Anticholinergic Toxicity

Article Author:
Erin Broderick
Article Editor:
Brianna Crosby
Updated:
12/1/2018 11:26:32 PM
PubMed Link:
Anticholinergic Toxicity

Introduction

Anticholinergic toxicity is common in the emergency department but rarely fatal.[1] According to the 2015 annual American Association of Poison Control Centers (AAPCC) report, there were just under 14,000 exposures reported to poison control centers that year, none of which were fatal.[1] However, in prior years, up to 51 cases have been reported as fatal.[2][3][4] Overdoses of compounds with anticholinergic activity can be accidental or intentional. This is an important topic as anticholinergics are readily accessible, and many medications have anticholinergic side-effects. Medications with anticholinergic properties are used in the treatment of motion sickness, nausea, insomnia, parkinsonism, and allergic reactions.

Etiology

Anticholinergic toxicity is typically secondary to an overdose of anticholinergic agents, although mild toxicity can be seen in the form of medication side effects. Substances with anticholinergic activity are used and misused extensively worldwide. The vast majority of these agents are orally ingested. The naturally occurring compounds atropine, hyoscyamine, and scopolamine are the prototypical anticholinergics from which others are synthesized. The prototypical anticholinergic agent atropine is used as an antidote for cholinergic toxicity from organophosphates and nerve agents.[5] Atropine is also used as an acute treatment for bradyarrhythmias.[6]

Other therapeutic uses of anticholinergics include antihistamines, antiparkinson drugs, sleep aids, antiemetics, and drugs for overactive bladder. Still, other medications have unrelated primary actions but also have anticholinergic side effects. These include tricyclic antidepressants, muscle relaxants, and antipsychotics. The effects of multiple anticholinergic medications are synergistic. This is especially important for elderly patients on multiple medications.[7][8] The most common source of an anticholinergic drug overdose is antihistamines.[1]

Plants are also a common source of accidental and intentional anticholinergic ingestion.[9] Plants that contain belladonna alkaloids are often abused due to their hallucinogenic properties.[10] Illicit drugs including cocaine and heroin have been known to be contaminated with anticholinergics such as scopolamine or atropine.[11][12][13] Toxicity has been reported with topical application.[14][15]

Epidemiology

As mentioned above, according to the AAPCC 2015 annual report, there were nearly 14,000 anticholinergic exposures reported to poison control centers.[1] The following year, there were 2,159,032 total cases of human exposure reported to poison control centers. Antihistamines were the sixth most frequently involved category of substances involved in human exposure at 4.19%.[16] These figures probably grossly underestimate the total number of exposures as many go unreported to poison control centers.

Pathophysiology

Anticholinergic agents competitively inhibit acetylcholine at muscarinic receptors. They would be more accurately described as antimuscarinic agents as they only act on muscarinic receptors. Anticholinergics do not affect nicotinic receptors. Muscarinic acetylcholine receptors are located in smooth muscle, the ciliary body of the eye, salivary glands, sweat glands, and in the central nervous system (CNS). Muscarinic receptors are not found at the neuromuscular junction.[17][18][19]

Toxicokinetics

Most anticholinergic agents are orally ingested. The onset of action of orally ingested compounds is within 2 hours.[20] The pharmacological actions of scopolamine can last for over 24 hours.[21] The cardiovascular effects have been found to be of a much shorter duration than central nervous system (CNS) effects, which can last over 8 hours.[22]

History and Physical

A thorough history and physical exam are critical to the identification of patients with anticholinergic poisoning. Patients may present with a history of intentional ingestion of common anticholinergic agents such as antihistamines or jimson weed.[9] Often, the history is less straightforward. Patients may present after a suicide attempt and be unwilling or unable to disclose what they ingested. Young children may be brought in by a caretaker/parent with somnolence or other anticholinergic symptoms although the ingestion may have been unwitnessed by the caretaker. Any history of potential co-ingestion should be obtained.

Due to potential difficulty in obtaining a reliable history, it is critical that the clinician be familiar with the anticholinergic toxidrome. The memory aid “red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask” is helpful to remember the classic signs and symptoms of anticholinergic poisoning which include flushing, anhydrosis, dry mucous membranes, mydriasis, altered mental status, fever, and urinary retention. Decreased bowel sounds are also a common physical exam finding. CNS effects may include delirium, hallucinations, agitation, restlessness, confusion, staccato speech, and picking at clothing and bedding. Seizures and jerking movements are possible.[23][24] Diphenhydramine, in particular, has been reported to be associated with wide-complex tachycardia and QT prolongation.[25][26]

Evaluation

The clinician should utilize a standard approach to any suspected poisoned patient. As with any potentially critically ill patient, evaluation of the patient’s airway, respiratory, and circulatory status should immediately be performed. Vital signs including temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation should be obtained. The patient should be fully exposed to assess for topical sources of toxicity, such as a scopolamine patch. The patient should also be placed on continuous cardiac monitoring and have intravenous (IV) access established. 

