contributes to cognitive
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14
impairment and negative functional outcomes in the
elderly and in those with mental illness. Some evidence
suggests anticholinergic activity may also hasten
neurodegeneration in the elderly.
. Anticholinergic agents have a number of clinical
indications, including incontinence and respiratory
disorders, while many other classes of medications have
anticholinergic properties, such as antihistamines,
antipsychotics and antidepressants.
. A scale or table that lists the anticholinergic activity of
commonly prescribed drugs (e.g., Anticholinergic Drug
Scale, Figure 5 or Table 2 in Chew et al. [2]) or indicates
drugs not recommended for use in the elderly (i.e.,
Beers Criteria) can guide clinical decision-making to limit
anticholinergic load.
For personal use only.
. Many novel agents from different classes of medications
that have minimal-to-no adverse anticholinergic effects
are clinically available.
This box summarizes key points contained in the article.
and tricyclic antidepressants can cause cardiac conduction
abnormalities through potassium or fast sodium channel
blockade [7-9].
Many of the clinical conditions with indications for
anticholinergic medications tend to occur in the elderly (e.g.
overactive bladder syndrome, hypertension, respiratory disor-
ders) or in those who are mentally ill (e.g. depression or
schizophrenia). Both the elderly and the mentally ill are
particularly vulnerable to the adverse neuropsychiatric effects
of agents with anticholinergic properties as individuals
within these groups often already have evidence of cognitive
impairment (e.g., mild cognitive impairment, dementia,
depression or schizophrenia) [5,6,9].
Recently, advances have occurred in a number of areas
related to anticholinergic drug use and safety, including link-
ing anticholinergic load to cognitive impairment; quantifying
the anticholinergicity of common drugs; and the development
of medications with benign anticholinergic adverse effect pro-
files from varied drug classes. The goal of this work is to syn-
thesize these findings. Specifically, the aims are i) to briefly
review the neural pathways of the cholinergic system; ii) to
outline the current uses and adverse effects of anticholinergic
agents on both the central (CNS) and the peripheral nervous
system (PNS); iii) and to discuss anticholinergic safety
monitoring. Special attention will be given to the cognitive
752 Expert Opin. Drug Saf. (2011) 10(5)
effects of medications with anticholinergic properties as these
are often subtle and occur without more overt signs of
anticholinergic toxicity.
Of note, as most drugs with anticholinergic activity medi-
ate their effects via muscarinic receptor antagonism, the
term ‘anticholinergic’ is used synonymously with ‘antimus-
carinic’. The nicotinic branch of the cholinergic system and
nicotinic antagonists are only briefly discussed in the
following sections.
2. The cholinergic system
Acetylcholine (ACh), the main neurotransmitter of the cho-
linergic system, is synthesized primarily within cholinergic
neurons from acetyl-CoA and choline by the enzyme choline
acetyltransferase [10,11]. ACh is stored within the neuron in
synaptic vesicles and released into the synaptic cleft after neu-
ronal activation. ACh binds to either a pre- or a postsynaptic
receptor site or is inactivated through hydrolysis by the
enzyme cholinesterase (site of action of cholinesterase inhibi-
tors). Once inactivated, choline is recycled through choline
transporters back into the presynaptic neuron for the synthesis
of more ACh (Figure 1) [10,11].
ACh acts on two principal classes of receptors, nicotinic
and muscarinic, aptly named for the specific binding of nico-
tine and muscarine, respectively. Nicotinic receptors are
ligand gated ion channels of which there are nine known
receptor subtypes, six alpha subunits and three beta subunits,
which have varying degrees of sensitivity to nicotine and rates
of desensitization [10,12].
In contrast to nicotinic receptors, muscarinic receptors are
plasma membrane-bound metabotropic G protein coupled
receptors. Five related muscarinic receptor subtypes have
been identified (M1 -- M5): odd-numbered receptors (M1,
M3, M5) are considered excitatory, promoting ACh release,
whereas even numbered receptors (M2, M4) are predomi-
nantly inhibitory, reducing neurotransmitter release through
the inhibition of adenylyl cyclase and modulation of
potassium and calcium channel function [10,12,13].
Peripherally, the parasympathetic nervous system is entirely
cholinergic, whereas only the preganglionic neurons in the
sympathetic nervous system are cholinergic (i.e., nicotinic)
(Figure 2) [14]. Acetylcholine is also released at neuromuscular
junctions of the somatic nervous system and acts on exocrine
glands (e.g. salivary and sweat). [10]. Nicotinic receptors are
present on the postganglionic dendrites and cell bodies of
both sympathetic and parasympathetic postganglionic nerves
and in motor end plates of the neuromuscular junction.
Muscarinic receptors are present on all effector cells of the
parasympathetic nervous system, and also on sweat glands
innervated by the sympathetic nervous system. Although
described as ‘anticholinergic’, medications with anti-
cholinergic properties exert their influence predominantly
through muscarinic receptors, and, therefore, would be more
appropriately named ‘antimuscarinic’ (Figure 2) [14].
 Gerretsen & Pollock

Choline
Acetyl-CoA reuptake
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Acetylcholine(ACh)

Choline
For personal use only.

