AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

Anticholinergic syndrome (ACS) is produced by the inhibition of cholinergic neurotransmission at muscarinic receptor sites.

For a related CME activity, see CME - New Risk Score Predicts Risk for Anticholinergic Adverse Effects. 

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.

Frequency

United States

Anticholinergic syndrome may be caused by intentional overdose, inadvertent ingestion, medical noncompliance, and 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.

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.

According to the American Association of Poison Control Centers, almost 2.4 million cases of human poison exposure were reported to 65 US poison control centers in 2003.¹

In 2003, the Toxic Exposure Surveillance System reported 3094 symptomatic anticholinergic drug presentations with unintentional ingestions in 52%, intentional ingestions in 38%, and adverse reactions occurring in 7% of cases; moderate morbidity (requiring specific treatment) was reported in 20%, major morbidity (life-threatening) in 3.7%, and death in 5 cases (case-fatality proportion = 0.16%).¹

In 2003, the Toxic Exposure Surveillance System reported 70,251 symptomatic antihistamine presentations with 28,092 specific to diphenhydramine. A total of 64 deaths were attributed to antihistamine toxicity of which 38 were specifically diphenhydramine related for case-fatality proportions of 0.09% and 0.14%, respectively.¹

Patients with severe central manifestations (eg, hallucinations, psychoses, seizures, coma) have the highest morbidity rates.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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).

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, and hot as a hare." The mnemonic refers to the symptoms of flushing, dry skin and mucous membranes, mydriasis with loss of accommodation, altered mental status (AMS), and fever, respectively.
• Additional manifestations include sinus tachycardia, decreased bowel sounds, functional ileus, urinary retention, hypertension, tremulousness, and myoclonic jerking.
• Patients with central anticholinergic syndrome may present with ataxia, disorientation, short-term memory loss, confusion, hallucinations (visual, auditory), psychosis, agitated delirium, seizures (rare), coma, respiratory failure, and cardiovascular collapse.

Causes

Agents with anticholinergic properties are as follows:

• Anticholinergics
• • Atropine, scopolamine
  • Glycopyrrolate
  • Benztropine, trihexyphenidyl
• Antihistamines
• • Chlorpheniramine
  • Cyproheptadine
  • Doxylamine
  • Hydroxyzine
  • Dimenhydrinate
  • Diphenhydramine
  • Meclizine
  • Promethazine
• Antipsychotics
• • Chlorpromazine
  • Clozapine
  • Mesoridazine
  • Olanzapine
  • Quetiapine
  • Thioridazine
• Antispasmodics
  • Clidinium
  • Dicyclomine
  • Hyoscyamine
  • Oxybutynin
  • Propantheline
• Cyclic antidepressants
• • Amitriptyline
  • Amoxapine
  • Clomipramine
  • Desipramine
  • Doxepin
  • Imipramine
  • Nortriptyline
  • Protriptyline
• Mydriatics
  • Cyclopentolate
  • Homatropine
  • Tropicamide
• Plants
• • Amanita muscaria (fly agaric)
  • Amanita pantherina (panther mushroom)
  • Arctium lappa (burdock root)
  • Atropa belladonna (deadly nightshade)
  • Cestrum nocturnum (night blooming jessamine)
  • Datura suaveolens (angel's trumpet)
  • Datura stramonium (jimson weed)
  • Hyoscyamus niger (black henbane)
  • Lantana camara (red sage)
  • Solanum carolinensis (wild tomato)
  • Solanum dulcamara (bittersweet)
  • Solanum pseudocapsicum (Jerusalem cherry)
  • Solanum tuberosum (potato)
  • Miscellaneous, including carbamazepine, cyclobenzaprine, and orphenadrine

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab 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, perform screening for acetaminophen and salicylate in all intentional poisonings because combination medication preparations and multiple ingestions often occur.
• Consider blood and urine cultures in febrile patients.
• Serum chemistry and electrolyte analysis may provide clues to the intoxicating agents and co-ingestants. Obtain a creatine kinase (CK) in patients with psychomotor agitation to rule out associated rhabdomyolysis.
• Perform 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.
• Perform a urine pregnancy test on all women of childbearing age.

Imaging Studies

• Consider CT scan of the head and MRI imaging in patients with altered mental status that is insufficiently explained by the ingested agent or in patients that are unresponsive to appropriate intervention.

Other Tests

• Immediately perform electrocardiogram (ECG) analysis on all patients with suspected toxic ingestions.

Procedures

• Consider lumbar puncture (LP) in all patients with fever and altered mental status.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Prehospital Care

• 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 IV access and frequently monitor vital signs. Administer naloxone and thiamine and assess for hypoglycemia in patients with altered mental status.
• Manage seizures with benzodiazepines.
• Physostigmine is not recommended in the prehospital setting.
• Avoid ipecac syrup and defer administration of activated charcoal unless a prolonged transport time is anticipated.

