Professional Documents
Culture Documents
Anticholinergic Toxicity: Signs and Symptoms
Anticholinergic Toxicity: Signs and Symptoms
com/article/812644-print
emedicine.medscape.com
Anticholinergic Toxicity
Updated: Jan 14, 2019
Author: Mityanand Ramnarine, MD, FACEP; Chief Editor: David Vearrier, MD, MPH
Overview
Practice Essentials
Anticholinergic syndrome (ACS) is produced by the inhibition of cholinergic neurotransmission at muscarinic receptor sites.
It may follow the ingestion of a wide variety of prescription and over-the-counter medications.[1, 2, 3] This syndrome may be
caused by intentional overdose, inadvertent ingestion, medical noncompliance, or geriatric polypharmacy; systemic effects
also have resulted from topical eye drops.
Clinical manifestations are caused by CNS effects, peripheral nervous system effects, or both. Common manifestations are
as follows:
Flushing
Fever
Sinus tachycardia
Functional ileus
Urinary retention
Hypertension
Tremulousness
Myoclonic jerking
Diagnosis
No specific diagnostic studies exist for anticholinergic overdoses. Laboratory studies that may be helpful include the
following:
CT of the head and MRI imaging - for patients in whom AMS is insufficiently explained by the ingested agent or who
are unresponsive to appropriate intervention
Lumbar puncture - for patients with fever and AMS in whom CNS infection is suspected as a possible etiology
Management
Patients presenting with anticholinergic toxicity should be transported to the nearest emergency facility with advanced life
support (ALS) capabilities. Avoid administering ipecac syrup.
In patients with recent (< 1 hour), clinically significant ingestions that are anticipated to result in moderate-to-severe
anticholinergic toxicity, single-dose activated charcoal may be administered to minimize absorption of the ingested
medication. In patients with depressed level of consciousness or impaired airway reflexes, definitive control of the airway
(endotracheal intubation with a cuffed endotracheal tube) should be obtained prior to adminstration of activated charcoal via
orogastric tube to minimize the risk of charcoal aspiration.
The antidote for anticholinergic toxicity is physostigmine salicylate. Most patients can be safely treated without it, but it is
recommended when tachydysrhythmia with subsequent hemodynamic compromise, intractable seizure, severe agitation or
psychosis, or some combination thereof is present. Physostigmine is contraindicated in patients with cardiac conduction
disturbancese agitation or psychosis, or some combination thereof is present. Physostigmine is contraindicated in patients
with cardiac conduction disturbances on ECG.
Pathophysiology
Substances with anticholinergic properties competitively antagonize acetylcholine muscarinic receptors; this predominantly
occurs at peripheral (eg, heart, salivary glands, sweat glands, GI tract, GU tract) postganglionic parasympathetic muscarinic
receptors. Anticholinergic substances minimally compete with acetylcholine at other sites (eg, autonomic ganglia).
Central nervous system (CNS) manifestations result from central cortical and subcortical muscarinic receptor antagonism.
The degree of CNS manifestation is related to the drug's ability to cross the blood-brain barrier.
Epidemiology
United States
Anticholinergic syndrome may be caused by intentional overdose, inadvertent ingestion, medical noncompliance, or geriatric
polypharmacy. Systemic effects also have resulted from topical eye drops. Anticholinergic syndrome commonly follows the
ingestion of a wide variety of prescription and over-the-counter medications.[1, 2, 3]
Intentional abuse with hallucinogenic plants (eg, Datura stramonium [jimson weed]) and mushrooms (eg, Amanita muscaria)
can cause anticholinergic syndrome due to the presence of anticholinergic tropane alkaloids. Scopolamine has been used in
beverages as "knockout drops," and several cases of anticholinergic syndrome have been reported following Chinese
herbal tea consumption.