Acetylcholinesterase(AChE)

Nicotinic Muscarinic
receptor receptor
Legend

Choline
Acetyl-CoA
Acetylcholine(ACh)
Acetylcholinesterase(AChE)

Storage vesicle

Figure 1. Cholinergic neurotransmission. ACh is synthesized within cholinergic neurons from acetyl-CoA and choline by the
enzyme choline acetyltransferase (not depicted). ACh is stored within the neuron in synaptic vesicles and released into the
synaptic cleft after neuronal activation. ACh binds to either a pre- (not shown) or a postsynaptic receptor site or is inactivated
through hydrolysis by the enzyme cholinesterase (site of action of cholinesterase inhibitors). Once inactivated, choline is
recycled through choline transporters back into the presynaptic neuron for the synthesis of more ACh. Of note, there are
other factors involved in the production of acetylcholine and cholinergic neurotransmission that are not graphically
represented here. www.silvermedia.ca.

Centrally, the cholinergic projection nuclei are primarily
located in the basal forebrain and the rostral midbrain within
the mesopontine area (Figure 3) [15,16]. Basal forebrain nuclei
that project to most of the cortex, hippocampus and
amygdala are thought to play a major role in cognition. Their
degeneration is a major contributing factor to memory,
learning, executive dysfunction and other cognitive deficits
attributable to neurodegenerative disorders such as Alzheim-
er’s disease and other dementias [17-19]. The mesopontine
nuclei provide cholinergic transmission to a number of brain
regions, including the thalamus, ventral tegmental area,
substantia nigra and basal forebrain. Mesopontine cholinergic

Expert Opin. Drug Saf. (2011) 10(5) 753

 Drugs with anticholinergic properties: a current perspective on use and safety

Sympathetic division

Nicotinic receptors Adrenergic receptors

Effector cell
Ganglion

ACh NE
Presynaptic neuron Postsynaptic neuron
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Parasympathetic division

Nicotinic receptors Muscarinic receptors

For personal use only.

ACh

Figure 2. Sympathetic versus parasympathetic neurotransmission of the ANS. Presynaptic neurotransmission within both the
sympathetic and parasympathetic divisions of the ANS is mediated by acetylcholine binding to nicotinic receptors.
Postsynaptic neurotransmission at effector cells is carried out through norepinephrine binding to adrenergic receptors in the
sympathetic division and acetylcholine binding to muscarinic receptors in the parasympathetic division. www.silvermedia.ca.
ANS: Autonomic nervous system.

neurons are implicated in arousal, sleep, cognition and the
regulation of other neurotransmitters, including dopamine,
norepinephrine and serotonin [12]. In the striatum, cholinergic
neurons are mainly interneurons and are thought to be
involved in motivation and regulation of body weight and
metabolism [20].
3.Adverse effects of drugs with
anticholinergic effects
Most medications with anticholinergic properties mediate
their effects through muscarinic receptor antagonism. Musca-
rinic blockade is associated with a number of adverse effects
on the PNS and CNS, ranging from mild, such as flushing,
to more serious, including hyperthermia and delirium [21].
Adverse effects can occur at toxic, but also at therapeutic,
doses when taken by vulnerable individuals, such as the
elderly or those with mental illnesses [22-26].
Drugs with predominant antinicotinic effects are typically
prescribed for the purposes of neuromuscular blockade in
the context of surgery or intensive care (e.g., vancuronium,
succinylcholine etc.), or are limited to the research setting
(e.g., ganglionic blockers, such as mecamylamine, once used
to manage hypertension) [27-29]. As a full discussion of nico-
tinic antagonists (Section 4.8) is beyond the scope of this
review, the following sections will be limited for the most
part to a discussion of the PNS and CNS effects of drugs
with antimuscarinic properties, and the symptoms associated
with antimuscarinic toxicity.
3.1 PNS effects
The parasympathetic branch of the autonomic nervous sys-
tem is entirely cholinergic. Muscarinic receptors are present
on all effector cells of the parasympathetic nervous system
and also on sweat glands innervated by sympathetic nervous
system. Adverse PNS drug effects are a result of excess mus-
carinic blockade of cholinergic neurotransmission at the
target organ.
Antimuscarinic agents can have complex effects on the
cardiovascular system resulting in tachycardia, flushing and
possibly arrhythmia [21,30,31].
Muscarinic antagonists can adversely influence the gastro-
intestinal system in a number of ways by causing reduced
gut motility, constipation, nausea and vomiting [21].

754 Expert Opin. Drug Saf. (2011) 10(5)

 Gerretsen & Pollock

Cortical cholinergic neuron

Parietal
cortex

l
nta
Fro rtex
co
O
c
co cipi
rte tal
x
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Striatum
Thalamus

Te cort Cerebellum
m ex
po

Medical septal nucleus/hippocampus

ra
l

Br
Vertical diagonal band of broca/hippocampus

ain
ste
Nucleus basalis of meynert/multiple cortical and

m
subcortical destination Pedunculopontine nucleus and
parabrachial nucleus/thalamus
For personal use only.

Hippocampus and amygdala

Nuclei/projection site

Figure 3. Central cholinergic system [20,108]. Groups of cholinergic neurons and their primary projection destinations. www.
silvermedia.ca.
Reproduced in an altered form with permission from [20,108].

