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:
Additional manifestations include the following:
See Presentation for more detail.
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.
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.
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.
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.{ref123-INVALID REFERENCE}
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 2017, the American Association of Poison Control Centers (AAPC) National Poison Data System Annual Report documented 4394 single exposures to anticholinergic drugs, excluding cough and cold preparations. Unintentional ingestions accounted for 3958 presentations. Moderate morbidity (requiring specific treatment) was reported in 167 cases, major morbidity (life-threatening) in 12, but no deaths were reported.[4] Patients with severe central manifestations (eg, hallucinations, psychoses, seizures, coma) have the highest morbidity rates.
Antihistamines also have anticholinergic properties. In 2017, the AAPCC documented 76,152 single exposures to antihistamines, with 31,736 specific to diphenhydramine. A total of 21 deaths were attributed to antihistamine toxicity; 18 were specifically diphenhydramine related.[4]
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:
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]
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:
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:
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.
Immediately perform an electrocardiogram (ECG) on all patients with suspected toxic ingestions.
Consider lumbar puncture (LP) in patients with fever and altered mental status in whom CNS infection is considered as a possible etiology.
Prehospital care includes the following:
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.
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.
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.
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]
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.
Clinical Context: Depresses all levels of CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.
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.
Clinical Context: Used for patients refractory to diazepam or lorazepam.
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.
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.
Clinical Context: Anecdotally, has been effective in treating antihistamine induced QRS prolongation (>100 ms) with a quinidinelike ECG pattern.
Used only when patient is diagnosed with tricyclic antidepressant overdose or when evidence of sodium channel blockade is present. Routine use is not recommended.
Clinical Context: Inhibits destruction of acetylcholine by acetylcholinesterase, which facilitates transmission of impulses across myoneural junction.
Clinical effects last 20-60 min. Repeat prn.
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.