In 2016, the American Association of Poison Control Centers (AAPC) National Poison Data System Annual Report
documented 6231 single exposures to anticholinergic drugs, excluding cough and cold preparations. Unintentional
ingestions accounted for 5731 presentations. Moderate morbidity (requiring specific treatment) was reported in 173 cases,
major morbidity (life-threatening) in 20, and one death were reported.[4] Patients with severe central manifestations (eg,
hallucinations, psychoses, seizures, coma) have the highest morbidity rates.
Antihistamines also have anticholinergic properties. In 2016, the AAPCC documented 75,833 single exposures to
antihistamines, with 32,416 specific to diphenhydramine. A total of 16 deaths were attributed to antihistamine toxicity, all of
them specifically diphenhydramine related.[4]
https://emedicine.medscape.com/article/812644-print 2/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Presentation
History
For all patients with suspected poisoning, determine the precise substance(s) ingested, time of ingestion, quantity ingested,
rationale for ingestion, and co-ingestants. Ascertain patient compliance, medical history, prescription medications, and
nonprescription medications (including natural or herbal products).
Many medications have anticholinergic properties, which can result in additive toxicity. Always inquire about use of dermally
applied drugs (ie, scopolamine transdermal delivery system).
In a study that included 30 patients with chronic pain and 30 control patients, the pain patients were at higher cognitive risk
from anticholinergic burden, especially those aged 30 to 39 years. The average number of medications used by patients in
the chronic pain group was 3.93, compared with 1.20 in the control group. None of the patients were taking opioid
analgesics. The medications used by patients in this age group were more likely to have anticholinergic properties than
those used by older patients.[5]
In older adults, long-term use of anticholinergic drugs has been linked to cognitive impairment. A study in patients aged 65
years and older found that the risk for cognitive impairment was increased by 50% in those who had taken three or more
mild anticholinergic drugs for more than 90 days and by 100% in those taking one or more strong anticholinergics for more
than 60 days.[6, 7] The Drug Burden Index (DBI), a non-invasive method to quantify patients’ anticholinergic and sedative
drug burden from their prescriptions, can be useful in older patients with polypharmacy.[8, 9]
Anticholinesterase inhibitors (eg, donepezil) are used in treatment of Parkinson disease dementia. Mantri et al reported that
concurrent use of anticholinergic medications is a common prescribing error in these patients.[10]
Physical
Anticholinergic syndrome results from the inhibition of muscarinic cholinergic neurotransmission. Clinical manifestations are
caused by CNS effects, peripheral nervous system effects, or both.
Remember common signs and symptoms with the mnemonic, "red as a beet, dry as a bone, blind as a bat, mad as a hatter,
hot as a hare, and full as a flask." The mnemonic refers to the symptoms of flushing, dry skin and mucous membranes,
mydriasis with loss of accommodation, altered mental status (AMS), fever, and urinary retention, respectively.
Sinus tachycardia
Decreased bowel sounds
Functional ileus
Hypertension
Tremulousness
Myoclonic jerking
Patients with central anticholinergic syndrome may present with the following:
Ataxia
Disorientation
Short-term memory loss
Confusion
Hallucinations (visual, auditory)
Psychosis
Agitated delirium
Seizures (rare)
Coma
Respiratory failure
Cardiovascular collapse
https://emedicine.medscape.com/article/812644-print 3/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Causes
In addition to anticholinergics, drug classes that have anticholinergic properties include antihistamines, antipsychotics,
antispasmodics, cyclic antidepressants, and mydriatics. Furthermore, several varieties of plants and mushrooms contain
anticholinergic substances.
Atropine, scopolamine
Glycopyrrolate
Benztropine, trihexyphenidyl
Chlorpheniramine
Cyproheptadine
Doxylamine
Hydroxyzine
Dimenhydrinate
Diphenhydramine
Meclizine
Promethazine
Chlorpromazine
Clozapine
Mesoridazine
Olanzapine
Quetiapine
Thioridazine
Clidinium
Dicyclomine
Hyoscyamine
Oxybutynin
Propantheline
Amitriptyline
Amoxapine
Clomipramine
Desipramine
Doxepin
Imipramine
Nortriptyline
https://emedicine.medscape.com/article/812644-print 4/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Protriptyline
Cyclopentolate
Homatropine
Tropicamide
Carbamazepine
Cyclobenzaprine
Orphenadrine
Brugmansia spp.