Cholinergic activity at the neuromuscular junctions of the
bladder is required for bladder contraction and urination, while
constant adrenergic stimulation at the bladder neck prevents
involuntary incontinence. Anticholinergic agents can cause uri-
nary hesitation and retention through the inhibition of detrusor
muscle contraction. Reduced bladder contraction is the pri-
mary aim in the treatment of urinary urge incontinence, but
these symptoms may occur inadvertently when anticholinergic
drugs are prescribed with other purposes in mind [21,32,33].
Anticholinergics can also have metabolic side effects,
primarily hyperthermia, which may also be secondary to
anhidrosis [21].
ACh is a principal neurotransmitter involved in the pro-
duction of saliva, tears and sweat by exocrine glands. Anticho-
linergics can contribute to anhidrosis and ocular, mouth and
nasal dryness [21].
Blurred vision and mydriasis are other common adverse
effects of medications with anticholinergic properties. Atro-
pine and other anticholinergic drops are purposely used to
dilate the pupil to better visualize the retina. Anticholinergics
can, however, precipitate angle-closure glaucoma (also known
as narrow-angle glaucoma), which may result in permanent
loss of vision [21].
3.2 CNS effects
Some of the common anticholinergic CNS adverse effects
include headache, pain, anxiety and insomnia. At higher
doses, manifestations of muscarinic receptor blockade in the
CNS may include agitation, dysarthria, confusion, disorienta-
tion, bizarre behavior, delirium, psychosis (hallucinations and
paranoia), coma and seizures [21].
The elderly and those with comorbid medical or psychiatric
conditions, such as schizophrenia or dementia, are particularly
vulnerable to the more subtle cognitive effects (e.g., attention
and memory deficits) of drugs with anticholinergic properties.
Age-related peripheral and central pharmacokinetic
changes and pharmacodynamic effects on neurotransmis-
sion may contribute to the phenomena of increased drug
sensitivity in the elderly [34,35].
Cholinergic deficits figure prominently in the patho-
physiology of Alzheimer’s disease and may also accompany
aging, thus increasing older individuals’ sensitivity to

Expert Opin. Drug Saf. (2011) 10(5) 755

 Drugs with anticholinergic properties: a current perspective on use and safety
anticholinergic drugs [3,22,23]. In one study of 201 commu-
nity-based elderly subjects, a significant association was
found between serum anticholinergic activity (SAA) and
lower Mini Mental State Exam scores [36]. Subjects
with SAA at or above their sample’s 90th percentile
(‡ 2.80 pmol/ml) were 13 times more likely than subjects
with undetectable SAA to have a Mini Mental State Exami-
nation score of £ 24 (sample’s 10th percentile). Another
study found that detectable, even very low, levels of anticho-
linergic activity were associated with impaired cognition in
the elderly [37]. In a more recent study of 750 persons
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aged ‡ 65 years, individuals using drugs with anticholinergic
effects were 2 -- 3 times more likely to have cognitive
impairment than those using non-anticholinergic medica-
tions [22]. Moreover, SAA was also associated with self-care
capacity in a population of nursing homes residents [38]. Of
note, one cross-sectional study found that caffeine use may
have a protective effect against the cognitive slowing
associated with increased SAA [39].
More so than cognitively intact older persons, individuals
with dementia may be especially vulnerable to the deleterious
neuropsychiatric effects of greater anticholinergic burden. In
one study, SAA was associated with lower cognitive perfor-
mance in subjects with moderate-to-severe dementia [40]. In
For personal use only.
another, increased SAA was related to impairment on meas-
ures of recognition and concentration in subjects with mild-
moderate Alzheimer’s disease as compared with depressed
elderly patients without dementia [41]. Moreover, anticholin-
ergic drug use may place persons with Alzheimer’s disease at
increased risk of psychosis [42].
Anticholinergic activity is also found to contribute to the
cognitive impairment that can occur in serious mental illness
such as schizophrenia [24-26,36,43-47]. Higher anticholinergic
load is specifically associated with impaired attention, learn-
ing and memory in patients with schizophrenia taking medi-
cations with anticholinergic activity [24,25,43-45,47]. Similarly,
studies that explored the cognitive effects of antidepressants
and antipsychotics with known anticholinergic properties
have found that cognitive deficits persist despite improvement
in either mood or psychosis [26,46].
More alarming are reports that have linked chronic anti-
muscarinic exposure with a hastening of neurodegeneration
and worse clinical outcomes [48,49]. In one study, for example,
amyloid plaque densities were 2.5 times higher in individuals
with Parkinson’s disease receiving long-term treatment with
antimuscarinic drugs compared with untreated or short-term
treated cases [50]. Similarly, epidemiological and longitudinal
observational studies have found that chronic anticholinergic
use is associated with ~ 1.5 -- 2 times greater risk of develop-
ing cognitive impairment and dementia in both European
and African American samples [51-53]. Although preliminary,
these findings raise the concern that chronic anticholinergic
exposure may contribute to irreversible brain pathology.
This risk may be mitigated by discontinuing drugs with
antimuscarinic properties [53].
756 Expert Opin. Drug Saf. (2011) 10(5)
Anticholinergics can also contribute to fatigue, weakness
and falls in the elderly [54]. A study by Nebes et al.
(2007) [55] found a significant association between elevated
SAA and psychomotor slowing as measured by reduced gait
speed and simple manual response time.
3.3 Anticholinergic toxicity
The toxidrome of anticholinergic overdose is characterized
by the extreme of the aforementioned central and peripheral
effects (Figure 4) [56]. The clinical manifestations are remem-
bered by the mnemonics, ‘dry as a bone’ (anhidrosis), ‘hot as
a hare’ (anhidrotic hyperthermia), ‘red as a beet’ (vasodila-
tion causing flushing), ‘blind as a bat’ (mydriasis), ‘full as a
flask’ (urinary retention) and ‘mad as a hatter’ (delirium,
agitation, delusions, hallucinations). Other signs and symp-
toms include decreased or absent bowel sounds and tachy-
cardia, which is one of the earliest signs of anticholinergic
toxicity [56,57].
Although the management of anticholinergic toxicity is
beyond the scope of this paper, emergency medical assess-
ment and consultation with a regional poison control center
are required. An ECG is essential to identify cardiac conduc-
tion disturbances. Decontamination with activated charcoal
and/or treatment with an antidote (i.e. the cholinesterase
inhibitor physostigmine), may be required if not otherwise
contraindicated as in the case of tricyclic antidepressant
poisoning. [58,59]. The use of physostigmine in this context
is controversial. For further review, see Kerr [7] and
Suchard [60].
4.Some common uses and adverse effects of
anticholinergic drugs
Due to the ubiquity of cholinergic neurotransmission
throughout the CNS and PNS, it is not surprising that med-
ications with anticholinergic effects have a number of diverse
indications. In the following sections we present some of the
common indications for anticholinergic drugs and common
adverse effects.
4.1Urge incontinence and overactive bladder
syndrome
Urinary urge incontinence and overactive bladder syndrome
are presumed to result from uninhibited bladder contrac-
tions or detrusor overactivity. Clinically, it is associated with
urinary urgency, frequency and nocturia, with or without
incontinence [32]. The incidence of overactive bladder
syndrome occurs increasingly with age with ~ 25% of
individuals > 65 years experiencing a portion of the symp-
toms [33]. Detrusor overactivity can also occur in patients
with spinal cord injury or brain lesions affecting the cortical
and subcortical micturition centres, as in multiple sclerosis,
Parkinson’s disease or stroke, etc. [61].
The sympathetic and the parasympathetic nervous systems
work in synchrony to retain and eliminate urine through a
 Gerretsen & Pollock

