Anticholinergic Toxicity

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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.

Signs and symptoms

Clinical manifestations are caused by CNS effects, peripheral nervous system effects, or both. Common manifestations are as follows:

Additional manifestations include the following:

See Clinical Presentation for more detail.

Diagnosis

No specific diagnostic studies exist for anticholinergic overdoses. Laboratory studies that may be helpful include the following:

Additional studies that may be useful are as follows:

See Workup for more detail.

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.

See Treatment and Medication for more detail.

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]

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.

Additional manifestations include the following:

Patients with central anticholinergic syndrome may present with the following:

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.

Anticholinergics include the following:

Antihistamines with anticholinergic properties include the following:

Antipsychotics with anticholinergic properties include the following:

Antispasmodics with anticholinergic properties include the following:

Cyclic antidepressants with anticholinergic properties include the following:

Mydriatics with anticholinergic properties include the following:

Miscellaneous drugs with anticholinergic properties include the following:

Plants with anticholinergic properties include the following:

Mushrooms with anticholinergic properties include:

 

 

 

 

 

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:

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.

Prehospital Care

Prehospital care includes the following:

Emergency Department Care

Initial assessment and stabilization are required in the emergency department (ED). Upon arrival, ensure that the airway is adequate and that breathing is present and maintained.[3] Provide oxygen and intubate if significant central nervous system (CNS) or respiratory depression exists. Assess circulation and initiate cardiac and pulse oximetry monitoring. Examine the patient's body for transdermal drug delivery patches (eg, scopolamine) and remove any if found.

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.

Agitated patients may respond to reassurance. If pharmacological intervention is required, physostigmine or benzodiazepines may be used.

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.

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:

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]

Activated charcoal (Liqui-Char)

Clinical Context:  Most useful if administered within 4 h of ingestion. Repeat doses may be used, especially with ingestion of sustained release agents. Limited outcome studies exist, especially when administration is more than 1 h of ingestion.

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

Empirically used to minimize systemic absorption of the toxin.

Diazepam (Valium)

Clinical Context:  Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Lorazepam (Ativan)

Clinical Context:  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)

Clinical Context:  Used for patients refractory to diazepam or lorazepam.

Midazolam (Versed)

Clinical Context:  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.

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.

Sodium bicarbonate

Clinical Context:  Anecdotally, has been effective in treating antihistamine induced QRS prolongation (>100 ms) with a quinidinelike ECG pattern.

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.

Physostigmine (Antilirium)

Clinical Context:  Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across myoneural junction.

Clinical effects last 20-60 min. Repeat prn.

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.

Further Inpatient Care

Admission decisions are based on patient symptomatology. Patients without anticholinergic signs or symptoms can be discharged after a 4-6 hour observation period. Individuals with initial mild toxicity that resolves during initial observation also may be discharged.

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.

What is anticholinergic syndrome (ACS)?What are the signs and symptoms of anticholinergic syndrome (ACS)?How is anticholinergic overdose diagnosed?What is the initial treatment for anticholinergic toxicity?How is anticholinergic toxicity managed?What is the pathophysiology of anticholinergic toxicity?What causes anticholinergic syndrome (ACS)?What is the incidence of anticholinergic drug exposure in the US?What is the focus of history in suspected anticholinergic toxicity?What is the role of anticholinergic toxicity in cognitive impairment?What are common signs and symptoms of anticholinergic toxicity?What are less common symptoms of anticholinergic toxicity?Which drug classes have anticholinergic properties?Which antihistamines have anticholinergic properties?Which antipsychotics have anticholinergic properties?Which antispasmodics have anticholinergic properties?Which cyclic antidepressants have anticholinergic properties?Which mydriatics have anticholinergic properties?Which miscellaneous drugs have anticholinergic properties?Which plants have anticholinergic properties?Which mushrooms have anticholinergic properties?What are the differential diagnoses for Anticholinergic Toxicity?What is the role of lab studies in the diagnosis of anticholinergic toxicity?What is the role of imaging studies in the diagnosis of anticholinergic toxicity?What is the role of electrocardiogram (ECG) in the diagnosis of anticholinergic toxicity?What is the role of lumbar puncture (LP) in the diagnosis of anticholinergic toxicity?What is included in prehospital care for anticholinergic toxicity?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?Which treatments are ineffective for anticholinergic toxicity?What supportive care may be needed in the treatment of anticholinergic toxicity?How should seizures and hallucinations be managed in anticholinergic toxicity?What is the antidote for anticholinergic toxicity and how does it work?What are common side effects of physostigmine salicylate for anticholinergic toxicity?What is the role of benzodiazepines in the treatment of anticholinergic toxicity?When is physostigmine contraindicated in the treatment of anticholinergic toxicity?Which specialist consultations may be beneficial in the treatment of anticholinergic toxicity?Which medications are used in the treatment of anticholinergic toxicity?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?What is included in inpatient care for anticholinergic toxicity?

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

Disclosure: Nothing to disclose.

Coauthor(s)

Danish A Ahmad, MD, Resident Physician, Departments of Emergency Medicine and Internal Medicine, Long Island Jewish Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

John T VanDeVoort, PharmD, Regional Director of Pharmacy, Sacred Heart and St Joseph's Hospitals

Disclosure: Nothing to disclose.

Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center

Disclosure: Nothing to disclose.

Chief Editor

David Vearrier, MD, MPH, Associate Professor, Medical Toxicology Fellowship Director, Department of Emergency Medicine, Drexel University College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

David C Lee, MD, Research Director, Department of Emergency Medicine, Associate Professor, North Shore University Hospital and New York University Medical School

Disclosure: Nothing to disclose.

References

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  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. [View Abstract]
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  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. [View Abstract]
  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. [View Abstract]
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