Clitocybe spp.
Inocybe spp
DDx
Differential Diagnoses
Acute Hypoglycemia
Amphetamine Toxicity
Antidepressant Toxicity
Carbamazepine Toxicity
Cocaine Toxicity
Hallucinogen Toxicity
Lithium Toxicity
https://emedicine.medscape.com/article/812644-print 5/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Meningitis
Methamphetamine Toxicity
Phencyclidine Toxicity
Sympathomimetic Toxicity
Workup
Workup
Laboratory Studies
No specific diagnostic studies exist for anticholinergic overdoses. Serum drug concentrations are not helpful and results
rarely are available to aid in initial management. However, screening for acetaminophen and salicylate is indicated in all
intentional poisonings because combination medication preparations and multiple ingestions often occur. In addition, studies
that may be helpful include the following:
Serum chemistry and electrolyte analysis, which may provide clues to the intoxicating agents and co-ingestants
Creatine kinase (CK) level in patients with psychomotor agitation, to rule out associated rhabdomyolysis
Electrolyte and arterial blood gas (ABG) analysis when bicarbonate therapy has been instituted for agents that also
produce type 1A cardiac conduction disturbances; blood pH should be 7.45-7.55
Imaging Studies
Consider a computed tomography (CT) or magnetic resonance imaging (MRI) scan of the brain in patients with altered
mental status that is insufficiently explained by the ingested agent or in patients who are unresponsive to appropriate
intervention.
Other Tests
Immediately perform an electrocardiogram (ECG) on all patients with suspected toxic ingestions.
Procedures
Consider lumbar puncture (LP) in patients with fever and altered mental status in whom CNS infection is considered as a
possible etiology.
https://emedicine.medscape.com/article/812644-print 6/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Treatment
Prehospital Care
Prehospital care includes the following:
Rapidly transport the patient to the nearest emergency facility with advanced life support (ALS) capabilities.
Focus primary assessment on circulatory, respiratory, and neurologic systems.
Obtain intravenous access and frequently monitor vital signs.
Administer naloxone if respiratory depression due to opioid intoxication is suspected.
Assess for hypoglycemia in patients with altered mental status.
Manage seizures with benzodiazepines.
Physostigmine is not recommended in the prehospital setting.
Avoid ipecac syrup.
Obtain an electrocardiogram (ECG) soon after ED arrival. Sinus tachycardia is common and does not require treatment in
the stable patient. Consider administration of sodium bicarbonate to patients with signs of sodium channel blockade such as
QRS prolongation (>100 milliseconds) or a terminal R wave in aVR >3 mm on the ECG.
Collect blood for laboratory analysis and quick glucose measurement while obtaining intravenous access. Closely examine
patients for signs of trauma.
Following initial stabilization, gastrointestinal (GI) decontamination may be undertaken in patients with recent (typically < 1
hour), clnically significant ingestions that are anticipated to result in moderate-to-severe anticholinergic toxicity. For the vast
majority of patients, a single dose of activated charcoal (1 g/kg) by mouth is sufficient for GI decontamination. Administration
of activated charcoal may be considered in patients with more remote ingestions (>1 hr) if it is suspected that a significant
amount of drug remains in the GI tract (eg, bezoar formation or delayed absoption due to anticholinergic ileus).
Patients with altered mental status or impaired airway protective reflexes are at risk for charcoal aspiration and pneumonitis.
These patients should be intubated with a cuffed endotracheal tube to prevent aspiration prior to administration of activated
charcoal via orogastric tube. Gastric lavage is typically not indicated following anticholinergic medication overdose.
Most anticholinergic agents have large volumes of distribution and are highly protein bound. Therefore, hemodialysis and
hemoperfusion are ineffective treatment methods.