Signs and symptoms of contraction occurs chiefly via stimulation of alpha-adrenergic

acute anticholinergic poisoning
receptors. Once filling leads to altered afferent signaling from
the bladder, parasympathetic pathways are activated causing
concurrent detrusor contraction and inhibition of the bladder
+++tachycardia outlet. Parasympathetic detrusor stimulation occurs via
+++mydriasis smooth muscle muscarinic receptors [62].
+++blurred vision The anticholinergic drugs oxybutynin, tolterodine and
Fast and weak pulse
red, hot and dry skin
trospium chloride are often used in the treatment of urge
10.0 mg incontinence and detrusor overactivity. The mechanism to
Ataxia
Agitation achieve symptom control occurs though inhibition of choliner-
Delirium gic stimulation of detrusor muscle contraction. A metaanalysis
Hallucinations
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Delusions
of the efficacy and safety among different anticholinergic med-
Coma ications prescribed for overactive bladder syndrome identified
little difference between drugs in terms of efficacy. All anticho-
++tachycardia linergics apart from oxybutynin were found to be well toler-
++mydriasis ated, however, they had different adverse effect and safety
Dysarthria profiles [63]. Special caution should be exercised in patients
Dysphagia with neurogenic detrusor overactivity secondary to a CNS
5.0 mg
Restlessness
Fatigue lesion as they may be especially susceptible to negative central
Headache anticholinergic effects. As a rule, drugs that are less lipophilic,
Hot and dry skin are larger molecules and are either neutral or have a lower
Urinary retention degree of ionization are less likely to cross the blood-brain
Decreased gut motility
barrier and cause central anticholinergic effects [64,65].
A prime example is the nonselective anticholinergic agent,
For personal use only.