Diagnostics including urinalysis, urine drug screen, finger-stick glucose, salicylate and acetaminophen level, electrocardiogram, and pregnancy test for females should be obtained. If seizures or significant hyperthermia is present, the clinician should obtain further laboratory evaluation including a metabolic panel, liver enzymes, and creatine kinase. However, it is important to understand that anticholinergic toxicity is a clinical diagnosis. Anticholinergic toxicity can be confused with sympathomimetic toxicity. However, the absence of sweating indicates anticholinergic toxicity.[23]

Treatment / Management

Supportive care is usually all that is required for treatment of anticholinergic toxicity. However, physostigmine may be indicated in severe cases.[27] Benzodiazepines should be administered for seizure activity. IV fluids should be administered in the case of hypotension or if rhabdomyolysis is suspected. Cooling measures should be initiated if significant hyperthermia is present.[28] Activated charcoal should be considered if the ingestion was within one hour prior to presentation. However, administration somewhat outside this window may be appropriate, as anticholinergics decrease gastrointestinal motility.[29][30] If wide-complex dysrhythmias develop, IV sodium bicarbonate should be administered.[26][31]

Physostigmine is usually only given in the case of both peripheral and central signs and symptoms of anticholinergic poisoning.[27] Physostigmine is an acetylcholinesterase inhibitor active in both the central and peripheral nervous systems. Resuscitation equipment including atropine should be readily available before physostigmine is given. The recommended dose is 0.5- to 2-mg IV for adults and 0.02 mg/kg IV for pediatric patients with a maximum pediatric dose of 0.5 mg.[32] Repeat dosing may be required after approximately 30 minutes if symptoms recur.[33] In general, physostigmine is only recommended in pure anticholinergic poisoning.[34] Intravenous fat emulsion has been reported as a successful treatment for severe diphenhydramine overdose refractory to other interventions.[35]

Differential Diagnosis

Many conditions can cause agitated delirium, especially in the elderly. Side effects of other medications and polypharmacy should be considered. Meningitis, sepsis, uremia, sympathomimetic toxicity, salicylate toxicity, and serotonin syndrome can all present similarly to anticholinergic poisoning.[36] Pure anticholinergic toxicity versus mixed toxicity, as seen with tricyclic antidepressants and phenothiazines, should be considered.

Prognosis

Overall, with early identification and adequate supportive care, the prognosis of anticholinergic toxicity is good.

Complications

  • Respiratory failure
  • Cardiovascular collapse
  • Rhabdomyolysis
  • Seizures
  • Coma
  • Permanent disability
  • Death

Consultations

Depending on severity, the following consults may be indicated:

  • Poison Control can be reached 24 hours a day in the United States at 1-800-222-1222.
  • Intensivist for intensive care unit (ICU) admission
  • Psychiatry if the ingestion was intentional self-harm
  • Nephrology if dialysis is necessary

Deterrence and Patient Education

Patients taking multiple medications should be educated that anticholinergic side effects are common. Parents and guardians should be educated to keep anticholinergic medications in a safe place that is inaccessible to children. All patients should be educated not to take their medications more frequently than prescribed and not to take more than the recommended dose of over-the-counter medications. Patients should also be counseled not to drive after taking sedating anticholinergics such as antihistamines.

Pearls and Other Issues

  • Always consider anticholinergic toxicity in patients taking multiple medications, especially the elderly.
  • Always consider anticholinergic toxicity in young children who present somnolent or lethargic.
  • Remember the memory aid "red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask."
  • Confirmatory testing is not usually readily available in the emergency setting. Anticholinergic toxicity is a clinical diagnosis.

Enhancing Healthcare Team Outcomes

The prevention and treatment of anticholinergic toxicity can be maximized by adopting a team-based approach. Psychiatry services should see any patient with anticholinergic poisoning as an inpatient and refer to outpatient behavioral health resources if the ingestion is due to intentional self-harm. Pharmacists and pharmacy technicians in the hospital and in the community are an excellent resource for education of patients and the community regarding medication side effects, dosage, and synergistic effects of taking more than one anticholinergic agent. In many emergency departments, pharmacy technicians perform routine reconciliation of patients’ home medications. Thus, pharmacy technicians have a prime opportunity to recognize and alert providers of potential drug interactions which would place a patient at higher risk for anticholinergic toxicity. Both nursing staff and pharmacy staff can play an increased role in patient education at the time of discharge from the hospital regarding the appropriate consumption of anticholinergic drugs. Nursing staff should also assist in educating all patients on anticholinergic agents on how to keep them out of reach of children. Prehospital providers can also aid clinicians in making the diagnosis of anticholinergic poisoning by interviewing bystanders and observing the scene for any medications or substances that may have been available to the patient.[37][38][39][40] (Level V)