Patients often recover well with supportive care. Tachycardia may be responsive to crystalloid infusions, control of agitation
(eg, benzodiazepines), and control of hyperthermia (eg, fluids, antipyretics, active cooling measures). Administer a trial dose
of physostigmine over 2-5 minutes for patients with narrow QRS supraventricular tachydysrhythmias resulting in
hemodynamic deterioration or ischemic pain. Ventricular arrhythmias can be treated with lidocaine.
Manage seizures with benzodiazepines, preferably diazepam or lorazepam. Use phenobarbital and other barbiturates for
intractable seizures. Phenytoin has no proven role for toxin-induced seizures and should not be used. Perform a repeat
ECG immediately following seizure activity because acidosis can potentiate conduction aberrancies with certain agents.
Patients with hallucinations often respond to reassurance and do not require specific treatment unless they also have
significant psychomotor agitation. Agitation may be treated with the specific antidote, physostigmine, or nonspecifically with
benzodiazepines. Although its use is controversial, physostigmine is safe and effective for controlling agitated delirium if the
ECG indicates the absence of prolonged PR and QRS intervals. Phenothiazines are contraindicated because of their
anticholinergic properties. Perform bladder catheterization if the patient shows signs or symptoms of urinary retention.
https://emedicine.medscape.com/article/812644-print 7/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
The antidote for anticholinergic toxicity is physostigmine salicylate. Physostigmine is the only reversible acetylcholinesterase
inhibitor capable of directly antagonizing the CNS manifestations of anticholinergic toxicity; it is an uncharged tertiary amine
that efficiently crosses the blood-brain barrier.
By inhibiting acetylcholinesterase, the enzyme responsible for the hydrolysis of acetylcholine, an increased concentration of
acetylcholine augments stimulation at muscarinic and nicotinic receptors. Physostigmine can reverse the central effects of
coma, seizures, severe dyskinesias, hallucinations, agitation, and respiratory depression. The most common indication for
physostigmine is to control agitated delirium.
The most common adverse effects from physostigmine are peripheral cholinergic manifestations (eg, vomiting, diarrhea,
abdominal cramps, diaphoresis). Physostigmine also may produce seizures, a complication frequently reported when
administered to individuals with tricyclic antidepressant poisoning. Rarely, physostigmine may produce bradyasystole; three
cases of this complication have been reported in literature, and all occurred in patients given physostigmine for severe
tricyclic antidepressant poisoning. To avoid bradyasystole, do not administer physostigmine to patients whose ECG shows a
prolonged PR or QRS interval.
Most patients can be treated safely without physostigmine, but its use is recommended when at least one of the following
aberrations is present:
Although some authors recommend the use of benzodiazepines as first-line agents for the control of agitation associated
with the anticholinergic syndrome, one study suggests that physostigmine is significantly more effective and no less safe for
use in this setting.[11]
Physostigmine is contraindicated in patients with cardiac conduction disturbances (prolonged PR and QRS intervals) on
ECG.
Consultations
See the list below:
Consult with a regional poison center and/or toxicologist in all toxic exposures for assistance with decontamination
and therapeutic intervention decisions, particularly regarding the use of physostigmine.
Medication
Medication Summary
Medical therapy consists of anticonvulsants, antitachydysrhythmics, sodium bicarbonate, physostigmine, and sedatives. The
standard dose of physostigmine is 0.5-2 mg, given by slow iintravenous push (not to exceed 1 mg/min). However, because
higher doses of physostigmine can lead to cholinergic toxicity (eg, seizures, cardiotoxic effects), Dawson and Buckley
recommend giving a titrated dose of 0.5 to 1 mg in adults and waiting at least 10-15 min before re-dosing.[12]
GI decontaminant
Class Summary
Empirically used to minimize systemic absorption of the toxin.
https://emedicine.medscape.com/article/812644-print 8/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Administration of charcoal by itself (in aqueous solution), as opposed to coadministration with a cathartic is becoming the
current practice standard; this is because studies have not shown benefit from cathartics and, while most drugs and toxins
are absorbed within 30-90 min, laxatives take hours to work. Also, dangerous fluid and electrolyte shifts have occurred when
cathartics are used in small children.