trospium, which is hydrophilic and has a permanent cationic

+tachycardia charge at physiological pH, limiting its ability to cross the
+mydriasis blood-brain barrier. A recent study by Staskin et al. found
++mouth dryness 2.0 mg undetectable levels of trospium in the CNS of 72 elderly
Palpitations
Blurred vision subjects [66,67].
Solifenacin and darifenacin are newer agents available for
the management of urinary incontinence purported to have
less central anticholinergic effects due to their selectivity for
Tachycardia
M3 receptors, which are located primarily throughout the
Mydriasis gut and bladder [68]. Recent studies suggest that their adverse
+mouth dryness 1.0 mg effect profile is for the most part limited to dry mouth and
Thirst constipation, without the cognitive effects attributed to
nonselective agents [69-71].
Atropine dose
Mouth dryness equivalents 4.2 Respiratory disorders
anhidrosis 5 mg Asthma and chronic obstructive pulmonary disorder (COPD)
are two respiratory disorders that feature bronchoconstriction.
Physiologically, parasympathetic vagus nerve stimulation of
the airway releases ACh that binds to smooth muscle and sub-
Figure 4. Acute anticholinergic toxicity based on atropine
mucosal gland muscarinic receptors causing constriction of
dose equivalents [56]. Of note, there is significant inter-
individual variability regarding anticholinergic dose and the bronchioles. By antagonizing muscarinic receptors, anti-
manifestations of signs and symptoms of toxicity. cholinergics promote bronchodilation. Anticholinergics for
Reproduced in altered form with permission from The McGraw-Hill Compa- asthma and COPD are typically inhaled in order to act locally
nies. www.silvermedia.ca and to limit systemic effects. Commonly prescribed inhaled
antimuscarinics include ipratropium and its long-acting struc-
reflex arc that includes the pontine micturition centers, lower tural analogue, tiotropium. As explained by Rabe [72],
spinal cord, bladder and bladder outlet. Higher order cortical although systemic adverse effects such as tachycardia are
centers also play an influential role in micturition [62]. In gen- unlikely due to poor absorption through the gastrointestinal
eral, sympathetic pathways promote urine storage and reten- tract and lungs [73], there is evidence to suggest that long-
tion via stimulation of the bladder outlet and inhibition of acting tiotropium is the safer alternative to short-acting
the detrusor. Urethral smooth muscle (bladder outlet) ipratropium. Retrospective large cohort analyses frequently

Expert Opin. Drug Saf. (2011) 10(5) 757

 Drugs with anticholinergic properties: a current perspective on use and safety
conclude that the short-acting ipratropium has a small but
consistent effect on cardiovascular safety, that is, more acute
coronary syndromes, heart failure, dysrhythmias and
cardiovascular-associated deaths. Conversely, tiotropium is
not associated with negative cardiovascular outcomes.
4.3 Antiparkinsonian
Anticholinergic drugs are commonly used in the management
of extrapyramidal symptoms, namely tremor and rigidity. The
cholinergic system participates in the modulation of move-
ment through the basal ganglia. Anticholinergic medications
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counter the effects of reduced dopaminergic transmission sec-
ondary to Parkinson’s disease or dopaminergic receptor block-
ade by antipsychotic drugs. As the anticholinergic agents used
for parkinsonism, such as benztropine or trihexyphenidyl, are
nearly equipotent with atropine and scopolamine, it is not
surprising that they are associated with significant systemic
and cognitive effects.
While once a common practice in conjunction with first
generation antipsychotic medications, in 1990 the World
Health Organization recommended against routine prophy-
lactic use of anticholinergics in those treated with antipsy-
chotics [3]. Despite this recommendation, it is only recently
that research has strong evidence to refute the claim that first
For personal use only.
generation antipsychotics prescribed together with an anticho-
linergic medication (e.g., benztropine, procyclidine) are ‘just
as good’ as second generation antipsychotics. A study by
Vinogradov et al. [74], in which higher patient serum anticho-
linergic load was correlated with cognitive impairment,
underscores the cognitive cost of prescribing medications
that carry a high anticholinergic burden.
4.4 Antipsychotics
Antipsychotic drugs are used mainly for the treatment of
schizophrenia, bipolar spectrum disorders, psychotic depres-
sion, delirium and other conditions associated with psychosis
and behavioral disturbances. Conversely, first generation anti-
psychotic drugs with less affinity for dopamine receptors tend
also to have greater blockade of the cerebral muscarinic recep-
tors, and thus, a lower propensity for extrapyramidal effects.
The tradeoff is increased anticholinergic adverse effects [75,76].
Haloperidol, perphenazine and chlorpromazine are repre-
sentative of high, medium and low potency first generation
antipsychotics, respectively. Of the second generation anti-
psychotic drugs, clozapine, followed by olanzapine and
quetiapine, is the most anticholinergic, while risperidone,
aripiprazole and ziprasidone are the least [77,78].
Common strategies adopted by physicians to mitigate
anticholinergic effects secondary to antipsychotic drugs
include dose reduction and switching to higher potency, less
anticholinergic antipsychotics. The axiom that higher potency
antipsychotics are less anticholinergic, however, is no longer
applicable to newer second generation antipsychotics, such
as aripiprazole or ziprasidone, which have low anticholinergic
effects independent of potency and dopamine receptor
758 Expert Opin. Drug Saf. (2011) 10(5)
binding properties. In fact, agents recently approved by the
FDA, including paliperidone, lurasidone, iloperidone and
asenapine, have little-to-no anticholinergic activity [79,80].
Interestingly, the second generation antipsychotic medica-
tion clozapine, which is commonly used for treatment refrac-
tory cases of schizophrenia because of its greater efficacy in
comparison with other agents, exhibits both anticholinergic
(e.g., constipation) and procholinergic activity (i.e., sialorrhea).
Its range of cholinergic effects may be due to different actions
by the parent drug or its metabolite (N-demethylclozapine,
NMDC) on muscarinic receptor subtypes [81-83].
4.5 Antidepressants
Antidepressants have numerous indications and off-label uses
outside the treatment of depressive disorders, including anxi-
ety disorders, insomnia, neuropathic pain, fibromyalgia, agi-
tation and aggression, impulsivity etc. Since the advent of
selective serotonin reuptake inhibitors (SSRIs), tricyclic anti-
depressant (TCA) associated cardiotoxicity (i.e., prolongation
of the QRS complex and the PR/QT intervals predisposing to
arrhythmia) and anticholinergic adverse effects have been less
of a concern for clinicians [7]. Of the TCAs, the tertiary
amines (e.g., amitriptyline, doxepin etc.) are among the
most anticholinergic antidepressants. The secondary amines,
such as nortriptyline (the metabolite of amitriptyline),
although less so than their precursors, continue to have signif-
icant anticholinergic effects [2,3]. The SSRI paroxetine is mod-
erately anticholinergic and appears to have the greatest
anticholinergic activity among newer agents [4]. Other SSRIs,
serotonin-norepinephrine reuptake inhibitors (venlafaxine
and duloxetine), mirtazapine, bupropion and trazadone have
low-to-nil SAA [2].
4.6 Mydriatics
Ophthalmic drugs with anticholinergic properties are often
overlooked by patients and clinicians [3]. Both short- and
long-term use of these agents is associated with CNS effects,
mental status changes and psychosis [84-86]. Although systemic
effects from mydriatics can be severe they may not be
accompanied by peripheral anticholinergic signs or symp-
toms. Ophthalmic drugs for pupil dilation are absorbed
through the conjunctiva or nasal mucosa and avoid first pass
metabolism through the liver. Patient education regarding
proper use or administration by a caregiver for forgetful or
physically impaired individuals may be necessary to limit
systemic effects [3].
4.7 Antihistamines
H1-antihistamine receptor antagonists are commonly
prescribed or taken over-the-counter for the management of
allergic reactions, cold and flu symptoms, nausea and vomit-
ing. First generation antihistamines (e.g., diphenhydramine,
dimenhydrinate etc.) are sedating and have strong antimuscar-
inic effects [5]. They may also be cardiotoxic in overdose, caus-
ing QTc prolongation, and rarely, ventricular arrhythmias