Emergency Department Care

Initial assessment and stabilization are required. Upon ED arrival, ensure an adequate airway and check that breathing is present and maintained. Provide oxygen and intubate if significant 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, if found. Obtain an ECG soon after ED arrival. Sinus tachycardia is common and does not require treatment in the stable patient. Administer sodium bicarbonate to patients with QRS prolongation (>100 milliseconds) or the presence of terminal right axis (R wave in aVR > 3 mm) on the ECG. Collect blood for laboratory analysis and quick glucose measurement while obtaining IV access. Closely examine patients for signs of trauma. Agitated patients may respond to reassurance. If chemical restraint is required, physostigmine or benzodiazepines may be used.

• Following initial stabilization, GI decontamination usually is necessary after anticholinergic poisoning by ingestion. Ipecac syrup is contraindicated because of the potential for AMS and seizures.
• • For the vast majority of patients, single dose activated charcoal (1 g/kg with or without a cathartic) by mouth or nasogastric tube is sufficient for GI decontamination. Gastric lavage (followed by activated charcoal administration) is acceptable for patients presenting obtunded and within one hour of ingestion. GI decontamination with activated charcoal is recommended, even when patients present many hours postingestion, because of delayed gut emptying of anticholinergic agents and slowed peristalsis. Repeated doses of activated charcoal are not necessary for most patients.
  • Most anticholinergic agents have large volumes of distribution and are highly protein-bound; therefore, hemodialysis and hemoperfusion are ineffective treatment methods.
• Following GI decontamination, patients often recover well with supportive care. Tachycardia often resolves with crystalloid infusions, control of agitation (eg, benzodiazepines), and fever control (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. Repeat ECG analysis 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 associated with significant psychomotor agitation. Agitation may be treated with the specific antidote, physostigmine, or nonspecifically with benzodiazepines. Although its use is controversial, physostigmine administration 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 signs or symptoms of urinary retention exist.
• 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; this complication has been reported 3 times in literature, and each occurred when physostigmine was administered to patients with severe tricyclic antidepressant poisoning. To avoid bradyasystole in patients, do not administer physostigmine in the presence of prolonged PR or QRS intervals on the ECG.
  • Most patients can be treated safely without physostigmine, but it is recommended for use when at least one of the following aberrations are present: tachydysrhythmias with subsequent hemodynamic compromise, intractable seizures, or severe agitation or psychosis (in which the patient is considered a threat to self or others).
  • Although some recommend the use of benzodiazepines as first-line agents for the control of agitation associated with the anticholinergic syndrome, a recent study suggests that physostigmine is significantly more effective and no less safe for use in this setting.
  • Physostigmine is contraindicated in patients with cardiac conduction disturbances (prolonged PR and QRS intervals) on ECG analysis.

Consultations

• 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.
• Psychiatric consultation is mandatory in all intentional ingestions.
• In chronic intoxication or overmedication, contact the prescribing physician to prevent recurrence.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical therapy consists of anticonvulsants, antitachydysrhythmics, sodium bicarbonate, physostigmine, and sedatives.

Drug Category: GI decontaminant

Empirically used to minimize systemic absorption of the toxin.

Drug Category: Benzodiazepines and other sedatives

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.

Drug Category: Cardiovascular agents

Used only when patient is diagnosed with tricyclic antidepressant overdose or when evidence of sodium channel blockade is present. Routine use is not recommended.

Drug Category: Cholinergic agents

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.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Inpatient Care

• Admission decisions are based on patient symptomatology. Asymptomatic patients without anticholinergic signs or symptoms can be discharged after a 4-6 hour observation period. Individuals with initial mild toxicity that resolve 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.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

1. Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. Sep 2004;22(5):335-404. [Medline]. [Full Text].
2. Bryson P. Comprehensive Review in Toxicology. Hemisphere Publishing; 1989:3-11, 75-83, 566-7.
3. Burns MJ, Linden CH, Graudins A, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. Apr 2000;35(4):374-81. [Medline].
4. Daunderer M. Physostigmine salicylate as an antidote. Int J Clin Pharmacol Ther Toxicol. Dec 1980;18(12):523-35. [Medline].
5. Ellenhorn MJ, Barceloux D. Medical toxicology. In: Elsevier Applied Science. Elsevier Science; 1988:16, 25-31, 83, 93, 106-9, 117, 407, 472, 474, 592, 666.
6. Goldfrank L, Flomenbaum N, Lewin N, et al. Anticholinergic poisoning. J Toxicol Clin Toxicol. Mar 1982;19(1):17-25. [Medline].
7. Haddad LM, Winchester JF, eds. Clinical Management of Poisoning and Drug Overdose. 2^nd ed. WB Saunders Co; 1990:861-7, 83, 231, 385.
8. Kaye S. Handbook of Emergency Toxicology: A Guide for the Identification, Diagnosis and Treatment of Poisoning. 5^th ed. Charles C Thomas Pub Ltd; 1988:31-44.
9. Lu F. Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment. 3^rd ed. Taylor & Francis; 1996:52-4, 65, 279-84.
10. McFarland KA. Anticholinergic poisoning. In: Emergency Medicine. 1998.
11. Nice A, Leikin JB, Maturen A, et al. Toxidrome recognition to improve efficiency of emergency urine drug screens. Ann Emerg Med. Jul 1988;17(7):676-80. [Medline].

Article Last Updated: Mar 26, 2008