When ingested dose is known, charcoal may be given at 10 times ingested dose of agent over 1 or 2 doses.
Class Summary
For patients with agitation or psychosis, verbal reassurance and a quiet dimly lit room may be effective. When
pharmacological intervention is required, control of agitation may be achieved with the administration of physostigmine or
benzodiazepines (DOC). Treat seizures initially with benzodiazepines.
Diazepam (Valium)
Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
Lorazepam (Ativan)
Sedative hypnotic with short onset of effects and relatively long half-life.
By increasing the action of GABA, which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS,
including limbic and reticular formation.
Monitoring patient's blood pressure after administering dose is important. Adjust prn.
Phenobarbital (Luminal)
Used for patients refractory to diazepam or lorazepam.
Midazolam (Versed)
Used as alternative in termination of refractory status epilepticus. Because water soluble, takes approximately 3 times
longer than diazepam to peak EEG effects. Thus, clinician must wait 2-3 min to fully evaluate sedative effects before
initiating procedure or repeating dose. Has twice the affinity for benzodiazepine receptors than diazepam. May be
administered IM if unable to obtain vascular access.
Cardiovascular agents
Class Summary
Used only when patient is diagnosed with tricyclic antidepressant overdose or when evidence of sodium channel blockade is
present. Routine use is not recommended.
Sodium bicarbonate
https://emedicine.medscape.com/article/812644-print 9/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Anecdotally, has been effective in treating antihistamine induced QRS prolongation (>100 ms) with a quinidinelike ECG
pattern.
Cholinergic agents
Class Summary
Reversible anticholinesterase inhibitor that increases the concentration of ACh at the sites of cholinergic neurotransmission.
Readily crosses the blood-brain barrier to produce desired CNS effects.
Physostigmine (Antilirium)
Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across myoneural
junction.
Follow-up
Admit and monitor symptomatic patients, usually in an ICU setting, until a symptom-free period of 4 hours without the aid of
antidotes or supportive therapy is documented.
Presentation
DDX
Workup
What is the role of lumbar puncture (LP) in the diagnosis of anticholinergic toxicity?
Treatment
What is included in the initial emergency department (ED) response to suspected anticholinergic toxicity?
What is included in emergency department (ED) care for anticholinergic toxicity following initial stabilization?
What is the antidote for anticholinergic toxicity and how does it work?
What are common side effects of physostigmine salicylate for anticholinergic toxicity?
Medications
Which medications in the drug class Cholinergic agents are used in the treatment of Anticholinergic Toxicity?
Which medications in the drug class Cardiovascular agents are used in the treatment of Anticholinergic Toxicity?
Which medications in the drug class Benzodiazepines and other sedatives are used in the treatment of Anticholinergic
Toxicity?
Which medications in the drug class GI decontaminant are used in the treatment of Anticholinergic Toxicity?