possibly secondary to potassium channel or fast sodium chan-
nel blockade [5,6,9]. The early second generation antihist-
amines astemizole and terfenadine were withdrawn from the
market because of their association with QTc prolongation
and the potentially lethal ventricular arrhythmia torsades de
pointes [5,9,87]. No clinically significant cardiac effects have
been reported for the second generation antihistamines lorata-
dine, fexofenadine, mizolastine, ebastine, azelastine, cetirizine
desloratadine and levocetirizine [5]. Most of the newer agents,
including desloratadine, levocetirizine and fexofenadine, have
limited CNS effects and are not known to have clinically rel-
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14
evant antimuscarinic activity [88,89]. Desloratadine is among
the least sedating of newer antihistamines with somnolence
rates comparable to placebo [89].
4.8 Other uses of antimuscarinic agents
In addition to the aforementioned indications, anticholinergic
drugs are also used as antisecretory and antiemetic agents. For
example, anticholinergics are used in the palliative care setting
to dry respiratory and oropharyngeal secretions, which cause
the crackling, moaning or ‘death rattle’ that occur during
later stages of dying [90]. Transdermal scopolamine, a potent
anticholinergic, is available for use prophylactically as an
antiemetic [91].
For personal use only.
4.9 Nicotinic receptor antagonists
As described earlier, drugs with predominant peripheral
antinicotinic effects are typically prescribed for the purposes
of neuromuscular blockade in the context of surgery or
intensive care (e.g., vancuronium, succinylcholine etc.),
or are limited to the research setting (e.g., ganglionic block-
ers, such as mecamylamine, once used to manage
hypertension) [27-29]. Generally referred to as a dopamine
and norepinephrine reuptake inhibitor, bupropion is one
of the few commonly prescribed drugs with significant cen-
tral antinicotinic effects [92]. It primarily antagonizes the
a4b3 subunit, but also the a4b2 and a1 nicotinic receptor
subunits [93,94]. In addition to indications for the management
of depression and anxiety, it is also efficacious for smoking ces-
sation [95]. Serious, but rare, side effects include hypertension
and seizure [92,96]. Bupropion should not be prescribed to
patients with serious hypertension, kidney disease, epilepsy or
conditions that lower the seizure threshold, such as alcohol
withdrawal or eating disorders.
The more recently approved smoking cessation agent
varenicline, unlike bupropion, is a partial nicotinic agonist.
Although varenicline appears to be highly efficacious for
smoking cessation, there are concerns that its use may be asso-
ciated with an increased risk of behavior change, agitation,
depressed mood and suicidality. It is unclear if these effects
are secondary to nicotine withdrawal [97].
Mecamylamine is another nicotinic receptor antagonist
released originally in the 1950s as the first oral antihyperten-
sive [28]. It is not widely prescribed clinically because of its
ganglionic effects at antihypertensive doses. Ongoing research,
Expert Opin. Drug Saf. (2011) 10(5)
Gerretsen & Pollock
however, continues to explore mecamylamine’s properties as a
central nicotinic antagonist for the treatment of a variety of
neuropsychiatric conditions, including substance, mood and
cognitive disorders, schizophrenia and Tourette’s syndrome [28].
Of note, the dissociative anesthetic agent ketamine, which
is classified as an NMDA receptor antagonist, also has antini-
cotinic properties at or below levels used for anesthesia [98]. It
is actively being researched as an antidepressant following the
observation that a low-dose infusion ameliorated mood symp-
toms in patients being treated for complex regional pain syn-
drome [99,100]. The role of its antinicotinic properties,
however, remains unclear.
5. Anticholinergic monitoring
5.1 Serum anticholinergic activity
The serum anticholinergic radioreceptor assay measures an
individual’s level of anticholinergic activity [2]. It is thought
to reflect the cumulative antimuscarinic burden of all substan-
ces present in a person’s serum, including prescribed or over-
the-counter medications, drug metabolites and possibly
endogenous substances. The serum anticholinergic assay has
been used in multiple research studies, including recent
studies by Vinogradov et al. [74], in which SAA was asso-
ciated with cognitive impairment in schizophrenia patients,
and by Chew et al. [2], which quantified the anticholinergic
activity for 107 commonly used medications (Figure 5). As
described by Tune and Coyle [4,36,40,101], anticholinergic
compounds compete with quinuclidinyl benzilate (QNB), a
nonspecific muscarinic receptor antagonist, for binding to
prepared muscarinic membranes from rat forebrains. SAA is
reported in picomoles of atropine equivalents per milliliter
(pmol/ml) and ranges from the lowest detectable limit of
0.25 -- 25.00 pmol/ml [2,74].
The serum anticholinergic assay has helped stratify the risk
of commonly used drugs for adverse central anticholinergic
effects; moving beyond the dichotomous classification of
drugs as either anticholinergic or non-anticholinergic
(Figure 5) [2]. These findings may facilitate the clinician’s
determination of the risk-benefit ratio of a particular medica-
tion being considered for treatment, especially in the elderly
and in those with mental illness. Of note, the association
between SAA, adverse effects and toxicity is neither well stud-
ied nor established. A recent retrospective study by
Nishtala et al. [102] found that drugs with high SAA were
not always associated with greater odds of neuropsychiatric
sequelae. Nevertheless, the investigators observed a signi-
ficant interaction between age ‡ 65 years and exposure to
medications with anticholinergic properties, which reinforces
the need for cautious use and monitoring of drugs with
anticholinergic activity in older individuals [102].
Recently, some have questioned the serum anticholinergic
assay’s validity in seriously medically ill or post-op delirious
patients [103]. It was argued that the serum anticholinergic
assay may not be an accurate measure of anticholinergic
759
 Drugs with anticholinergic properties: a current perspective on use and safety

Commonly prescribed medications with the divergent findings [2,101]. For example, the acquisition time
highest serum anticholinergic activity
points of subjects’ serum in relation to medication adminis-
> 15 pmol/ml tration was unclear. Plasma filtering discrepancies of subjects’
samples may have also altered assay levels, possibly resulting in
a lack of standardization with the atropine curve; or perhaps,
the premature removal of protein-bound drug prevented
High (> 15 pmol/ml) ample time for drug equilibration between plasma protein,
Amitriptyline muscarinic receptor and unbound states. Nonetheless, the
Doxepin serum anticholinergic assay is laborious and may be subject
Clozapine
Thioridazine to considerable inter-laboratory variation.
Atropine The serum anticholinergic assay is limited by its lack of

High
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14

Dicyclomine specificity for muscarinic receptor subtypes and its inability

L-hyoscyamine to measure CNS levels of anticholinergic activity directly.
Tolterodine
M3 selective receptor antagonists, such as darifenacin, may
be measured by the assay as having high SAA, yet produce
minimal CNS effects due to the low levels of M3 receptors
centrally [69]. Similarly, anticholinergic agents that tend not
to cross the blood-brain barrier (e.g., trospium chloride)
15 pmol/ml
may be identified by the assay as having elevated SAA despite
the lack of CNS effects [66].
A source of the serum anticholinergic assay’s variability
occurs during the dissection and preparation of the rat fore-
brain and striatum from which the muscarinic receptors are
Moderate (5 – 15 pmol/ml)
Nortriptyline
derived. This process could be replaced in the future with
For personal use only.