Follow-up
https://emedicine.medscape.com/article/812644-print 11/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
Author
Mityanand Ramnarine, MD, FACEP Assistant Professor of Emergency Medicine, Associate Chair, Department of
Emergency Medicine, Program Director, Emergency/Internal Medicine/Critical Care, Hofstra Northwell School of Medicine at
Hofstra University; Attending Physician, Department of Emergency Medicine, Long Island Jewish Medical Center
Mityanand Ramnarine, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American College
of Emergency Physicians, American College of Physicians, American Medical Association
Coauthor(s)
Danish A Ahmad, MD Resident Physician, Departments of Emergency Medicine and Internal Medicine, Long Island Jewish
Medical Center
John T VanDeVoort, PharmD Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals
John T VanDeVoort, PharmD is a member of the following medical societies: American Society of Health-System
Pharmacists
Michael J Burns, MD Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel
Deaconess Medical Center
Michael J Burns, MD is a member of the following medical societies: American Academy of Clinical Toxicology, American
College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine
Chief Editor
David Vearrier, MD, MPH Associate Professor, Medical Toxicology Fellowship Director, Department of Emergency
Medicine, Drexel University College of Medicine
David Vearrier, MD, MPH is a member of the following medical societies: American Academy of Clinical Toxicology,
American Academy of Emergency Medicine, American College of Medical Toxicology, American College of Occupational
and Environmental Medicine
Additional Contributors
David C Lee, MD Research Director, Department of Emergency Medicine, Associate Professor, North Shore University
Hospital and New York University Medical School
David C Lee, MD is a member of the following medical societies: American Academy of Emergency Medicine, American
College of Emergency Physicians, American College of Medical Toxicology, Society for Academic Emergency Medicine
References
1. Magin PJ, Morgan S, Tapley A, McCowan C, Parkinson L, Henderson KM, et al. Anticholinergic medicines in an older primary
care population: a cross-sectional analysis of medicines' levels of anticholinergic activity and clinical indications. J Clin Pharm
Ther. 2016 Jun 27. 59 (5):582-90. [Medline].
2. Madhuvrata P, Singh M, Hasafa Z, Abdel-Fattah M. Anticholinergic Drugs for Adult Neurogenic Detrusor Overactivity: A
Systematic Review and Meta-analysis. Eur Urol. 2012 Feb 25. [Medline].
3. Quizon A, Colin AA, Pelosi U, Rossi GA. Treatment of Disorders Characterized by Reversible Airway Obstruction in Childhood:
are Anti-cholinergic Agents the Answer?. Curr Pharm Des. 2012 Feb 27. [Medline].
4. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of
Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol (Phila). 2017 Dec. 55
https://emedicine.medscape.com/article/812644-print 12/13
7/29/2019 https://emedicine.medscape.com/article/812644-print
(10):1072-1252. [Medline]. [Full Text].
5. Anderson P. Pain patients at cognitive risk from anticholinergic burden?. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/782520. April 15, 2013; Accessed: November 2, 2018.
6. Anderson PA. Just 2 Months' Exposure to Anticholinergics Affects Cognition. Medscape Medical News. Available at
http://www.medscape.com/viewarticle/804558. May 22, 2013; Accessed: November 2, 2018.
7. Cai X, Campbell N, Khan B, Callahan C, Boustani M. Long-term anticholinergic use and the aging brain. Alzheimers Dement.
2012 Nov 22. [Medline].
8. Wouters H, van der Meer H, Taxis K. Quantification of anticholinergic and sedative drug load with the Drug Burden Index: a
review of outcomes and methodological quality of studies. Eur J Clin Pharmacol. 2017 Mar. 73 (3):257-266. [Medline]. [Full
Text].
9. Kröger E, Simard M, Sirois MJ, Giroux M, Sirois C, Kouladjian-O'Donnell L, et al. Is the Drug Burden Index Related to Declining
Functional Status at Follow-up in Community-Dwelling Seniors Consulting for Minor Injuries? Results from the Canadian
Emergency Team Initiative Cohort Study. Drugs Aging. 2018 Oct 31. [Medline].
10. Mantri S, Fullard M, Gray SL, Weintraub D, Hubbard RA, Hennessy S, et al. Patterns of Dementia Treatment and Frank
Prescribing Errors in Older Adults With Parkinson Disease. JAMA Neurol. 2018 Oct 1. [Medline].
11. Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of
anticholinergic poisoning. Ann Emerg Med. 2000 Apr. 35(4):374-81. [Medline].
12. Dawson AH, Buckley NA. Pharmacological management of anticholinergic delirium - theory, evidence and practice. Br J Clin
Pharmacol. 2016 Mar. 81 (3):516-24. [Medline].
13. Wilson ME, Lee GK, Chandra A, Kane GC. Central anticholinergic syndrome following dobutamine-atropine stress
echocardiography. Echocardiography. 2011 Nov. 28(10):E205-6. [Medline].
https://emedicine.medscape.com/article/812644-print 13/13