Paroxetine cloned human muscarinic receptors selective for specific sub-

Chlorpromazine types (e.g., M1 receptor), which would improve the specificity
te

Olanzapine of the test for CNS effects and possibly its reliability.
Modera

Oxybutynin

5.2 Anticholinergic Drug Scale

The Anticholinergic Drug Scale (ADS) was developed with
the purpose of reducing the risk of anticholinergic-
induced adverse events [104]. While an elevated SAA may sug-
gest anticholinergic effects, it does not provide guidance as to
which drugs might be discontinued. The ADS could theoret-
Mild (0.5 – 5 pmol/ml) ically identify those at risk of adverse events and provide
Citalopram guidance for interventions.
Escitalopram 5 pmol/ml The ADS rates drugs in an ordinal fashion from 0 to 3,
Fluoxetine
with 0 signifying no known anticholinergic activity and 3 sig-
Mirtazapine
Quetiapine nifying marked anticholinergic activity. Scores of all medica-
Temazepam tions are summed to determine a total score. To ascertain
ild

Atropine
M

Ranitidine the clinical utility of the ADS, studies were performed to

equivalents
Lithium
0.5 pmol/ml
Figure 5. Commonly prescribed medications with the high-
est anticholinergic activity [2]. Drug serum anticholinergic
activity is presented in atropine equivalents.
www.silvermedia.ca. Reproduced in an altered form with permission from [2].
activity because of extensive binding of the radiotracer QNB
to plasma proteins, which may inhibit its desired binding to
muscarinic receptors. Their study, however, appears to have
a number of methodological differences from prior studies
using the serum anticholinergic assay that may explain their
determine its strength of association with the serum anticho-
linergic assay. Although reliable, the ADS explained < 10%
of the variance in the assay [105]. Even after modifying the scale
to factor in drug dosing there was no improvement in the
ADS’s explanatory power [104]. Possible reasons for its inabil-
ity to account for greater variance include differing potencies
of anticholinergic drugs, interindividual pharmacokinetic var-
iability and the possibility of endogenous substances with
anticholinergic activity. Although the ADS may have use as
a tool for measuring anticholinergic burden, further studies
are required to determine if ADS scores are associated with
clinical outcomes related to anticholinergic effects and
whether or not the ADS can guide clinical decisions to reduce
anticholinergic load.

760 Expert Opin. Drug Saf. (2011) 10(5)


6. Conclusion
In this article the common indications and adverse effects of
drugs with anticholinergic properties were reviewed and
methods of monitoring anticholinergic burden and safety
were discussed. Drugs with anticholinergic properties are
often prescribed to the elderly and the mentally ill who are
vulnerable to their sometimes subtle neuropsychiatric effects.
Scales, such as the ADS, and tables that list either drugs
with known anticholinergic effects (Figure 5) or medications
considered inappropriate for use in the elderly (i.e., Beers
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Newcastle Upon Tyne on 12/19/14
Criteria [106,107]) can guide clinical decision-making to limit
anticholinergic load.
7. Expert opinion
Drugs with anticholinergic properties have a number of
clinical indications, but also unintended adverse effects that
range from mild-to-severe to potentially lethal. The aim clin-
ically (as with all drugs) is to maximize the intended effects
and limit the adverse outcomes. With the growing elderly
population it is necessary to be vigilant for the adverse effects
of medications that may not manifest at younger ages.
As there are numerous commonly prescribed drugs that influ-
For personal use only.
ence the cholinergic system, it is especially prudent to be
mindful of the anticholinergic impact on cognition and the
cumulative effect of multiple medications of modest anti-
muscarinic activity. When considering a medication with
anticholinergic properties, the clinician should carefully
Expert Opin. Drug Saf. (2011) 10(5)
Gerretsen & Pollock
consider the risks versus benefits, and impact on quality of
life. He or she should assess for cognitive impairment,
dementia, history of delirium and previous adverse effects
attributable to anticholinergic agents.
Despite the clinical promise of an anticholinergic assay, it
remains unavailable for clinical use and continues to pose
technical issues, such as inter-laboratory variation. Scales and
tables that list the anticholinergic activity of commonly pre-
scribed medications remain the best aids to guide clinical
decision-making (e.g., ADS, Figure 5, Beers Criteria). By uti-
lizing a list or scale to obtain a sense of the anticholinergic
load already attributable to the patient’s current medication
regimen, the physician can assess whether or not to start or
add a drug with anticholinergic activity versus select an effica-
ciously equivalent agent associated with less adverse effects.
Future research should focus on the continued development
of muscarinic receptor subtype specific drugs and agents
that do not cross the blood-brain barrier in order to limit
unintended, negative anticholinergic outcomes.
Declaration of interest
Within the last 5 years, B Pollock has been a member of the
advisory board for Lundbeck Canada (final meeting was in
May 2009) and Forest (final meeting was in March 2008).
He has served as a consultant for Wyeth (October 2008) and
Takeda (July 2007). He was a faculty member of the Lundbeck
International Neuroscience foundation (final meeting was in
April 2010).
761
 Drugs with anticholinergic properties: a current perspective on use and safety
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Affiliation
Philip Gerretsen1,2,3 MD MSW &
Bruce G Pollock†4,5 MD PhD FRCPC
†
Author for correspondence
1
Geriatric Mental Health Program,
Centre for Addiction & Mental Health,
Canada
2
Department of Psychiatry,
University of Toronto,
Canada
3
Multimodal Imaging Group,
Centre for Addiction & Mental Health,
Canada
4
Vice President,
Research,
Centre for Addiction and Mental Health,
Canada
5
Professor and Head Division of
Geriatric Psychiatry,
University of Toronto,
Faculty of Medicine,
Department of Psychiatry,
33 Russell Street, T 109,
Toronto, ON M5S 2S1, Canada
Tel: +1 416 979 6890; Fax: +1 416 260 4206;
E-mail: bruce_pollock@camh.net
765